MISSION

MISSION 

FAMRI is an Independent Not-For-Profit Foundation 

Sponsoring Medical and Scientific Research to 

Combat the Diseases Caused by Exposure to 

Tobacco Smoke and to Ensure that Health Care 

Providers ask the Right Questions of Their Patients 

about Second Hand Tobacco Smoke Exposure.

IN MEMORY OF: 

JULIUS B. RICHMOND, M.D. 

PAST SURGEON GENERAL OF THE UNITED STATES AND 

CHAIRMAN OF FAMRI’S MEDICAL ADVISORY BOARD 

(1916-2008) 

Stanley Rosenblatt questioning Dr. 

Richmond at the Flight Attendant Class 

Action Trial in 1997 

RONALD M. DAVIS, M.D. 

PAST PRESIDENT OF THE AMERICAN MEDICAL ASSOCIATION AND 

FAMRI WILLIAM CAHAN DISTINGUISHED PROFESSOR 

(1956-2008) 

Dr. Ron Davis being cross examined 

at the Trial 

4 P A G E

FOREWORD 

David Sidransky, MD, Vice-Chairman, FAMRI’s Medical Advisory Board, The Johns Hopkins University 

This publication contains summaries of projects funded by the Flight Attendant Medical Research 

Institute’s (FAMRI) grants program on the health effects of second hand tobacco smoke. The progress in 

FAMRI supported research is inspiring and sets the stage for rich discoveries and better prevention and 

treatment of tobacco related diseases. The rich history of FAMRI, which made this research possible, 

always merits telling. 

For decades flight attendants were involuntarily exposed to second hand tobacco smoke as they worked 

in the cabins of aircraft. As they became aware of their health hazards caused by second hand tobacco 

smoke, they began to seek remedies. They realized that they had formidable adversaries in the tobacco 

industry that had never lost a lawsuit brought by people who sought redress for the health consequences 

of smoking. 

Although the tobacco industry attorneys tried to deny the harmful health effects of smoking, the data 

presented to Surgeon-General Luther Terry by his Advisory Committee on Smoking and Health in 1964 

undermined their effectiveness. They took refuge in the notion that there was no scientific evidence for 

health effects of second hand tobacco smoke. These forces, however, underestimated a hardy band of 

flight attendants who knew better. They saw themselves as “canaries in the coal mines” calling attention 

to the growing scientific evidence for the harmful effects of second hand tobacco smoke. By 1986 Dr. C. 

Everett Koop’s Surgeon-General’s Report, “The Health Consequences of Involuntary Smoking” clearly 

established effects of second hand tobacco smoke on health. The flight attendants persisted in their creative 

efforts to curb the tobacco industry’s influence through litigation and legislation. By 1988 smoking 

on domestic flights was banned by Congress. Despite these successes, legal action was more difficult 

because the resources of the tobacco industry discouraged attorneys from taking action. Fortunately, the 

flight attendants persevered and they found their way to attorneys Susan and Stanley Rosenblatt in 1991, 

who were willing to take the risk of bringing the industry to trial. After years of preparation, the case 

came to trial in 1997. 

The combined perseverance and creativity of the flight attendants and their attorneys along with their 

witnesses made legal history. Four months into the jury trial, and after extensive negotiations with Class 

Counsel, Stanley and Susan Rosenblatt, the tobacco industry agreed to a settlement that provided many 

benefits to flight attendants, including $300 million allocated for the establishment of a research entity. 

The Rosenblatts, with court approval, formed the Flight Attendant Medical Research Institute, and pursuant 

to the settlement, they then appointed a Board of Trustees, consisting of a majority of flight attendants 

who served as class representatives in the underlying litigation. 

We are all indebted to the flight attendants for their courage in bringing their suit and to their attorneys 

for their remarkable legal skills and commitment to improving the public’s health. The flight attendants 

and the attorneys who constitute the Board have carried on the tradition of the intrepid group, which pursued 

legal action. 

The Medical Advisory Board (MAB), which I chair, is composed of distinguished scientists and physicians 

who are devoted to medical research and share FAMRI's vision of making an impact in the fight 

against disease caused by unwilling exposure to tobacco smoke. We sorely miss our former Chairman, 

Julius Richmond MD , Former Surgeon General of the United States and Former Professor at Harvard 

University. Under his leadership, the MAB took on an important role in helping to shape the structure and 

goals of the peer reviewed research grant program at FAMRI. He was a consummate spokesperson and 

ambassador of FAMRI’s research endeavors. The program continues to emphasize basic and applied 

research into the diseases caused by second hand tobacco smoke and has successfully funded a large cadre 

of young scientists, innovative approaches, and several centers of excellence. As this review of the contributions 

by the scientists who have current awards indicates, FAMRI is making important contributions to 

improving public health. We are in very difficult financial times at this writing, witnessing a historic ablation 

of wealth and monetary resources across the globe. We thus remain very much indebted to the foundation's 

founders and their ongoing support of this invaluable program during these difficult years. 

P A G E 5

CONTENTS 

MISSION ..............................................................................................................................................................................................1 

DEDICATION .......................................................................................................................................................................................2 

FOREWORD 

David Sidransky, MD; Vice-Chairman, FAMRI’s Medical Advisory Board, The Johns Hopkins University 3 

CONTENTS ...........................................................................................................................................................................................4 

INTRODUCTION..............................................................................................................................................................................12 

FAMRI ORGANIZATIONAL STRUCTURE ......................................................................................................................13 

FAMRI AWARD CATEGORIES...............................................................................................................................................14 

Peer Reviewed Awards ......................................................................................................................................................14 

Center Of Excellence Award ........................................................................................................................................14 

The Clinical Innovator Award Program ......................................................................................................................14 

The Young Clinical Scientist Award Program............................................................................................................14 

Board Designated Awards .................................................................................................................................................14 

The William Cahan Distinguished Professor Award Program................................................................................14 

The Bland Lane InteRNational Distinguished Professor Award Program............................................................14 

Other Board Designated Awards.................................................................................................................................14 

GEOGRAPHIC DISTRIBUTION .............................................................................................................................................15 

International..........................................................................................................................................................................15 

United States.........................................................................................................................................................................15 

HIGHLIGHTED RESEARCH......................................................................................................................................................16 

Second Hand Tobacco Smoke And Cardiovascular Dysfunction In Children..........................................................16 

Judith Groner, MD and John A. Bauer, PhD; Ohio State University; CIA 2006 ....................................................16 

Research And Education On Smoke-Free Air For Pets And Families........................................................................17 

Ronald M. Davis, MD (Sharon A. Milberger, ScD); Henry Ford Health System; CIA 2006.................................17 

Effect Of Second Hand Tobacco Smoke On Respiratory And Reproductive Tract Epithelial Cell Production 

And Release Of Ccl20 ..........................................................................................................................................................17 

Mardi Crane-Godreau, PhD; Dartmouth College; YCSA 2006 .................................................................................17 

Role Of SHS On Somatic Alterations In Bladder Cancer .............................................................................................18 

Carmen J. Marsit, PhD; Brown University;YCSA 2006 .............................................................................................18 

Usurping Signaling Characteristics Of Breast, Cervical, And Prostate Cancer 

To Target Them With A ‘Signal-Smart’ Virus ..................................................................................................................19 

Faris Farassati, PhD, PharMD; University of Kansas; YCSA 2006 ..........................................................................19 

Elastin Degradation In Pulmonary Diseases ..................................................................................................................20 

Yong Y. Lin, PhD and Gerald Turino, MD; St. Luke’s-Roosevelt Hospital Center; BDA 2005 ..............................20 

Second Hand Tobacco Smoke And Worker Health.......................................................................................................21 

David J. Lee, PhD; University of Miami; CIA 2002, 2003, 2006, 2009.......................................................................21 

Rage-Mediated Effects Of Pulmonary Inflammation And Emphysema......................................................................22 

Paul R. Reynolds, PhD; University of Utah; YCSA 2007 ............................................................................................22 

Functional Characterization Of Sccro..............................................................................................................................22 

Bhuvanesh Singh, MD, FAC; Memorial Sloan-Kettering Cancer Center; CIA 2006 ............................................22 

Amelioration Of Allergic Rhinitis By Multi-Functional Anti-Inflammatory Drugs: 

Results Of A Phase Ii Clinical Study ................................................................................................................................23 

Saul Yedgar, PhD; Hebrew University of Jerusalem; BDA 2008.............................................................................23 

Household Smoking Bans: A Comprehensive Analysis ...............................................................................................23 

Nancy Rigotti, MD; Massachusetts General Hospital; CIA 2006, 2009..................................................................23

FAMRI CENTERS OF EXCELLENCE...................................................................................................................................25 

FAMRI-BLAND LANE CENTER OF EXCELLENCE ON SECOND HAND SMOKE AT 

UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, 2002, RENEWED 2007 ...............................................................................25 

Director: Neal L. Benowitz, MD..........................................................................................................................................25 

Tobacco Gene-Environment Interactions In African American And Latino Asthmatics........................................27 

Esteban Gonzalez-Burchard, MD, MPH .....................................................................................................................27 

Acute Effects Of Second Hand Tobacco Smoke Exposure In The Upper And Lower Respiratory Tract ............27 

John Balmes, MD ...........................................................................................................................................................27 

The Impact Of SHS Exposure On Pulmonary Function, Disability, And Cardiovascular Disease........................28 

Mark Eisner, MD, MPH..................................................................................................................................................28 

Second Hand Tobacco Exposure Assessment Core......................................................................................................28 

Neal L. Benowitz, MD ....................................................................................................................................................28 

Flight Attendant Medical Research Clinical Practice..................................................................................................29 

Rita Redberg, MD............................................................................................................................................................29 

Chronic Effects Of Second Hand Tobacco Smoke Exposure On Lung Function Of Flight Attendants.................29 

Warren M. Gold, MD ......................................................................................................................................................29 

Economic Burden Of Second Hand Tobacco Smoke ....................................................................................................29 

Wendy Max, PhD ............................................................................................................................................................29 

Implementing The Evidence...............................................................................................................................................30 

Lisa A. Bero, PhD............................................................................................................................................................30 

FAMRI CENTER OF EXCELLENCE AT THE WEIZMANN INSTITUTE OF SCIENCE, 2004, RENEWED 2009.........................30 

Director: Varda Rotter, PhD.................................................................................................................................................30 

The Pro-Apoptotic Dap-Kinase Gene: Molecular Basis Of Its Tumor Suppressive Functions And Implications 

In Lung Cancer Diagnosis/Prognosis/Therapy ...............................................................................................................30 

Adi Kimchi, PhD...............................................................................................................................................................30 

Correlation Of DNA Polymorphisms And Large-Scale Gene Expression With Susceptibility To Evolution And 

Progression To Tobacco Smoke-Related Lung Cancer.................................................................................................32 

Gideon Rechavi, MD, PhD.............................................................................................................................................32 

In Vitro Model For Tumor Progression Of Lung-Derived Cell: Biological And Molecular Characterization And 

Functional Analysis Of P53 Gene Alterations.................................................................................................................33 

Moshe Oren, PhD............................................................................................................................................................33 

Reduced Repair Of The Oxidative Dna Lesion 8-Oxyguanine As A Risk Factor In Lung Cancer.........................34 

Zvi Livneh, PhD................................................................................................................................................................34 

FAMRI CENTER OF EXCELLENCE AT THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER, 

THE THE JOHNS HOPKINS UNIVERSITY, 2005............................................................................................................................35 

Director: Charles M. Rudin, MD, PhD ...............................................................................................................................35 

Administrative Core .............................................................................................................................................................36 

Charles M. Rudin, MD, PhD ..........................................................................................................................................36 

Clinical Core..........................................................................................................................................................................36 

Charles M. Rudin, MD, PhD ..........................................................................................................................................36 

Drug Discovery Core............................................................................................................................................................37 

Phillip Cole, MD, PhD .....................................................................................................................................................37 

Synthetic Chemistry Core Component Of The Drug Discovery Core..........................................................................37 

David Meyers, PhD.........................................................................................................................................................37 

Clinical Compound Screening Initiative Core Component Of The Drug Discovery Core.......................................37 

Jun Liu, PhD.....................................................................................................................................................................37 

Drug Screening Core ...........................................................................................................................................................38 

Rhoda Alani, MD .............................................................................................................................................................38 

Pharmacokinetic Core.........................................................................................................................................................38 

Michelle A. Rudek, PhD, Pharm D ...............................................................................................................................38 

Angiogenesis Core...............................................................................................................................................................38 

Rhoda Alani, MD .............................................................................................................................................................38 

Translation Of Evidence Core ............................................................................................................................................39 

David Holtgrave, PhD .....................................................................................................................................................39 

Developmental Project 1: Prodrug Strategies For Lung Cancer .................................................................................39 

Caren Meyers, PhD ........................................................................................................................................................39

CONTENTS 

Developmental Project 2: Therapeutic Strategies To Overcome Resistance To Anti-Vegf Treatments .............39 

Roberto Pili, MD ..............................................................................................................................................................39 

Developmental Project 3: Ox-Ldl Results In Early Endothelial Arginase Activation .............................................40 

Jeffrey Rade, MD, PhD ..................................................................................................................................................40 

Developmental Project 5: Epidemiology And Intervention Research In Armenia...................................................40 

Frances Stillman, EdD, EdM and Narine Movsisyan, MD, MPH ............................................................................40 

THE JULIUS B. RICHMOND CENTER OF EXCELLENCE AT THE AMERICAN ACADEMY FOR PEDIATRICS, 2006............41 

Director: Jonathan D. Klein, MD, MPH.............................................................................................................................41 

Dissemination Of Best Practices To Reduce SHS Exposure Of Children: Smoke-Free Homes/Pediatric 

Tobacco Champions.............................................................................................................................................................43 

Dana Best, MD, MPH.....................................................................................................................................................43 

Rapid Quantitative Assessment Of Second Hand Tobacco Smoke Exposure For Use In Clinical Pediatric 

Settings (Measurement)......................................................................................................................................................43 

Dana Best, MD, MPH.....................................................................................................................................................43 

Richmond Center Core.........................................................................................................................................................44 

Jonathan D. Klein, MD, MPH........................................................................................................................................44 

Building The Field: Education, Workforce Development And Clinical Policy Project ..........................................44 

Jonathan D. Klein, MD, MPH........................................................................................................................................44 

Clinical Effort Against Second Hand (Tobacco) Smoke (Cease) Project..................................................................44 

Jonathan P. Winickoff, MD, MPH ................................................................................................................................44 

Legal And Regulatory Research On Children’s Exposure To Second Hand Tobacco Smoke ...............................45 

Mark Gottlieb, JD............................................................................................................................................................45 

Document, Data, Dataset Repository, And Analysis......................................................................................................45 

Michael Weitzman, MD .................................................................................................................................................45 

Messages For Motivation And Support For Behavioral Changes In Parent Smoking............................................45 

Susanne E. Tanski, MD ..................................................................................................................................................45 

FAMRI-IELCAP COLLABORATIVE NETWORK, 2007 ....................................................................................................................46 

Director: Claudia I. Henschke, PhD, MD ..........................................................................................................................46 

Urinary Pge-M: A Noninvasive Biomarker Of Tobacco Smoke-Induced Pulmonary Injury..................................46 

Andrew Dannenberg, MD .............................................................................................................................................46 

Pulmonary Diseases From Second Hand Tobacco Smoke ..........................................................................................47 

Claudia I. Henschke, PhD, MD .....................................................................................................................................47 

Cardiac Risk From Second Hand Tobacco Smoke ........................................................................................................47 

David F. Yankelevitz, MD................................................................................................................................................47 

Effect Of Tobacco Smoke On The Histone Code ............................................................................................................47 

Kotha Subbaramaiah, PhD............................................................................................................................................47 

Rhinologic Disease From Second Hand Tobacco Smoke ............................................................................................47 

Michael Stewart, MD, MPH..........................................................................................................................................47 

FAMRI-FUNDED RESEARCH COMBATING EFFECT OF TOBACCO SMOKE.........................................48 

ACUTE LUNG INJURY ......................................................................................................................................................................48 

Current Research..................................................................................................................................................................48 

Impact Of Tobacco Smoke Exposure On Acute Lung Injury ........................................................................................48 

Carolyn Calfee, MD; University of California, San Francisco; YCSA 2007 ............................................................48 

AIRWAY DISEASES ..........................................................................................................................................................................48 


Comparative Studies Of Human Buccal Cells Of Smokers And Non-Smokers .......................................................48 

John L. Pauly, PhD; Roswell Park Cancer Institute; CIA 2002, 2005 ......................................................................48 

Effect Of Side-Stream Cigarette Smoke On Lung Endothelial Angiogenesis Induced By Epidermal Growth 

Factor ......................................................................................................................................................................................49 

Yunchao Su, MD, PhD; Medical College of Georgia; CIA 2004...............................................................................49 

Sidestream Tobacco Smoke And Nitric Oxide Modification Of Calpains In Airway Epithelial Repair .............49 

Yunchao Su, MD, PhD; Medical College of Georgia; CIA 2008...............................................................................49 

Protein Fingerprint Of Airway Inflammation Induced By Viral Infection And Second Hand Tobacco Smoke 

Exposure ................................................................................................................................................................................50 

Roberto P. Garofalo, MD; University of Texas Medical Branch At Galveston; CIA 2005....................................50

PAI-1 And Airway Remodeling In Second Hand Tobacco Smoke Exposure............................................................50 

Steven Idell, MD, PhD; University of Texas Health Center At Tyler; CIA 2005 .....................................................50 

Second Hand Cigarette Smoke And Immunity To Tuberculosis..................................................................................50 

Homayoun Shams, Dvm, PhD; University of Texas Health Center At Tyler; CIA 2006 ........................................50 

Second Hand Tobacco Smoke Exacerbates Allergic Asthma ....................................................................................51 

Julie A. Wilder, PhD; Lovelace Respiratory Research Institute; CIA 2006...........................................................51 

The Impact Of Second Hand Tobacco Smoke On T Cell Immune Response: 

Implications For Upper And Lower Airways Disease...................................................................................................51 

Stephen M. Canfield, MD, PhD; Columbia University; CIA 2006.............................................................................51 

Fetal-Postnatal Smoke Exposure: Response To Rsv Infection....................................................................................51 

Edward G. Barrett, PhD; Lovelace Respiratory Research Institute; CIA 2007 .....................................................51 

SHS And Sex Differences In Airway Development.......................................................................................................52 

Laura S. Van Winkle, PhD; University of California, Davis; CIA 2007.....................................................................52 

Second Hand Tobacco Smoke And Airway Infection...................................................................................................52 

Veena Antony, MD; University of Florida; CIA 2007..................................................................................................52 

Tobacco Smoke And Oxidative Stress In Rsv Bronchiolitis........................................................................................53 

Antonella Casola, MD; University of Texas Medical Branch At Galveston; CIA 2008........................................53 

Tobacco Aldehydes And Allergic Airway Inflammation..............................................................................................53 

Albert Van Der Vliet, PhD; University Of Vermont; CIA 2008 ...................................................................................53 

Second Hand Tobacco Smoke Exposure And Susceptibility To Respiratory Viral Infection................................54 

Adriana Elisa Kajon, PhD; Lovelace Respiratory Research Institute; CIA 2008 ..................................................54 

Air Filtration Systems, Second Hand Tobacco Smoke And Respiratory Disease ...................................................54 

Chris A. Pritsos, PhD; University Of Nevada, Reno; CIA 2008.................................................................................54 

Effects Of Cigarette Smoke On Airway Epithelial Barrier Function ..........................................................................55 

Venkataramana Sidhaye, MD; The Johns Hopkins University; YCSA 2008 ..........................................................55 

The Effects Of Secondhand Tobacco Smoke On Cystic Fibrosis................................................................................55 

Garry R. Cutting, MD; The Johns Hopkins University; CIA 2008 .............................................................................55 

Airways Diseases ................................................................................................................................................................56 

Completed Research............................................................................................................................................................56 

Smoke And Susceptibiltiy To Respiratory Infection .....................................................................................................56 

Lester Kobzik, MD; Harvard University; CIA, 2002 ....................................................................................................56 

Passive Smoke Exposure In Asthmatics: Relationship To Matrix Metalloproteases ............................................56 

Jeanine M. D’armiento, MD, PhD; Columbia University; CIA 2004 ........................................................................56 

Smoke-Induced Dysregulation Of Airway Aquaporins.................................................................................................56 

Landon S. King, MD; The Johns Hopkins University; CIA 2004...............................................................................56 

Impact Of Second Hand Tobacco Smoke On Respiratory Health Of Non-Smoking Adults...................................57 

Archana Mishra, MD, Ms; State University Of New York At Buffalo; YCSA 2002 ...............................................57 

ARTHRITIS..........................................................................................................................................................................................57 


Tobacco-Caused Rheumatoid Arthritis; Genes, Mechanisms, And Specific Therapy ...........................................57 

Lars Klareskog, MD, PhD; Karolinska Institutet; CIA 2004 ......................................................................................57 

CANCER: ANGIOGENESIS...............................................................................................................................................................57 


Regulation Of Tumor Angiogenesis By Combostatin ....................................................................................................57 

Sudhakar Akulapalli, PhD; Boys Town National Research Hospital; YCSA 2007 ................................................57 

CANCER: CHEMOTHERAPEUTIC AGENTS ...................................................................................................................................58 


The Role Of Cdk5 In Cancer And Metastasis..................................................................................................................58 

Barry Nelkin, PhD; The Johns Hopkins University; CIA 2006..................................................................................58 

CANCER: BLADDER ..........................................................................................................................................................................58 


The GPI Transamidase Complex Subunits As Oncogenes In Bladder Cancer.........................................................58 

Barry Trink, PhD; The Johns Hopkins University; CIA 2003, CIA 2007 ...................................................................58 

Functional Role Of Cdc91l1-Containing Complex In Human Bladder Cancers........................................................59 

Edward Ratovitski, PhD; The Johns Hopkins University; CIA 2005 ........................................................................59 

Developing Dmapt, A Nf-Kappa B Inhibitor For Bladder Cancer................................................................................59 

Harikrishna Nakshatri, PhD; Indiana University; CIA 2006 ......................................................................................59

CONTENTS 

Bladder Cancer Associated Gene Expression Signatures Identified By Profiling Of Exfoliated Urothelia ......60 

Charles J. Rosser, MD; University of Florida; CIA 2008 ...........................................................................................60 

Cigarette Smoke Impairment Of Bladder Cancer Treatment .......................................................................................60 

Warren D. W. Heston, PhD; Cleveland Clinic; CIA 2008...........................................................................................60 

Hedgehog Signaling Links Cancer And Injury Repair In Bladder Epithelium .........................................................61 

Sunil S. Karhadkar, MBBS; The Johns Hopkins University; YCSA 2004 ...............................................................61 

Markers Of Response To Intravesical Bladder Cancer Therapy ................................................................................61 

Ashish Kamat, MD; University of Texas M. D. Anderson Cancer Center; YCSA 2005 ........................................61 

Genetic And Epigenetic Alterations In Bladder Cancer By Tobacco Smoke...........................................................62 

Mohammad O. Hoque, DDS, PhD; The Johns Hopkins University; YCSA 2006....................................................62 

The Effect Of Adenylate Kinase 3 On Tobacco Smoke-Induced Cisplatin Resistance In Bladder Cells............64 

Aditi Chatterjee, PhD: The Johns Hopkins University;YCSA 2008..........................................................................64 

Completed Research ...........................................................................................................................................................64 

Adenoviral Bladder Cancer Gene Therapy .....................................................................................................................64 

Ronald Rodriguez, MD, PhD; The Johns Hopkins University; CIA 2002 ................................................................64 

A Marker For Bladder Cancer In Involuntary Smokers ................................................................................................64 

Robert H. Getzenberg, PhD; The Johns Hopkins University; CIA 2005..................................................................64 

CANCER: BREAST.............................................................................................................................................................................64 


Translational Control And Breast Cancer Development ..............................................................................................64 

Ronald B. Gartenhaus, MD; University of Maryland; CIA 2008...............................................................................64 

Activation Of Ddx3 By Benzo[A]Pyrene Diol Epoxide, A Component Of Second Hand Tobacco Smoke In 

Transformation Of Human Breast Cells: A Potential Mechanism For Neoplastic Transformation......................65 

Venu Raman, PhD; The Johns Hopkins University; CIA 2003, 2006........................................................................65 

Mechanisms Of SHS Induced Breast Carcinogenesis .................................................................................................65 

Satya Narayan, PhD; University of Florida; CIA 2003 ...............................................................................................65 

Mechanism Of Second Hand Cigarette Smoke-Induced Transformation Of Normal 

Human Breast Epithelial Cells...........................................................................................................................................66 

Satya Narayan, PhD; University of Florida; CIA 2008 ...............................................................................................66 

Estrogen Receptor Signaling In Normal And Cancerous Breast Epithelial Cells...................................................68 

Ben-Ho Park, MD, PhD; The Johns Hopkins University; YCSA 2003 .....................................................................68 

Activation Of Cubgp1 In Breast By Second Hand Tobacco Smoke............................................................................69 

Cynthia Zahnow, PhD; The Johns Hopkins University; CIA 2004 ...........................................................................69 

Second Hand Smoke And Its Role In Breast Cancer ....................................................................................................70 

Cynthia Zahnow, PhD; The Johns Hopkins University; CIA 2008 ...........................................................................70 

Epoxygenase Mechanisms Of Breast Cancer Progression .........................................................................................70 

David A. Potter, MD, PhD; University Of Minnesota Twin Cities; CIA 2005 ..........................................................70 

Environmental And Genetic Risk Factors Of Breast Cancer .......................................................................................72 

Yun-Ling Zheng, PhD, MPH; Georgetown University; CIA 2005..............................................................................72 

Nicotine: Signaling And Mitogenesis In The Breast ....................................................................................................72 

Chang-Yan Chen, MD, PhD; Harvard University; CIA 2007......................................................................................72 

Nicotine Induced Src Signaling In Lung Metastasis ....................................................................................................73 

Hong-Gang Wang, PhD; The Pennsylvania State University; CIA 2007 ................................................................73 

Targeting The Src Oncogene In Breast Cancer Therapy..............................................................................................73 

Joyce Slingerland, MD, PhD; University of Miami; CIA 2007..................................................................................73 

Role Of Second Tobacco Hand Smoke In Breast Cancer Angiogenesis And Metastasis.....................................74 

Shalom Avraham, MD, PhD; Harvard University; CIA 2007 .....................................................................................74 

How Second-Hand Tobacco Smoke Affects Breast Tumor Dormancy In The Lung................................................74 

Stuart S. Martin, PhD; University of Maryland; CIA 2007 ........................................................................................74 

Role Of Pbrs In Breast Cancer Induced By Second Hand Tobacco Smoke..............................................................75 

Salil K. Das, ScD, Dsc; Meharry Medical College; CIA 2007...................................................................................75 

Telomere Dysfunction And Breast Cancer Detection ...................................................................................................76 

David P. Gilley, PhD; Indiana University; CIA 2008 ....................................................................................................76 

Role Of Transcription Factor Tbx2 In Breast Cancer.....................................................................................................76 

Karoline J. Briegel, PhD; University of Miami Miller School Of Medicine; CIA 2008 .........................................76

Promoter Hypermethylation As A Molecular Marker For Breast Cancer.................................................................77 

Hetty E. Carraway, MD; The Johns Hopkins University; YCSA 2004......................................................................77 

HDGF, A New Potential Target For Breast Cancer Therapy.........................................................................................77 

Jun Yang, PhD; The Johns Hopkins University; YCSA 2005 ....................................................................................77 

Targeting The Trop-2 Receptor Pathway In Cancer ......................................................................................................77 

Loren Michel, MD; Washington University; 2006 YCSA...........................................................................................77 

Second Hand Tobacco Smoke And Hmg-Iy In Breast Cancer.....................................................................................78 

Francescopaolo Di Cello, PhD; The Johns Hopkins University; YCSA 2007.........................................................78 

Chemical Genetic Validation Of Polo-Like Kinase-1 As A Breast Cancer Drug Target.........................................78 

Mark E. Burkard, MD, PhD; University Of Wisconsin; YCSA 2007 .........................................................................78 

Targeting Nrf2/Are By Hdac Inhibition In Breast Cancer.............................................................................................79 

Qun Zhou, MD, PhD; The University of Maryland; YCSA 2008................................................................................79 

Discovery And Characterization Of Novel Tumor Suppressor Genes In Breast Cancer 

Using Genome-Wide Genetic And Epigenetic Analysis ..............................................................................................79 

Timothy A. Chan, MD, PhD; Memorial Sloan-Kettering Cancer Center; YCSA 2008...........................................79 


The Role Of Lysine Histone Methyltransferase Set 7/9 In Breast Cancer.................................................................80 

Nickolai A. Barlev, PhD; Tufts-New England Medical Center Hospitals; CIA 2005 ............................................80 

An MVA Vaccine Targeting p53 In Breast Cancer .........................................................................................................80 

Joshua Ellenhorn, MD; City of Hope; CIA 2005..........................................................................................................80 

Oncogenic Role Of Rhbdf1 In Breast Cancer..................................................................................................................81 

Luyuan Li, PhD: University of Pittsburgh; CIA 2005...................................................................................................81 

The Role Of Wt 1 In The Pathogenesis Of Breast Cancer ............................................................................................81 

David M. Loeb MD, PhD; The Johns Hopkins University; YCSA 2002 ...................................................................81 

Novel Drug Development For Breast Cancer..................................................................................................................82 

Saeed R. Khan, PhD; The Johns Hopkins University; YCSA 2003...........................................................................82 

CANCER: CERVICAL..........................................................................................................................................................................82 


Synergy Of Hpvs And Tobacco Smoke In Cervical Cancer..........................................................................................82 

Hans-Ulrich Bernard, PhD, Msc; University of California, Irvine; CIA 2007 .........................................................82 


Genetic Susceptibitlity To Cervical Cancer In Second Hand Tobacco Smokers ....................................................84 

Ramin Mirhashemi, MD; Torrance Memorial Medical Center; CIA 2003..............................................................84 

Enhancing Cisplatin Efficiency With A Copper Chelator .............................................................................................84 

Douglas Hanahan, PhD; University of California, San Francisco; CIA 2005.........................................................84 

Development Of Novel Human Immunology Assays For Hpv Vaccine Trials...........................................................84 

Chien-Fu Hung, PhD; The Johns Hopkins University; YCSA 2003 ..........................................................................84 

CANCER: GASTRIC ...........................................................................................................................................................................85 


Gastric Cancer: Molecular Pathogenesis And Biomarker Discovery .......................................................................85 

Florin M. Selaru, MD; The The Johns Hopkins University; YCSA 2008 .................................................................85 

CANCER: HEAD AND NECK ............................................................................................................................................................86 


Chronic Cigarette Smoke Extract Treatment Selects For Apoptotic Dysfunction 

And Mitochondrial Mutations In Minimally Transformed Oral Keratinocytes ........................................................86 

Joseph A. Califano, MD.................................................................................................................................................86 

Molecular Disruption Of Rad50 Sensitizes Tumor Cells To Cisplatin-Based Chemotherapy................................86 

Daqing Li, MD; University Of Pennsylvania; YCSA 2002 ..........................................................................................86 

Detection Of Premalignant Lesions In The Oral Cavity Induced By Tobacco Related Carcinogens With 

Replication-Competent, Herpes Simplex Virus, Nv1066, And Prevention Of Its Development Into Cancer.......88 

Yuman Fong, MD; Memorial Sloan-Kettering Cancer Center; CIA 2007 ...............................................................88 

Targeting The Ink4a/Arf Locus In Head And Neck Cancers ........................................................................................89 

James W. Rocco, MD, PhD; Harvard University; CIA 2004 .....................................................................................89 

Erythropoietin Signaling In Head And Neck Cancer.....................................................................................................89 

Stephen Y. Lai, MD, PhD; MD Anderson Cancer Center; YCSA 2005 ....................................................................89 

Analysis Of Serum Peptides Associated With Squamous Cell Carcinoma Of The Head And Neck (HNSCC)..........90 

Radoslav Goldman, PhD; Georgetown University; CIA 2006 ...................................................................................90

CONTENTS 

Roles Of Dna Promoter Hypermethylation In Head And Neck Cancer Cisplatin Resistance ...............................90 

Zhongmin Guo, MD, PhD; Indiana University; YCSA 2007 .......................................................................................90 

Second Hand Tobacco Smoke And Alcohol In Head And Neck Cancer...................................................................91 

Michael Mcclean, ScD; Boston University; YCSA 2007...........................................................................................91 

Role Of egr3 In Smoking Induced Cancer .......................................................................................................................91 

Sanjai Sharma, MD; West Los Angeles Va Medical Center; YCSA 2007..............................................................91 

Epigenetic Alterations In Progression Of Esophogeal Squamous Cell Carcinoma By Tobacco Smoking.........91 

Myoung Sook Kim, PhD; The Johns Hopkins University; YCSA 2007 ....................................................................91 

Smoking-Gene-Environment Interactions In Esophageal Adenocarcinoma............................................................91 

Rihong Zhai, MD, PhD; Harvard University; YCSA 2007...........................................................................................91 

Optimizing Fusion Hybrids For Cancer Immunotherapy ...............................................................................................92 

Walter T. Lee, MD; Duke University; YCSA 2007........................................................................................................92 

Use Of PDE5 Inhibitors For The Immune Therapy Of HNSCC.......................................................................................93 

Paolo Serafini, PhD; University of Miami Miller School Of Medicine; YCSA 2008..............................................93 

Development Of PKC Epsilon Inhibitors For Treating Head And Neck Cancer........................................................93 

Quintin Pan, PhD; Ohio State University; YCSA 2008................................................................................................93 


Tobacco-Induced Mitochondrial Alterations In Upper Aerodigestive Mucosa ......................................................94 

Joseph A. Califano, MD; The The Johns Hopkins University; CIA 2002................................................................94 

Apoptosis Of Effector T Cells In Cancer: Implications For Immune Therapy ...........................................................94 

Robert L. Ferris, PhD; University of Pittsburgh; YCSA 2003.....................................................................................94 

PKC-Epsilon Expression On The Outcome Of Chemotherapy......................................................................................95 

Lei Xiao, PhD; University of Florida; CIA 2002............................................................................................................95 

Adenoviral Gene Transfer Of FRNk And P53 For Treatment Of Head And Neck Cancer: In Vitro Studies .........95 

Lori J. Kornberg, PhD; University of Florida; CIA 2003 .............................................................................................95 

Role Of Epidermal Growth Factor Receptor (EGFR) And Its Downstream Targets In 

Head And Neck Cancers Of Smoking Patients ..............................................................................................................95 

Alexey Fomenkov, Ph.D; The Johns Hopkins University; CIA 2003........................................................................95 

Markers And Mechanisms For Head And Neck Cancer ..............................................................................................96 

Elizabeth Franzmann, MD; University of Miami; YCSA 2002 ...................................................................................96 

CANCER: KIDNEY..............................................................................................................................................................................97 


Tumor Vaccine After Myeloablative Allogenic Stem Cell Transplantation For Kidney Cancer ...........................97 

Ephraim J. Fuchs, MD; The Johns Hopkins University; CIA 2003...........................................................................97 

Early Detection Of Bladder And Renal Cell Cancer By Hypermethylation...............................................................97 

Paul Cairns, PhD; Fox Chase Cancer Center; YCSA 2002 ........................................................................................97 

CANCER: LUNG .................................................................................................................................................................................98 


Development Of Structure-Based Small Molecule Anti-Lung Cancer Drug(s) By Targeting Bax .......................98 

Xingming Deng, MD, PhD; University of Florida; CIA 2002, 2005, 2008..................................................................98 

MCL-1 Is A Nicotine Target In Lung Cancer Cells .........................................................................................................98 

Xingming Deng, MD, PhD; University of Florida; CIA 2009 ......................................................................................98 

Lung Cancer Susceptibility And Chemoprevention.......................................................................................................99 

Shyam Biswal, PhD; The Johns Hopkins University; YCSA 2002, CIA 2008..........................................................99 

Regulation Of Non-Small Cell Lung Cancer By Notch................................................................................................100 

Douglas W. Ball, MD; The Johns Hopkins University; CIA 2003, 2007.................................................................100 

Modulation Of Stereotactic Body Radiation Therapy To Improve Therapeutic Ratio ..........................................101 

Debabrata Saha, PhD; University of Texas Southwestern; CIA 2008 ..................................................................101 

Early Detection Of Lung Cancer In African Americans Exposed To Second Hand Smoke .................................101 

Feng Jiang, MD, PhD; University of Maryland; CIA 2008.......................................................................................101 

Tetravalent Vaccine Against Sclc: A Pilot Trial...........................................................................................................101 

Lee M. Krug, MD; Memorial Sloan-Kettering Cancer Center; CIA 2008 .............................................................101 

Smoking, Polymorphisms, And Lung Cancer Prognosis.............................................................................................102 

Zhaoxi (Michael) Wang, MD, PhD; Harvard School of Public Health; CIA 2008 ...............................................102 

Role Of IRF-5 As A Tumor Suppressor In A Non-Small Cell Lung Cancer...............................................................102 

Betsy J. Barnes, PhD; UMDNJ-New Jersey Medical School; YCSA 2003 ........................................................102

Expression Profiling Of Blood In Lung Cancer Chemoprevention............................................................................103 

Christopher D. Coldren, PhD; University of Colorado; YCSA 2004........................................................................103 

Development Of Stem Cell Model Systems Of Lung Cancer And Tobacco-Damaged Airway Epithelium.......104 

Balazs Halmos, MD, MS; Case WesteRN Reserve University; YCSA 2004 ........................................................104 

Targeting MYC For The Treatment Of Lung Cancer .....................................................................................................105 

Catherine M. Shachaf, PhD; Stanford University; YCSA 2004 ..............................................................................105 

Transcriptional Regulation Of Puma In Lung Cancer..................................................................................................107 

Jian Yu, PhD; University of Pittsburgh; YCSA 2004 .................................................................................................107 

Targeting The Estrogen Receptor And Epithelial Growth Factor Receptor For Lung Cancer Therapy .............108 

Laura A. Stabile, PhD; University of Pittsburgh; YCSA 2004..................................................................................108 

Second Hand Tobacco Smoke And Lung Cancer Risk................................................................................................108 

Olga Y. Gorlova, PhD; M. D. Anderson Cancer Center; YCSA 2004......................................................................108 

PPar-Gamma In Tumorogenesis And Therapy Of Non-Small Cell Lung Cancer....................................................109 

Venkateshwar Keshamouni, PhD; University of Michigan; YCSA 2004...............................................................109 

Smoking, Polymorphisms, And Lung Cancer Prognosis.............................................................................................110 

Wei Zhou, MD, PhD; Harvard University; YCSA 2004 .............................................................................................110 

The Role Of The Transcription Factor C/Ebp Alpha In Normal Lung Development And In Murine 

Models Of Lung Cancer And Tobacco-Damaged Airway Epithelium ......................................................................111 

Elena Levantini, PhD; Harvard University; YCSA 2006............................................................................................111 

Developing NRF2 Inhibitors For Cancer Chemotherapy .............................................................................................112 

Anju Singh, PhD; The Johns Hopkins University; YCSA 2007 ...............................................................................112 

Using Novel Tumor Models And Novel Therapeutics To Define Tumor Progenitors In Small Lung Cancer .........112 

Christine L. Hann, MD, PhD; The Johns Hopkins University; YCSA 2007............................................................112 

MEK-Induced Growth Arrest In Small Cell Lung Cancer Cells.................................................................................113 

Jong-In Park, PhD; Medical College of Wisconsin; YCSA 2007 ...........................................................................113 

Targeting Epigenetic Changes In Metastatic Lung Cancer .......................................................................................113 

Rosalyn Juergens, MD; The Johns Hopkins University; YCSA 2007....................................................................113 

Combination AD.P53-DC Immunotherapy/Chemotherapy For SCLC .........................................................................113 

Terri B. Hunter, PhD; H. Lee Moffitt Cancer Center; YCSA 2007...........................................................................113 

Hedgehog Signaling In Small Cell Lung Cancer Stem Cells .....................................................................................114 

Craig D. Peacock, PhD; The Johns Hopkins University; YCSA 2008....................................................................114 

Therapeutic Targets In K-RAS-Induced Lung Cancer .................................................................................................115 

Daniela S. Basseres, PhD; University of North Carolina at Chapel Hill; YCSA 2008.........................................115 

Tolerance Of Tobacco Smoke-Induced Dna Damage In Lung...................................................................................115 

Laura Barkley-Elliman, PhD; Galway University Foundation; YCSA 2008 ...........................................................115 

Gender Differences In The Efficacy Of Antiangiogenic Therapies: The Role Of EGFR/Estrogen Receptor 

Interactions In NSCLC .......................................................................................................................................................116 

Matthew H. Herynk, PhD; University of Texas M. D. Anderson Cancer Center; YCSA 2008...........................116 

Allelic Imbalance And MiRNa Regulation By Tobacco Smoke In Nsclc ...............................................................117 

Shahnaz Begum, Mbbs, PhD; The Johns Hopkins University; YCSA 2008 .........................................................117 

Lung Cancer Chemoprevention: The Role Of Rosiglitazone ......................................................................................117 

Saswati Hazra, PhD; University of California, Los Angeles; YCSA 2005 .............................................................117 

Completed Research..........................................................................................................................................................118 

Methylation Analysis Of Lung Cancers From Smoking And Non-Smoking Women................................................... 

William P. Bennett, MD, MS; City of Hope; CIA 2004..............................................................................................118 

TGF Beta Signaling In Lung Cancer: A Therapeutic Target .......................................................................................118 

Pran Datta, PhD; Vanderbilt University; CIA 2005 ...................................................................................................118 

Nucleolar Expression Of PTHRP And Outcome In Non-Small Cell Lung Cancer (NSCLC)..................................119 

Leonard Deftos, MD; VA San Diego Healthcare System; CIA 2002 .....................................................................119 

LOH And Gene Expression Profiles In Lung Carcinoma.............................................................................................119 

Matthew Meyerson, MD, PhD; Harvard University; CIA 2002 ..............................................................................119 

Role Of Aldehyde Dehydrogenases In The Pathogenesis And Biology Of Lung Cancer .....................................120 

Jan Moreb, MD; University of Florida; CIA 2003 .....................................................................................................120 

Identification Of New Molecular Targets In Lung Cancer.........................................................................................120 

Pierre P. Massion, MD; Vanderbilt University; CIA 2003 ........................................................................................120

CONTENTS 

The Implication Of Potential Tumor Suppression Function Of DAXX 

In C-MET-Dependent Lung Malignancy.........................................................................................................................121 

Alexander M. Ishov, PhD: University of Florida; CIA 2004.....................................................................................121 

The Small Molecule Inhibitors Of BCL-2 As Novel Therapeutics For Lung Cancer .............................................121 

Charles M. Rudin, MD, PhD; The Johns Hopkins University; CIA 2004...............................................................121 

A Transgenic Animal Model To Control The Angiogenic Switch In Lung Cancer ................................................121 

Douglas A. Arenberg, MD; University of Michigan; CIA 2004...............................................................................121 

Epigenetic Control Of Human Prostacyclin Synthase.................................................................................................121 

Robert S. Stearman, PhD; University of Colorado; CIA 2004.................................................................................121 

PatteRNs Of Gene Expression In Early Lung Lesions .................................................................................................122 

Scott Wadler (Maureen Lane, PhD), MD; CoRNell University; CIA 2004 ............................................................122 

The Molecular Epidemiology Of Second Hand Tobacco Smoke-Associated Lung Cancer ................................122 

David P. Miller, ScD, SM; Harvard University; YCSA 2002.....................................................................................122 

Cyclopamine Inhibits Hedgehog Signaling And Growth In Lung Cancer Cells.....................................................123 

D. Neil Watkins, MD, PhD; The Johns Hopkins University; YCSA 2002...............................................................123 

The Role Of HMG-I/Y In The Pathogenesis Of Lung Cancer......................................................................................123 

Raka Bhattacharya, PhD; The Johns Hopkins University; YCSA 2002 ................................................................123 

CANCER: LYMPHOMA ...................................................................................................................................................................124 

Current Research................................................................................................................................................................124 

Functional Analysis Of The MMSET Oncogene In Translocation 4;14 Multiple Myeloma..................................124 

Josh Lauring, MD, PhD; The Johns Hopkins University; YCSA 2007 ...................................................................124 


Transformed Follicular LyMPHoma: Smoke Related?.................................................................................................125 

Ronald B. Gartenhaus, MD; University of Maryland; CIA 2002.............................................................................125 

CANCER: MULTIPLE .......................................................................................................................................................................125 


Roles Of The Checkpoint Kinases In The Responses Of Human Cancer Cells To Dna Damage ........................125 

Fred Bunz, MD, PhD; The Johns Hopkins University; YCSA 2003 ........................................................................125 

Targeting The Atr Kinase In Second Hand Tobacco Smoke-Related Cancers ......................................................125 

Fred Bunz, MD, PhD; The Johns Hopkins University; CIA 2008............................................................................125 

Sensitivity Of Tobacco-Induced Cancer To Herpes Viral Oncolysis........................................................................126 

Richard J. Wong, MD; Memorial Sloan-Kettering Cancer Center; CIA 2004, 2007 ...........................................126 

Early Detection And Screening Of Smoking-Related Cancers By Use Of Green Fluorescent Protein 

Expressing Herpes Simplex Virus ..................................................................................................................................127 

Yuman Fong, MD; Memorial Sloan-Kettering Cancer Center; CIA 2004 .............................................................126 

The Impact Of SWI/SNF Complex In Cancer.................................................................................................................128 

David N. Reisman, MD, PhD; University of Michigan; CIA 2005...........................................................................128 

Somatic Cell Knock-In Of A Mutant K-RAS Gene For Understanding And Targeting Ras-Induced 

Cancers Related To Second Hand Tobacco Smoke ....................................................................................................129 

Ben-Ho Park, MD, PhD; The Johns Hopkins University; YCSA 2006 ...................................................................129 

Regulation Of TGF Beta Signaling In Prostate Cancer ...............................................................................................130 

Paula J. Hurley, PhD; The Johns Hopkins University; YCSA 2007........................................................................130 


Organismal Effect Of Tobacco Smoke On Telomerase Null Mice............................................................................130 

Kwok-Kin Wong, MD, PhD; Harvard University; CIA 2005.....................................................................................130 

Inhibitors Of Histone Acetyltransferase (HAT) As Novel Therapies For HPV-Associated Malignancies........130 

Rhoda M. Alani, MD; The Johns Hopkins University; YCSA 2002 ........................................................................130 

CANCER: OVARIAN.........................................................................................................................................................................131 


Antibodies For Smoking-Related Mucinous Ovarian Cancer ...................................................................................131 

Shu-Wing Ng, PhD; Brigham and Women’s Hospital; CIA 2006 ...........................................................................131 

CANCER: PROSTATE.......................................................................................................................................................................131 


Cigarette Smoke And Impaired Selenoprotein Production .......................................................................................131 

Charles B. Foster, MD; Cleveland Clinic; CIA 2007 .................................................................................................131 

Small Peptide Therapy On Metastatic Prostate Cancer.............................................................................................132 

Jer-Tsong Hsieh, PhD; University of Texas Southwestern; CIA 2008 ..................................................................132

Inhibition Of Hedgehog Signaling By Cyclopamine Prodrug For Prostate Cancer...............................................132 

Anirban Maitra, MBBS; The Johns Hopkins University; CIA 2008.......................................................................132 

DNA Methylation Biomarkers In Prostate Cancer And Towards A Better Understanding 

And Targeting Of Epigenetic Proteins In Prostate Cancer.........................................................................................133 

Joshi J. Alumkal, MD; Oregon Health and Sciences Center; YCSA 2006...........................................................133 

NDRG1 Modulation To Decrease Prostate Cancer Invasion .....................................................................................134 

Sushant K. Kachhap, PhD; The Johns Hopkins University; YCSA 2007 ..............................................................134 

CANCER: THYROID .........................................................................................................................................................................134 


BRAF Mutation And Other Common Genetic And Epigenetic Alterations In Thyroid Cancer: 

Relationship With Smoking And Clinical Applications .............................................................................................134 

Michael M. Xing, MD, PhD; The Johns Hopkins University; CIA 2004 ................................................................134 

CARDIOVASCULAR.........................................................................................................................................................................135 


The Risk Of Coronary Heart Disease Among Women Exposed To Second Hand Tobacco Smoke....................135 

Wael K. Al-Delaimy, MD, PhD; University of California, San Diego; YCSA 2002, CIA 2009..............................135 

Carbon Monoxide Hypoxia In Tobacco Smoke Induced Disease ............................................................................135 

J. Timothy O’Neill, PhD; Uniformed Services University of the Health Science; CIA 2005..............................135 

LDL Oxidation By Second Hand Tobacco Smoke ........................................................................................................136 

Jeanclare Seagrave, PhD; Lovelace Respiratory Research Institute; CIA 2005 ...............................................136 

Second Hand Tobacco Smoke-Induced Heart And Brain Injury...............................................................................136 

Mark S. Gold, MD; University of Florida; CIA 2006..................................................................................................136 

Regulation Of Matrix Metalloproteinase-1 By Cigarette Smoke In Aortic Endothelial Cells ............................136 

Vincent Lemaitre, PhD; Columbia University; CIA 2007..........................................................................................136 

Role Of Heat Shock Protein 90 In Tobacco Smoke-Induced Heart Disease ..........................................................137 

Kathleen L. Gabrielson, DVM, PhD; The Johns Hopkins University; CIA 2008...................................................137 

Effects Of Second Hand Cigarette Smoke Exposure On Adinopectin, MTOR, And Vascular Disease..............137 

Kathleen A. Martin, PhD; Dartmouth College; CIA 2008 ........................................................................................137 

Long-Term Vascular Effects Of Second Hand Tobacco Smoke.................................................................................138 

Matthew L. Springer, PhD; University of California, San Francisco; CIA 2008 ..................................................138 

Exacerbation Of Viral Myocarditis By Tobacco Smoke Through Increased Viral Load 

And Cardiac Apoptosis......................................................................................................................................................138 

James P. Morgan, MD, PhD; Caritis St. Elizabeth’s Medical Center; CIA 2006..................................................138 

Impact Of Passive Smoking And Early Atherosclerosis In Children With Type I Diabetes Mellitus................138 

Petru Liuba, MD, PhD; Lund University; YCSA 2004 ...............................................................................................138 

Small Diameter Blood Vessel Regeneration By Biomimetic Engineering .............................................................139 

Feng Zhao, PhD; Florida State University; YCSA 2007............................................................................................139 


Second Hand Tobacco Smoke Platelet Activation And Cardiovascular Risk .......................................................140 

Danny Bluestein, PhD; State University of New York at Stony Brook; CIA 2002, 2004.....................................140 

SHS And Outcomes In Congestive Heart Failure .........................................................................................................140 

Kirsten Fleischmann, MD, MPH; University of California, San Francisco; CIA 2003 ........................................140 

The Effect Of Second Hand Tobacco Smoke On Exercise Capacity And Clinical Outcomes 

In Pulmonary Arterial Hypertension...............................................................................................................................140 

Teresa De Marco, MD; University of California, San Francisco; CIA 2003.........................................................140 

Peripheral Vascular Hemodynamics And Ventricular Mechanics In Passive Smokers .....................................141 

Theodore P. Abraham, MD; The Johns Hopkins University; CIA 2004.................................................................141 

Nicotine Regulation Of Manganese Superoxide Dismutase.....................................................................................141 

Richard J. Rogers, MD, PhD; University of Florida; YCSA 2004............................................................................141 

Alteration In Expression Of Vascular G-Protein Coupled Receptors As A Novel Mechanism 

Responsible For Cardiovascular Morbidity By Cigarette Smoking..........................................................................141 

Lars Edvinsson, MD PhD; Lund University; CIA 2005 .............................................................................................141 

Effects Of Second Hand Tobacco Smoke On Susceptibility Of Ventricular Myocytes To Ischemic Injury......142 

William H. Barry, MD; University of Utah; CIA 2005................................................................................................142 

Treating Vascular Disease By Targeting Elastin Signaling .......................................................................................142 

Dean Y. Li, MD, PhD; University of Utah; CIA 2005..................................................................................................142

CONTENTS 

The Effect Of Second Hand Tobacco Smoke On The Risk Of Developing Atrial Fibrillation 

In Patients With Pacemakers And Defibrillators ........................................................................................................142 

Byron K. Lee, MD; University of California, San Francisco; YCSA 2004..............................................................142 

CHRONIC KIDNEY DISEASE..........................................................................................................................................................143 


Mechanisms Of Endothelial Dysfunction In Smokers ................................................................................................143 

Edgar A. Jaimes, MD; University of Alabama at Birmingham; YCSA 2003.........................................................143 

Role Of Nicotine As Mediator Of The Effects Of Tobacco In The Progression Of Chronic Kidney Disease....143 

Edgar A. Jaimes, MD; University of Alabama at Birmingham; CIA 2008 ............................................................143 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE....................................................................................................................144 


Targeting NRF2 For Intervening Emphysema ................................................................................................................144 

Shyam Biswal, PhD; The Johns Hopkins University; YCSA 2002, CIA 2008........................................................144 

The Effect Of PLTP Induction In Smokers......................................................................................................................145 

Robert F. Foronjy, MD; YCSA 2003, CIA 2008 ............................................................................................................145 

Second Hand Tobacco Smoke-Induced Lung Cell Death 

Via Nitric Oxide-Cytochrome C Oxidase Signaling ....................................................................................................146 

Jianliang Zhang, PhD; University of Florida; CIA 2004 ...........................................................................................146 

Exhaled Smoke-Induced Lung Endothelial Apoptosis Via Peroxynitrite-Bax Signaling ....................................147 

Jianliang Zhang, PhD; University of Florida; CIA 2007 ...........................................................................................147 

Host Defence Functions Of Airway Epithelial Cells In COPD ...................................................................................147 

Hong Wei Chu, MD; National Jewish Medical and Research Center; CIA 2005, 2008.....................................147 

A Novel Anti-Inflammatory Role For Adam15 In Emphysema ...................................................................................147 

Caroline A. Owen, MD, PhD; Brigham and Women’s Hospital; CIA 2006 ...........................................................147 

Smoking Impairs Alpha 1-Antitrypsin’s Pro-Survival Effect In The Lung................................................................148 

Irina Petrache, MD; Indiana University; CIA 2006...................................................................................................148 

Neuropilin-1 And Emphysema .........................................................................................................................................149 

Patrice M. Becker, MD; The Johns Hopkins University; CIA 2006.......................................................................149 

Elastin Fragment Inhibition As A Therapy For COPD ..................................................................................................149 

Steven D. Shapiro, MD; University of Pittsburgh; CIA 2006 ..................................................................................149 

Does Second Hand Cigarette Smoke Modulate Vitamin E Uptake In Lung Tissue?.............................................149 

Giuseppe Valacchi, PhD; University of Siena; CIA 2007 ........................................................................................149 

Reduced Neutrophil Death In Tobacco-Induced COPD..............................................................................................150 

Hongbo R. Luo, PhD; Harvard University; CIA 2007 ................................................................................................150 

Cigarette Smoke Impairs Removal Of Apoptotic Cells (Efferocytosis) Through RHOA-Dependent 

And Independent Mechanisms........................................................................................................................................150 

R. William Vandivier, MD; University of Colorado; CIA 2007 .................................................................................150 

Goblet Cell Hyperplasia In Chronic Bronchitis............................................................................................................151 

Yohannes Tesfaigzi, PhD; Lovelace Respiratory Research Institute; CIA 2007..................................................151 

Role Of Cyclic Guanosine Monophosphate In Tobacco Smoke-Induced Lung Endothelial Dysfunction 

And Emphysema .................................................................................................................................................................151 

David B. Pearse, MD; The Johns Hopkins University; CIA 2008...........................................................................151 

Host Defence Functions Of Airway Epithelial Cells In COPD Immune Responses To 

Second Hand Cigarette Smoke Exposure......................................................................................................................152 

Laimute Taraseviciene-Stewart, PhD; National Jewish Medical and Research Center; CIA 2008 ...............152 

Noninvasive Measurement Of Alveolar Surface Area ...............................................................................................152 

Samuel Patz, PhD; Brigham And Women’s Hospital; CIA 2008.............................................................................152 

The Role Of Bronchio-Alveolar Stem Cells In Cigarette Smoke-Related Emphysema ........................................153 

Shivraj Tyagi, PhD; Brigham And Women’s Hospital; CIA 2008............................................................................153 

Haemophilus Influenzae Tolerance: A Mechanism For Chronic Colonization In COPD ......................................153 

Tricia D. Levan, PhD; University Of Nebraska; CIA 2008........................................................................................153 

Cigarette Smoke Exposure And Influenza Virus Infection In Human Lung.............................................................154 

Wenxin Wu, PhD; University of Oklahoma Health Sciences Center; CIA 2008..................................................154 

Neurotrophins In Cigarette Smoke Induced Airway Hyperreactivity......................................................................154 

Y. S. Prakash, MD, PhD; Mayo Clinic; CIA 2008.......................................................................................................154 

Role Of Nicotine In COPD Progression..........................................................................................................................155 

Diane L. Carlisle, PhD; Magee Women’s Health Corporation; YCSA 2005..........................................................155

Genetic Epidemiology Of Pulmonary Function And COPD.........................................................................................155 

Jemma B. Wilk, Dsc; Boston University; YCSA 2005..............................................................................................155 

Peripheral Blood Mononuclear Cell Profiling In Tobacco Exposure: Susceptibility Markers For COPD........156 

Michael G. Edwards, PhD; University of Colorado; YCSA 2005 ............................................................................156 

Identification Of Pathogenic Cd4+ T Cells In The Lungs Of Patients With Severe Emphysema ........................156 

Michael Falta, MD, PhD; University of Colorado; YCSA 2005 ...............................................................................156 

Molecular Phenotype Of Early Emphysema..................................................................................................................157 

Russell Bowler, MD, PhD; National Jewish Medical and Research Center; YCSA 2005.................................157 

Biology Of IL-13 And 5-LO In The Pathogenesis Of COPD..........................................................................................157 

Yun M. Shim, MD; University of Virginia; YCSA 2005..............................................................................................157 

Cigarette Smoke And Mechanical Stretch In COPD ...................................................................................................157 

James C. Lavelle, MD; University of Colorado at Denver and Health Sciences Center; YCSA 2006.............157 

Serine Protease Inhibitor E2 And COPD ........................................................................................................................158 

Sorachai Srisuma, MD, PhD; Thai-American Physicians Foundation; YCSA 2006 ...........................................158 

Cell-Based Therapy For Cigarette Smoke-Related Lung Disease............................................................................158 

Andrew A. Wilson, MD; Boston University; YCSA 2007.........................................................................................158 

Influence Of ARHGEF1 On Pulmonary Immunity ..........................................................................................................159 

John M. Hartney, PhD; University of Colorado; YCSA 2007...................................................................................159 

The Role Of Thrombospondin-1 In Emphysema............................................................................................................159 

Michael E. Ezzie, MD; Ohio State University; YCSA 2007 ......................................................................................159 

CXCL5 Is Central To Cigarette Smoke-Induced Neutrophil Influx ............................................................................159 

Sambithamby Jeyaseelan, Dvm, PhD, Louisiana State University; YCSA 2007 .................................................159 

Regulators Of Cigarette-Induced Endothelial Cell Apoptosis...................................................................................160 

Rachel Damico, MD, PhD; The Johns Hopkins University; YCSA 2008...............................................................160 

Role Of The WNT-Beta-Catenin Pathway In Epithelial Injury By Pmn In Emphysema ........................................161 

Rachel L. Zemans, MD; National Jewish Medical and Research Center; YCSA 2008 .....................................161 


Noninvasive Assessment Of The Lower Respiratory Tract In Response To Second Hand Tobacco Smoke...........161 

Richard A. Robbins, MD, PhD; Carl T. Hayden Va Medical Center; CIA 2003 ....................................................161 

Matrix-Induced Epithelial Activation In Bronchitis....................................................................................................162 

Maureen Horton, MD; The Johns Hopkins University; YCSA 2003 ......................................................................162 

Biomarkers Of Chronic Obstructive Pulmonary Disease ...........................................................................................162 

Robert E. Walter, MD; Boston University; YCSA 2003 ............................................................................................162 

DIAGNOSTIC TECHNIQUES ..........................................................................................................................................................162 


Detection of Passive Smoke Exposure in Children and Adults Using Oral Based Rapid Test Technology.............162 

R. Sam Niedbala, PhD; Lehigh University; CIA 2006...............................................................................................162 

Screening And Diagnosis Of Laryngeal Cancer With Oct .........................................................................................163 

Brian J. F. Wong, MD, PhD; University of California, Irvine Medical Center; CIA 2007....................................163 

Production Of Anti-Cotinine Monoclonal Antibody And Detection 

Of Second-Hand Tobacco Smoke Exposure .................................................................................................................164 

Zhiyong Cui, PhD; Dartmouth College; YCSA 2006..................................................................................................164 


Novel Microvessel Structure Imaging Strategies For Early Detection Of Lung Cancer Related 

To SHS Exposure ................................................................................................................................................................164 

Justin D. Pearlman, MD, PhD; Dartmouth College; CIA 2003................................................................................164 

Risk Factors For Chronic Obstructive Pulmonary Disease ........................................................................................165 

Francine L. Jacobson, MD; Harvard University; CIA 2004.....................................................................................165 

ECG-Gated Multidetector CT Of Aortic Distensibility.................................................................................................165 

Joel Fletcher, MD; Mayo Clinic; CIA 2004 ................................................................................................................165 

Diffusion Helium Mri-Diagnosis Pre-Clinical Emphysema........................................................................................166 

Talissa Altes, MD; University of Virginia; CIA 2004.................................................................................................166 

Diagnosis Of Premalignant Oral Lesions Via A Multiparametric Cell Scanning System....................................166 

Abraham Hirshberg, MD, DMD; Tel Aviv University; CIA 2005 .............................................................................166 

The Macronome As A Tool For Early Cancer Diagnosis ............................................................................................167 

Samuel R. Denmeade, MD; The Johns Hopkins University; CIA 2005.................................................................167

CONTENTS 

DISEASE PREVENTION..................................................................................................................................................................167 


Second Hand Tobacco Smoke Global Research Network ........................................................................................167 

Andrew Hyland, PhD; Roswell Park Cancer Institute; YCSA 2002; CIA 2007, 2008 ...........................................167 

Changing Pediatric Practice To Address Second Hand Tobacco Smoke Exposure.............................................170 

Jonathan P. Winickoff, MD, MPH; Massachusetts General Hospital; 2003 YCSA ............................................170 

Reversing Tobacco Market Research On Young Adults And Bar Interventions To Decrease 

Young Adult Smoking ........................................................................................................................................................170 

Pamela Ling, MD MPH; University of California, San Francisco; YCSA 2004 ....................................................170 

Second Hand Tobacco Smoke In Mexican American Households..........................................................................171 

Alexander V. Prokhorov, MD, PhD; University of Texas M.D. Anderson Cancer Center; CIA 2006................171 

Prevalence Of Smoke-Free Campuses In U.S. Hospitals And Best Practices For Implementation ..................172 

Sharon Milberger, ScD; Henry Ford Health System; CIA 2007 .............................................................................172 

Advances In Monitoring Exposure To Second Hand Tobacco Smoke In The Air And In The Body ..................172 

Mark J. Travers, PhD; Roswell Park Cancer Center; YCSA 2006 .........................................................................172 

Health Impact Study Of Smokefree Policies In Latin America .................................................................................174 

ERNesto Sebrié, MD MPH; Roswell Park Cancer Institute; YCSA 2008 .............................................................174 

Evaluating The Characteristics That Influence Persuasiveness Of Second Hand Tobacco Smoke 

Advertisements...................................................................................................................................................................175 

Maansi Bansal-Travers, PhD; Roswell Park Cancer Center; YCSA 2008............................................................175 


Development And Implementation Of Smoking Restriction Policies ......................................................................175 

Lisa A. Bero, PhD; University of California, San Francisco; CIA 2003 .................................................................175 

Reducing SHS: Cardiac And Asthma Outcomes ..........................................................................................................176 

Ellen J. Hahn, Dns, RN; University of Kentucky; CIA 2004.....................................................................................176 

Prevention Of Tobacco-Related Disease.......................................................................................................................176 

Stephen P. Teret, JD, MPH; The Johns Hopkins University; CIA 2004.................................................................176 

EDUCATION......................................................................................................................................................................................176 


Increasing Second Hand Tobacco Smoke Awareness, Competency, And Screening Among Medical 

Professionals: Expanding The Medical Curriculum....................................................................................................176 

Mark S. Gold, MD; University of Florida; CIA 2007..................................................................................................176 

Second Hand Tobacco Smoke Counseling For Parents Of Hospitalized Pediatric Patients ..............................177 

Alan C. Geller, PH, RN; Harvard University; CIA 2007.............................................................................................177 

EXPANDING GRANTEES RESEARCH CAPABILITIES THROUGH PRESERVATION 

OF TOBACCO DISEASE DOCUMENTS ........................................................................................................................................177 


Airline And Airport Smoking Restrictions As Reflected In The Tobacco Institute’s Documents.......................177 

Anthony Brown, BS; Roswell Park Cancer Institute; BDA 2003...........................................................................177 

FAMRI-Guilford Digital Library Of Documents .............................................................................................................177 


Karen Butter, MLS; University of California, San Francisco; 2003 Bda...............................................................177 

EXPOSURE TO SECOND HAND TOBACCO SMOKE..................................................................................................................178 


Chronic Cigarette Smoke Extract Treatment Selects For Apoptotic Dysfunction 

And Mitochondrial Mutations In Minimally Transformed Oral Keratinocytes ......................................................178 

Joseph A. Califano, MD; The Johns Hopkins University; CIA 2006......................................................................178 

Second Hand Tobacco Smoke Exposure Among Bar And Nightclub Employees .................................................178 

Ana Navas-Acien, MD, PhD; The Johns Hopkins University; CIA 2006 ..............................................................178 

Second Hand Tobacco Smoke And Sids: A Laryngeal Connection?........................................................................179 

Donald Bartlett, Jr., MD; Dartmouth College; CIA 2007..........................................................................................179 

Second Hand Tobacco Smoke Emissions Of Reduced Exposure Products............................................................179 

Gregory N. Connolly, DMD, MPH; Harvard School of Public Health; CIA 2007 .................................................179 

Smoke-Free Air Laws, Exposure And Health In Adolescents...................................................................................180 

Gregory N. Connolly, DMD, MPH; Harvard School of Public Health; CIA 2008 .................................................180 

Tobacco Smoke Endotoxin ...............................................................................................................................................180 

Lennart P. Larsson, PhD; Lund University; CIA 2007 ...............................................................................................180

Reducing Second Hand Tobacco Smoke Exposure Among Young Children..........................................................181 

Abu S. Abdullah, MD, PhD, MPH, MFPH; Boston University; CIA 2008 ..............................................................181 

A Multiple Stakeholder Study Regarding The Impact Of 

Second Hand Tobacco Smoke In Multiunit Housing ..................................................................................................181 

Andrew Hyland, PhD; Roswell Park Cancer Institute; CIA 2008...........................................................................181 

Fetal And Infant Exposure To SHS And Its Role In Chronic Disease .......................................................................182 

Manolis Kogevinas, MD, PhD; University of Crete; CIA 2008................................................................................182 

Evaluating Online Clinical Office-Systems Training To Address 

Second Hand Tobacco Smoke Exposure Of Children .................................................................................................183 

Jonathan P. Winickoff, MD, MPH; Massachusetts General Hospital; CIA 2008................................................183 

Trends In Second Hand Tobacco Smoke Exposure And Pediatric Illness In The U.S..........................................183 

Hillel R. Alpert, BSc, SM; Harvard School of Public Health; CIA 2008 ................................................................183 

Second Hand Tobacco Smoke And Head And Neck Cancer.....................................................................................184 

Edward Peters, DMD, SM, ScD; Louisiana State University; YCSA 2003 ...........................................................184 

Childhood Second Hand Tobacco Smoke Exposure: Delayed Neuropsychiatric Effects....................................184 

Adriaan W. Bruijnzeel, PhD; University of Florida; YCSA 2006 .............................................................................184 

Simulation Of Second Hand Tobacco Smoke Deposition In The Airways .............................................................185 

Jeffrey J. Heys, PhD; Arizona State University; YCSA 2006..................................................................................185 

Hookah Use And Second Hand Tobacco Smoke .........................................................................................................186 

Nada Kassem, PhD; San Diego State University; YCSA 2006 ...............................................................................186 

PSE Rates And Correlates: Koreans/Korean Americans ............................................................................................186 

Suzanne C. Hughes, PhD, MPH; San Diego State University; YCSA 2006 ..........................................................186 

Second Hand Tobacco Smoke, Pediatric Healthcare Use, And Spending.............................................................187 

Douglas Levy, PhD; Harvard Medical School; YCSA 2008 ....................................................................................187 

Well-Baby Clinic-Based Intervention ............................................................................................................................187 

Laura Rosen, PhD; Tel Aviv University; YCSA 2008.................................................................................................187 


Quantifying Human Exposure To SHS ............................................................................................................................188 

Paul Switzer, PhD; Stanford University; CIA 2003 ...................................................................................................188 

Airway Resistance And Cytogenetic Abnormalities Associated With Tobacco Smoke Exposure ...................188 

Martin Mahoney, MD, PhD; Roswell Park Cancer Institute; CIA 2003................................................................188 

Second Hand Tobacco Smoke Exposure And Health In A Blue-Collar Population..............................................189 

Francine Laden, ScD; Harvard University; YCSA 2002 ...........................................................................................189 

Adult Health Consequences Of Prenatal And Postnatal Second Hand Tobacco Exposure ................................189 

Stephen L. Buka, ScD; Harvard School of Public Health; CIA 2006....................................................................189 

HORMONAL CHANGES FROM TOBACCO EXPOSURE .............................................................................................................189 


Steroid Hormones Concentrations Associated With Active And Passive Cigarette Smoking...........................189 

Offie P. Soldin, PhD, MBA, MSc; Georgetown University; CIA 2006....................................................................189 

Randomized Controlled Trials (Rct) Of Family Interventions To Reduce Second Hand 

Tobacco Smoke (SHS) Exposure In Infants And Mothers ..........................................................................................190 

Sophia Siuchee Chan, PhD; University of Hong Kong; CIA 2007..........................................................................190 

IMMUNE FUNCTION IMPACTED BY TOBACCO SMOKE.........................................................................................................191 


A2A Receptor Antagonism As A Novel Means To Enhance Vaccine Therapy For The Treatment And 

Prevention Of Breast Cancer ...........................................................................................................................................191 

Jonathan D. Powell, MD, PhD; Columbia University; CIA 2006 ............................................................................191 

Second Hand Tobacco Smoke, Immunity And Allograft Rejection ..........................................................................191 

Zhenhua Dai, MD, PhD; University of Texas Health Center At Tyler; CIA 2008..................................................191 

Alterations In Dendritic Cell-Mediated Immunity Caused By Smoking..................................................................191 

Robert Vassallo, MD; Mayo Clinic; YCSA 2005........................................................................................................191 

Innate Immunity And Tobacco Smoke............................................................................................................................192 

Maria Antonieta Guerrero-Plata, PhD; University of Texas Medical Branch at Galveston; YCSA 2007 .......192 

Molecular Mechanism Of Phosphatidylinositol 3-Kinase (Pi-3k) Activation In Flagellin/Toll-Like 

Receptor 5-Dependent Signaling....................................................................................................................................192 

Sang Hoon Rhee, PhD; University of California, Los Angeles; YCSA 2007 .........................................................192

CONTENTS 

Role Of SERPINB1 In Cigarette Smoke-Induced Defective Antimicrobial Defense .............................................192 

Charaf Benarafa, DVM, PhD; Immune Disease Institute; YCSA 2008..................................................................193 

The Influence Of Second Hand Cigarette Smoke On The Innate Immune Function Of Nasal Epithelial Cells .......193 

James A. Jukosky, PhD; Dartmouth College; YCSA 2008 ......................................................................................193 


Ontogeny Of Cytokine Immune Responses: Role Of Second Hand Tobacco Smoke ............................................194 

Deborah A. Gentile, MD; Allegheny-Singer Research Institute; CIA 2004 .........................................................194 

INFECTIOUS DISEASES .................................................................................................................................................................194 


SHS And Influenza-Induced Responses In Nasal Epthelium.....................................................................................194 

Ilona Jaspers, PhD; University of North Carolina at Chapel Hill; CIA 2006 ........................................................194 

MENOPAUSE ...................................................................................................................................................................................195 


Smoke And Early Menopause: Mechanisms And Model Systems ..........................................................................195 

Diego H. Castrillon, MD, PhD; University of Texas Southwestern; CIA 2006......................................................195 

NEUROBEHAVIORAL CONSEQUENCES OF TOBACCO EXPOSURE........................................................................................195 


Tobacco Smoke And Early Human Neurobehavior .....................................................................................................195 

Kimberly Yolton, PhD; Cincinnati Children’s Hospital; CIA 2007............................................................................195 

Mechanisms Of Environmental Tobacco Smoke-Induced Nervous System Malformations And Cancers ......196 

Annie W. Chan, MD; Massachusetts General Hospital; CIA 2008 .......................................................................196 


Second Hand Tobacco Smoke And Thyroid Disease..................................................................................................196 

Rachel Ying Vun Chong, MD; The Johns Hopkins University; CIA 2002..............................................................196 

Functional Mri Investigation Of Impaired Leptin Regulation Due To Second Hand Tobacco Smoke...............197 

Yijun Liu, PhD; University of Florida; CIA 2004 .........................................................................................................197 

PREGNANCY AND PERINATAL EFFECTS FROM TOBACCO EXPOSURE...............................................................................197 


Perinatal Nicotine, Carbon Monoxide And Neurodevelopment...............................................................................197 

J. Timothy O’Neill, PhD; Uniformed Services University of the Health Science; CIA 2008..............................197 

Role Of Erk In Ahr In Prenatal Tobacco Smoke Exposure .........................................................................................198 

Shashibushan P. Singh, PhD; Lovelace Respiratory Research Institute; CIA 2005...........................................198 

Effects Of Second-Hand Tobacco On The Immature Lung .........................................................................................198 

Kathleen J. Haley, MD; Harvard University; CIA 2007............................................................................................198 

Maternal Smoking: Fetuses In Withdrawal? ................................................................................................................199 

Laura Stroud, PhD; The Miriam Hospital, Brown University; CIA 2007 ...............................................................199 

Second-Hand Tobacco Smoke And Neonates And Predisposition To COPD And Durable Effects 

Of Newborn Cigarette Smoke Exposure On The Adult Lung .....................................................................................200 

Sharon A. Mcgrath-Morrow, MD; The Johns Hopkins University; CIA 2007 .....................................................200 

Effect Of Second Hand Tobacco Smoke On Fetal Body Size And Brain Size ........................................................201 

Hamisu M. Salihu, MD; University of Medicine and Dentistry of New Jersey; YCSA 2003 ............................201 

Maternal Exposure To Second Hand Tobacco Smoke And Pregnancy Outcomes ...............................................202 

John D. Meeker, MS, ScD; University of Michigan; YCSA 2005...........................................................................202 

Altered Gene Expression In Vascular Endothelial Cells In Response To Oxidative Stress From 

Second Hand Tobacco Smoke.........................................................................................................................................203 

Mark L. Martinez, MD; University of Utah; YCSA 2006...........................................................................................203 

Low Level Prenatal Tobacco Exposure And Infant Wheeze......................................................................................203 

Adam Spanier, MD, PhD, MPH; Cincinnati Children’s Hospital; YCSA 2007.......................................................203 

Effects Of Second Hand Tobacco Smoke On Placental Stem Cell Differentiation ...............................................204 

Teresa M. Erb, MD; Magee Women’s Health Corporation; YCSA 2007...............................................................204 


Effect Of Secondhand Cigarette Smoke, Rsv Bronchiolitis And Parental Asthma On Urinary Cysteinyl LTE4 .......204 

Jesse P. Joad, MD, MS; University of California, Davis; CIA 2002.......................................................................204 

Causes Of Perinatal And Infant Mortality Due To Fetal Nicotine Exposure...........................................................205 

Hugo Lagercrantz, MD, PhD; Karolinska Institutet; CIA 2005 ...............................................................................205 

Effects Of Passive Smoking And Nicotine On The Development Of CNS Body Image And Motor Skill ..........205 

Jens Schouenborg, MD; Lund University; CIA 2005 ...............................................................................................205

SINUSITIS ........................................................................................................................................................................................205 


Pathogenesis Of Chronic Sinusitis In Relationship To Tobacco Smoke Exposure...............................................205 

Daniel L. Hamilos, MD; Massachusetts General Hospital; CIA 2003...................................................................205 

Pathogenesis Of Chronic Rhinosinusitis In Relation To Second Hand Cigarette Smoke And Abnormal 

Epithelial Innate Immunity................................................................................................................................................206 

Daniel L. Hamilos, MD; Massachusetts General Hospital; CIA 2008...................................................................206 

Tobacco Smoke Exposure, Innate Immunity, And Chronic Sinusitis .......................................................................206 

Andrew P. Lane, MD; The Johns Hopkins University; CIA 2004, 2007 .................................................................206 

Contribution Of Second Hand Tobacco Smoke To Sinusitis......................................................................................207 

Noam A. Cohen, MD, PhD; University Of Pennsylvania; YCSA 2004....................................................................207 

Laboratory Studies Of Human Nasal Epithelium..........................................................................................................207 

Johnny L. Carson, PhD; University of North Carolina at Chapel Hill; CIA 2004, 2007........................................207 

Epithelium And Immunomodulation In Chronic Rhinosinusitis (CRS) .....................................................................208 

Jean Kim, MD, PhD; The Johns Hopkins University; CIA 2004 .............................................................................208 

Second Hand Tobacco Smoke Exposure Increases Biofilms Formation 

And Subsequent Ciliary Dysfunction..............................................................................................................................208 

James N. Palmer, MD; University of Pennsylvania; CIA 2006...............................................................................208 

Effects Of Second Hand Tobacco Smoke On Sinonasal Immunity...........................................................................208 

Rodney J. Schlosser, MD; Charleston Research Institute; CIA 2006...................................................................208 

Evaluating CD137 As A Novel Treatment In A New Tobacco-Exacerbated Model Of Chronic Sinusitis .........209 

Rodney J. Taylor, MD, MPH; University of Maryland; CIA 2007 ...........................................................................209 

Second-Hand Smoke And Sinusitis: Effect Of Sidestream Smoke On Sinus Ostial Patency .............................209 

John Balmes, MD; and Dennis Shusterman MD, MPH; University of California, San Francisco; CIA 2008 ......209 

Second Hand Tobacco Smoke Exacerbation Of Allergic Rhinitis............................................................................209 

M. Boyd Gillespie, MD; Charleston Research Institute; CIA 2008........................................................................209 

Molecular Mechanisms Of Spatiotemporal Regulation Of Leukocyte Chemotaxis And Its 

Dysregulation Involved In Chronic Sinusitis ................................................................................................................210 

Jin Zhang, PhD; The Johns Hopkins University; YCSA 2004 .................................................................................210 

Reversal Of Tobacco-Related Chronic Sinusitis..........................................................................................................211 

Bradford A. Woodworth, MD; University of Alabama at Birmingham; YCSA 2008 ...........................................211 


Tobacco Smoke And Gene Expression In Sinus Mucosa ..........................................................................................211 

Vladimir Vincek, MD, PhD; University of Miami; CIA 2004 ....................................................................................211 

Correlation Of Chronic Sinusitis And Tobacco Smoke...............................................................................................211 

Jeffrey S. Wolf, MD; University of Maryland; CIA 2004 .........................................................................................211 

SKIN AND SECOND HAND SMOKE.............................................................................................................................................212 


Passive Cigarette Smoke In The Pathogenesis Of Skin Cancer...............................................................................212 

Barry Starcher, PhD; University of Texas Health Center At Tyler; CIA 2004.......................................................212 


Nicotinic Receptors Alter Gene Expression In Keratinocytes..................................................................................212 

Sergei A. Grando, MD, PhD, DSc; University of California, Irvine; CIA 2002, 2005 ...........................................212 

SPERMATOGENESIS......................................................................................................................................................................213 


Second Hand Tobacco Smoke As A Potential Cause Of Spermatogenic Failures And Male Infertility...........213 

Margarita Vigodner, PhD; Stern College, Yeshiva University; YCSA 2008 ..........................................................213 

VISION ..............................................................................................................................................................................................214 


Gene Profiling Second Hand Tobacco Smoke And Macular Degeneration...........................................................214 

George Inana, MD, PhD; University of Miami; CIA 2007........................................................................................214 

Role Of Smoking In Age-Related Macular Degeneration ..........................................................................................214 

Maria Marin-Castano, MD, PhD; University of Miami; CIA 2008..........................................................................214 

A Role For Cathepsin B In Second Hand Tobacco Smoke-Related Vascular Diseases ......................................215 

Eunok Im, PhD; University of California, Los Angeles; YCSA 2006.......................................................................215 

Completed Research..........................................................................................................................................................215

CONTENTS 

Inflammation, Smoking, And Blindness From Ocular Neovascularization.............................................................215 

Scott W. Cousins, MD; Duke University; CIA 2004..................................................................................................215 

FAMRI DISTINGUISHED PROFESSORS ............................................................................................................................................216 

The Bland Lane International Distinguished Professor Award: Battling To Prevent And Cure 

Diseases From Tobacco Smoke On An International Level.......................................................................................216 

Lars Edvinsson, MD PhD; 2005 ...................................................................................................................................216 

The Dr. William Cahan Distinguished Professors: Battling To Prevent And Cure Diseases From 

Tobacco Smoke ..................................................................................................................................................................216 

Alan Blum, MD; 2002 ....................................................................................................................................................216 

David M. Burns, MD; 2002...........................................................................................................................................217 

Ronald M. Davis, MD, (died 2008) Henry Ford Health System; 2002....................................................................217 

Stanton A. Glantz, PhD; 2002.......................................................................................................................................217 

Steven S. Hecht, PhD; 2002.........................................................................................................................................218 

James Repace, MSc; 2002..........................................................................................................................................218 

Nancy Rigotti, MD; 2002 ..............................................................................................................................................219 

Michael B. Siegel, MD, MPH; 2002............................................................................................................................220 

Allan M. Brandt, PhD; 2003 .........................................................................................................................................221 

Richard D. Hurt, MD, Mayo Clinic; 2003....................................................................................................................222 

Thomas L. Petty, MD; 2003 ..........................................................................................................................................222 

Jonathan Samet, MD; 2003 .........................................................................................................................................222 

John F. Banzhaf III, JD; 2004.......................................................................................................................................223 

Gregory N. Connolly, DMD, MPH; 2004.....................................................................................................................223 

Margaret R. Spitz, MD, MPH; 2004 ............................................................................................................................223 

K. Michael Cummings, PhD; 2005...............................................................................................................................225 

Richard A. Daynard, JD, PhD; 2005 ...........................................................................................................................226 

William Grossman, MD; 2008......................................................................................................................................226 

S. Katherine Hammond, PhD; 2008 ............................................................................................................................226 

FAMRI GRANTEE PORTAL...................................................................................................................................................................227 

PERSONAL THOUGHTS FROM THE FLIGHT ATTENDANT MEMBERS OF THE BOARD OF TRUSTEES.................................228 

INDICES ..................................................................................................................................................................................................230 

List of FAMRI Grantees......................................................................................................................................................230 

Acronyms .............................................................................................................................................................................242 

Supported Publications and Meeting Abstracts..........................................................................................................242 

Author Index........................................................................................................................................................................290 

Subject Index ......................................................................................................................................................................291 

Attribution............................................................................................................................................................................292

INTRODUCTION 

David M. Burns, MD, Professor Emeritus University of California, San Diego, Scientific Editor 

This volume is a compendium of the substantial body of work funded by the Flight Attendants Medical 

Research Institute (FAMRI) and will leave even the most jaded reader impressed with the broad reach 

FAMRI has manifested in fulfillment of its mission. Funding has provided for centers where multidisciplinary 

teams of investigators combine their understanding and efforts to unravel the mysteries of a common 

set of problems. Senior investigators are funded to follow their own insights on the path of research 

inquiry, and young investigators are supported and nurtured in their transition from students to independent 

research scientist. 

A glance at the table of contents reveals efforts directed at specific diseases, approaches to early detection 

and disease prevention, inquiry into the basic mechanisms by which tobacco smoke causes disease, search 

for new and better treatments, tools for early detection, public health approaches to surveillance and intervention, 

and efforts to educate health care practitioners to enable more effective assessment and management 

of second hand tobacco smoke exposure. 

Funded projects cover a waterfront of diseases and conditions. Cancers of the bladder, breast, cervix, 

stomach, head and neck, kidney, lung, ovary, prostate, thyroid and lymphoma are all covered as areas of 

funded investigation. These projects include efforts to discover the mechanisms by which tobacco smoke 

causes disease, to identify promising biomarkers for early detection and risk assessment, to develop methods 

to detect and treat disease progression, and to describe a number of potential new targets for disease 

intervention at the molecular level. These efforts are complimented by the work being done at FAMRI 

Centers in Israel, at John Hopkins, and by FAMRI I-ELCAP, which are focused on early detection and 

better treatment of these diseases. 

Cardiovascular disease investigations are also well represented in these pages examining the mechanisms 

by which tobacco smoke exposure causes heart and vascular disease, identifying new targets for disease 

intervention and exploring the impact of tobacco smoke exposure on the progression of disease caused by 

diabetes and viral injury. The dramatic effects of second hand tobacco smoke exposure on vascular compliance 

and endothelial changes provide enticing mechanistic links to disease manifestation. These links are 

extended into the exposures that occur in childhood in an effort to fill in the gaps in our understanding of 

the impact and evolution of second hand tobacco smoke exposure in childhood as a cause of disease in 

adulthood or in creating vulnerabilities to vascular disease in the exposed populations. 

Lung diseases are also well represented by investigations, which cover the role of inflammation in lung 

injury, the links between inflammation and emphysema formation, new biomarkers to detect inflammation 

and emphysema, and promising targets for intervention with new treatments. These investigations are particularly 

timely with the discovery of early lung changes consistent with emphysema among flight attendants 

exposed to second hand tobacco smoke on airplanes by the FAMRI center at UCSF. 

These disease-focused investigations are complimented by other investigators who are attempting to 

understand and change the behaviors which influence second hand tobacco smoke exposure, particularly 

for children. The efforts to provide a comprehensive description of the exposure to second hand tobacco 

smoke and the effect of restrictions on smoking in the home on these exposures will provide the foundation 

for effective awareness and educational efforts attempting to minimize these exposures. Collaborative 

efforts to develop accurate and cost effective office based testing for second hand tobacco smoke exposure 

by the UCSF and Julius B. Richmond FAMRI Centers will give pediatricians a powerful new tool to intervene 

in parental exposure of children to tobacco smoke. The educational and outreach efforts by the 

Richmond center both translate what we know about second hand tobacco smoke exposure into effective 

change in pediatric standards of care and also provide valuable models for similar changes in the practice of 

other health care providers. 

Finally, it is impossible to close without acknowledging the enormous loss the last year has brought to 

the FAMRI family with the deaths of Ron Davis and Julius Richmond. On a personal level I feel their loss 

deeply and their formative and ongoing contribution to FAMRI’s mission will be impossible to replace. 

Their selfless dedication and energy must remain as an inspiration to all of us as we continue the work they 

cared for so deeply. 

1 2 P A G E

FAMRI ORGANIZATIONAL STRUCTURE 

FAMRI BOARD OF TRUSTEES 

Stanley M. Rosenblatt, Esq., Chairman, Class Counsel 

Patricia L. Young, Secretary, Flight Attendant Trustee 

Lani Blissard, Treasurer, Flight Attendant Trustee 

Leisa Sudderth, Flight Attendant Trustee 

* 

Susan Rosenblatt, Esq., Trustee, Class Counsel 

John B. Ostrow, Esq., Trustee 

*Bland Lane (1929-2007) 

FAMRI MEDICAL 

ADVISORY BOARD 

* 

David Sidransky, MD, Director Head and Neck 

Cancer Research, Professor of Otolaryngology, 

Oncology, Pathology, Cellular and Molecular 

Medicine and Urology, Johns Hopkins University 

School of Medicine 

W. Jarrard Goodwin, MD, Director Sylvester 

Comprehensive Cancer Center, University of 

Miami School of Medicine 

Eloise Harmon, MD, Professor of Medicine, 

Division of Pulmonary and Critical Care 

Medicine, University of Florida College of 

Medicine 

David W. Kennedy, MD, Rhinology Professor 

and Vice Dean for Professional Services, 

University of Pennsylvania School of Medicine 

Michael Fiore, MD, MPH, Professor of Medicine, 

Director of the Center for Tobacco Research, 

University of Wisconsin 

* Julius B. Richmond, MD. Past Chairman, 

former Surgeon General of the United States 

(1916-2008) 

ADMINISTRATION 

Stanley M. Rosenblatt, Esq., 

CEO 

Elizabeth A. Kress, MJ 

Executive Director 

Marti Gammon, 

Administrative Assistant 

Rachel Gdanski, 

Program Assistant 

FAMRI LAY 

ADVISORY BOARD 

Rev. Michael H. Crosby, OFMCap, Chairman, 

Coordinator of the Tobacco Program at Interfaith 

Center of Corporate Responsibility 

Jack Cannon, former Treasurer and Chairman of 

the Smoking and Health Committee of the 

American Lung Association 

Joseph W. Cherner, established Smoke Free 

Educational Services, Inc. 

Amos Hausner, Esq., an Israeli attorney and a 

major force in international tobacco control who 

helped eliminate smoking from EL Al Airlines 

and has been active in controlling second hand 

tobacco smoke worldwide 

Billy Williams, retired Pan American Airlines’ 

avionics mechanic and union shop steward 

Rita H. Zemlock, President of GASP (Group 

Against Smoker’s Pollution) of Florida 

P A G E 1 3

FAMRI AWARD CATEGORIES 

The Board of Trustees, with the guidance of the Medical Advisory Board, decided on the following unique 

categories: 

PEER REVIEWED AWARDS 

CENTER OF EXCELLENCE AWARD 

The Center of Excellence Award (CoE) was established to provide funds for multiple research projects at 

an academic institution, linking physicians and scientists from various disciplines into multidisciplinary programs, 

inpatient care and research connected to tobacco smoke and disease. The aims of a Center are to 

enhance the knowledge base relating to diseases caused by exposure to second hand tobacco smoke, to serve 

as a new source for more effective approaches to detection, diagnosis, therapy and cure of diseases caused 

from such exposure as well as to serve as developing and providing medical advances for flight attendants 

suffering from such exposure. Currently, there is a moratorium on applications for these Centers. 

THE CLINICAL INNOVATOR AWARD PROGRAM 

The Clinical Innovator Awards (CIA) Program was established to stimulate novel medical and clinical 

research studies addressing the many diseases resulting from exposure to tobacco smoke. FAMRI solicits 

researchers for this award who have significant previous experience in their fields and who wish to pursue 

novel bench or clinical research on diseases caused by tobacco smoke. 

THE YOUNG CLINICAL SCIENTIST AWARD PROGRAM 

The Young Clinical Scientist Award (YCSA) was established by FAMRI to fund new investigators with 

an MD, PhD, or a combination of MD/PhD, at the level of post-doctoral fellow or junior faculty, in 

research on disorders caused by tobacco smoke. This program is designed to provide funding to 

researchers in the early stages of their careers. By promoting these young investigators to perform research 

on diseases caused by tobacco smoke, FAMRI hopes to facilitate the establishment of a cadre of young 

investigators whose careers are devoted to the prevention, treatment and cure of these diseases. 

The CIA and YCSA awards are peer reviewed in an annual panel meeting of highly qualified, nationally 

recognized experts convened by FAMRI’s grants’ consultant, the American Institute of Biological Sciences 

Scientific Peer Advisory and Review Services (AIBS/SPARS) Department of Reston, Virginia. Final awards 

are distributed based on decisions made by the Board of Trustees, utilizing the results of the peer review, 

and the recommendations of the Medical Advisory Board. 

BOARD DESIGNATED AWARDS 

THE WILLIAM CAHAN DISTINGUISHED PROFESSOR AWARD PROGRAM 

The late William G. Cahan, MD, was a thoracic surgeon at Memorial Sloan-Kettering Cancer Center, and a 

former member of FAMRI’s Medical Advisory Board. Dr. Cahan was a pioneer in medical and governmental 

efforts to combat cigarette smoking. In his memory, FAMRI established the Dr. William Cahan 

Distinguished Professor Award, to honor American scientists who have spent their careers in the study of the 

effects of tobacco-caused diseases. The Cahan Awardees have pursued a variety of topics including clinical and 

basic science research, education of the public and health care providers about the dangers of second hand 

tobacco smoke, and historical research regarding tobacco use and the effects of second hand tobacco smoke. 

THE BLAND LANE INTERNATIONAL DISTINGUISHED PROFESSOR AWARD PROGRAM 

This award, for international scientists who have contributed to the study of the effects of tobaccocaused 

diseases, was created in 2007 in memory of Bland Lane, who was a founding member of FAMRI’s 

Board of Trustees. Bland was an early promoter of non-smokers’ rights for airline flight attendants and 

passengers, and one of the original class representatives in the class action lawsuit filed in 1991 that ultimately 

created FAMRI. 

OTHER BOARD DESIGNATED AWARDS 

FAMRI will consider funding investigators or organizations that provide special information that supports 

the mission of FAMRI. 

1 4 P A G E

GEOGRAPHIC DISTRIBUTION OF FAMRI AWARDS 

UNITED STATES 

INTERNATIONAL 

P A G E 1 5

HIGHLIGHTED FAMRI FUNDED RESEARCH 

COMBATING EFFECTS OF TOBACCO SMOKE 

Each year FAMRI chooses a few specific topics to highlight from the prodigious volume of research that 

they have funded. Several such topics are presented below: 

SECOND HAND TOBACCO SMOKE AND 

CARDIOVASCULAR DYSFUNCTION IN CHILDREN 

Judith Groner, MD and John A. Bauer, PhD; Ohio State University; CIA 2006 

Links between second hand tobacco smoke (SHS) exposure and cardiovascular disease and death in 

adults are well established, but little is known about the impact of SHS exposure on cardiovascular status 

in children. Many forms of chronic cardiovascular disease are initiated in childhood and young adulthood, 

and at least one quarter of children in the United States are exposed to SHS. Dr. Groner and colleagues 

hypothesized that SHS-exposed children would have endothelial dysfunction, decreased prevalence of 

endothelial progenitor cells (EPCs), and greater inflammation and endothelial stress compared to nonexposed 

children. The research team established an off-campus site for routine and noninvasive evaluations 

of vascular performance in children and a database for organized capture of all measured endpoints for the 

complete study. In addition they developed a data management strategy that will aid in statistical analyses, 

and enlisted a statistical coordinator for guidance for such issues. This specific database will allow addition 

of variables using an online system that is connected from the remote clinic site to the central campus 

hospital and research institute. The approach will integrate vascular performance measurements such as 

venous occlusion plethysmography (VOP) seamlessly. The team also developed and optimized analytical 

assays for measurement of inflammation markers from low-volume blood samples. These assays are key 

components of the study and the investigators have determined optimal approaches for blood sample 

collection at the remote clinic site and storage/handling conditions, as well as analytical requirements for 

the samples to be efficiently used in the research labs. Enrollment for the study has been initiated and a 

pilot for repeated measures of vascular function has been prepared. Fifty-seven children ages 2-5 and 68 

youth and adolescents ages 9-14 were studied. Data on younger children was obtained by questionnaire, 

analysis of hair for nicotine, and measurements of inflammatory markers and endothelial progenitor cells 

(EPCs). Data from the older group included all of the above with the addition of measurements of 

forearm blood flow via VOP. 

The investigators found negative and positive relationships among the younger children (age 2-5) 

between number of smokers in the home and EPC prevalence. They also found a significantly positive 

relationship between exposure to SHS and soluble intracellular adherence molecule (s-ICAM), a marker of 

endothelial stress in children ages 2-5. Toddlers ages 2-5 had higher mean hair nicotine compared to 

children ages 9-14 despite having the same reported home exposure to SHS . Furthermore, SHS exposure 

was related to high sensitivity C-reactive protein, (hs-CRP), a marker of inflammation in children ages 9- 

14. An interaction was found between, childhood obesity, another cardiovascular risk factor, and SHS 

exposure and inflammation. Obese children who were SHS exposed had much higher hs-CRP levels than 

obese, non-SHS exposed children. These levels are quite high and extremely abnormal. Thus, the 

investigators conclude that SHS may affect different age groups of children differently; younger children 

receive a ‘higher’ dose of SHS exposure with similar exposure history than older children. Importantly, 

SHS exposure is related to inflammation in children and may be compounded in the presence of childhood 

obesity. 

FAMRI Supported Publications 

Groner JA, Joshi M, Bauer J. Pediatric precursors of adult cardiovascular disease. Pediatrics 

2006;188:1681-1691. 

Groner JA, Joshi M, Huang H, Bauer J. Cardiovascular effects of passive smoking in children and adults. 

In: Frank Columbus, ed. Passive Smoking and Health Research, Nova Publications 2007. 

Groner JA, Huang H, Nicholson L, Frock D, Schroeder C, Bauer JA. Secondhand smoke exposure and 

endothelial progenitor cell prevalence in children. Circulation 2008;117:e249. 

Groner JA, Huang H, Nicholson L, Frock D, Schroeder C, Foley S, Bauer JA. Secondhand smoke 

exposure and endothelial progenitor cell prevalence in children. Platform presentation, Society for 

Research on Nicotine and Tobacco Annual Meeting, February 28, 2008, Portland OR. 

1 6 P A G E

Groner JA, Huang H, Nicholson L, Frock D, Schroeder C, Foley S, Bauer JA. Poster Presentation, 

American Heart Association 48th Cardiovascular Epidemiology and prevention Conference, Colorado 

Springs, CO, March 14, 2008. 

Groner JA, Huang H, Nicholson L, Frock D, Schroeder C, Foley S, Bauer JA. Platform Presentation, 

Pediatric Academic Societies Meeting, Honolulu HI, May 4, 2008. 

Groner JA, Nicholson L, Huang H, Hoffman R, Kuck J, Bauer JA. Racial differences in endothelial 

progenitor cell prevalence in children. Poster presentation, Pediatric Academic Societies Meeting, 

Honolulu HI, May 4, 2008 

RESEARCH AND EDUCATION ON SMOKE-FREE AIR FOR PETS AND FAMILIES 

Ronald M. Davis, MD (presented by Sharon A. Milberger, ScD); Henry Ford Health System; CIA 2006 

FAMRI regrets to report the passing of Dr. Ronald M. Davis in 2008. Dr. Sharon Milberger continued 

his work on this FAMRI CIA grant. In this innovative project, Dr. Milberger aims to both assess the 

linkage of SHS exposure to pet health conditions and determine whether knowledge about the effects of 

SHS on the health of companion animals can be a persuasive motivator for smokers to change their 

smoking behaviors. In 2006 and early 2007, Dr. Davis and collaborators had developed a World Wide 

Web-based survey to be completed by at least 2,100 pet owners across Southeast Michigan. The survey 

was jointly promoted by HFHS, Pet Supplies Plus, the locally owned national chain of pet-supply stores, 

and the Michigan Humane Society. This promotional effort prompted responses from over 3,000 pet 

owners in Michigan and beyond. Significant associations were found between selected health conditions in 

pets and exposure to second hand tobacco smoke in the home. The project also moved into its 

intervention phase, to determine the effectiveness of persuading pet owners of the effects of second hand 

tobacco smoke on their pets’ health in motivating smoking cessation and the adoption of smoke-free 

homes. Pet owners who smoked or lived with smokers were recruited to intervention and control arms of 

an email program providing information on quitting smoking and keeping a smoke-free home. Data 

analysis to determine whether information specific to the health effects of SHS on pets will persuade 

smokers to consider quitting and motivate all pet owners to maintain a smoke-free home is ongoing. 

FAMRI supported publications 

Milberger S, Davis RM, Holm AL. Pet owners’ attitudes and behaviors related to smoking and secondhand 

smoke: A pilot study. Tob Control Feb:2009; [Epub ahead of print]. 

EFFECT OF SECOND HAND TOBACCO SMOKE ON RESPIRATORY AND REPRODUCTIVE 

TRACT EPITHELIAL CELL PRODUCTION AND RELEASE OF CCL20 

Mardi Crane-Godreau, PhD; Dartmouth College; YCSA 2006 

Competent functioning of the innate immune system at mucosal surfaces is necessary to maintain 

normal secretory and physical barriers that protect against infection. Dr. Crane-Godreau’s work tests the 

hypothesis that exposure to SHS interferes with normal innate immune protection, including disruption of 

production of chemokine C-C motif ligand 20 (CCL20), an antimicrobial and signaling peptide that is 

essential to competent innate immune protection. Studies have targeted the effects of SHS on CCL20 

expression and production, and effects on decreased bacterial killing by smoke exposed epithelial cells. In 

2007, Dr. Crane-Godreau worked to establish a cigarette smoke exposure facility at Dartmouth Medical 

School to support the work of other researchers involved in SHS exposure-associated diseases, such as 

sudden infant death syndrome, endocrine system disruption, cancer, and cardiovascular disease. In her role 

as director of that resource, Dr. Crane-Godreau invites FAMRI researchers to contact her if they should 

need support in the use of Teague smoke exposure chambers or for assistance in design of protocols using 

the Teague equipment. Dr. Crane-Godreau’s work is inspired by observations of health problems in 

coworkers during the 18 years she spent as an international flight attendant. 


Crane-Godreau M, Jukosky JA, Fiering S. Cigarette smoke exposure alters uterine immune defense. 

Presented at the Flight Attendants Medical Research Institute Annual Symposium. Boston, MA, May 

12-14, 2008. 

Crane-Godreau M, Maccani M, Eszterhas S, Fiering S, Tobacco smoke exposure disrupts CCL20 

production and antimicrobial activity of respiratory epithelial cells. Presented at the Flight Attendants 

Medical Research Institute Annual Symposium. Miami, FL, May 2007. 

P A G E 1 7

Xia L, Crane-Godreau M, Deng B, Leiter JC, Bartlett D, Jr. Prolongation of laryngeal chemoreflex by 

hyperthermia is exaggerated in pre-natally smoke-exposed rat pups. Presented at the Flight Attendants 

Medical Research Institute Annual Symposium, Boston Massachusetts, May 12-14, 2008. 

Xia L, Crane-Godreau, M, Leiter JC, Bartlett D, Jr. Gestational cigarette smoke exposure and 

hyperthermic enhancement of laryngeal chemoreflex in rat pups. Respir Physiol & Neurobiol 

2009;165:161-166. 

ROLE OF SHS ON SOMATIC ALTERATIONS IN BLADDER CANCER 

Carmen J. Marsit, PhD; Brown University; YCSA 2006 

Dr. Marsit’s research examines how exposure, lifestyle, and genetics interact and lead to pathogenesis, 

through examination of the somatic molecular profile of individuals in a population. This research is highly 

interdisciplinary and translational, and uses the tools and techniques of modern molecular biology and 

pathology, epidemiology, and biostatistics. To date, this research has focused on the examination of the 

epigenetic character of human tumors, concentrating on changes to the DNA methylation pattern, both 

gene-specific hypermethylation as well as global hypomethylation. These alterations are equivalent to mutation 

or deletion of tumor suppressor genes, leading to their transcriptional silencing, and are considered 

causal in the carcinogenic process. Dr. Marsit’s work in bladder cancer is focused on how primary and SHS 

exposures contribute to epigenetic alterations in bladder cancer. Additionally, he plans to identify if these 

or other somatic alterations can provide diagnostic or clinical utility in patients suffering from this disease. 

Dr. Marsit’s most recent publications in bladder cancer demonstrate that continuous exposure to tobacco 

carcinogens drives a propensity for epigenetic alteration, and that this greater propensity for alteration is 

associated with more aggressive bladder tumors and poorer patient survival. This work is now continuing 

as Dr. Marsit’s laboratory has begun to examine these alterations in an independent population of bladder 

tumors, in order to examine the reproducibility and generalizability of these findings. The PI is now taking 

a more genome-wide approach to the study of epigenetic alterations, utilizing state-of-the-art array-based 

technologies to perform methylation analyses, as well as novel statistical methodologies to examine these 

data. He has identified novel profiles of DNA methylation that are associated with bladder cancer and 

more specifically with invasive bladder cancers, the most deadly form of this disease. He has also examined 

how these profiles of DNA methylation associate with exposures experienced by the individuals, focusing 

on the role that tobacco smoke exposures, both primary and secondhand, play on driving these profiles of 

epigenetic alterations. This research is aimed at a better understanding of the etiology of these epigenetic 

alterations as well as understanding their utility in the medical field as novel, cost-effective, and minimally 

invasive screening strategies. 


Marsit CJ, Christensen BC, Houseman EA, Karagas MR, Wrensch MR, Yeh R-F, Nelson HH, Wiemels JL, 

Zheng S, Posner MR, McClean MD, Wiencke JK, Kelsey KT. Epigenetic profiling reveals etiologically 

distinct patterns of DNA methylation in head and neck squamous cell carcinoma. Carcinogenesis 

2009;30:416-22. 

Peters ES, Luckett BG, Applebaum KM, Marsit CJ, McClean MD, Kelsey KT, Dairy products, leanness, 

and head and neck squamous cell carcinoma. Head Neck 2008;30:1193-205. 

Houseman EA, Christensen BC, Yeh R-F, Marsit CJ, Karagas MR, Wrensch MR, Nelson HH, Wiemels J, 

Zheng S, Wiencke JK, Kelsey KT. Model-based clustering of methylation array data: a recursive-partitioning 

algorithm for high-dimensional data arising as a mixture of beta distributions. BMC 

Bioinformatics 2008;9:365-80. 

Marsit CJ, Posner MR, McClean MD, Kelsey KT. Hypermethylation of E-cadherin is an independent predictor 

of improved survival in head and neck squamous cell carcinoma. Cancer 2008;113:1566-71. 

Marsit CJ, Black CC, Posner MR, Kelsey KT. A genotype-phenotype examination of cyclin D1 on risk and 

outcome of squamous cell carcinoma of the head and neck. Clin Cancer Res 2008;14:371-7. 

Hsiung DT, Marsit CJ, Houseman EA, Eddy K, Furniss CS, McClean MD, Kelsey KT. Global DNA 

methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma. Cancer 

Epidemiol Biomarkers Prev 2007;16:108-14. 

Houseman EA, Marsit C, Karagas M, Ryan LM. Penalized item response theory models: application to 

epigenetic alterations in bladder cancer. Biometrics 2007;63:1269-77. 

Marsit CJ, Houseman EA, Schned AR, Karagas MR, Kelsey KT. Promoter hypermethylation is associated 

with current smoking, age, gender and survival in bladder cancer. Carcinogenesis 2007;28:1745-51. 

Marsit CJ, Eddy K, Kelsey KT. MicroRNA responses to cellular stress. Cancer Res 2006;66:10843-8. 

1 8 P A G E

Marsit CJ, Christensen BC, Houseman EA, Nelson HH, Wrensch MR, Wiemels JL, Zheng S, Wiencke JK, 

Schned AR, Karagas MR, Kelsey KT. CpG methylation arrays define novel genes associated with invasive 

bladder cancer. Presented at the Annual Meeting of the American Association for Cancer Research, April 

2009. 

Marsit CJ, Christensen BC, Houseman EA, Karagas MR, Wrensch MR, Yeh RF, Nelson HH, Wiemels JL, 

Zheng S, Posner MR, McClean MD, Wiencke JK, and Kelsey KT. Profiles of DNA methylation in head 

and neck squamous cell carcinoma: etiology and clinical significance. Presented at the Annual Meeting of 

the American Association for Cancer Research, April 2008. 

USURPING SIGNALING CHARACTERISTICS OF BREAST, CERVICAL, AND PROSTATE 

CANCER TO TARGET THEM WITH A ‘SIGNAL-SMART’ VIRUS 

Faris Farassati, PhD, PharmD; University of Kansas; YCSA 2006 

Cancer, such as many other diseases, is a product of imbalance in cell growth. The molecular machinery 

responsible for cell growth is under the control of a variety of signals that direct cells to speed up or slow 

down proliferation. An increase in the intensity of pro-growth signals leads to the abnormal proliferation of 

cells, resulting in a neoplasm, which literally means new growth, from the Greek neo (new) and plasma 

(growth). A neoplasm can develop into a malignancy only after the cells acquire additional genetic and signaling 

abnormalities causing the cells to invade nearby tissue and spread to other parts of the body. Dr. 

Farassati is pursuing the possibility of targeting cancer cells on the basis of their imbalanced signaling system 

with a mutated version of the herpes virus. The cancer promoting gene, Ras, is a signaling hub regulating 

many important cellular functions, including proliferation. Over activation of Ras can result in 

abnormally strong signals encouraging cells to proliferate and become malignant. Dr. Farassati’s team has 

now developed a mutated version of herpes simplex virus-1, called Signal-Smart 1 (SS1), which can 

respond to over activation of the Ras signaling pathway. This virus is designed to detect cells with over 

activation of the Ras pathway, and thereby replicates preferentially in cancer cells resulting in their death. 

The SS1 virus, however, cannot replicate in cells with low Ras activation, such as many non-malignant 

healthy cells, and therefore is incapable of infecting these cells. The preliminary results are promising and 

show that the SS1 virus efficiently replicates in prostate cancer cells inducing an elevated level of cell death 

in them. The invasiveness and colony formation capabilities of prostate cancer cells are also significantly 

reduced upon being targeted by the SS1 virus. The work now continues to further investigate the characteristics 

and efficiency/specificity of this virus against prostate, breast, and cervical cancer cells in vitro and 

also in related animal models. 

The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental 

role in normal and neoplastic physiology. Dr. Farassati and colleagues were interested in linking Ras 

activation to herpes simplex virus 1 (HSV-1) replication in a direct manner in order to generate a novel 

oncolytic herpes virus that can target cancer cells. To establish such a link, Dr. Farassati and colleagues 

developed a mutant HSV-1 in which the expression of infected cell protein-4 (ICP4, a viral protein necessary 

for replication) is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway 

and mainly activated by extracellular signal-regulated kinase (ERK), an important Ras effector pathway. 

This mutant HSV-1 was named Signal-smart 1 (SS1). A series of prostate cells were infected with the 

SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as 

demonstrated by increased levels of viral progeny, herpetic glycoprotein C, and overall SS1 viral protein 

production. Upon exposure to SS1, the proliferation, invasiveness, and colony formation capabilities of 

prostate cancer cells with increased ELK activation were significantly decreased, while the rate of apoptosis/necrosis 

in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a 

prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The 

results of this study reveal the potential for remodeling the host-herpes interaction to specifically interfere 

with the life of cancer cells with increased Ras signaling. 


Dudek AZ, Zwolak P, Jasinski P, Terai K, Gallus NJ, Ericson ME, Farassati F. Protein kinase C-beta 

inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic 

model of bone metastasis. Invest New Drugs 2008;26(1):13-24. 

Farassati F, Pan W, Yamoutpour F, Henke S, Piedra M, Frahm S, Al-Tawil S, Mangrum WI, Parada LF, 

Rabkin SD, Martuza RL, Kurtz A. Ras signaling influences permissiveness of malignant peripheral nerve 

sheath tumor cells to oncolytic herpes. Am J Pathol 2008;173(6):1861-1872. 

P A G E 1 9

Farassati F, Yang A-D, Lee P WK. Oncogenes in Ras signaling pathway dictate hosT cell permissiveness to 

herpes simplex virus 1. Nat Cell Biol 2001;3(8):745-750 (selected for international press release, 

reviewed in Lancet infect. Dis. & Readers Digest). 

Farassati F, Lee PWK. Ras signaling, a gateway for HSV-1 infection. ScientificWorldJournal 

2003;3(6):533-535. 

Frahm S, Kurtz A, Farassati F, Friedrich RE, Mautner VF. Sulindac derivatives inhibit cell growth and 

induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients. 

Cancer Cell Int 2004;4(1):4. 

Mangrum WI, Farassati F, Kadirvel R, Kolbert CP, Raghavakaimal S, Grill D, Khurana VG, Kallmes DF. 

mRNA expression in rabbit experimental aneurysms: a study using gene chip microarrays. Am J 

Neuroradiol 2007;28(5):864-869. 

Mashour GA, Drissel SN, Frahm S., Farassati F, Martuza RL, Mautner VF, Kindler-Röhrborn A, Kurtz A. 

Differential modulation of malignant peripheral nerve sheath tumor growth by omega-3 and omega-6 

fatty acids. Oncogene 2005;24(14):2367-2374. 

Norman K, Farassati F, Lee PWK. Oncolytic viruses and cancer therapy. Cytokine Growth Factor Rev 

2001;12(2-3):271-282. 

Park SE, Bodempudi V, Mauzy MJ, Pan W, Yamoutpoor F, Tindall DJ, Farassati F. Gene silencing for epidermal 

growth factor receptor variant-III induces cell-specific cytotoxicity by suppressing Ras pathway. 

Mol Cancer Ther 2008;7(11):3586-3597. 

Patel MR, Jacobson BA, Dee A, Frizelle S, Janne P, Whitson BA, Farassati F, Kratzke RA. Ras pathway 

activation in malignant mesothelioma. J Thorac Oncol 2007;2(9):789-795. 

ELASTIN DEGRADATION IN PULMONARY DISEASES 

Yong Y. Lin, PhD and Gerald Turino, MD; St. Luke’s-Roosevelt Hospital Center; BDA 2005 

Drs. Lin and Turino’s group is using high-performance liquid chromatography/electrospray tandem 

mass spectrometry (LC/ESI-MSMS) analysis to study lung elastin degradation, which occurs with development 

of emphysema in COPD. COPD currently affects over 18 million Americans and is the fourth 

leading cause of death in the United States. COPD is mainly caused by smoking. In addition, SHS exposure 

may impose a significant risk. Using the mass spectrometric analysis, they have established that measurements 

of desmosine and isodesmosine (D/I), two cross-linking pyridinium amino acids, can be used as 

biomarkers of elastin degradation in COPD, smokers, and SHS. Conjugated D/I in sputum and plasma, 

and free D/I in urine are found significantly higher in COPD patients compared to normal subjects. The 

D/I measurements have been applied to evaluate the efficacies of potential therapeutic agents for COPD, 

i.e., tiotropium and hyaluronan. Patients with COPD treated with tiotropium aerosol daily for 2 months 

have been shown to have statistically significant reductions in D/I in urine, plasma, and sputum. Also, 

analysis of bronchoalveolar lavage fluid of mice exposed to tobacco smoke daily and treated with hyaluronan 

aerosol showed significant reductions in D/I as compared with untreated controls. 

In collaboration with Richard Robbins (Carl T. Hayden Veterans Administration Medical Center) and 

Offie Soldin (Georgetown University), they have measured the levels of D/I in plasma or urine of 37 nonexposed, 

41 SHS exposed, and 43 smokers, and found that the levels of D/I are significantly elevated in 

SHS exposed and further in smokers. 

Using LC/ESI-MSMS analysis, they have also characterized 40 elastin-derived peptides from degradation 

of lung elastin by neutrophil and macrophage elastases. The peptides are being used to investigate 1) 

biomarkers for injury to extracellular matrix in COPD, smokers, and SHS exposed; 2) biological effects 

such as chemotaxis for neutrophils and macrophages involved in COPD, smoking, and SHS exposure; and 

3) pathological mechanisms in COPD and their relationship to injury caused by smoke or SHS exposure. 


Cantor JO, Shteyngart B, Cerreta JM, Ma S, Turino GM. Synergistic effect of hydrogen peroxide and elastase 

on elastic fiber injury in vitro. Exp Lung Res 2006;231:107-111. 

Cantor JO, Cerreta JM, Ochoa M, Ma S. Cow T, Turino GM. Aerosolized hyaluronan limits airspace 

enlargement in mouse model of cigarette smoke-induced pulmonary emphysema. Exp Lung Res 

2005;31:417-430. 

Luisetti M, Ma S, Ladarola P, Stone PJ, Viglio S, Cassado B, Lin YY, Snider GL, Turino GM. Desmosine 

as biomarker of elastin degradation in COPD: current status and future direction. Eur Respir J 

2008;32:1146-1157. 

Ma S, Lin YY, Tartell L, Turino GM. The effect of tiotropium therapy on markers of elastin degradation in 

2 0 P A G E

COPD. Respir Res 2009;10:12. 

Ma S, Lin YY, Turino GM. Measurement of desmosine and isodesmosine by mass spectrometry in COPD. 

Chest 2007;131:1363-1371. 

Nadkani PP, Kullkarni GS, Cerreta JM, Ma S, Cantor JO. Dichotomous effect of aerosolized hyalurolan in 

a hamster model of endotoxin-induced lung injury. Exp Lung Res 2005;31 807-808. 

Turino GM. Emphysema in COPD: consequences and causes. Thorax 2006;61:1031-1032. 

Turino GM. Therapeutic gains of prolonged bronchial dilation in chronic obstructive pulmonary disease. 

Ann Int Med 2005;143:386-387. 

SECOND HAND TOBACCO SMOKE AND WORKER HEALTH 

David J. Lee, PhD; University of Miami; CIA 2002, 2003, 2006, 2009 

Dr. Lee is continuing work from a number of FAMRI grants. The workplace remains a significant source 

of exposure to SHS. The health effects of SHS exposure may vary among workers who experience other 

workplace exposures known to adversely affect health outcomes. In this study Dr. Lee and colleagues have 

been analyzing data from three large population-based health surveys (n~90,000) representing 126 million 

Americans in the workforce, to study health outcomes associated with exposure. The findings to date 

include: 1) documentation of significant reductions in serum cotinine levels in all major non-smoking US 

worker groups examined, with the most dramatic reductions occurring in blue-collar workers; 2) part of 

these marked reductions among blue collar workers may be due to declining smoking rates among their 

co-workers, although smoking prevalence rate disparities persist among blue versus white collar workers; 3) 

workers are reasonably accurate when reporting their smoking status, but are less accurate when reporting 

SHS exposures; 4) second hand tobacco smoke exposure among workers is associated with higher levels of 

homocysteine, an inflammatory marker associated with an increased risk of coronary heart disease; and 5) 

second hand tobacco smoke exposure may be associated with previously understudied health outcomes 

including early menopause, hearing loss, and depressive symptoms. These interesting findings have been 

published in a number of journal articles. 


Arheart KL, Lee DJ, Dietz NA, Wilkinson JD, Clark JD, 3rd, LeBlanc WG, Serdar B, Fleming LE. 

Declining trends in serum cotinine levels in US worker groups: the power of policy. J Occup Environ 

Med 2008;50:57-63. 

Arheart KL, Lee DJ, Fleming LE, LeBlanc WG, Dietz NA, McCollister KE, Wilkinson JD, Lewis JE, 

Clark JD, Davila EP, Bandiera FC. Accuracy of self-reported smoking and secondhand smoke exposure 

in the US workforce: the National Health and Nutrition Examination Surveys. J Occup Environ Med 

2008;50:1414-1420. 

Clark JD, Wilkinson JD, LeBlanc WG, Diets NA, Arheart KL, Fleming LE, Lee DJ. Inflammatory markers 

and secondhand tobacco smoke exposure among US workers. Am J Industrial Med 2008;51:626-632. 

Dietz NA, Lee DJ, Arheart KL, Wilkinson JD, Clark JD, Caban AJ. Correlates of home smoking bans 

among young adults. Florida Public Health Rev 2007;4:8-11. 

Fleming LE, Levis S, LeBlanc WG, Dietz NA, Arheart KL, Wilkinson JD, Clark J, Serdar B, Davila EP, 

Lee DJ. Earlier age at menopause, work and tobacco smoke exposure. Menopause 2008;15:1103-1108. 

Lee DJ, Arheart KL, Trapido E, Soza-Vento R, Rodriguez R. Accuracy of parental and youth reporting of 

secondhand smoke exposure: the Florida youth cohort study. Addict Behav 2005;30:1555-1562. 

Lee DJ, Dietz NA, Arheart KL, Wilkinson JD, Clark JD, Caban AJ. Respiratory effects of secondhand 

smoke exposure among young adults residing in a “clean” indoor air state. J Community Health 2008; 

33:117-125. 

Lee DJ, Fleming LE, Arheart KL, LeBlanc WG, Caban AJ, Chung-Bridges K, Christ SL, McCollister KE, 

Pitman T. Smoking rate trends in U.S. occupational groups: the 1987 to 2004 National Health 

Interview Survey. J Occup Environ Med 2007;49:75-81. 

Lee DJ, Fleming LE, McCollister KE, Caban AJ, Arheart KL, LeBlanc WG, Chung-Bridges K, Christ SL, 

Dietz N, Clark JD, 3rd. Healthcare provider smoking cessation advice among US worker groups. Tob 

Control 2007;16:325-328. 

Lee DJ, Trapido E, Rodriguez R. Secondhand smoke and earaches in adolescents: the Florida youth 

cohort study. Nicotine Tob Res 2003;5:943-946. 

Wilkinson JD, Arheart KL, Lee DJ. Accuracy of parental reporting of secondhand smoke exposure: The 

National Health and Nutrition Examination Survey III. Nicotine Tob Res 2006;8:591-597. 

Wilkinson JD, Lee DJ, Arheart KL. Secondhand smoke exposure and c-reactive protein levels in youth. 

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Nicotine & Tobacco Research 2007;9:305-307. 

RAGE-MEDIATED EFFECTS OF PULMONARY INFLAMMATION AND EMPHYSEMA 

Paul R. Reynolds, PhD; University of Utah; YCSA 2007 

This research has focused on the potential role of receptors for advanced glycation end products 

(RAGE) in the perpetuation of cigarette smoke-induced inflammation in pulmonary epithelial cells. The PI 

has clarified temporal-spatial patterns of RAGE expression during development and identified direct regulation 

of RAGE by EGR-1, a mid-gestationally expressed transcription factor that is also markedly upregulated 

in the lungs of smokers, particularly in those already diagnosed with COPD. Significant inducibility 

of RAGE by tobacco smoke in pulmonary epithelial cells has been identified in emphysema-susceptible 

mouse lungs. Work is currently underway that focuses on the induction and prevalence of RAGE ligands in 

tobacco environments and the degree of proinflammatory cytokine elaboration directly influenced by 

RAGE signaling intermediates. A manuscript detailing some of this data has been published in the 

American Journal of Physiology: Lung. 


Kasteler SD, Reynolds PR, Hoidal JR. Downstream effects of receptors for advanced glycation end products 

(RAGE) in pulmonary epithelial cells exposed to cigarette smoke, 2008. Presented at the ATS 

International Meetings. Toronto, Canada, May 16-21, 2008. 

Reynolds PR, Hoidal JR. Expression and TTF-1-mediated transcriptional control of alpha-5 nAChRs in 

the mouse lung, 2007. Presented at the Society for Developmental Biologists Meeting. Cancun, Mexico, 

Jun 16-20, 2007. 

Reynolds PR, Kasteler SD, Hoidal JR. Cigarette smoke-mediated regulation of receptors for advanced glycation 

end products by Egr-1, 2007. Presented at the ATS International Meeting. San Francisco, CA, 

May 17-21, 2007. 

Reynolds PR, Kasteler SD, Cosio MG, Sturrock A, Huecksteadt TP, Hoidal JR. RAGE: developmental 

expression and positive feedback regulation by Egr-1 during cigarette smoke exposure in pulmonary 

epithelial cells. AJP: Lung Cell Mol Physiol 2008;294:L1094-L1101. 

Reynolds PR, Kasteler SD, Sturrock A, Sanders K, Kennedy TP, Hoidal JR. RAGE targeting leads to protection 

from hyperoxia-induced lung injury, 2008. Presented at the Experimental Biology Meeting. San 

Diego, CA, Apr 5-9, 2008. 

FUNCTIONAL CHARACTERIZATION OF SCCRO 

Bhuvanesh Singh, MD, FACS; Memorial Sloan-Kettering Cancer Center; CIA 2006 

Dr. Singh and colleagues continue to focus on the functional characterization of squamous cell carcinoma-related 

oncogene (SCCRO), using developmental and biochemical models to address the goals. 

SCCRO- /- mice have severe defects in spermatogenesis. In tandem experiments, it was found that while 

azoospermia is present at the end of the first round of spermatogenesis, gross defects in testicular mass are 

first detected at 3 months and progressively worsen with increasing age. Histopathological analysis suggests 

that the first round of sperm development proceeds normally until about 5.5 weeks of age, at which time 

abnormal sperm begin to appear in the seminiferous vesicles. The testis are progressively filled with seminiferous 

tubules containing Sertoli cells, representing ~20% of all seminiferous tubules by 3 months and 

~50% by 6 months. The sperm is grossly abnormal, with two predominant phenotypes seen, including 

sperm heads separated from the tail and those with multiple flagella and a markedly enlarged head. 

Scanning and transmission electromicroscopy show that the sperm have gross defects in mitochondrial 

arrangement, with detachment from the annulus and exposure of axonemes. 


Minhas KM, Singh B, Jiang WW, Sidransky D, Califano JA. Spindle assembly checkpoint defects and chromosomal 

instability in head and neck squamous cell carcinoma. Int J Cancer 2003;107:46-52. 

Sarkaria I, O-charoenrat P, Talbot SG, Reddy PG, Ngai I, Maghami E, Patel KN, Lee B, Yonekawa Y, 

Dudas M, Kaufman A, Ryan R, Ghossein R, Rao PH, Stoffel A, Ramanathan Y, Singh B. Squamous cell 

carcinoma related oncogene/DCUN1D1 is highly conserved and activated by amplification in squamous 

cell carcinomas. Cancer Res 2006;66:9437-9444. 

Yu Z, Adusumilli PS, Eisenberg DP, Darr E, Ghossein RA, Li S, Liu S, Singh B, Shah JP, Fong Y, Wong 

RJ. Nectin-1 Expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity. Mol 

Ther 2007;15:103-113. 

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Yu Z, Chan MK, O-charoenrat P, Eisenberg DP, Shah JP, Singh B, Fong Y, Wong RJ. Enhanced nectin-1 

expression and herpes oncolytic sensitivity in highly migratory and invasive carcinoma. Clin Cancer Res 

2005;11:4889-4897. 

AMELIORATION OF ALLERGIC RHINITIS BY MULTI-FUNCTIONAL 

ANTI-INFLAMMATORY DRUGS: RESULTS OF A PHASE II CLINICAL STUDY 

Saul Yedgar, PhD; Hebrew University of Jerusalem; BDA 2008 

Multi functional anti-inflammatory drugs (MFAIDs) are novel synthetic compounds that address two 

major needs in the treatment of inflammatory/allergic diseases: inhibiting the production of inflammatory 

lipid mediators (eicosanoids and lyso-phospholipids) resulting from the hydrolysis of membrane phospholipids 

by phospholipase A 2 and enriching the protective layer of cell-surface polysaccharides. The MFAIDs 

have been found effective in suppressing diverse inflammatory processes in cell cultures (e.g., production 

of acute respiratory distress syndrome (ARDS)-related chemokines by human lung microvascular endothelial 

cells) and in treating inflammatory conditions in animal models (including asthma, sepsis, inflammatory 

bowel disease, and central nervous system inflammation) as well in a clinical study of contact dermatitis 

patients. 

Supported by a FAMRI grant, Dr. Yedgar and colleagues have tested the MFAIDs’ safety and efficacy in 

treating allergic rhinitis (hay fever). This disease affects 20-25% of people and is a model for screening 

drugs for other airway inflammatory diseases, such as asthma. In a double-blind placebo-controlled study, 

105 non-smoking patients were treated intra-nasally for 6 days (b.i.d., twice a day) with MFAID, placebo, 

or steroid and then challenged with grass pollen. 

HOUSEHOLD SMOKING BANS: A COMPREHENSIVE ANALYSIS 

Nancy Rigotti, MD; Massachusetts General Hospital; CIA 2006, 2009 

Over 40% of children in the United States are exposed to SHS at home, placing them at risk for asthma, 

bronchiolitis, sinusitis, bacterial and viral respiratory and ear infections, decreased lung growth, decreased 

exercise tolerance, and sudden infant death syndrome, as well as potentially higher rates of smoking 

initiation. Past data have been inadequate in establishing the effectiveness of tobacco control approaches in 

the home environment. The goal of this project was to evaluate the impact of no-smoking policies in the 

home on youths’ attitudes about smoking and SHS, their exposure to SHS, and their subsequent smoking 

behavior. There is no prior longitudinal cohort study that assesses the impact of home smoking restrictions 

on adolescent attitudes toward SHS, their exposure to SHS, and their smoking behaviors, while 

simultaneously controlling for the individual-level and community-level factors that may affect these 

outcomes. Specifically, Dr. Rigotti’s goal was to determine whether adolescents living in households where 

smoking is banned are more likely to develop anti-smoking attitudes and less likely to progress to smoking. 

To accomplish these aims, the PI and her team analyzed data collected from a recent longitudinal study 

funded by the National Cancer Institute (NCI). A population-based random sample of Massachusetts 

youth (N=3,834) aged 12-17 were interviewed by telephone at baseline (2001-2002). Surveys were 

repeated two years later (72.8% follow-up rate) and four years later (57.8% follow-up rate). Longitudinal 

analyses using a three-level hierarchical linear model (HLM) assessed the relationships between baseline 

household smoking bans and youth outcomes at follow-up, including: 1) negative attitudes toward SHS 

and smoking; 2) actual exposure to SHS; and 3) specific smoking behaviors. The analyses adjusted for 

covariates at the town-level, the individual-level, and the household-level. Parental disapproval of smoking 

and parental smoking were examined as potential modifiers of any relationship found. Compared to youths 

who live with a smoker in a household with a complete smoking ban at baseline, those living with smokers 

in households without a ban had an 8.5-fold increase in the odds of reporting SHS exposure at home. The 

absence of a household ban had a smaller but still significant effect on smoke exposure among youths who 

did not live with a smoker. The absence of a household smoking ban increased the odds that youths 

perceived a high prevalence of adult smoking, both among youths living with a smoker and those living 

with non-smokers. There was no effect of a complete household smoking ban on overall progression from 

non-smoking to established smoking, either for youths who live with a smoker or for youths who live with 

non-smokers. However, among youths who live with non-smokers, the absence of a complete household 

smoking ban increased the odds of transitioning from non-smoking to experimentation. There was no 

effect of a complete smoking ban on the transition from non-smoking to experimentation among those 

who live with a smoker. 

The data set allowed Dr. Rigotti and colleagues to address a second related question about the impact of 

smoke-free homes on youth behaviors. This second analysis assessed whether adolescents living in parental 

P A G E 2 3

homes where smoking is banned are more likely to move into smoke-free living quarters when they leave 

home. Using the same dataset, a four-year, three-wave prospective study of a representative sample of 

Massachusetts adolescents (aged 12-17), the team examined the subset of 693 youths who resided in 

independent living quarters outside of the parental home at follow-up. The primary outcome was presence 

of a smoking ban in the living quarters at follow-up. The primary predictor was presence of a household 

smoking ban in the parental home, assessed two years prior to the outcome. Generalized linear mixed 

effects models were used to examine the effect of a parental household smoking ban on the odds of 

moving into smoke-free living quarters at follow-up overall and stratified by smoking status at follow-up. 

Youths leaving home had much higher odds of moving to smoke-free living quarters if their parental 

household had had a smoking ban. Other independent predictors included moving into a school or college 

residence, and not living with smokers at follow-up. 

From these extensive analyses the research team was able to conclude that presence of complete 

household smoking bans significantly decreases adolescents’ exposure to SHS at home and increases the 

likelihood that youths will develop anti-smoking attitudes. Having a home smoking ban reduced the odds 

that an adolescent would begin to experiment with cigarettes, but only in homes that did not contain 

smokers. The presence of a household smoking ban did not reduce progression to established smoking, 

regardless of whether a smoker lived in the home. Nonetheless, this study supports the notion that home 

smoking bans have potential to promote anti-smoking norms and to prevent adolescent smoking. A 

household smoking ban in the parental home appears to lead youths to prefer smoke-free living quarters 

once they leave home. Smoke-free homes appear to be transmitted across generations. 


Albers A, Biener L, Siegel M, Cheng D, Rigotti NA. Impact of parental home smoking policies on 

policy choices of independently living young adults. Tob Control 2009. 

Albers AB, Siegel M, Cheng D, Biener L, Rigotti NA. Household smoking bans and adolescent antismoking 

attitudes and smoking initiation: findings from a longitudinal study of a Massachusetts youth 

cohort. Am J Public Health 2008;98:1886-1893. 

2 4 P A G E

FAMRI CENTERS OF EXCELLENCE 

FAMRI-BLAND LANE CENTER OF EXCELLENCE ON SECOND HAND TOBACCO SMOKE 

AT UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, 2002, RENEWED 2007 

Director: Neal L. Benowitz, MD 

The FAMRI-Bland Lane Center of Excellence on Second Hand Tobacco Smoke at UCSF was established 

in 2002 and renewed in 2007 to promote scientific research on SHS and pulmonary disease, cardiovascular 

disease, exposure assessment, and public eduction. The Bland Lane Center uniquely spans the 

research in humans ranging from clinical and biochemical assessment to experimental human exposure to 

epidemiology to education related to SHS and health. The FAMRI-Bland Lane Center of Excellence has a 

clinical practice that is devoted to the health of flight attendants. FAMRI-supported peer-reviewed publications 

have resulted from research at the Bland Lane Center. Components of the Bland Lane Center follow 

the listing of publications. 


Apollonio DE, Bero LA. Forms of evidence used in statewide smoking restrictions. Paper presented at the 

Annual Meeting of the Midwest Political Science Association. Apr. 2006. 

Baba A, Cook D, McGarity T, Bero LA. Legislating “Sound Science” the role of the tobacco industry. Am 

J Public Health 2005;95:s20-s27. 

Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. 

Prog Cardiovasc Dis 2003;46:91-111. 

Blanc PD, Eisner MD, Trupin L, Yelin EH, Katz PP, Balmes JR. Past occupational exposures and respiratory-related 

work disability predict poorer outcomes in COPD [abstract]. Chest 2003;124:98s-99s. 

Blanc PD, Trupin L, Katz PP, Yelin EH, Eisner MD, Balmes JR. Screening for exposure to vapors, gas, 

dust, or fumes [abstract]. Am J Respir Crit Care Med 2004;169:A460. 

Chen H, Blanc PD, Teehankee CM, De Marco T. Measuring health-related quality of life in pulmonary 

arterial hypertension. Proc Am Thorac Soc;2:A200. 

Chen H, Eisner MD, Katz PP, Blanc PD. Validation of a modification of the airways questionnaire 20 

among adults with obstructive airways disease [abstract]. J Invest Med 2005;53:S163. 

Chen H, Eisner MD, Katz PP, Yelin EH, Blanc PD. Measuring disease-specific quality of life in obstructive 

airway disease: validation of a modified version of the airways questionnaire 20. Chest 2006;129:1644- 

1652. 

Chen H, Eisner MD, Teehankee CM, Blanc PD, DeMarco T. Environmental tobacco smoke and health 

status in patients with pulmonary arterial hypertension. Chest 2005;128(4):364S. 

Chen H, Eisner MD. Validation of a modification of the airways quest. J Invest Med 2005;53:S163 

Dalton S, Dunsby J, Bero LA. Narrative skills in the shaping of workplace smoking restrictions legislation. 

Paper presented at the Annual Meeting of the American Sociological Association. August, 2004. 

Eisner MD, Balmes J, Katz PP, Trupin L, Yelin EH, Blanc PD. Lifetime environmental tobacco smoke 

exposure and the risk of chronic obstructive pulmonary disease. Environ Health 2005;4:7. 

Eisner MD, Balmes J, Yelin EH, Katz PP, Hammond SK, Benowitz N, Blanc PD. Directly measured secondhand 

smoke exposure and COPD health outcomes. BMC Pulm Med 2006;6:12. 

Eisner MD, Balmes J, Yelin EH, Katz PP, Lactao GC, Blanc PD. Directly measured secondhand smoke 

exposure and COPD [abstract]. Proc Am Thorac Soc 2005;2:A599. 

Eisner MD, Balmes JB, Katz PP, Yelin EY, Trupin L, Blanc PD. Secondhand smoke exposure and health 

outcomes in COPD [abstract]. Am J Respir Crit Care Med 2004;169:A221. 

Eisner MD, Balmes JR, Katz PP, Yelin EH, Blanc PD. Workplace exposure to secondhand smoke and the 

risk of asthma [abstract]. Eur Respir J 2005;26:139s. 

Eisner MD, Katz PK, Yelin EH, Trupin L, Balmes J, Blanc PD. Secondhand smoke exposure and the risk 

of COPD [abstract]. Eur Respir J;24:434s. 

Eisner MD, Katz PP, Yelin EH, Trupin L, Blanc PD. Measurement of COPD severity: development and 

validation of a survey-based instrument. Chest 2005;127:1890-1897. 


validation of a survey-based instrument [abstract]. Eur Respir J 2003;22:353S. 


validation of a survey-based instrument. Eur Respir J 2003;22:353S. 

Eisner MD, Trupin L, Katz PP, Yelin EH, Earnest G, Balmes J, Blanc PD. Development and validation of 

P A G E 2 5

a survey-based COPD severity score. Chest 2005;127:1890-1897. 

Eisner MD, Wang Y, Haight TJ, Balmes J, Hammond SK, Tager IB. Secondhand smoke exposure, pulmonary 

function, and cardiovascular mortality. Ann Epidemiol 2007. 

Gold WM, Schiller N, Ren M, Redberg R, Murdoch CM, Seitzinger F. Changes in pulmonary function in 

flight attendants. Abstract presented at American Thoracic Society International Meeting. San Diego, 

CA. Proc Am Thor Soc 2006;657. 

Haight TJ, Barnes DE, Tager IB. Effects of secondhand smoke and cardiovascular disease on incident 

dementia in participants from the Cardiovascular Health Study. Abstract accepted for presentation at the 

American Academy of Neurology Meeting. Boston, MA, May, 2007. 

Hsu PYF, Dulbecco FL, Redberg RF, Fleischmann KE, Schiller NB. Doppler pulmonary vascular resistance 

response during supine exercise in healthy subjects. Presented at the 14th Annual Scientific Sessions of 

the American Society of Echocardiography. Las Vegas, Nevada, June 11-14, 2003. 

Jacob P, 3rd, Wilson M, Benowitz NL. Determination of phenolic metabolites of polycyclic aromatic 

hydrocarbons in human urine as their pentafluorobenzyl ether derivatives using liquid chromatography 

tandem mass spectrometry. Anal Chem 2007;79:587-598. 

Jewell C, Bero L. Public participation and claims making: evidence utilization and divergent policy frames 

in California’s ergonomics rulemaking. J Pub Admin Research and Theory 2006;Epub ahead of print. 

Jewell C, Rose D, Bero LA. Public Participation in the regulatory process: the case of California’s 

ergonomics rule. Presented at the Annual Meeting of the Law and Society Association, June, 2005. 

Katz PP, Blanc PD, Eisner MD, Balmes J. Disability and health services use among individual with COPD 

[abstract]. Proc Am Thorac Soc 2006;3:A601. 

Katz PP, Yelin EH, Eisner MD, Earnest G, Blanc PD. Relationship of self-reported cognitive function with 

disability in valued life activities in COPD [abstract]. Proc Am Thorac Soc 2006;3:A489. 

Lightwood JM, Coxson P, Bibbins-Domingo K, Williams L, Goldman L. Clinical burden of coronary 

heart disease from passive smoking. Poster presented the American Heart Association 7th Scientific 

Forum on Quality of Care and Outcomes research in Cardiovascular Disease and Stroke. Washington, 

DC, May, 2006. 

Lightwood JM, Coxson P, Bibbins-Domingo K, Williams L, Goldman L. Coronary heart disease benefits 

attributable to reduction in exposure to passive smoking. Presented at American Public Health 

Association 2006 Annual Meeting. Boston, MA, 2006. 

Lightwood JM, Coxson P, Bibbins-Domingo K, Williams L, Goldman L. Burden of coronary heart disease 

attributable to current exposure to passive smoking. Presented at American Public Health Association 

2006 Annual Meeting. Boston, MA, 2006. 

Lightwood JM, Coxson P, Bibbins-Domingo K, Williams L, Goldman L. Clinical benefits attributable to 

workplace smoking bans. Presented to American College of Occupational and Environmental Medicine 

2006 Annual Conference. Los Angeles, CA, 2006. 

Lightwood JM, Coxson P, Bibbins-Domingo K, Williams L, Goldman L. Cost of coronary heart disease 

and current exposure to passive smoking. Presented at Agency for Health Care Research and Quality 

Conference, 2006. 

Lightwood JM, Coxson P, Bibbins-Domingo K, Williams L, Goldman L. Coronary heart disease reductions 

attributable to existing workplace smoking restrictions in the U.S. Poster at the American College 

of Occupational and Environmental Medicine 2006 Annual Conference, 2006. 

Lopipero P, Bero LA. Tobacco interests or the public interest: 20 years of industry strategies to undermine 

airline smoking restrictions. Tob Control 2006;15:323-332. 

Matt GE, Hovell MF, Quantana PJC, Zakarian J, Liles S, Melzer SB, Benowitz NL. The variability of 

urine cotinine levels in young children: implications for measuring environmental tobacco smoke exposure. 

Biomarkers 2007;9:83-92. 

Matt GE, Quintana PJ, Liles S, Hovell MF, Zakarian JM, Jacob P, 3rd, Benowitz NL. Evaluation of urinary 

trans-3’-hydroxycotinine as a biomarker of children’s environmental tobacco smoke exposure. 

Biomarkers 2006;11:507-523. 

Mulcahy M, Evans DS, Hammond SK, Repace JL, Byrne M. Secondhand smoke exposure and risk following 

the Irish smoking ban: an assessment of salivary cotinine concentrations in hotel workers and air 

nicotine levels in bars. Tob Control 2005;14:384-388. 

Odierna, DH, and Bero, L. Evaluation of race, ethnicity, and income in systematic reviews used to develop 

drug formularies for state-provided healthcare. Poster. Cochrane Colloquium. Freiburg, Germany, 2008. 

Odierna, DH, and Bero, L. Systematic reviews reveal an unrepresentative evidence base for the develop- 

2 6 P A G E

ment of Medicaid drug formularies. Poster for Health Disparities Summit. National Institutes of 

Health/National Center for Minority Health and Health Disparities, Harbor, MD, 2008. 

Odierna, DH, and Bero, L. Systematic reviews reveal an unrepresentative evidence base for the development 

of Medicaid drug formularies. Poster for UCSF Health Disparities Symposium, University of 

California, San Francisco, 2008. 

TOBACCO GENE-ENVIRONMENT INTERACTIONS IN AFRICAN AMERICAN AND LATINO ASTHMATICS 

Esteban Gonzalez-Burchard, MD, MPH 

Primary and second hand tobacco smoke (SHS) have been associated with an increased risk of asthma, 

increased asthma exacerbations, and reduced lung function in the general population. Previous reports 

have suggested that there are racial differences in nicotine metabolism and tobacco-related clinical outcomes. 

Perez-Stable, Benowitz and colleagues demonstrated that African Americans have lower total and 

non-renal clearance of serum cotinine. Although there are many potential explanations for these results, 

one potential explanation is that there are racial/ethnic specific differences in the genes that interface with 

the environment or play a role in xenobiotic metabolism. In addition, there are known population-specific 

genetic variations (i.e., allele frequencies). The hypothesis is that genetically determined racial background 

and tobacco smoke interact to modify risk for development of asthma and for increased rate of lung function 

decline among former and current African American smokers. 

Asthma is the most common respiratory disease in childhood and is caused by the interaction of exposure 

to various environmental factors with genetic factors. There is strong epidemiologic evidence suggesting 

that SHS can cause asthma and worsen asthma symptoms. However, not all individuals exposed to 

SHS develop asthma. This would suggest that there are genetically susceptible individuals and gene-environment 

interactions play an important role in the development of asthma and the determination of asthma 

severity and exacerbations. The team has previously demonstrated that gene-environment interactions 

between SHS exposure and genetic variants in the CD14 gene result in more severe asthma and higher 

IgE levels among Mexican and Puerto Rican asthmatic children. 

Genetic variation in genes in innate immunity, xenobiotic metabolism, and antioxidative defense pathways 

may account for subject-to-subject variation in response to SHS exposures, population-specific genetic 

variation and population-based differences in environmental exposures may partly explain the striking 

racial/ethnic-specific variation in asthma prevalence, morbidity, and mortality in the United States. 

Analyses of tobacco exposure and gene-environment interactions in minority populations are being conducted 

for three important reasons. First, little information is available on these interactions with respect to 

asthma in minorities. Second, the striking four-fold difference in asthma prevalence, morbidity, and mortality 

between Puerto Ricans and Mexicans offers a unique opportunity to study genetic factors related to 

SHS exposure, asthma, asthma severity, and asthma exacerbations, since these two populations often share 

similar environments, ancestry, and socio-economic status. Third, African Americans and Puerto Ricans 

have the highest asthma morbidity and mortality rates in the United States. 

ACUTE EFFECTS OF SECOND HAND TOBACCO SMOKE EXPOSURE 

IN THE UPPER AND LOWER RESPIRATORY TRACT 

John Balmes, MD 

Using a controlled human exposure system, Dr. Balmes is studying the immediate effects of SHS 

exposure on the respiratory tract in non-smokers. SHS exposure is known to cause lung and nasal sinus 

cancer as well as COPD. It increases the rate of lower respiratory infections and ear infections in children, 

and causes and exacerbates asthma. However, the early effects on the respiratory tract remain unclear. The 

primary hypothesis driving the project is that acute exposures to concentrations of SHS encountered in 

real-world environments cause inflammation in both the upper and lower respiratory tract and these 

responses are enhanced by repeated exposures. The secondary hypothesis is that individuals who are 

allergic to aeroallergens are more sensitive to the inflammatory effects of SHS than non-allergic individuals. 

SHS is a complex mixture. Irritation of the nose and congestion are among the most common 

complaints among non-smokers exposed to tobacco smoke and elevated rates of rhinosinusitis are reported 

among groups with occupational exposure to SHS. Any exposure that increases nasal congestion and 

inflammation is likely to increase the risk of rhinosinusitis. To date, controlled SHS exposure studies, 

flawed by inadequate power and poor subject characterization, have not shown consistent dose-dependent 

SHS effects on lung function or on a limited range of lower airway inflammatory markers. Individuals with 

P A G E 2 7

allergic rhinitis have increased responses to inhaled irritants compared to normal individuals. In 

environments without comprehensive smoke-free regulations, repeated and chronic occupational exposures 

to SHS are typical. Repeated exposures to other respiratory tract toxicants such as sulfur dioxide and 

endotoxin can lead to greater effects than single exposure. However, repeated exposures to ozone have 

been shown to lead to attenuated airway inflammation compared to single exposures. Thus, it is important 

to determine whether repeated exposures to SHS enhance or attenuate airway inflammatory responses. 

Physiological tests of sino-nasal patency (rhinomanometry, tympanometry and sino-nasal nitrous oxide 

concentration during humming) will be combined with gene expression assays and analysis of blood-borne 

systemic inflammation markers to measure upper airway effects of SHS exposure. Pulmonary function tests 

and analysis of bronchoalveolar lavage fluid will be used to measure lower airway effects of SHS exposure. 

By studying the immediate effects of short-term exposures to SHS on non-smokers who are not normally 

exposed to SHS, Drs. Balmes and Schick hope to identify early biological responses that may lead to 

diseases of the upper and lower airway. 

THE IMPACT OF SHS EXPOSURE ON PULMONARY FUNCTION, DISABILITY, AND CARDIOVASCULAR DISEASE 

Mark Eisner, MD, MPH 

This study builds upon and expands an ongoing NIH-funded cohort study of how disability develops in 

COPD. In the Function, Living, Outcomes, and Work (FLOW) cohort study, Dr. Eisner and his team aim 

to elucidate how SHS exposure adversely affects patients with COPD. Specifically, the team will delineate 

the longitudinal impact of SHS exposure on pulmonary function decline among adults with COPD. The 

research team will also evaluate the prospective impact of SHS exposure on the risk of functional limitation 

and disability in COPD. The development of functional limitations is a critical intermediate step on the 

causal pathway from impairment to disability. The team will study the specific impact of SHS exposure on 

the risk of developing functional limitations in COPD (e.g., limitations in lower extremity function, skeletal 

muscle strength, and exercise performance). Using directly measured SHS exposure, the PI will elucidate 

how SHS exposure modulates the progression from functional limitation to disability and will also 

determine the impact of SHS exposure on the risk of cardiovascular disease outcomes among adults with 

COPD. The team will study the impact of SHS exposure on a broad array of cardiovascular disease outcomes 

in this high-risk group. Finally, the team will determine the extent to which the effect of SHS on 

pulmonary function decline, functional limitation, and disability is mediated by chronic inflammation. 

SECOND HAND TOBACCO EXPOSURE ASSESSMENT CORE 

Neal L. Benowitz, MD 

In this Core, Dr. Benowitz and colleagues address three aspects of exposure assessment. The first is the 

determination of the optimal use and development of new biomarkers to assess exposure to SHS. Studies 

are underway to determine how best to use cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 

and its glucuronides (NNAL) as markers of SHS-related disease risk. Particulates are a major source of 

exposure to carcinogens and other toxins, and there is a paucity of biomarkers for particulate phase exposure. 

Nicotelline, a minor tobacco-specific alkaloid, is being studied as potentially the best available marker 

of particulate exposure. Also, the Core serves as a service laboratory for other FAMRI investigators, providing 

state-of-the-art measurement techniques. 

In addition, the Core research team conducts clinical investigations on two important issues in SHS 

exposure: 1) exposure of individuals who are hospitalized; and 2) exposure of individuals in motor vehicles. 

Smoke exposure, either active or passive, can precipitate a variety of serious medical illness that include 

acute cardiovascular events and deterioration of pulmonary function. The history of active and passive 

smoking may not be accurately recorded in the medical record; consequently an important opportunity for 

prevention of further tobacco-related disease may be missed. The research team measures biomarkers of 

exposure from blood and urine samples taken from patients on admission to area hospitals. 

People spend a substantial percentage of their lives inside of motor vehicles. As state and local laws ban 

smoking in many public places, SHS exposure during motor vehicle travel will become the major remaining 

source of exposure. When smoking is allowed in motor vehicles, the levels of smoke pollutants are 

quite high. There is a major concern about adverse health effects, particularly for children where adults 

smoke in their vehicles. Many adults are ignorant of the harmful effects of SHS exposure in children. The 

Core is conducting a study on actual human exposure in motor vehicles using exposure biomarkers, the 

results of which are likely to be highly useful in promoting new laws restricting smoking in motor vehicles 

where children are present. The data from this core project will be used by the project being conducted by 

Dr. Bero. 

2 8 P A G E

FLIGHT ATTENDANT MEDICAL RESEARCH CLINICAL PRACTICE 

Rita Redberg, MD 

The clinical care plan is to evaluate any medical issues of non-smoking flight attendants and interpret the 

results of the pulmonary testing they undergo at UCSF. Flight attendants, as a group, have worked in 

unique conditions that put them at increased risk for certain health problems, i.e., many years of exposure 

to SHS pre-ban. To best address the health needs of flight attendants, health care providers must be aware 

of these conditions and must be experienced in recognizing and treating possible health consequences. In 

addition, most flight attendants are women, and disparities in women’s health care have been recognized, 

including inadequate attention to differences in health and disease, diminished use of advanced diagnostic 

and treatment approaches, failure to include women in research studies, and lack of public and professional 

education on women’s health issues. The established FAMRI-Bland Lane Center of Excellence on SHS at 

UCSF has been working to better understand the medical issues related to working conditions for flight 

attendants in order to improve flight attendant health and health care. The Flight Attendant Medical 

Research Clinical Practice (FAMRCP) at UCSF continues to be devoted to the special medical needs of 

flight attendants with a history of SHS exposure. The Center sees flight attendants after their FAMRI 

research studies at UCSF to review their medical history as well as to review the results of their testing and 

advise them accordingly. The Clinical Practice has a close relationship with the FAMRI research projects, 

so that all those enrolled in the research studies will be offered medical evaluation in the FAMRCP and 

patients seeking care in the FAMRCP are offered the opportunity to participate in the research program. 

This collaboration is enhanced by the dual role of many of the SHS clinical researchers who are also part of 

the FAMRCP. 

CHRONIC EFFECTS OF SECOND HAND TOBACCO SMOKE EXPOSURE 

ON LUNG FUNCTION OF FLIGHT ATTENDANTS 

Warren M. Gold, MD 

The main hypothesis of this study is that exposure to SHS in the confined workspace of commercial 

aircraft prior to the ban against cigarette smoking is responsible for long term damage to the lungs of nonsmoking 

flight attendants. Although only some flight attendants show evidence of this damage upon 

examination of their lung function at rest, the majority of the flight attendants have abnormal diffusing 

capacity during exercise. This is hypothesized to be the case because the damage may be too subtle to be 

detected with lung function measured at rest. To test this hypothesis, the investigators will compare preand 

post-ban flight attendants to each other and to two groups of age-matched, non-smoking controls 

living at sea level, stratified on the basis of SHS exposure. The results of the study should permit the 

investigators to determine whether SHS accounts for the lung damage in flight attendants. The specific 

aims of this study are to characterize the long-term effects of cumulative aircraft cabin SHS exposure on 

the resting lung function of pre-ban flight attendants. The investigators will measure the single breath 

carbon monoxide diffusing capacity at rest (DcoSB), maximal mid-expiratory flow rate (FEF25-75%), 

forced expiratory flows after 50% and 75% of expelled lung volume (FEF50% and FEF75%), and air 

trapping (difference between total lung capacity measured by different methods). As an additional measure 

and to confirm lung function findings, they will obtain and quantitatively analyze high resolution lung CT 

scans from these flight attendants to investigate for evidence (hyperlucency and air trapping) suggestive of 

pulmonary emphysema. The investigators will characterize the more subtle long-term effects of cumulative 

aircraft cabin SHS exposure on lung by measuring the lung function of pre-ban flight attendants during 

exercise. Specifically, they will measure the within-breath diffusing capacity (DcoWB) and the pulmonary 

blood flow at increasing exercise intensity and will determine whether the DcoWB increases appropriately 

with increasing pulmonary capillary blood flow. The investigators will determine whether the abnormalities 

in lung function of flight attendants at rest and during exercise are associated with the amount of exposure 

to SHS in aircraft cabins. 

ECONOMIC BURDEN OF SECOND HAND TOBACCO SMOKE 

Wendy Max, PhD 

Cigarette smoking is a leading cause of illness and death. Recent studies have found that exposure to 

SHS is also an important risk factor for illness and death. Though workplace smoking restrictions have 

become more and more common, many workers are still exposed to tobacco smoke at work, and these are 

more likely to be people of color. People also continue to be exposed to tobacco smoke at home. 

P A G E 2 9

However, while the economic costs attributed to active smoking have been documented, the economic 

costs associated with exposure to SHS have rarely been considered. This study will develop models of the 

costs attributable to SHS exposure for never smoking children aged 3-11, adolescents aged 12-19, and 

adults. Separate estimates will be made for African Americans, Hispanics, and others. Home and work 

exposure will both be taken into account. The investigators will estimate the direct healthcare costs of 

SHS-related illness as well as the indirect costs of time lost from work and other activities. The value of lost 

productivity from premature death due to SHS-related illness will also be estimated. Healthcare cost will 

be estimated using a series of econometric models describing the relationship of SHS exposure to the 

probability of being diagnosed with a smoking-related disease, self-reported poor health status, the 

probability of using healthcare services, and the level of healthcare expenditures for those who use them. 

The investigators will develop three measures for never smoking children, adolescents, and adults. The 

measures are the number of deaths attributed to SHS exposure, the years of potential life lost, and the 

value of lost productivity. The investigators will also use an econometric model to estimate the value of 

time lost from work and other activities due to SHS exposure. This study will provide the first 

comprehensive estimate of costs for people exposed to SHS at home and/or at work, and for children, 

adolescents, and adults. The study will extend previous work by looking at dose-response effects of 

exposure to SHS. Study findings will be useful to agents of change and other researchers in discussions of 

tobacco control education including smoke free workplaces and smoking restrictions in other public places. 

The study will also show what socioeconomic groups are most impacted by SHS and thus help in the 

design of regulations that can be targeted to the groups with the greatest burden. Findings will also be 

valuable for countering the economic arguments against smoking restrictions. 

IMPLEMENTING THE EVIDENCE 

Lisa A. Bero, PhD 

The project goal is to implement and evaluate a critical appraisal training to increase the ability of healthcare 

providers, journalists, and consumers to use methodologically sound research in communicating with 

others and in their own health care decision making, particularly decisions relevant to tobacco-related disease. 

The hypothesis is that individuals who participate in a critical appraisal skills training course will better 

incorporate evidence into their communications and health care decision-making. The investigators are 

particularly interested in examining how ethnic, social, economic, and educational characteristics of consumers 

might modify the effectiveness of a critical appraisal intervention in different populations. Thus, a 

special effort is being made to recruit diverse groups of consumers to participate in all phases of this project. 

The study population consists of three groups that are influential in individual health care decisionmaking: 

healthcare providers, journalists, and the consumers themselves. A critical appraisal intervention is 

being developed that is based on a small group, case-based approach. Workshop participants receive critical 

appraisal training (the intervention), covering evaluation of scientific studies and other sources of health 

information that teach participants about relevant databases like PubMed and the Cochrane Library. 

Following a problem-based learning strategy, real issues from life experience and work are introduced as a 

basis for forming questions that can be answered, such as finding the best available evidence, critically 

appraising that evidence, and applying it to decision-making. The established techniques to evaluate the 

effectiveness of this program focus on three levels of evaluation are: 1) attitude change; 2) knowledge 

change; and 3) behavior change. Evaluation of participant reaction will be done through investigator-led 

group discussion immediately after the critical appraisal workshop. Group discussions will be analyzed for 

recurrent themes, problems, and questions, to allow for modification of educational materials. Knowledge 

change (i.e., critical appraisal skills) will be measured through the pre- and post-interviews conducted 

immediately before and after the workshops. 

FAMRI CENTER OF EXCELLENCE AT THE WEIZMANN INSTITUTE OF SCIENCE, 2004, 

RENEWED 2009 

Director: Varda Rotter, PhD 

The FAMRI Center of Excellence at the Weizmann Institute (the Weizmann Center) in Israel was established 

in 2004. The purpose of the Weizmann Center is to provide molecular information that will deal 

with the important issues of early detection and genetic factors that may increase lung cancer susceptibility 

in individuals exposed to cigarette smoke. The Weizmann Center focus is to develop a broad understanding 

of the molecular events underlying the initiation and progression to lung cancer, a deadly consequence 

of cigarette smoke exposure. The research is being performed through parallel analysis of clinical material 

3 0 P A G E

from patient and high-risk individuals, as well as through tissue culture models and mice transgenic created 

by members of the Weizmann Center. The data from the Weizmann Center’s studies will improve the ability 

to identify individuals at increased risk, to improve early detection and to lead to enhanced preventive 

and therapeutic interventions in lung cancer. The Center’s Research is being performed through five key 

projects. The following FAMRI-supported peer-reviewed publications have resulted from research at the 

Weizmann Center. 


Adar S, Livneh Z. Translesion DNA synthesis across non-DNA segments in cultured human cells. DNA 

Repair 2006;5:479-490. 

Avkin S, Sevilya Z, Toube L, Geacintov N, Chaney SG, Oren M, Livneh Z. P53 and p21 regulate errorprone 

DNA repair to yield a lower mutation load. Mol. Cell 2006;22;407-413. 

Bialik S, Kimchi A. The death associated protein kinases: structure, function and beyond. Ann Rev Biochem 

2006;75:189-210. 

Gozuacik D, Kimchi A. Spotlight on cancer: DAPk protein family and cancer. Autophagy 2006;2(2):74-79. 

Livneh Z. Keeping mammalian mutation load in check: Regulation of the activity of error-prone DNA 

polymerases by p53 and p21. Cell Cycle 2006;5;1918-1922. 

Milyavsky M, Tabach Y, Shatz I, Erez N, Cohen Y, Tang X, Kalis M, Buganim Y, Goldfinger N, Ginsberg 

D, Harris CC, Domany E, Rotter V. Transcriptional programs following genetic alterations in p53, 

INK4A and H-Ras genes along defined stages of malignant transformation. Cancer Res 2005;65:4530- 

4543. 

Moskovits N, Kalinkovich A, Bar J, Lapidot Z, Oren M. P53 attenuates cancer cell migration and invasion 

through repression of SDF-1/CXCL12 expression in stromal fibroblasts. Cancer Res 2006;22:10671- 

10676 priority report. 

Paz-Elizur T, Ben-Yosef R, Elinger D, Vexler A, Krupsky M, Berrebi A, Shani A, Schechtman E, Freedman 

L, Livneh Z. Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck 

cancer. Cancer Res 2006;66:11683-11689. 

Paz-Elizur T, Brenner D, and Livneh Z. Interrogating DNA repair in cancer risk assessment. Cancer 


Paz-Elizur T, Elinger, Blumenstein S, Krupsky M, Berrebi A, Schechtman E and Livneh Z, Development 

of an enzymatic DNA repair test for molecular epidemiology studies: Distribution of OGG activity in 

healthy individuals. DNA Repair 2007;6:45-60. 

Paz-Elizur T, Krupsky M, Elinger D, Schechtman E, Livneh Z. Repair of the oxidative DNA damage 8- 

oxoguanine as a biomarker for lung cancer risk. Cancer Biomarkers 2005;1:201-205. 

Reef S, Shifman O, Oren M, Kimchi A. The autophagic inducer smARF interacts with and is stabilized by 

the mitochondrial p32 protein. Oncogene 2007;in revision. 

Reef S, Zalckvar E, Shifman O, Bialik S, Sabanay I, Oren M, Kimchi A. A novel mitochondrial short form 

of p19ARF induces autophagy and caspase-independent cell death. Mol Cell 2006;22;463-475. 

Reef S. Kimchi A. A smARF way to die: A novel short isoform of p19ARF is linked to autophagic cell 

death. Autophagy 2006; 2(4);328-330. 

Results presented at the 11th World Conference on Lung Cancer, Barcelona, Spain, July 2005 

Results presented at the 96th AACR Meeting, Washington DC, April 2006. 

Yarom N, Amariglio N, Taicher S, Rechavi G, Trakhtenbrot L, Hirshberg A. Chromosomal numerical 

aberrations in oral Lichen Planus. Presented at International Congress on Oral Cancer. Amsterdam, 

May, 2007. 

Zalcenstein A, Weisz L, Stambolsky P, Bar J, Rotter V, Oren M. Repression of the MSP/MST-1 gene contributes 

to the antiapoptotic gain of function of mutant p53. Oncogene 2006;25:359-369. 

THE PRO-APOPTOTIC DAP-KINASE GENE: MOLECULAR BASIS OF ITS TUMOR SUPPRESSIVE FUNCTIONS AND 

IMPLICATIONS IN LUNG CANCER DIAGNOSIS/PROGNOSIS/THERAPY 

Adi Kimchi, PhD 

This project is aimed at dissecting the cell death pathways that involve the death associated protein 

kinase (DAPk) family of proteins at the molecular level, and determining their relevance to cancer 

development. The study has clinical implications at the diagnostic, prognostic, and therapeutic levels. The 

link of DAP-kinase to the ADP-ribosylation factor/p53 (ARF/p53) pathway led to the discovery of short 

P A G E 3 1

mitochondrial adenosine diphosphate ribosylation factor (smARF), a novel mitochondrial isoform of 

p19ARF protein that causes the dissipation of the mitochondrial membrane potential and induction of 

autophagic cell death. Subsequent work has shown that this isoform binds to the mitochondrial p32 

protein and that this interaction stabilizes the protein, thus increasing its death promoting features. This 

research line was conducted in collaboration with the lab of Moshe Oren. Using another approach, DAPk 

was mapped within the cJun N-terminal kinase (JNK) signaling pathway, which is activated by oxidative 

stress. DAPk was proven to control JNK phosphorylation by activating protein kinase D (PKD). The 

DAPk/PKD interactions involve physical association that is increased under oxidative stress resulting in 

trans-phosphorylation of PKD by DAPk and in PKD activation. Depletion of DAPk from cells by short 

hairpin RNA (shRNA) or of PKD by a similar manner each reduced JNK activation. The cellular damage 

caused by oxidative stress was previously linked to activation of JNK signaling. 

The discovery that DAPk is indispensable for the activation of this important pathway has novelty in 

terms of identifying an upstream gene that leads to JNK activation during oxidative stress-induced cell 

death and has implications in understanding cancer development. In another research line novel DAPkinase 

substrates were identified by applying high throughput proteomic screens. To this end, a non-biased 

high throughput proteomic-based screen was performed with the intention of searching for novel DAPkinase 

substrates. Biochemical fractionation and mass spectrometric analysis were used to purify and 

identify several potential substrates. Two candidate substrates, the ribosomal protein, L5, and a replicationlicensing 

factor, Mcm3, were identified. Mcm3 was efficiently and specifically phosphorylated by DAPk on 

a unique site, Ser160. Importantly, shRNA-mediated knock-down of endogenous DAPk blocked both 

basal phosphorylation and Ca2+-induced phosphorylation, indicating that DAPk is both necessary and 

sufficient for Mcm3 Ser160 phosphorylation in vivo. Identification of Mcm3 as an in vivo DAPk substrate 

indicates the usefulness of this approach for identification of physiologically relevant substrates that may 

shed light on novel functions of the kinase. In collaboration with Varda Rotters’s group a research line was 

initiated for screening the status of the different DAP genes in a tissue culture model for lung cancer 

progression. Preliminary observations suggest that aberrant expression profiles of DAP1 and DAPk 

develop during certain stages in multi-step process of cancer development. 

CORRELATION OF DNA POLYMORPHISMS AND LARGE-SCALE GENE EXPRESSION WITH SUSCEPTIBILITY TO 

EVOLUTION AND PROGRESSION TO TOBACCO SMOKE-RELATED LUNG CANCER 

Gideon Rechavi, MD, PhD 

This project established a repository of lung cancer samples, healthy lung tissue samples, peripheral white 

blood cells, bronchial lavage, and sputum samples. These resources are necessary for genomic studies. Dr. 

Rechavi is studying known host candidate gene polymorphisms in a search for genetic predisposition to 

lung cancer. This involves analysis of single nucleotide polymorphisms (SNPs) that affect: 1) DNA repair 

systems; 2) p53 codon 72; and 3) apoptosis-related genes. The study includes cross-analysis of the 

polymorphisms in DNA repair and apoptosis genes. The investigators observed evidence of an association 

with lung cancer for CASP8 D302H heterozygosity. An analysis of global gene expression in human lung 

cancer, whole tumor gene expression, isolated discreet malignant lung cancer cells, and non-malignant cell 

populations is ongoing. Bioinformatics analysis of this data is expected to lead to the development of a 

multiparameter system for the detection of rare lung cancer cells by morphology, immuno-phenotyping, 

and molecular cytogenetics. 

This approach may lead to new early detection tools for lung cancer and minimal residual disease 

monitoring. To identify new molecular targets for rational therapy, identification of key components of 

signal transduction and apoptosis pathways are being determined by global gene expression of lung cancer 

and isolated cell populations. A study that investigates the occurrence of chromosomal aneuploidy in 

bronchoscopically obtained brushings and washings of cells and in non-invasively obtained sputum 

specimens is being carried out. This study is based on a powerful early detection technique that can 

ascertain small numbers of malignant cells through the combined analysis of bright field morphology and 

interphase fluorescence in situ hybridization (FISH) of individual cells without culturing the cells. This 

method has been verified in non-invasively obtained cells from human sputum. The projection is that this 

technique can lead to an earlier diagnosis of lung cancer. 

Twenty-three NSCLC tumors have been analyzed by array comparative genomic hybridization (CGH) 

and high-resolution mapping to determine frequent chromosomal gains and losses associated with this 

disease. To improve the ability to identify key genes residing in areas of chromosomal aberrations, array 

CGH was combined with gene expression profiling performed on the same tumor samples. Results of 

global functional analysis of the overexpressed and amplified genes will shed light on their relevance to the 

3 2 P A G E

pathogenesis of lung cancer. Brain metastases are common complications of lung cancer and carry a dismal 

prognosis for the affected patients. While brain metastases are extremely frequent in SCLC, preventive 

brain radiotherapy is common practice, however, in NSCLC, such metastases are found in about one fifth 

of cases and no such routine preventive radiotherapy is recommended. Thus a major challenge is to find 

biomarkers that can identify those NSCLC patients that are at increased risk for brain metastasis in order 

to treat this particular group of patients. DNA microarray studies on both primary lung tumors and brain 

metastases were used to compile a list of genes whose expression in primary tumors predicts CNS 

metastasis development. Quantitative PCR for 142 independent NSCLC tumors with known pathology 

staging and clinical outcome and enabled investigators to build a risk score for the prediction of metastatic 

spread to the CNS in NSCLC patients. This score may enable to guide prophylactic therapy such as cranial 

irradiation that may prevent or delay this devastating complication. 

IN VITRO MODEL FOR TUMOR PROGRESSION OF LUNG-DERIVED CELL: BIOLOGICAL AND MOLECULAR CHARAC- 

TERIZATION AND FUNCTIONAL ANALYSIS OF P53 GENE ALTERATIONS 

Moshe Oren, PhD 

The aims of this project are: 1) to establish a tissue culture model system for multistage progression of 

normal lung-derived cells to malignancy; 2) to characterize the molecular and biological events implicated 

in tumor progression in this experimental model; and 3) to evaluate the functional implications of loss of 

wild type p53 function and gain of mutant p53 function in lung-derived cells and in lung cancer. The 

investigators have developed an in vitro model of immortalized human primary cells of the lung that 

engineered several defined cancer-associated genetic alterations. Experiments included inactivation of p53 

tumor suppressors by several methods, overexpression of mutant p53, overexpression of the raps ontogeny, 

and various combinations of these genetic modifications. As a result, the investigators have obtained 

transformed cells that are capable of developing tumors in mice. This suggests that the in vitro developed 

system represents an authentic model of cancer development. To evaluate the gene networks that are 

associated with the malignant defined steps, investigators used a genome-wide approach, permitting the 

identification of gene clusters that are associated with the individual steps of malignant transformation that 

were defined. By taking this approach, they identified specific gene signatures associated with the specific 

genetic alterations along the process of cancer development. The focus has been on four important clusters 

that significantly represent this process. While establishing an in vitro system, the investigators noticed that 

although cells immortalized by human telomerase reverse transcriptase (hTERT) grow well in vitro, at a 

certain time point, varying between the various cell types studied, cells seem to undergo a certain crisis, or 

transition point, that is then followed by the emergence of cells with a faster cell growth rate. Analysis of 

that checkpoint revealed a loss of the p16 tumor suppressor gene. This concurs with other reports where it 

was shown that the p16 is undergoing methylation and thus is transcriptionally silenced. Gene cluster 

analysis indicated that at that time point there is a specific loss of gene clusters, consisting of typical cell 

differentiation (cluster 1) and a concomitant gain of a gene cluster that contains genes associated with cell 

proliferation (cluster 2). 

It was then confirmed that the immortalized WI-38 human fibroblasts lost their ability to undergo cell 

differentiation following a transforming growth factor beta (TGFb) trigger. Interestingly, restoration of 

p16 into fast growing cells recovered the capacity to undergo TGFb-induced differentiation and express 

the typical differentiation markers. In addition to the loss of p16, the investigators noticed a reduction in 

the myocardin gene. At that stage, myocardin was shown to be a specific transcription factor that plays a 

central role in smooth muscle differentiation. Using several assays, the team could show that the 

myocardin is lost at the point where slow growing cells are converted into fast growers and also found that 

myocardin expression is essential for their differentiation. Furthermore, studies have shown that myocardin 

overexpression caused cell growth arrest. Analysis of human cell lines and primary tumors indicated a trend 

of losing myocardin gene expression. Consequently, the investigators concluded that at this early step of 

cell transformation, the cell had already undergone genetic changes that brought about a defect in their 

capacity to undergo cell differentiation. 

This defect is associated with a loss in the expression of at least two tumor suppressor genes, p16 and 

myocardin. The role of p53 in the process leading to such a cell differentiation blockage is presently being 

investigated in this laboratory. The investigators expect that such an approach may indicate a defined role 

of p53 in cell differentiation at large. A third cluster of genes that was focused on consists of genes whose 

expression levels increased as a function of p53 and p16INK4A tumor suppressor’s inactivation. This 

cluster predominantly consists of cell cycle-related genes and constitutes a signature of a diverse group of 

cancers. Promoters of the genes in this cluster are enriched with five regulatory motifs, NFY, E2F, Elk1, 

P A G E 3 3

CHR, and CDE. The promoter architecture of many of the genes constitutes a “sum gate” output 

messenger RNA level correlating with the summated activity of the two suppressive channels of p53 and 

p16INK4A. Taking components of the mitotic spindle as an example, investigators experimentally verified 

predictions that p53-mediated transcriptional repression of several of these novel targets is dependent on 

the activities of p21, NFY, and E2F. 

The study demonstrates how a well-controlled transformation process allows the linking of three levels 

in a complex regulatory network, namely gene expression, promoter architecture, and activity of upstream 

tumor suppressors. A fourth-interesting cluster observed is a group of genes that are upregulated by the 

overexpression of the Ras oncogene and concomitantly downregulated by p53. This gene signature, which 

consists of a high number of chemokines, shows a significant increase and in some cases, a synergism in 

their expression as a result of overproducing Ras and are inactivated or knockdown of p53 expression. 

Based on the information obtained by this cluster expressed at an advanced phase of transformation a novel 

gene network was unraveled that connects the Ras and p53. In general, it seems that the clusters that have 

been discovered using this in vitro model agree with specific stages in transformation may thus serve as a 

specific hallmark signature of the stepwise malignant process. One recent exciting development in modern 

biology has been the discovery of microRNAs (miRs), small regulatory molecules that represent a novel 

important layer in the utilization of the cell’s genetic information. In view of reports that expression of 

particular miRs is altered in human cancer, the investigators hypothesized that the p53 tumor suppressor 

protein may also exert some of its anti-cancer effects via regulation of specific miRs. This conjecture was 

confirmed experimentally by demonstrating that p53 modulates the levels of a small subset of miRs. Most 

notably, p53 was found to upregulate miR-34a in lung cancer-derived cells as well as in several other cell 

types. Furthermore, miR-34a was shown to contribute to the killing of cancer-derived cells by 

chemotherapy. Delivery of miR-34a or mir-34a-mimics into tumor cells may thus be explored as a 

potential mechanism for increasing the efficacy of chemotherapy. In another study, done in collaboration 

with Dr. Jair Bar of the Sheba Medical Center, who is affiliated with the team of Professor Rechavi, and 

with Professor Arie Ben-Yehuda of the Hebrew University Medical School, the role of p53 in the cross talk 

between lung cancer-derived cells and stromal fibroblasts, representing the tumor cell microenvironment, 

has been examined. It was found that p53 suppresses the ability of normal fibroblasts to secrete the 

chemokine SDF-1, known to increase tumor cell survival and metastasis. This suggests a novel role of p53 

as a tumor suppressor, by depriving cancer cells of supportive factors produced by their microenvironment. 

Remarkably, in a tissue culture model, lung cancer-derived cells were found capable of repressing the levels 

of endogenous p53 in adjacent fibroblasts. Thus it appears plausible that tumor cells might become more 

malignant by acquiring the ability to manipulate p53 in the adjacent stroma, thereby promoting the 

creation of a more tumor-friendly microenvironment. 

REDUCED REPAIR OF THE OXIDATIVE DNA LESION 8-OXYGUANINE AS A RISK FACTOR IN LUNG CANCER 

Zvi Livneh, PhD 

The goal of this research is to provide the fundamental and applied basis for the role of DNA repair in 

tobacco smoke-related cancers, primarily lung cancer. Fueled by the discovery of this group that reduced 

enzymatic activity of the DNA repair enzyme, 8-oxoguanine DNA-glycosylase (OGG), is associated with 

increased risk of lung cancer, the emphasis of the research is on DNA repair enzymes that operate on 8- 

oxoguanine (repaired by OGG) and other tobacco smoke-induced DNA damage. Low OGG is now 

known to be an independent risk factor of lung as well as head and neck cancer, both of which are caused 

by tobacco smoke. Moreover, the combination of low OGG activity and smoking cause a much higher 

relative risk to develop these types of cancer. To facilitate translation of the OGG test to the public health 

arena, several translational research directions were taken. First, an improved method for the isolation of 

human peripheral blood mononuclear cells (PBMC) was developed, which yields highly purified PBMC. 

This will be very useful for epidemiological studies for the OGG DNA repair test, as well as other DNA 

repair tests that are being developed. Moreover, a new version of the OGG blood test was developed, 

which is based on fluorescence, instead of radioactivity labeling used in the original assay. In collaboration 

with Dr. Rotter, the fluorescent assay is used to analyze the fate of OGG activity in a model lung 

carcinogenesis cellular system developed in her lab. 

Error-prone DNA repair (translesion DNA synthesis) is an important protective response to DNA 

damage, yet it is a double-edged sword, since it is mutagenic in nature. When it is out of control, it may 

cause genetic damage rather than protection. The investigators have previously shown that error-prone 

repair in lung cancer cells, as well as other cell types, is tightly regulated by the tumor suppressor p53 

3 4 P A G E

through the cell cycle inhibitor p21. The latter exerts its effect by interacting with proliferating cell nuclear 

antigen (PCNA), the sliding DNA clamp of DNA polymerases, and modulating its monoubiquitination. 

They analyzed the involvement of specific DNA polymerases in this error-prone replication across various 

lesions, using genetic methods of gene silencing, combined with specialized DNA substrates carrying 

engineered site-specific lesions. These included DNA lesions caused by benzopyrene, a potent tobacco 

smoke carcinogen, as well as cisplatin, a drug used in lung cancer therapy. The study has uncovered that 

there is a regulated and ordered activity of these polymerases, which cooperate to exert a protective effect 

on the cells, despite their inherent mutagenic nature. Further studies are performed to elucidate the 

operation principles of these polymerases, and to examine whether imbalances in their activity facilitate 

carcinogenesis. 

FAMRI CENTER OF EXCELLENCE AT THE SIDNEY KIMMEL COMPREHENSIVE CANCER 

CENTER, THE JOHNS HOPKINS UNIVERSITY, 2005 

DIRECTOR: CHARLES M. RUDIN, MD, PHD 

The FAMRI Center of Excellence at The Johns Hopkins Medical University (the Johns Hopkins 

Center) was funded in 2005, with the overall purpose of creating synergy among the individual FAMRIfunded 

researchers at the Johns Hopkins Medical Institutions (JHMI) and easing translation of research 

findings into action for the enhancement of patient care and public health protection. The Johns Hopkins 

Center is designed to create a unique collaborative infrastructure within the Hopkins Schools of Medicine 

and Public Health. The overall aims of the center are: 1) translation of basic science discoveries to clinical 

application, focusing on targeted drug development against tobacco related malignancies; and 2) conversion 

of laboratory and epidemiologic data into integrated public health recommendations. The Johns 

Hopkins Center supports Core resources focused on critical barriers to research translation. 


Alani RM, Silverthorn CF, Orosz K. Tumor angiogenesis in mice and men. Cancer Biol Ther 2004;3:41- 

42. 

Barnoya J, Mendoza-Montano C, Navas-Acien A. Secondhand smoke exposure in public places in 

Guatemala: comparison with other Latin American countries. Cancer Epidemiol Biomarkers Prev 

2007;16:2730-2735. 

Bivalacqua TJ, Sussan TE, Gebska MA, Strong TD, Berkowitz DE, Biswal S, Burnett AL, Champion HC. 

Sildenafil inhibits superoxide formation and prevents endothelial dysfunction in a mouse model of secondhand 

smoke induced erectile dysfunction. J Urol 2009;181:899-906. 

Cole PA. Chemical probes for histone-modifying enzymes. Nature Chem Biol 2008;4:590-597. 

Cummings SD, Ryu B, Samuels MA, Yu X, Meeker AK, Healey MA, Alani RM. Id1 delays senescence of 

primary human melanocytes. Mol Carcinog 2008;47:653-659. 

DeLuca AM, Srinivas A, Alani RM. BRAF kinase in melanoma development and progression. Expert Rev 

Mol Med 2008;10:e6. Review. 

Dunlap S, Yu X-B, Cheng L-Z, Civin CI, Alani RM. High-efficiency stable gene transduction in primary 

human melanocytes using a lentiviral expression system. J Investig Dermatol 2004;122:549-551. 

Govindarajan B, Shah A, Cohen C, Arnold RS, Schechner J, Chung J, Mercurio AM, Alani R, Ryu B, Fan 

CY, Cuezva JM, Martinez M, Arbiser JL. Malignant transformation of human cells by constitutive 

expression of platelet derived growth factor-BB (PDGF-BB). J Biol Chem 2005;280:13936-13943. 

Guidez F, Howell L, Isalan M, Cebrat M, Alani RM, Ivins S, Hormaeche I, McConnell MJ, Pierce S, Cole 

PA, Licht J, Zelent A. Histone acetyltransfeRase activity of p300 is required for transcriptional repression 

by the promyelocytic leukemia zinc finger protein. Mol Cell Biol 2005;25:5552-5566. 

Hammers H, Paesante S, Rudek M, Pili R. Combination of the VEGF receptor tyrosine kinase sunitinib 

and the mTOR inhibitor rapamycin leads to tumor regression in the RENCA model. Presented at the 

AACR Annual meeting. 2008. 

Hammers HJ, Salumbides B, Shen L, Paesante S, Rudek M, Verheul HM, Pili R. From bedside to the 

bench: tumor microenvironment is responsible for the acquired resistance to tyrosine kinase inhibitors in 

renal cell carcinoma. Presented at the AACR Annual meeting 2008. 

Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, 

Watkins DN, Rudin CM. Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell 

lung cancer. Cancer Res 2008;68:2321-2328. 

Hann CL, Rudin CM. Fast, hungry and unstable: finding the Achilles’ heel of small-cell lung cancer. 

P A G E 3 5

Trends Mol Medicine 2007;13:150-157. 

Hann CL, Rudin CM. Management of small-cell lung cancer: incremental changes but hope for the 

future. Oncology 2008;22:1486-1492. 

Jiang T, Collins BJ, Jin N, Watkins DN, Brock MV, Matsui W, Nelkin BD, Ball DW. Achaete-scute complex 

homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res 

2009;69:845-854. 

Larson AR, Konat E, Alani RM. Melanoma biomarkers: current status and vision for the future. Nat Clin 

Pract Oncol 2009;6:105-117. 

Lee K, Qian D Z, Rey S, Wei H, Liu JO, Semenza GL. Anthracycline chemotherapy inhibits HIF-1 transcriptional 

activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci 

USA 2009;106:2353-2358. 

Li J, Jameson MB, Baguley BC, Pili R, Baker SD. Population pharmacokineticpharmacodynamic model of 

the vascular-disrupting agent 5,6-dimethylxanthenone-4- acetic acid in cancer patients. Clin Cancer Res 

2008;14:2102-2110. 

Liu Y, Dentin R, Chen D, Hedrick S, Ravnskaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J, Olefsky 

J, Guarente L, Montminy M. A fasting inducible acetylase/deacetylase switch modulates gluconeogenesis 

through activator-coactivator exchange. Nature 2008;456:269-273. 

Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg 

J, Pare P, Tuder RM, Biswal S. Decline in NRF2-regulated antioxidant defenses in the lungs of advanced 

COPD patients due to loss of its positive regulator DJ-1. Am J Resp Critical Care Med 2008;178:592- 

604. 

Orita H, Coulter J, Tully E, Kuhajda FP, Gabrielson E. Inhibiting fatty acid synthase for chemoprevention 

of chemically induced lung tumors. Clin Cancer Res 2008;14:2458-2464. 

Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J, Dang Y, Zhang J, Jiang H, Penner R, Liu J. 

Clofazimine inhibits human Kv1.3 potassium channel and perturbs calcium oscillation frequency in T 

lymphocytes. PLoS ONE 2008;3:e4009. 

Rudin CM, Hann CL, Peacock C, Watkins DN. Novel therapeutic approaches to small cell lung cancer. J 

Natl Compr Canc Netw 2008;6:315-322. 

Ryu B, Keefe MJ, Kim D, Meeker AK, Alani RM. Physiologic levels of BRAFE600 promote growth of primary 

human melanocytes. Nature 2005 (revision under review). care and public health protection. 

Ryu B, Kim DS, Deluca AM, Alani RM. Comprehensive expression profiling of tumor cell lines identifies 

molecular signatures of melanoma progression. PLoS ONE 2007;2:e594. 

Ryu B, Kim DS, DeLuca AM, Healey MA, Dunlap S, Fackler MJ, Herman J, Alani RM. Id1 expression is 

transcriptionally regulated in radial growth phase melanomas. Int J Cancer 2007;121:1705-1709. 

Singh A, Ling G, Suhasini AN, Zhang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler 

TW, Watson WH, Biswal S. Nrf2 dependent sulfiredoxin-1 expression protects against cigarette smoke 

induced oxidative stress in lungs. Free Radic Biol Med 2009;46:376-386. 

Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu 

JO, Semenza GL. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor 

growth. Proc Natl Acad Sci USA 2008;105:19579-19586. 

ADMINISTRATIVE CORE 

Charles M. Rudin, MD, PhD 

The Administration Core provides overall administrative support and integration to the entire Center of 

Excellence. Its functions include management of budgets for all projects and cores within the Center, 

including tracking expenditures and managing subcontracts, and decisions to review, renew, and replace 

Developmental Research Projects within the Center. Its membership comprises the Center Director, and 

leaders of each of the primary research Cores. 

CLINICAL CORE 

Charles M. Rudin, MD, PhD 

The goal of this Core is to provide support for the conduct of innovative clinical trials focused on tobacco-related 

disease, including both preventive and therapeutic approaches. A major focus is to provide support 

for investigator-initiated clinical trials while the investigative teams are in the process of seeking independent 

grant support to continue these studies. This allows innovative concepts to move immediately into 

clinical implementation while applications for other sources of external peer-reviewed funding are pending. 

3 6 P A G E

DRUG DISCOVERY CORE 

Phillip Cole, MD, PhD 

The Drug Discovery Core is designed to support the ongoing research efforts in FAMRI laboratories at 

Johns Hopkins by providing access to small molecules and screening technologies. There are three principal 

components within this Core. First, a synthetic chemistry component directed by Dr. Meyers is charged 

with preparation and optimization of small molecules for biological, preclinical, and ultimately human 

studies. The other two components are based on different but complementary high throughput screening 

approaches. Dr. Jun Liu has assembled a library of existing approved chemical compounds in clinical use, 

to be screened for single agent and combinatorial activity against biological targets of interest. This library 

has the advantage of being immediately translatable to clinical inquiry. Dr. Min Li directs the ChemCORE 

facility within the Institute for Cellular Engineering, a semi-automated high throughput screening facility 

currently performing screens of up to 80,000 compounds, using a variety of biologically relevant high 

throughput assays. 

SYNTHETIC CHEMISTRY CORE COMPONENT OF THE DRUG DISCOVERY CORE 

David Meyers, PhD 

Dr. Meyers and his collaborators have started synthetic efforts to optimize small molecule inhibitors, for 

which they have received additional NIH support. Another project is the design and synthesis of mTOR 

inhibitors for FAMRI investigator Dr. Jonathan Powell. Over 26 analogs have been synthesized and have 

either been submitted for testing or are awaiting purification and/or characterization. The synthesis of a 

fluorogenic peptide that will be used to assay cells for convertase activity has been completed, and the peptide 

has been given to FAMRI investigator, Dr. Christine Hann. The synthesis of an agonist of the sonic 

hedgehog pathway (Shh) has also been completed. 

CLINICAL COMPOUND SCREENING INITIATIVE CORE COMPONENT OF THE DRUG DISCOVERY CORE 

Jun Liu, PhD 

Work in the past year has been focused on the following directions: 1) maintenance of the Johns 

Hopkins Drug Library (JHDL) and the distribution of JHDL to other FAMRI-supported faculty members 

for their screens; 2) characterization of nitroxoline as a novel inhibitor of angiogenesis and of the type 2 

methionine aminopeptidase (MetAP2); 3) identification of digoxin and other cardiac glycosides as 

inhibitors of hypoxia Inducible Factor 1 alpha (HIF-1 alpha) synthesis; 4) identification and characterization 

of the anti-leprosy drug clofazimine as a novel inhibitor of the human Kv1.3 potassium channel; 5) 

identification and characterization of the effect of anthracycline on the transcriptional activity of HIF-1 

alpha; and 6) identification and characterization of inhibitors of the multidrug resistance transporter, 

ABCG2. The JHDL is maintained by replenishing drugs when they become exhausted. 

Some of the screens initiated by FAMRI-supported groups include melanoma cell proliferation, hypoxia, 

breast cancer resistant protein, lymphoma and activation of EBV viral lytic cycle, have yielded exciting hits 

that were further validated and characterized. Several new screens were initiated in the past year, including 

screens against cutaneous squamous cell carcinoma and pancreatic cancer. Dr. Liu and collaborators have 

investigated the molecular mechanism of angiogenesis inhibition by nitroxoline and found that it inhibits 

endothelial cell proliferation due in part to its selective inhibition of MetAP2. MetAP2 is an established 

target for a number of small molecule inhibitors of angiogenesis. MetAP2 also has the ability to inhibit 

xenografts of breast and prostate cancers in animal models. 

In the screen for inhibitors of HIF-1, digoxin and ten other cardiac glycosides were identified as potent 

hits. Further characterization revealed that these drugs work by blocking the synthesis of HIF-1 alpha at 

the protein level. It was further demonstrated that administration of digoxin led to inhibition of tumor 

xenografts in vivo. In a separate large prospective cohort study, it was found digoxin users, especially men 

taking the drug for a long duration, had a lower risk of being diagnosed with prostate cancer, suggesting 

that digoxin may have potential as both a chemopreventive and therapeutic agent for this disease. In addition 

to digoxin, the well known anticancer drugs doxorubicin and daunorobicin were also found to inhibit 

HIF-1-dependent gene activation. The anthracyclines were found to inhibit the DNA binding of HIF-1. 

Further, it was demonstrated that anthracyclines inhibited angiogenesis in addition to tumor cell growth in 

vivo, shedding new light on the molecular basis of antitumor activity of the anthracyclines. 

Another screen of the JHDL in a T cell activation assay led to the identification of an anti-leprosy drug, 

clofazimine, as a potent inhibitor of the intracellular calcium signaling pathway leading to IL-2 production. 

It was shown that clofazimine directly binds and inhibits the activity of a unique voltage-gated potassium 

channel, Kv1.3, thereby perturbing the oscillation frequency of the calcium influx into T cells. Clofazimine 

P A G E 3 7

was also demonstrated to be effective in a skin-graft transplantation model, with efficacy comparable to 

that of the immunosuppressive drug FK506. Because Kv1.3 has been implicated in a number of autoimmune 

diseases, clofazimine could have novel therapeutic effect on such diseases as rheumatoid arthritis and 

multiple sclerosis. 

The synthetic core component has provided key HAT inhibitory compounds for 50 labs inside and outside 

of Hopkins. 

DRUG SCREENING CORE 

Rhoda Alani, MD 

Detailed in vivo modeling to assess the bioavailability, activity, pharmacokinetic and pharmacodynamic 

profiles, and toxicity of novel therapeutic approaches is an essential component of drug development, and 

typically exceeds the financial and technical capacity of individual laboratory-based investigators. The Drug 

Screening Core is designed to offer support for preclinical modeling of potential therapies for diseases 

caused by SHS exposure, with a primary focus on lung cancer as the largest single cause of death due to 

tobacco. This core consists of three components with distinct roles in preclinical drug testing. The first 

component will support studies using a novel primary xenograft system that has several distinct advantages 

over traditional cell line based xenograft models. The second component exploits models of in vivo angiogenesis 

to support several studies targeting tumor-associated blood vessels. The final component incorporates 

the strengths of the Analytical Pharmacology group for detailed pharmacokinetic and drug metabolic 

analysis. Together these three resources comprise a drug screening core to advance preclinical evaluation of 

novel therapeutic approaches identified by FAMRI-supported laboratories at Johns Hopkins. 

PHARMACOKINETIC CORE 

Michelle A. Rudek, PhD, Pharm D 

During the past 4 years, an analytical method based on high-performance liquid chromatography 

(HPLC) and tandem mass spectrometric detection (LC/MS/MS) was developed and optimized for measuring 

FAS93 concentration in murine biological fluids to support pharmacokinetic studies in conjunction 

with Dr. Edward Gabrielson’s Developmental Project entitled “Fatty acid synthase inhibitors as a novel 

therapy for lung cancer”. Specific techniques were developed for detection by LC/MS/MS and isolation 

of FAS93 from murine plasma, liver, and tumor. The method was used to characterize the pharmacokinetics 

of FAS93 in mice. 

The uptake of various drugs by platelets will complement the angiogenic targeting developmental 

research program in collaboration with Dr. Roberto Pili’s laboratory. Thus far it has been observed that 

VEGF-Trap, an antibody-based VEGF inhibitor in clinical development, is taken up by platelets in vitro. 

The investigators are seeking to determine whether three tyrosine kinase inhibitors (sorafenib, sunitinib, 

and PTK787) are taken up by and affect platelet function. 

There is a growing awareness of the need for better models that preserve the integrity of cancer stem 

cells and the three-dimensional interactions between tumor and stroma. Dr. Rudek and collaborators 

believe that maintaining tumors in 3D in vitro environments provides a more realistic preclinical model of 

cancer for the purposes of studying basic biology and drug discovery. Thus they have refined and optimized 

techniques for creating primary human cancer xenografts. 

The function of this Core is to develop, propagate and characterize aerodigestive tract xenografts lines, 

and provide them as a collaborative resource to FAMRI investigators. Extensive optimization of methodologies 

has resulted in high efficiency engraftment from even small amounts of tissue or tumor needle aspirates. 

Fresh tumor tissue obtained from surgical resections, bronchial biopsies or pleural effusions is stored 

for histological, DNA, and RNA analysis whenever the size of the sample permits. Tumor cells from solid 

lung tumors have been isolated and injected subcutaneously into non-obese diabetic/severe combined 

immunodeficiency (NOD/SCID) mice and harvested before passage into other mice and/or cryopreservation 

for future re-injection and distribution. By conventional histologic criteria, the primary human tumor 

is indistinguishable from the xenograft over multiple passages; this similarity extends to the RNA transcription 

level. 

ANGIOGENESIS CORE 

Rhoda Alani, MD 

The scope of the Angiogenesis Core is to provide the technical support for projects that are testing 

novel therapeutic strategies for blocking tumor angiogenesis. Ongoing studies initiated through the core 

include exploring combination strategies targeting tumor-associated angiogenesis to evaluate the effect of 

3 8 P A G E

combining a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (sunitinib) and 

a mammalian target of rapamycin (mTOR) inhibitor (rapamycin) in murine syngeneic renal cell carcinoma 

cells (RENCA). The data suggest a greater inhibitory effect when sunitinb and rapamycin are combined. 

Subsequently, RENCA were injected orthotopically into the renal capsule of Balb/c female mice. This 

“prevention” model treatment was initiated with sunitinib or rapamycin or in combination on day 4. A 

dramatic inhibition of tumor growth was observed in all three groups. The combination was tested in an 

“intervention model” where the treatment was started on day 10. The results showed a modest inhibition 

by each agent singly but significant tumor regression was seen with the combination. Histological studies 

showed that in the sunitinib-treated tumors, despite induction of apoptosis, persistence of blood vessel is 

observed. Sequence-specific studies are ongoing to determine the effect of sunitinib and rapamycin as 

sequential rather than concomitant approach. 

TRANSLATION OF EVIDENCE CORE 

David Holtgrave, PhD 

Dr. Holtgrave chairs the Department of Health, Behavior, and Society in the Bloomberg School of 

Public Health. He assumed the reins of this Core from Dr. Jonathan Samet, who has taken a position at 

the University of Southern California. The overall goal of the Core is to translate evidence broadly related 

to SHS for the ultimate purpose of facilitating and enhancing practical implementation of the research 

findings generated by FAMRI investigators at The Johns Hopkins University and elsewhere. This Core 

provides Hopkins’ FAMRI investigators a platform from which they can disseminate information about 

their individual and combined research on exposure to tobacco smoke. It also seeks to enhance the ability 

of others, particularly researchers in developing countries, to develop their research capacity and apply their 

findings in practical ways that diminish the burden of tobacco-related disease. Through evidence synthesis, 

knowledge networking, and educational activities this Core will broaden the medical and public health 

impact of the Johns Hopkins FAMRI Center and of research completed by others who are addressing SHS 

and the diseases that it causes. 

DEVELOPMENTAL PROJECT 1: PRODRUG STRATEGIES FOR LUNG CANCER 

Caren Meyers, PhD 

Poor prognosis associated with advanced lung cancer demands the development of new therapies. Dr. 

Meyers’ studies aim to test the hypothesis that prodrug approaches can be devised to deliver agents whose 

therapeutic use is limited. Recent studies support the potential benefit of bisphosphonates (BPs) in lung 

cancer therapy; however, cell permeability and bioavailability of these agents are poor, due to the polyanionic 

structure of these compounds. A second promising strategy for the treatment of lung cancer involves 

combination therapy with the nucleoside analog gemcitabine and the histone deacetylase inhibitor (HDI) 

suberoylanilide hydroxamic acid (SAHA). However, inhibition of transport and intracellular phosphorylation 

are major mechanisms of resistance to gemcitabine, and SAHA is metabolically unstable. Dr. Meyers 

hypothesizes that issues of cell permeability, stability and drug resistance in these systems can be resolved 

using phosphoramidate-based prodrug strategies. The objective is to exploit the remarkably efficient phosphoramidate 

cyclization reaction developed for nucleotide prodrugs for the intracellular delivery of BPs 

and drug combinations. Two distinct prodrug approaches have been targeted for the delivery of nitrogencontaining 

BPs (N-BPs) and nucleotide/hydroxamic acid drug combinations. Both strategies employ 

nitroaryl delivery moieties known to undergo bioactivation in hypoxic tumor cells, further imparting selectivity 

for prodrug activation. As one of the most deadly smoking-related diseases, lung cancer places a 

tremendous burden on healthcare, and the search for new therapeutics remains a priority of FAMRI. 

DEVELOPMENTAL PROJECT 2: THERAPEUTIC STRATEGIES TO OVERCOME RESISTANCE 

TO ANTI-VEGF TREATMENTS 

Roberto Pili, MD 

Metastatic renal disease management is a challenge, and new therapeutic alternatives are needed. Since 

renal cancers are angiogenesis- and hypoxia-driven, an approach using ASA404 (formerly DMXAA, 5, 6- 

dimethylxanthenone-4-acetic acid), a flavanoid tumor vascular disrupting agent (VDA), is being utilized in 

combination with everolimus, an mTOR inhibitor to target tumor vasculature. In this study Dr. Pili performed 

a preclinical study to determine pharmacodynamic markers and to explore the activity of the single 

agents/combination of both the drugs to circumvent the resistance mechanisms in chemotherapy in an in 

vivo model of renal cancer. Anti-VEGF therapies have been shown to have preclinical and clinical activity in 

renal cell carcinoma. Vascular disrupting VDAs such as ASA404 have been tested in several tumor types 

P A G E 3 9

and are currently in clinical testing. VDAs have been reported to induce rapid vascular shut down and 

intratumor hypoxia/necrosis. However, tumor progression is still generally observed. This is usually associated 

with persistent viable outer rim of the tumors and intense angiogenesis that is probably induced by 

the central hypoxia. Based on this preclinical evidence, it is reasonable to combine a VDA with hypoxia 

inducible factor 1 alpha (HIF-1alpha) inhibitors to achieve greater antitumor activity. Because of the 

intense HIF-1 alpha/ VEGF-driven tumor vascularization, renal cell carcinoma represents an ideal tumor 

type to test this rational combination strategy both preclinically and clinically. VEGF production and signaling 

is partly dependent on mTOR-induced expression of HIF-1 alpha. Thus, this study is aimed at the 

preclinical assessment of tumor response to VDAs in combination with mTOR inhibitors targeting tumor 

endothelium, which is associated with early anatomic and functional changes in the blood vessels. These 

changes in tumor vasculature might act as predictors of antitumor effects. 

DEVELOPMENTAL PROJECT 3: OX-LDL RESULTS IN EARLY ENDOTHELIAL ARGINASE ACTIVATION 

Dan Berkowitz, MD 

Atherosclerotic vascular disease is the leading cause of morbidity and mortality in the developed world. 

Although a complex process resulting from numerous genetic and environmental factors, it is well recognized 

that oxidized low density lipoproteins (Ox-LDL) produces pro-atherogenic effects in endothelial 

cells by inducing the expression of adhesion molecules, stimulating endothelial cell apoptosis, inducing 

superoxide anion formation (reactive oxygen species, ROS), and impairing protective endothelial nitric 

oxide (NO) formation. Exposure to SHS or active smoking further exacerbates this process by enhancing 

oxidation of low density lipoproteins (LDL) as well as increasing the oxidant stress in the endothelium. Dr. 

Berkowitz demonstrated that Ox-LDL results in early endothelial arginase activation and later transcriptional 

upregulation with a reciprocal decrease in NO production and vascular endothelial dysfunction. The 

data suggest that the enzyme arginase reciprocally regulates nitrous oxide systems (NOS) and NO production 

by competing for the common substrate L-arginine. Current results show ~2.5 fold induction of 

arginase activity in control mice, endothelial dysfunction as measured by decreased NO production, 

increased ROS production, increased vascular stiffness, and impaired vasorelaxation following 2 weeks of 

cigarette smoke exposure. Interestingly LOX-/- (Ox-LDL receptor knock out) mice showed a decrease in 

cigarette smoke-induced arginase activity. LOX-/- mice also demonstrated improved endothelial function 

when assessed in aortic ring studies in organ chambers as well as a less profound increase in vascular stiffness 

compared to normal controls. OxLDL is coupled to arginase activation through the LOX 1 receptor, 

thus the investigators are currently investigating the effect of smoke in ArgII-/- mice. Preliminary data 

suggests that while normal mice develop a profound decrease in endothelial NO in response to smoke, 

ArgII-/- mice are almost completely protected. The investigators have proposed studying the effect of 

smoking on atherogenensis in the ApoE-/- atherogenic prone mice with a particular focus on the role of 

arginase II. 

DEVELOPMENTAL PROJECT 4: EFFECT OF TOBACCO SMOKE EXPOSURE ON PLATELET HYPER-REACTIVITY, VEIN 

GRAFT THROMBOSIS AND OUTCOME AFTER CORONARY ARTERY BYPASS SURGERY 

Jeffrey Rade, MD, PhD 

Saphenous vein grafts (SVG) are the most widely used conduits for coronary artery bypass grafting 

(CABG) surgery. Recent data from the Johns Hopkins Reduction in Graft Occlusion Rates Study indicate 

that over 20% of SVG develop occlusive thrombosis within 6 months of surgery. Further preliminary data 

have identified increased aspirin-insensitive thromboxane generation and consequent platelet hyper-reactivity 

as a novel risk factor for early vein graft thrombosis. From previous studies, it is known that thromboxane 

synthesis is increased in subjects with both active and passive exposure to tobacco smoke. It is not 

known what contribution tobacco smoke exposure makes to aspirin-insensitive thromboxane generation 

and what effect this has on platelet reactivity and clinical outcome. This study is designed to explore the 

hypothesis that both active and passive exposure to tobacco smoke promote aspirin-insensitive thromboxane 

generation and platelet hyper-reactivity that contribute both to early SVG thrombosis and adverse clinical 

events in patients undergoing CABG surgery. 

DEVELOPMENTAL PROJECT 5: EPIDEMIOLOGY AND INTERVENTION RESEARCH IN ARMENIA 

Frances Stillman, EdD, EdM and Narine Movsisyan, MD, MPH 

Smoking rates in Armenia and surrounding countries are remarkably high in men (59.6%) and very low in 

women (2.1%). As a result, women and children are involuntarily exposed to high concentrations of SHS; 

therefore, they are at increased risk of death and disease. This at-risk population is exposed in public places 

4 0 P A G E

where smokefree laws are not enforced and in the home where smokefree practices rarely exist. This project 

establishes a program of developmental research and capacity development, in collaboration with the 

American University of Armenia (AUA). The objective is to reduce SHS exposure in Armenia and its neighbors 

through approaches aimed at increasing compliance with workplace smoking practices and to change 

behaviors in the home. Regionally appropriate interventions to reduce SHS exposure are being developed 

and tested in Armenia and then will be extended by the AUA, as a regional center, to neighboring countries 

with modification as needed. A number of hypotheses will be tested by the investigators. The first hypothesis 

is that measurement of SHS markers in the air and implementation of specific strategies to change behavior 

and attitudes of employees will increase acceptance and compliance with smokefree worksite practices. 

The second hypothesis is that measurement of women and children’s SHS exposure at home can be used in 

an intervention package to educate smokers on the danger of their smoking to others; and thereby reduce 

SHS exposure among women and children. Protocols have been developed to make measurements of SHS 

in legally smokefree buildings, e.g., hospitals and universities, and will be used to inform interventions in 

specific workplaces. The utility of this approach is being assessed by the AUA in Yerevan. The second 

hypothesis, a clinical trial, will soon be carried out in Yerevan, involving homes with women and children 

living with a male smoker. Protocols have been developed for particulate matter less than 2.5 microns in 

diameter (PM 2.5 ) and airborne nicotine monitoring of homes and the SHS exposure of women and children 

living in the homes. Based on the monitoring results, interventions will be developed to motivate 

smokefree home practices and behavioral change. Personal nicotine exposure will be measured through personal 

nicotine badges and hair nicotine measures. In the second phase of the project, the AUA team will 

identify and train collaborators in neighboring countries to disseminate the protocols and intervention 

approaches. A Center of Excellence for Tobacco Control Research will be established for this purpose. 

THE JULIUS B. RICHMOND CENTER OF EXCELLENCE AT THE AMERICAN ACADEMY 

FOR PEDIATRICS, 2006 

Director: Jonathan D. Klein, MD, MPH 

In 2006, FAMRI established its fourth center, the Julius B. Richmond Center at the American Academy 

of Pediatrics (AAP), a virtual center dedicated to the elimination of children’s exposure to tobacco and 

SHS, and to ensuring that every pediatrician has the tools they need to help families eliminate tobacco and 

SHS from children’s lives. As a virtual center, the Julius B. Richmond Center (the Richmond Center) has 

research programs at multiple sites. The Richmond Center is administered through the AAP headquarters 

in Elk Grove Village, Illinois, and at the University of Rochester, and has six major projects, involving 

researchers from the University of Rochester, Dartmouth College, Children’s National Medical Center, 

Cincinnati Children’s Hospital, George Washington University, Harvard Medical School, New York 

University, the Public Health Institute/Tobacco Control Resource Center, and Mississippi State University. 

With the establishment of the Richmond Center at the AAP, child health researchers inform clinical interventions 

and the education, training and tools needed to effectively intervene to protect children from the 

harmful effects of SHS. 

The Richmond Center aims include: 1) providing core data sources and analyses about children and 

SHS; 2) training the next generation of anti-SHS scholars; 3) training child health clinicians to deliver 

brief, effective counseling to reduce/eliminate children’s exposure to SHS and to act as tobacco control 

champions within their states and communities; 4) synthesizing and providing scientific information for 

development and implementation of new strategies to reduce children’s exposure to SHS; 5) developing 

and testing a rapid, in-office test for SHS exposure in children and; 6) developing and testing targeted, 

family-centered, theory-driven communication strategies for preventing children’s exposure to SHS. The 

center is named in honor of Julius B. Richmond, MD, founding Chair of the FAMRI Medical Advisory 

Board, John D. MacArthur Professor of Health Policy Emeritus at Harvard Medical School, and former 

Surgeon General of the United States. Dr. Richmond, a pediatrician and founding director of the Head 

Start Program, was also known for developing and implementing quantitative goals for public health, first 

published in 1979 as Healthy People: The Surgeon General’s Report on Health Promotion and Disease 

Prevention. During his tenure a Surgeon General’s Report entitled Smoking and Health was released, with 

a section on Involuntary Smoking, in which the harmful effects of SHS were described for the first time. 

FAMRI-supported peer-reviewed publications have resulted from research at the Richmond Center. 

Components of the Richmond Center follow the listing of publications. 


Best D, Tanski SE, McMillen RC, Klein JD. Smoke-free hospital grounds: Is it time? Poster. Pediatric 

P A G E 4 1

Academic Societies’ Meeting. Honolulu, Hawaii May 3-6, 2008. 

Cutler CB, Fryer GE, Jr, Miyoshi T, Weitzman M. Adult smoking as a risk factor for household food insecurity. 

Poster. Pediatric Academic Societies’ Meeting. Toronto, Canada, May 5-8, 2007. 

Friebely J, Sesselberg TS, Hipple B, Klein JD, Winickoff JP. Correlation of parental smokers health beliefs 

about the parent-child dyad and association with readiness to quit. Poster. Pediatric Academic Societies’ 

Meeting. Honolulu, Hawaii May 3-6, 2008. 

Gottlieb M, Alderman J. Reducing secondhand tobacco smoke exposure among children in public places. 

Presentation. National Conference on Tobacco OR Health. Minneapolis, MN, Oct 24-26, 2007. 

Iida H, Auinger P, Billings RJ, Weitzman M, MD. The association between infant breastfeeding and early 

childhood caries in the United States. Pediatrics 2007;120; e944-e952. 

Jenssen BP, Klein JD, Best D, Kamara S, Sesselberg T. Eliminating children’s exposure to tobacco and secondhand 

smoke: Evaluating dissemination of best practices. Poster Symposium. Pediatric Academic 

Societies’ Meeting. Honolulu, Hawaii May 3-6, 2008. 

Jenssen BP, Klein JD, Salazar LF, DiClemente RJ, Daluga NA. Pro-smoking media use by adolescents on 

the Internet: A Content Analysis. Poster. Pediatric Academic Societies’ Meeting. Honolulu, Hawaii May 

3-6, 2008. 

King K, Herman M, Martynenko M, Fryer GE, Jr, Weitzman M. Utilization of health care by children 

with asthma living with smokers. Poster. Pediatric Academic Societies’ Meeting, Honolulu. Hawaii May 

3-6, 2008. 

King K, Martynenko M, Herman M, Fryer GE, Jr, Weitzman M. Who exposes children to secondhand 

smoke in their homes? Poster. Pediatric Academic Societies’ Meeting. Honolulu, Hawaii May 3-6, 2008. 

Klein JD, Graff Havens C. Comparing telephone and online survey reliability. Platform presentation. 

Pediatric Academic Societies’ Meeting. Honolulu, Hawaii May 3-6, 2008. 

Klein JD, McMillen RC, Winickoff JP. Are we asking the right questions about secondhand smoke? Poster. 


Klein JD, Thomas RK, Sutter EJ. History of childhood candy cigarette use is associated with tobacco 

smoking by adults. Prev Med 2007;45:26-30. 

Klein JD, Thomas RK, Sutter EJ. Self-reported smoking in online surveys: prevalence estimate validity and 

item format effects. Med Care 2007;45:691-695. 

Klein, JD. Milestones in the natural course of cigarette use onset in adolescents: The first puff may be the 

worst. Canadian Medical Association Journal 2006 Aug 1;175(3):262 (Commentary) 

Liu Y, Romanos E, Fryer GE, Jr, Miyoshi T, Weitzman M. Secondhand smoke exposure is associated with 

increased rates of childhood obesity. Platform presentation. Pediatric Academic Societies’ Meeting. 

Honolulu, Hawaii May 3-6, 2008. 

Gottlieb M, Klein J. Workshop Presentation. Children and tobacco control: preliminary research findings 

on legal and policy approaches to reduce the secondhand tobacco smoke expose of children. AAP 

Chapter Advocacy Summit. Williamsburg, VA, Nov, 2007. 

Gottlieb M, and Texas State Senator Ellis. Texas Lottery Commission should clear the air. Austin American 

Statesman Newspaper 12/22/07. (In support of requiring Texas lottery sales locations to prohibit 

smoking under the requirements of the Americans with Disabilities Act). 

McMillen RC, Tanski SE, Winickoff JP, Valentine N. Attitudes about smoking in the movies. Presentation. 

Legacy/AMA Alliance SmokeFree Movies event. Washington, DC, Feb 12, 2007. 

McMillen RC, Winickoff JP, Tanski SE, Klein JD, Weitzman M. Changes from 2000 to 2006 in U.S. 

Adult attitudes and practices regarding children’s exposure to secondhand smoke. Platform presentation. 

Pediatric Academic Societies’ Meeting. Toronto, Canada, May 5-8, 2007. 

Poole-Di Salvo E, Fryer GE, Jr, Miyoshi T, Weitzman M. Adult household smoking and child emotional 

and behavioral problems. Poster. Pediatric Academic Societies’ Meeting. Honolulu, Hawaii May 3-6, 

2008. 

Romanos E, Poole-Di Salvo E, Welch-Horan T, Fryer GE, Jr, Winickoff JP, Weitzman M. Parental perception 

of overall health status of children differs between homes with and without adult smokers. Poster. 


Tanski SE, McMillen RC, Winickoff JP, Sargent J. Increasing support for movie smoking restrictions from 

2004 - 2006 among a US sample of parents. Poster. Pediatric Academic Societies’ Meeting. Toronto, 

Canada, May 5-8, 2007. 

Welch-Horan TB, Poole-Di Salvo E, Romanos E, Fryer GE, Jr, Weitzman M. Health status of children 

with asthma in smoking vs. non-smoking households. Poster. Pediatric Academic Societies’ Meeting. 


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Winickoff JP, McMillen RC, Tanski SE, Best D, Klein JD. US parent attitudes about serum documentation 

of their children’s secondhand smoke exposure. Poster. Pediatric Academic Societies’ Meeting. Toronto, 

Canada, May 5-8, 2007. 

Winickoff JP, Tanski SE, McMillen RC, et al. A national survey of the acceptability of quitlines to help parents 

quit smoking. Pediatrics 2006;117: e695-e700. 

Winickoff JP, Tanski SE, McMillen RC, Klein JD, Weitzman M, Best D. Counseling and perceived control 

over no smoking policies in homes and cars. Platform. Pediatric Academic Societies’ Meeting. Toronto, 

Canada, May 5-8, 2007. 

Yin HS, Winickoff JP, Fryer GE, Jr, Miyoshi T, Weitzman M. Missed opportunities to protect children 

from secondhand smoke in their homes. Platform presentation. Pediatric Academic Societies’ Meeting, 

Toronto. Canada, May 5-8, 2007. 

DISSEMINATION OF BEST PRACTICES TO REDUCE SHS EXPOSURE OF CHILDREN: SMOKE-FREE 

HOMES/PEDIATRIC TOBACCO CHAMPIONS 

Dana Best, MD, MPH 

The overall goal of the Dissemination of Best Practices project is the dissemination of Smoke Free 

Champions training interventions and other educational activities to pediatric clinicians and their 

administrative staff. This training intervention is disseminated at state/regional/national conferences and 

in clinical practice settings. The objectives of the training intervention are to 1) educate pediatric clinicians 

on the harms of tobacco use and SHS exposure; 2) disseminate best practices and tools in parental 

smoking cessation counseling and SHS reduction that can be implemented in the pediatric practice setting 

and; 3) change clinical practice to improve counseling of families to reduce and eliminate tobacco use and 

SHS exposure. Subsequent to a Dissemination of Best Practices Project Planning meeting in 2006, a pilot 

study of Smoke Free Champions Training was conducted at three practices in Virginia, and a 

Dissemination of Best Practices to Promote Smoke Free Homes Conference took place on July 27, 2007 

in Richmond, VA. Fifteen AAP Chapter leaders participated in this session. The training and prework/collaborative 

learning was difficult to implement, leading to reassessment of strategies to engage 

pediatricians and AAP Chapters in commitments to implementation over time. Further training in 

conjunction with the AAP’s Future of Pediatrics conference was held in the winter of 2009. Several bestpractice 

resources for clinicians and researchers are now available on the Richmond Center and SmokeFree 

Homes Web sites (www.kidslivesmokefree.org), which provide comprehensive training for pediatric 

clinicians in brief, effective methods to reduce childrens SHS exposure through parental smoking cessation 

and harm reduction. 

Three Disseminating Best Practices/Smokefree Homes free online CME modules are also available on 

the Web. These were publicized through an AAP News article and a card stock advertisement in the 

February 2008 issue. A Disseminating Best Practices workshop in tobacco control was accepted for the 

2008 American Psychological Association (APA) meeting in Hawaii in May 2008, and also for the AAP 

National Conference and Exhibition in October, 2008. Dr. Best served as the visiting lecturer for two of 

the 2007 Visiting Lecture awardees, and is working with Dr. Kristen Anderson to help her prepare 

curriculum materials for use in pediatric residency training. Dr. Anderson will be presenting on the impact 

of her project and how the visiting lecture helped establish their tobacco curriculum to the Association of 

Pediatric Program Directors (APPD) in May, 2008. A follow up survey was conducted of participants in 

the 2005 EPA/FAMRI supported SmokeFree Homes/Tobacco Champions conference was conducted. An 

abstract based on this was accepted for the 2008 PAS meetings. The availability of anti-smoking materials 

was also publicized in the AAP On-Call and other venues; materials now also include a new CDC Office of 

Smoking and Health English/Spanish-language toolkit to help promote in-home protection against SHS 

in Hispanic/Latino populations. 

RAPID QUANTITATIVE ASSESSMENT OF SECOND HAND TOBACCO SMOKE EXPOSURE FOR USE IN CLINICAL 

PEDIATRIC SETTINGS (MEASUREMENT) 

Dana Best, MD, MPH 

The overall goal of the project is to develop and pilot a rapid in-office test for SHS exposure of children 

aged 0-6 years for use in the pediatric practice setting. The test will be designed to provide immediate 

feedback to parents regarding their child’s SHS exposure. This project also includes collaborative activities 

between the Richmond Center and the FAMRI-Bland Land Center at UCSF. Current project activities 

include 1) producing a manuscript summarizing ways to measure SHS exposure of children, including a 

complete review of studies reporting such measures; 2) conducting a study to address the feasibility, 

P A G E 4 3

acceptability, and usefulness of using cotinine or other nicotine metabolite tests in the pediatric care 

setting, and to validate the specificity and sensitivity of the NicAlert assay from Nymox Pharmaceutical 

Corporation. In project Year 1, an expert meeting was held to discuss and generate questions surrounding 

the following topics: potential uses for a test (office system change, patient level change, use in research), 

characteristics of the “perfect” test (type of results, range of results, which sample to measure, financial 

considerations), status of potential technologies, and validation approaches. The practice based feasibility 

study was presented at the Summer 2007 Pediatric Research in Office Settings Coordinators Meeting, and 

breakout groups discussed practical application of the questions identified at the experts’ meeting. A 

manuscript addressing measurement in all populations, with special attention to methods used with 

pediatric populations has been submitted to the Journal of Environmental Health. This will also be used to 

help inform the products of the collaboration between FAMRI Centers of Excellence (Johns Hopkins 

Center, Richmond Center, and FAMRI-Bland Lane Center at UCSF) on a consensus conference on 

measurement standards. Once a sufficiently accurate test is available or deveolped, a second study will be 

conducted in pediatric practice-based settings to assess validity and feasibility of its use. Collaboration with 

FAMRI and/or industry to inform clinicians of the test’s availablity will follow. 

RICHMOND CENTER CORE 

Jonathan D. Klein, MD, MPH 

The administrative core of the Richmond Center is directed by Jonathan Klein, MD, MPH. Jonathan 

Winickoff, MD, MPH is the Coordinator of Translational Research and Chair of the AAP Tobacco 

Consortium. Laura Murray, MPH, is the Program Manager and Helene LeRoux is the Senior Health 

Project Coordinator. The primary goal of the Richmond Center core is to optimize interactions and 

synergy between Richmond Center collaborators and maximize outcomes of center projects. The core will: 

1) promote collaborative efforts and coordinate meetings between investigators, the Richmond Center’s 

Scientific and Project Advisory Committees and the AAP Tobacco Consortium; 2) provide administrative, 

logistical, and technical support to Richmond Center investigators; 3) ensure timely and effective 

communication of the Richmond Center’s work with individuals and organizations important to the 

Center’s mission; and 4) support the development of programs to protect children from SHS exposure. 

Information about the Richmond Center’s programs can be found at www.aap.org/RichmondCenter. 

BUILDING THE FIELD: EDUCATION, WORKFORCE DEVELOPMENT AND CLINICAL PROJECT 

Jonathan D. Klein, MD, MPH 

The project is working to support research, clinical services and policies essential to protecting the 

nation’s children from SHS. The goal is to advance broad-based awareness, commitment, and skills within 

the pediatric community to support efforts to reduce children’s exposure to SHS exposure. The project 

aims are to: 1) stimulate development of anti-SHS scholars; 2) utilize the resources of the AAP in 

dissemination and educational initiatives; 3) stimulate future research efforts via small grant programs; and 

4) raise awareness and influence attitudes among pediatricians nationwide, contributing to clinical SHS 

service delivery in pediatric practice. These aims will be met by providing opportunities for small grant 

programs, fellowship programs, visiting lectureships and Community Access to Child Health (CATCH) 

grants. 

The call for 2007-2008 CATCH Implementation grants includes a call for projects that address SHS; 

these will be considered along with all CATCH application. Potentially, that two or more Julius B. 

Richmond CATCH grants will be awarded this fall and each year to projects that address eliminating 

children’s exposure to SHS. Year 2 applications are currently under review. For more information about 

CATCH, see: http://www.aap.org/catch. Richmond Center Practice Change Projects Several Julius B. 

Richmond Center projects address research into changing practice in clinical and community health 

settings. These include: Dissemination of Best Practices (community and clinical education); 

Legal/Regulatory (community public health systems interventions); CEASE (office systems change); 

Measurement (clinical tools to assess exposure); and Messaging (interactions between clinicians and 

smokers). 

CLINICAL EFFORT AGAINST SECOND HAND (TOBACCO) SMOKE (CEASE) PROJECT 

Jonathan P. Winickoff, MD, MPH 

The CEASE Module was developed to help child healthcare clinicians tailor their office setting to 

address parental tobacco use in a routine and effective manner. Implementation strategies employed by the 

CEASE Module demonstrate how to link parents who want to quit smoking with state or national 

4 4 P A G E

smoking cessation services through the use of a flexible set of materials. The CEASE Module guides child 

healthcare clinicians in each evidence-based step of addressing parental tobacco use. CEASE was developed 

under the leadership of Jonathan Winickoff, MD, at Harvard/MGH and is available to help other child 

healthcare clinicians adjust their office setting to address parental tobacco use in a routine and effective 

manner. Dr. Winickoff’s new 5-year $3.85 million dollar CEASE R01 proposal, Addressing Parental 

Smoking by Changing Pediatric Office Systems, a randomized controlled trial of effectiveness of 

counseling parents and changing systems is underway in the AAP Pediatric Research in Office Settings 

(PROS) practice-based research network. (www.ceasetobacco.org). While the CEASE research efforts are 

funded independently from the Center, FAMRI support also helps keep CEASE materials closely 

coordinated with the dissemination of best practices project, as the office change materials are key to 

implementation in the practice setting. FAMRI’s recent grant to develop an AAP PediaLink module, an 

online system to train pediatric offices in ways to address the problem of children’s exposure to SHS, will 

also support further intervention and evaluation of strategies to educate child health clinicians. 

LEGAL AND REGULATORY RESEARCH ON CHILDREN’S EXPOSURE TO SECOND HAND TOBACCO SMOKE 

Mark Gottlieb, JD 

The Legal and Regulatory Project goals are to research and analyze multiple settings involving exposure 

of children to SHS and to provide analyses of various strategies for community public health systems’ 

interventions to key decision makers at the local, state, federal, and institutional levels, including child 

health care clinicians, child care workers, and lawyers involved with children’s health issues. Findings will 

help inform development and implementation of protocols that will further reduce children’s exposure to 

SHS in these multiple settings. The project will develop at least three articles focused on exposure settings 

that examine and compare approaches to eliminating pediatric SHS exposure in order to help to create 

smoke-free public places to protect children. 

DOCUMENT, DATA, DATASET REPOSITORY, AND ANALYSIS 

Michael Weitzman, MD 

The project aims are: 1) to use large datasets to conduct and publish two to four peer-reviewed original 

papers per year on aspects of SHS exposure and its effects on children, rates of exposure, effectiveness of 

pediatric and education efforts to reduce exposure and effects, and, changes in public and clinical attitudes 

and behaviors; 2) to make resources of this project an integral part, wherever possible, of all Richmond 

Center activities by providing Web site links to national datasets containing data pertaining to SHS effects 

on children and interventions to reduce such exposure and effects and by providing statistical 

programming to facilitate analyses by other Richmond Center faculty, fellows and junior faculty working 

with Center faculty, and small grant recipients; 3) to identify, systematically synthesize and make available 

to the public on the Web site’s relevant articles from peer-reviewed journals published since the most 

recent Surgeon General’s report; and 4) to periodically publish and widely disseminate a comprehensive 

State of the Field review report concerning children’s SHS exposure. 

MESSAGES FOR MOTIVATION AND SUPPORT FOR BEHAVIORAL CHANGES IN PARENT SMOKING 

Susanne E. Tanski, MD 

The goal of the project is to conceptualize, develop, and pilot-test targeted, family-centered, theorydriven 

tobacco-related communication and adjunct strategies that have potential for preventing child 

exposure to SHS. This practice change research project will develop specific SHS exposure prevention 

messages to be delivered within the pediatric clinical setting that can change mediating attitudes among 

smoking families and lead to behavior changes such as reducing or deferring smoking, or enforcing an 

indoor smoking ban. Further, ways will be explored to examine for smokers to use nicotine replacement 

therapy (NRT) as a smoking reduction agent in order to reduce smoking when doing so would expose the 

child to SHS. This project will design a communication toolkit to teach pediatricians the most effective 

methods to influence smoking behaviors of parents. By bringing together a multidisciplinary team that 

includes behavioral scientists, marketing experts, and creative art professionals that can view the problem 

from new perspectives, an effective set of communications tools will be designed. The focus will be on two 

phases of the communication process: motivating parents to address SHS exposure and supporting parents 

to reduce such exposure. 

This project initially experienced difficulty in recruiting subjects using existing advertising modes of 

posters, letters and phone invitations for focus groups (with child care, food. and reimbursement). Based 

on the suggestion from the Richmond Center Scientific Advisory Committee, change of modalities to 

P A G E 4 5

utilize telephone conference call focus groups were implemented that has allowed successful recruitment of 

parent smokers. The project has completed several focus groups. With the success of this mode of focus 

group recruitment, the PI intends to use this format to interview a wider sample of subjects in other 

geographic locations without travel or time expenses usually associated with using other sites. A revision 

was submitted to their IRB to expand their recruitment to include print newspaper advertisements outside 

of existing clinical catchment area. To date, 16 former smoking women have been interviewed. Using their 

new modality, a greater variety of subjects will be attracted. This project is also designed to become an 

integral component of the Dissemination of Best Practices initiative. Message testing with existing CEASE 

materials will begin shortly with early focus group participants, as the phone script for live messages are 

developed and responses are captured. For the greatest convenience of their participants, selections of 

messages will be presented in a mailed packet, and have the packet opened during the phone interview 

using a protocol that has been successful in obesity messaging research. In addition, the pilot practices will 

be recruited, and the practitioners similarly invited to respond to the messages as they are developed. 

FAMRI-IELCAP COLLABORATIVE NETWORK, 2007 

Director: Claudia I. Henschke, PhD, MD 

The FAMRI-IELCAP Collaborative Network is a multi-disciplinary research and clinical program to 

enhance early detection and treatment of lung, cardiovascular, and sinus diseases related to SHS exposure. 

The approach encompasses a wide range of disciplines ranging from the use of CT for early detection of 

these diseases combined with advanced imaging processing, to laboratory development of key biomarkers. 


Lane ME, Yankelevitz DF, Henschke CI, Vazquez MF, Xiang Z, Kimmel M, Kramer A, Wadler S. 

Hierarchical cluster analysis of pulmonary fine needle aspirates reveals distinct subgroups of adenocarcinomas 

Presented at the 12th International Conference on Screening for Lung Cancer. Nara, Japan, April 

2005. 

Lane WE, Yankelevitz DF, Henschke CI, Vazquez MF, Xiang Z, Kimmel M, Kramer A, Wadler S. Patterns 

of gene expression in pulmonary fine needle aspirates (FNA) with diverse radiographic appearances 

Presented at the 11th International Conference on Screening for Lung Cancer. Rome, Italy, October 

2005. 


Pulmonary fine needle aspirates (FNA) with diverse radiographic appearances exhibit distinct patterns of 

gene expression. Proc Amer Assoc Cancer Res #876 2005. 

Lane ME, Yankelevitz DF, Henschke CI, Vazquez MF, Xiang Z, Kimmel M, Kramer A, Wadler S. Patterns 


exhibit distinct patterns of gene expression. Proc Amer Assoc Cancer Res 2004 45:5589. 

URINARY PGE-M: A NONINVASIVE BIOMARKER OF TOBACCO SMOKE-INDUCED PULMONARY INJURY 

Andrew Dannenberg, MD 

COPD is one of the leading causes of disability and death worldwide. Unfortunately, tobacco smokeinduced 

lung disease, including COPD, is frequently not recognized until severe damage has occurred. 

The goal is to develop a simple, noninvasive urinary test of pulmonary inflammation for individuals or 

populations exposed to tobacco smoke, including SHS. This approach may facilitate the early detection of 

disease and provide the foundation for pharmacological and behavioral strategies that alter the natural 

history of tobacco smoke-induced disease. The first specific aims of this project is to compare levels of an 

inflammatory biomarker in the urine among groups of individuals that vary in smoke exposure. Levels of 

the urinary metabolite will be correlated with severity of pulmonary disease as assessed by spiral computer 

tomography and pulmonary function tests. The second specific aim is to evaluate the effect of smoking 

reduction and/or cessation on levels of the urinary biomarker of inflammation. The PI hypothesizes that 

levels of the urinary marker will decrease in current smokers as they reduce and/or quit smoking and that 

it may be useful for personalized risk assessments, to increase motivation among smokers contemplating 

quitting and to reinforce the health benefits of reducing tobacco smoke exposure. The third specific aim is 

to determine whether the magnitude of elevation of the urinary biomarker of inflammation varies by 

genetic polymorphism status for a given level of tobacco smoke exposure. This information may provide 

new insights into the link between tobacco smoke, host susceptibility, and pulmonary inflammation. 

During the past year, an opportunity presented itself to evaluate the effects of SHS on levels of an 

4 6 P A G E

inflammatory biomarker in urine in a separate, but related investigation. Specific aims of this ancillary 

project are 1) to determine whether urinary biomarker concentrations are elevated in healthy never 

smokers actively exposed to SHS, compared to healthy never smokers who are currently not exposed to 

SHS; and 2) to correlate levels of the urinary biomarker with self-reported frequency and duration of SHS 

exposure. The PI hypothesizes that levels of the urinary biomarker of lung inflammation will be increased 

in individuals exposed to SHS and that this study, combined with the original FAMRI studies, will 

strengthen the rationale for public health education designed to reduce exposure in the workplace and 

provide a benchmark for determining the consequences of interventions designed to reduce SHS exposure. 

PULMONARY DISEASES FROM SECOND HAND TOBACCO SMOKE 

Claudia I. Henschke, PhD, MD 

Project 1 will determine the probability of specific respiratory diseases (lung cancer, emphysema, chronic 

bronchitis, bronchiectasis, focal pneumonia, mediastinal cancers) among individuals who are screened. This 

will include the way in which this probability relates to the indicators of risk and CT findings and 

quantitative lung health indices (e.g., age, SHS exposure, nodules, and other findings in the chest) in order 

to develop appropriate clinical, screening, and treatment programs. To this end, 5,000 people exposed to 

SHS will undergo low-dose CT screening of the chest and complete the background questionnaire over 5 

years. Contracts have been entered into with six existing IELCAP screening sites around the country and 

in Israel, with additional sites in the process of being trained for participation in the FAMRI-IELCAP 

Collaborative Network. At the Coordinating Center at Weill Cornell, each participant will also receive a 

pulmonary function test, and provide blood, urine, and buccal cells. Computer-aided tools for 

quantification of lung parenchymal health will also be developed and incorporated. This project also 

provides the CT findings and tissue specimens for the other projects and includes the Coordinating Center 

for the collaborative network. 

CARDIAC RISK FROM SECOND HAND TOBACCO SMOKE 

David F. Yankelevitz, MD 

Project 2 will assess the increased risk of cardiovascular disease (CVD) from SHS, independent of other 

risk factors. Using the coronary artery calcification score obtained from the CT scan and cardiovascular risk 

lipid profile obtained in Project 1, a comprehensive CVD risk assessment will be done for participants. For 

those found to have an elevated overall risk score CT angiography will be offered. This is a non-invasive 

scan that measures the overall amount of plaque formation (soft and hard) in the coronary arteries and will 

thus characterize the relationship between SHS and atherogenic effect on the coronary arteries, controlling 

for other risk indicators. The extent to which coronary calcification predicts overall plaque burden will be 

determined as well. 

EFFECT OF TOBACCO SMOKE ON THE HISTONE CODE 

Kotha Subbaramaiah, PhD 

The Center will support two pilot projects per year. This provides for flexibility to investigate important 

findings that emerge. The pilot project, Effect of Tobacco Smoke on the Histone Code directed by Dr. 

Kotha Subbaramaiah, will focus on defining the signal transduction pathway that is activated by tobacco 

smoke leading to changes in histone H3 phosphorylation and identifying the changes in target gene 

expression, e.g., cyclooxygenase-2, that are mediated by histone H3 phosphorylation. This will provide a 

platform for rational targeted interventions; recently a change in histones has been linked to tobaccorelated 

lung disease. 

RHINOLOGIC DISEASE FROM SECOND HAND TOBACCO SMOKE 

Michael Stewart, MD, MPH 

The project entitled, Rhinologic Disease from Second Hand Tobacco Smoke, obtains the relevant 

history, performs a thorough physical examination of the nasal cavity and nasopharynx, and for those with 

chronic rhinosinusitis (CRS), provides a CT scan of the paranasal sinuses and interpretation. 

P A G E 4 7

FAMRI-FUNDED RESEARCH 

COMBATING EFFECTS OF TOBACCO SMOKE 

ACUTE LUNG INJURY 

CURRENT RESEARCH 

IMPACT OF TOBACCO SMOKE EXPOSURE ON ACUTE LUNG INJURY 

Carolyn Calfee, MD; University of California, San Francisco; YCSA 2007 

The objective of this project is to study the relationship between cigarette smoke exposure and acute 

lung injury (ALI) in order to better understand the pathogenesis of ALI and expand knowledge of the 

health effects of active and passive smoke exposure. ALI is a common cause of respiratory failure in critically 

ill patients, affecting almost 200,000 patients per year in the United States alone, and has a mortality of 

30-40%. No prospective clinical studies have examined the association between active and passive smoke 

exposure and ALI. Under investigation is the relationship between active and passive smoke exposure and 

ALI in two large cohorts: one cohort of severely injured trauma patients at a county hospital, and one 

cohort of medical and surgical intensive care unit (ICU) patients at a large tertiary care center. To date, 

250 patients have been enrolled in the trauma cohort, and over 700 patients have been enrolled in the 

mixed ICU cohort; measurements of biomarkers reflecting active and passive smoking are in progress. In 

addition, investigation into the mechanistic relationship between cigarette smoke exposure and ALI by 

measuring biomarkers of endothelial injury, lung epithelial injury, and disordered coagulation in patients 

enrolled in these cohorts is being performed. These analyses will provide important insights into the mechanisms 

by which smoke exposure promotes ALI, knowledge that will help design future preventative or 

therapeutic strategies for this frequently fatal syndrome. 


Briot R, Frank JA, Uchida T, Lee JW, Calfee CS, Matthay MA. Elevated levels of RAGE, a marker of alveolar 

epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human 

lungs. Chest 2009;135:269-275. 

Calfee CS, Eisner MD, Parsons PE, Thompson BT, Matthay MA, Ware LB. Soluble intercellular adhesion 

molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med 2009;35:248- 

257. 

Calfee CS, Ware LB, Eisner MD, Parsons PE, Thompson BT, Wickersham N, Calfee CS, Ware LB. 

Biomarkers of lung injury in primary graft dysfunction following lung transplantation. Biomark Med 

2007;1:285-291. 

Collard HR, Calfee CS, Song JW, Brady S, Ishizaka A, Wolters PJ, King TE Jr, Matthay MA, Kim 

DS. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Presented at 

the American Thoracic Society International Conference. Toronto, ON, May 2008. 

Fremont RD, Koyama T, Calfee CS, Wu W, Dossett LA, Bossert FR, Mitchell D, Wickersham N, Bernard 

GR, Matthay MA, May AK, Ware LB. Acute lung injury in patients with traumatic injuries using a panel 

of biomarkers for diagnosis and pathogenesis. Presented at the American Thoracic Society International 

Conference. Toronto, ON, May, 2008. 

Matthay MA, Calfee CS. Aerosolized beta-adrenergic agonist therapy reduces pulmonary edema following 

lung surgery. Chest 2008;133:833-835. 

Matthay MA. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung 

injury. Thorax 2008;63:1083-1089. 

AIRWAY DISEASES 


COMPARATIVE STUDIES OF HUMAN BUCCAL CELLS OF SMOKERS AND NON-SMOKERS 

John L. Pauly, PhD; Roswell Park Cancer Institute; CIA 2002, 2005 

A comprehensive review of the literature that addresses changes in human buccal cells (HBC) that are 

associated with the use of smoking and smokeless tobacco has been completed, and clinicopathological 

studies that have correlated HBC changes with oral cancer. Studies have been undertaken to identify a 

high-throughput technology that would advance efforts to use HBC as biomarkers of tobacco exposure 

4 8 P A G E

and as surrogate biomarkers of tobacco-associated oral disease. A recent publication has reported that: 1) a 

relatively large (mean ± S.D., 2.1 ± 1.4 x 105 cells) population of HBC can be collected in a noninvasive 

manner with a tooth brush and purified ( > 98% HBC; N = 138 samples of the oral mucosa; N = 69 

donors); 2) despite their large size (diameter, ~ 65 m), the HBC were analyzed successfully with a single 

laser cytometer (FACScanÔ) and an advanced multispectral cytometer (FACSAriaÔ), having three lasers 

and nine distinct emission channels; 3) cytometry revealed that the buccal cells expressed a high level of 

autofluorescence that was displayed over a broad spectrum; 4) autofluorescence of HBC collected from the 

left and right cheek was consistent, illustrating the reproducibility of the sample collection and assay procedure; 

5) HBC autofluorescence differed significantly among 69 adult subjects; and 6) a statistical difference 

(p = 0.018) between current, former, and never smokers was seen. This research is thought to be the 

first to show the application of flow cytometry for assaying HBC. It identifies buccal cell autofluorescence 

as a candidate biomarker of tobacco smoking. 


Allison EM, Paszkiewicz GM, Timm E, Podniesinski E, Wallace PK, Pauly JL. Phenotypic analysis of surface 

membrane antigens of fluorescent human lung macrophages (‘smoker cells’) from surgically excised 

lung tissues of patients with lung cancer. Presented at the Annual FAMRI Meeting. Miami, FL, May 12- 

14, 2004. 

Pauly JL, Allison EM, Hurley EL, Nwogu CE, Wallace PK, Paszkiewicz GM. Fluorescent human lung 

macrophages analyzed by spectral confocal laser scanning microscopy and multispectral cytometry. 

Microsc Res Tech 2005;67:79-89. 

Proia NK, Paszkiewicz GM, Nasca MA, Franke GE, Pauly JL. Smoking and smokeless tobacco-associated 

human buccal cell mutations and their association with oral cancer—a review. Cancer Epidemiol 

Biomarkers Prev 2006;15:1061-77. 

EFFECT OF SIDE-STREAM CIGARETTE SMOKE ON LUNG ENDOTHELIAL ANGIOGENESIS INDUCED BY EPIDERMAL 

GROWTH FACTOR 

Yunchao Su, MD, PhD; Medical College of Georgia; CIA 2004 

Dr. Su’s hypothesis states that sidestream cigarette smoke extract inhibits epidermal growth factor 

(EGF)’s angiogenic effect and that this inhibition is caused by decreased calpain (a calcium activated protease) 

activity involving actin cytoskeleton reorganization. The research aims are: 1) identifying the effect 

of side-stream cigarette smoke extract on EGF’s angiogenic effect; 2) determining whether the effect of 

sidestream cigarette smoke extract on EGF’s angiogenic effect is due to calpain inhibition; and 3) determining 

whether the effect of sidestream cigarette smoke extract on EGF’s angiogenic effect involves calpain-mediated 

alteration in the actin cytoskeleton. Proof of the role of calpain in sidestream cigarette 

smoke extract-induced inhibition of EGF’s angiogenic effect will provide a strong rationale for manipulating 

calpain in the treatment of disorders caused by tobacco smoke exposure, such as emphysema and pulmonary 

hypertension. 


Cui Z, Han Z, Li Z, Hu H, Patel JM, Antony V, Block ER, Su Y. Involvement of calpain-calpastatin in cigarette 

smoke-induced inhibition of lung endothelial NOS. Am J Respir Cell Mol Biol 2005;33:513-520. 

Kondrikov D, Han HR, Block ER, Su Y. Growth and density-dependent regulation of NO synthase by the 

actin cytoskeleton in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 

2006;290:L41-L50. 

Su Y, Kondrikov D, Block ER. Cytoskeletal regulation of nitric oxide synthase. Cell Biochem Biophys 

2005;43:439-449. 

SIDESTREAM TOBACCO SMOKE AND NITRIC OXIDE MODIFICATION OF CALPAINS IN AIRWAY EPITHELIAL 

REPAIR 

Yunchao Su, MD, PhD; Medical College of Georgia; CIA 2008 

Sidestream smoke (STS) otherwise known as SHS is a major risk factors in COPD. Compromised lung 

epithelial repair is implicated in the pathogenesis of human lung diseases such as bronchiolitis, emphysema, 

asthma, and pulmonary fibrosis. In these conditions, lung cells, including airway epithelial cells, are 

exposed to varying amounts of nitric oxide (NO) that is exogenous, i.e., from STS and/or endogenous, 

i.e., secondary to induction of inducible nitric oxide synthase (iNOS) in tobacco smoke-activated alveolar 

macrophage. Calpains are a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases that 

P A G E 4 9

act via limited proteolysis of substrate proteins in mammalian cells, including airway epithelial cells. The 

objective of this project is to study the novel hypothesis that calpains mediate airway epithelial repair and 

that calpains inhibition is responsible for SHS–NO-induced impairment of airway epithelial repair. 

To test this hypothesis, first, it will be confirmed that calpains mediate airway epithelial repair. It will 

then be examined whether STS–NO causes calpain nitrosylation leading to calpain inhibition and whether 

STS–NO inhibits airway epithelial repair via NO-induced inhibition of calpains. Cultured bronchial epithelial 

cells and a smoking animal model will be used. Calpain activity changes in the bronchial epithelial 

repair processes will be measured and it will be evaluated whether inhibition of calpain by specific calpain 

inhibitor calpeptin, small interfering RNA (siRNA), and gene transfer technology affects bronchial epithelial 

repair. Calpain nitrosylation will be determined in purified calpain proteins and cultured bronchial 

epithelial cells exposed to STS or NO and bronchial epithelium of mice exposed to STS. It will be 

observed whether NO scavenger and overexpression of calpains prevent the inhibitory effects of STS-NO 

on bronchial epithelial repair. Proof of the role of calpain in STS-NO-induced alteration of airway epithelial 

repair may provide a strong rationale for manipulating calpain activities in the treatment of smokingrelated 

diseases such as bronchiolitis, emphysema, asthma, and pulmonary fibrosis. 

PROTEIN FINGERPRINT OF AIRWAY INFLAMMATION INDUCED BY VIRAL INFECTION AND SECOND HAND 

TOBACCO SMOKE EXPOSURE 

Roberto P. Garofalo, MD; University of Texas Medical Branch at Galveston; CIA 2005 

Dr. Garofalo’s hypothesis is that exposure to SHS exacerbates airway disease by enhancing or modifying 

the pattern of production of cytokines and other immunomodulatory and/or inflammatory protein mediators 

triggered by viral infection. To test this hypothesis, nasopharyngeal secretions are being obtained from 

infants during the acute phase of antigen/culture-positive respiratory syncytial virus (RSV) infection of different 

clinical severities. The specific aims are: 1) to examine the profile of mucosal cytokines in infants 

with RSV infection and determine whether pattern of expression and/or abundance is affected by exposure 

to SHS; and 2) to analyze whether distinct protein patterns at the airway mucosal site can discriminate 

among infants with different severities of the RSV illness or exposure to SHS. 

PAI-1 AND AIRWAY REMODELING IN SECOND HAND TOBACCO SMOKE EXPOSURE 

Steven Idell, MD, PhD; University of Texas Health Center at Tyler; CIA 2005 

Dr. Idell is determining the role of derangements of the blood clot dissolution system in the progression 

of airway injury produced by SHS exposure. The research hypothesis is that SHS induces excessive plasminogen 

activator inhibitor 1 (PAI-1) expression by airway epithelial cells to promote pathophysiologic airway 

remodeling typical of COPD. The research aims are as follows: 1) to determine the effects of SHS on 

PAI-1 expression by airway epithelial cells and determine mechanisms by which expression is altered in vitro; 

2) to determine the effects of SHS on PAI-1-dependent pathophysiologic responses relevant to epithelial 

injury and repair; and 3) to determine the role of PAI-1 in SHS-induced airway remodeling in vivo. 

SECOND HAND CIGARETTE SMOKE AND IMMUNITY TO TUBERCULOSIS 

Homayoun Shams, DVM, PhD; University of Texas Health Center at Tyler; CIA 2006 

Smoking has clearly been shown to predispose patients to pulmonary infectious diseases. However, little 

is known about the relationship of SHS exposure to susceptibility to tuberculosis, which claims two million 

deaths annually worldwide, and is one of the leading causes of death from a single infectious agent. The 

growing population of human immunodeficiency virus (HIV)-infected persons with enhanced susceptibility 

to tuberculosis and the dramatic emergence of multidrug-resistant tuberculosis are clear indications that 

tuberculosis will remain a major health problem for decades to come. Protective immunity against tuberculosis 

is mediated by macrophages and T-lymphocytes. T-lymphocytes lyse Mycobacterium tuberculosis-infected 

cells and produce IFN gamma, which activates macrophages to kill intracellular M. tuberculosis. The 

main focus of this research is to evaluate the effect of exposure to SHS on susceptibility to pulmonary 

tuberculosis. Dr. Shams and colleagues are currently assessing the effect of SHS on in vivo growth of M. 

tuberculosis. They will determine the effect of SHS on T cell function, including production of 

IFN gamma and cytolytic T cell activity against macrophages pulsed with mycobacterial antigens. They 

will also determine the mechanisms by which SHS reduces IFN gamma production, affects the capacity of 

macrophages to process and present antigens, and alters the development of memory T cells. These studies 

will yield new and essential insights into the mechanisms through which SHS contributes to enhanced susceptibility 

to tuberculosis. These findings can also be extrapolated to design new approaches to protect 

patients exposed to SHS against the morbidity of pulmonary tuberculosis. 

5 0 P A G E

SECOND HAND TOBACCO SMOKE EXACERBATES ALLERGIC ASTHMA 

Julie A. Wilder, PhD; Lovelace Respiratory Research Institute; CIA 2006 

Exposure to SHS heightens the development and severity of allergic asthma in young children, particularly 

those of smoking mothers. Dr. Wilder and colleagues have been studying the effects of SHS exposure 

on the development of allergic asthma in mice. The team has previously shown that chronic exposure to 

SHS increased the sensitivity of the muscles surrounding the airways in the lung, making it much more 

likely that the airway would constrict upon inhalation of an allergen. They have also discovered that chronic 

SHS exposure of young adult mice heightens the ability of allergen-specific immune cells to come into 

the lung in response to inhaled allergen, such that there are more cells in the lung than if the mice were 

exposed to allergen alone. Interestingly, SHS also initially inhibited the movement of allergen-specific cells 

to the lung, presumably due to the nicotine contained in the smoke, which is known to inhibit the 

immune response. Most recently, the team has discovered that inhaled nicotine in combination with allergen 

does not mimic the effects of SHS. That is, inhaled nicotine does not inhibit cell infiltration of the 

lung when provided to the mice in combination with the allergen, nor does it heighten the cellular infiltration 

to allergen as SHS does. Indeed, after 2 weeks of exposure to nicotine in combination with allergen, 

the number of cells infiltrating the lung is even greater than after allergen exposure alone. It remains the 

goal of these studies to better understand the ways in which SHS heightens, while initially inhibiting, allergic 

asthmatic inflammation. Dr. Wilder and colleagues continue to compare the activation status of the 

lung cells after exposure to allergen only, allergen and SHS, and allergen and nicotine. They are examining 

which proteins the lung cells are secreting that might direct other cells to migrate to the lung. The knowledge 

gained can aid in the future design of targeted drugs that are capable of inhibiting lung inflammation 

or hastening its resolution. 

THE IMPACT OF SECOND HAND TOBACCO SMOKE ON T CELL IMMUNE RESPONSE: IMPLICATIONS FOR UPPER 

AND LOWER AIRWAYS DISEASE 

Stephen M. Canfield, MD, PhD; Columbia University; CIA 2006 

Analysis of the 501-child cohort has continued over the past year. Total immunoglobulin E (IgE) as well 

as specific IgE to dust mite, cockroach, mouse, and cat have been assayed in serum samples obtained from 

all study participants, age four. From these analyses, the investigators have identified striking associations 

between parents’ and children’s IgE levels. Total IgE levels among children correlate well with levels in 

both mother and father, and this correlation is strengthened among children living in a home with at least 

one smoker. Inclusion of SHS in a linear regression model relating parental and child total IgE strengthened 

the correlations with a magnitude of effect similar to inclusion of national origin. Inclusion of SHS 

exposure and national origin simultaneously produced an additive effect. These results, currently in press at 

the Journal of Allergy and Clinical Immunology, show an exacerbating influence of SHS on the allergic susceptibility 

of the children. Over the past year, an additional 130 children have been recruited from among 

the original 501 participants in the above serum study. In this group, the influence of home SHS exposure 

on atopic predisposition by directly examining cluster of differentiation 4 (CD4) + T cell reactivity to 

tetanus toxoid (a typical TH1-response antigen) as well as to dust mite, mouse, and cat (common TH2- 

response antigens) is being pursued. This arm of the study is examining both proliferative response and 

cytokine profile among responding CD4 + T cells. These data will provide insight into the mechanism of 

the SHS effect on allergic susceptibility. 

FETAL-POSTNATAL SMOKE EXPOSURE: RESPONSE TO RSV INFECTION 

Edward G. Barrett, PhD; Lovelace Respiratory Research Institute; CIA 2007 

Respiratory syncytial virus (RSV) infects ~90% of young children by the age of 2. Exposure to SHS has 

been identified as a major risk factor that increases the incidences and severity of respiratory infections. 

Nicotine (nic), a major component of SHS, is known to have a significant effect on immune function. It is 

hypothesized that it is the nic component of SHS that is responsible for altering the immune response following 

RSV infection in a neonatal model. BALB/c mice were exposed to air or 150 ug/m 3 of nic from 

day 1 up to 34 days of age for 6hours/day, 7days/week. Mice were infected with vehicle or RSV by nasal 

instillation on day 7 (6x105 pfu) and rechallenged at 28 days of age (2x106 pfu). A subset of mice was 

infected with influenza (IFZ; 7x104 pfu). Immune responses were assessed 2-, 4- and 6-days post 28-day 

infection (PI). Nic exposed- and RSV-infected mice (Nic:RSV) had higher levels of eosinophils at 2 days 

and 4 days PI, although not significant, compared to mice exposed to air and infected with RSV 

(Air:RSV). Nic:RSV mice had significantly higher levels of bronchoalveolar lavage (BAL) TNF- at 2 days 

PI compared to Air:RSV (p

was significantly higher in Nic:RSV mice (p

TOBACCO SMOKE AND OXIDATIVE STRESS IN RSV BRONCHIOLITIS 

Antonella Casola, MD; University of Texas Medical Branch at Galveston; CIA 2008 

The World Health Organization (WHO) estimated that in 1998 about 3.5 million deaths occurred 

worldwide from acute lower respiratory tract infections (LRTI), of which 55% were children under the age 

of five. Bronchiolitis, a major clinical syndrome in hospitalized infants, accounts for up to 60% of all LRTI 

during the first year of life and is primarily caused by respiratory syncytial virus (RSV) infections. Exposure 

to SHS occurs in up to 60% of the infants with RSV bronchiolitis in the United States, and different studies 

have suggested that SHS is a risk factor for the development of severe RSV infection. Oxidative stress 

response in the airways plays a major role in the pathogenesis of severe RSV LRTI, particularly if the 

process is enhanced by the exposure to pro-oxidative toxicants such as tobacco smoke. 

Dr. Casola recently discovered that RSV potently inhibits the expression of antioxidant genes in epithelial 

cells, including glutathione S-transferases (GSTs), major cytosolic enzymes involved in the detoxification 

pathways of polycyclic aromatic hydrocarbons. There is also evidence that nuclear NF-E2 related factor 

3 (Nrf-3), which negatively regulates antioxidant gene expression, is strongly induced by RSV infection 

in epithelial cells, while level of Nrf2, which positively regulates expression of antioxidant genes, is largely 

unaffected by infection. Moreover, exposure of epithelial cells to cigarette smoke condensate (CSC) in 

combination with RSV infection synergistically increases oxidative stress responses and generation of reactive 

oxygen species (ROS). 

It is hypothesized that combination of SHS-induced ROS production and virus-mediated inhibition of 

antioxidant enzymes leads to severe manifestations of bronchiolitis. Moreover, it is hypothesized that the 

effect of SHS on severity of RSV infection is linked to certain GST genotypes, such as the GST M1 null 

genotype, which are associated with a complete lack of the enzyme. 

In Aim 1, nasopharyngeal secretions (NPS) will be obtained from infants during the acute phase of naturally 

acquired RSV infection. GST genotypes will be performed from NPS cell DNA. NPS samples will be 

tested for a panel of oxidative stress markers. As objective assessment of exposure to SHS, levels of cotinine 

will be measured in urine of RSV infected infants. Aim 2 will focus on in vitro studies of human epithelial 

cells to dissect the role of Nrf3 in inhibition of antioxidant gene expression in response to RSV in combination 

with CSC and to determine whether antioxidant treatment ameliorates RSV and CSC-induced 

oxidative stress by increasing Nrf2 activation and antioxidant gene expression. 

The outcome of these studies will lead to the identification of novel antioxidative pharmacologic interventions 

to treat viral respiratory infections that are caused or exacerbated by tobacco smoke. 

TOBACCO ALDEHYDES AND ALLERGIC AIRWAY INFLAMMATION 

Albert van der Vliet, PhD; University of Vermont; CIA 2008 

Acrolein (2,3-propenal) is one of the major reactive components of cigarette smoke (CS), and has been 

recognized as an important air pollutant that can exacerbate asthma and may be one of the factors that 

links SHS exposure to exacerbation of allergic disease and asthma in children. Animal studies have shown 

that SHS exposure can promote exaggerated Th2-type immune responses leading to enhanced allergic 

responses to common inhaled antigens, but the mechanisms are not completely understood. In their recent 

studies, in which mice were exposed to relevant concentrations of acrolein, they demonstrated attenuation 

of Th1 cytokine production during airway inflammation, primarily IL-12 and interferon-gamma (IFN- ). 

Because these cytokines suppress Th2 responses that are prominent in allergic diseases such as asthma, the 

results suggest that acrolein may be an important factor in CS-mediated immune responses. Accordingly, 

preliminary data indicate that acrolein inhalation enhances airways eosinophilia and Th2 cytokine production 

in a mouse model of allergic airway inflammation. 

Therefore, it is proposed that acrolein is a major responsible factor that links SHS exposure to alterations 

in immune responses in favor of Th2 responses, and thereby enhances allergic responses to common allergens 

and contributes to asthma exacerbations. Oxidative stress is widely regarded as a central mechanism 

by which CS exposure affects biological systems. Indeed, changes in cellular glutathione (GSH) levels or 

redox status are known to have important consequences for regulation of Th1 and Th2 immune response 

patterns, due to alterations in inflammatory signaling pathways, including nuclear factor kappaB (NF B) 

and c-Jun-N-terminal kinase (JNK). Because acrolein is among the main reactive CS components that 

deplete GSH and critical redox-sensitive proteins such as thioredoxin reductase (TrxR), it is proposed that 

acrolein-induced changes in cellular redox signaling affect NF B and JNK-mediated pathways and result 

in altered Th1/Th2 cytokine responses. The specific aims of this proposal are 1) to evaluate the impact of 

acrolein inhalation on allergen sensitization and inflammatory responses to allergen challenge in mice; 2) 

to determine the signaling mechanisms by which acrolein affects Th1/Th2 cytokine production by antigen 

P A G E 5 3

presenting cells (APC) in vitro; and 3) to evaluate the importance of acrolein-induced modification of 

TrxR, a major cellular target for acrolein and a critical regulator of NF B and JNK signaling, on redox 

regulation of Th1/Th2 responses. These studies will highlight the central role of acrolein as a main contributor 

to CS-related diseases such as allergic asthma, and may offer new opportunities for therapeutic 

strategies to manage allergic airway diseases. 

SECOND HAND TOBACCO SMOKE EXPOSURE AND SUSCEPTIBILITY TO RESPIRATORY VIRAL INFECTION 

Adriana Elisa Kajon, PhD; Lovelace Respiratory Research Institute; CIA 2008 

Cigarette smoking is a well-recognized risk factor for viral respiratory infection. Data generated by a 

diversity of epidemiological studies have documented the association between smoking and increased risk 

of respiratory infection. It is estimated that children exposed to SHS have increased respiratory tract infections, 

resulting in up to 15,000 hospitalizations each year. The specific mechanisms by which cigarette 

smoking increases the risk of respiratory infections are not completely understood and likely to be multifactorial, 

interactive in their effects, and include both structural and immunological components. 

Identifying the mechanisms responsible for increased susceptibility to respiratory infection by SHS exposure 

will allow for the development of intervention, thus, reducing the burden of respiratory disease. This 

project will investigate the mechanisms by which SHS increases viral infectivity in lung epithelial cells using 

two prevalent human respiratory viruses as models: rhinovirus and adenovirus. It is hypothesized that SHS 

exposure increases the infectivity of respiratory viruses by increasing the availability of receptor molecules 

and facilitating cell entry. The general hypothesis is tested by pursuing the following three specific aims: 1) 

to determine the effect of SHS exposure on airway epithelial cell permeability and virus receptor abundance 

and availability; 2) to determine the effect of SHS exposure on respiratory virus infectivity of airway 

epithelial cells in vitro; and 3) to determine the effects of SHS exposure on the proinflammatory response 

to viral infection. 

The accomplishment of the aims will help clarify important aspects of the interplay between viral infection 

and SHS exposure, leading to human respiratory disease. 

AIR FILTRATION SYSTEMS, SECOND HAND TOBACCO SMOKE AND RESPIRATORY DISEASE 

Chris A. Pritsos, PhD; University of Nevada, Reno; CIA 2008 

SHS is a major indoor air pollutant. It is estimated that between 35,000 and 62,000 Americans die each 

year due to SHS exposure primarily from cardiovascular disease and cancer. SHS is also responsible for 

many respiratory diseases caused by inflammation including asthma, bronchitis, pneumonia, and ottitis 

media. Despite these health effects, most states have not passed comprehensive smoke-free workplace laws. 

Only 22 states to date have comprehensive laws that include restaurants and bars. Even in these 22 states, 

casinos or other similar gambling institutions obtain exemptions from these laws. These exemptions are 

generally made due to economic concerns and the suggestion that ventilation systems are capable of minimizing 

this exposure. The CDC on the other hand says that no level of SHS is safe and American Society 

of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE) states that smoking bans are the 

only current means of eliminating health risks from SHS. To date, no comprehensive studies have looked 

at the impact of ventilation systems on SHS-induced health effects. 

It is proposed to study whether standard air filtration systems used by businesses, charcoal and or high 

efficiency particulate air (HEPA) filters, can reduce the health effects from SHS exposure. Using SHS generated 

from a smoking machine as a surrogate for SHS, BALB/c mice will be exposed for 6 hours/day, 3 

days a week for 8 weeks. Five groups of animals will be used in these studies. Group 1 will be a control 

group with no SHS exposure. Group 2 will receive a full dose of the SHS exposure. Groups 3, 4, and 5 

will receive the full dose of SHS, which has passed through one of the air filtration systems (charcoal, 

HEPA or both). Following SHS exposure, biomarkers of inflammation and oxidative stress will be determined 

in various tissues from these animals. Inflammatory cell infiltration of the lung will be assessed in 

bronchoalveolar lavage (BAL) and digested lung tissue by flow cytometry. Cytokines, chemokines, and 

growth factors will also be measured using the specialized Luminex flow cytometer from BAL. Biomarkers 

of oxidative stress, including superoxide dismutase, glutathione peroxidase, lipid peroxidation, total antioxidant 

capacity, and DNA damage will be assessed in heart, liver, and lung tissues from these same animals. 

Students T-test and analysis of variance (ANOVA) will be used for comparison between the various groups. 

These studies will provide the first data that address whether standard air ventilation systems are capable of 

reducing the health effects associated with SHS exposure. 

5 4 P A G E

EFFECTS OF CIGARETTE SMOKE ON AIRWAY EPITHELIAL BARRIER FUNCTION 

Venkataramana Sidhaye, MD; The Johns Hopkins University; YCSA 2008 

Cigarette smoking is the main cause of COPD but the biologic mechanisms behind its effects remain 

unclear. The respiratory epithelium serves as a barrier that regulates airway physiology. As the interface 

with the outside, the airway epithelium serves as the first barrier and defense to potentially harmful inhaled 

materials such as cigarette smoke. 

Dr. Sidhaye has exciting novel data suggesting that changes in the aquaporin-5 expression, an apical 

water channel that is known to be the primary determinant of transmembrane water permeability, seems to 

regulate paracellular permeability in response to physiologic stresses such as shear stress. Alterations in 

epithelial permeability have been linked to the pathogenesis of reactive airway disease with increased 

subepithelial exposure to luminal allergens. The addition of cigarette smoke to the inspired airstream 

increases epithelial permeability and a disruption of the protective mechanisms created by shear stress. 

Preliminary studies indicate that cigarette smoke extract leads to disruption of the shear-induced epithelial 

paracellular permeability. Human small nucleotide polymorphisms (SNPs) in AQP5 have been identified to 

cause further susceptibility to reactive airways and COPD. Specifically, an identified SNP in the exon 4 of 

AQP5 was studied, which results in a nonsynonymous amino acid change from an Asn to Lys, and using 

site-directed mutagenesis at amino acid 228 with degenerate primers, this SNP was created in human- 

AQP5 plasmid. 

HBE-16 (a human bronchial epithelial cell line) was transiently transfected with either the wild-type 

AQP5 plasmid or SNP expressing plasmid and AQP5 abundance and localization was assessed by 

immunoblots and confocal immunofluorescence under control and stimulated conditions, such as shear 

stress and treatment with cigarette smoke extract (CSE 10%). Under control conditions, there was similar 

abundance and membrane localization in both cells transfected with the wild-type AQP5 plasmid and 

N228K AQP5 plasmid. Shear stress leads to a decrease in AQP5 abundance after 2 hours; however, similar 

changes in AQP5 were not noted in cells transfected with N228K AQP5 with no change in abundance 

after shear stress. CSE leads to decreased AQP5 abundance in 8 hours, and again there was no change in 

the N228K AQP5 plasmid abundance. Localization in response to these stimuli was not altered in 

response to either shear stress or CSE. In HBE16 cells, the N228K AQP5 resulting from an identified 

SNP altered AQP5 abundance in response to physiologic stimuli such as shear stress as well as pathologic 

stimuli such as cigarette smoke extract. It is believed that these studies will generate novel data regarding 

the effects of cigarette smoke on altered airway epithelial cell barrier function and provide insight into the 

pathogenesis of airway reactivity and chronic bronchitis due to cigarette smoke exposure. 

THE EFFECTS OF SECOND HAND TOBACCO SMOKE ON CYSTIC FIBROSIS 

Garry R. Cutting, MD; The Johns Hopkins University; CIA 2008 

SHS has many deleterious effects on health which are more severe or accelerated in people with chronic 

diseases, particularly people with lung diseases. Cystic fibrosis (CF) is a fatal genetic disorder that affects 

thousands of people in the United States, which primarily targets the lungs, sinuses, pancreas, liver, reproductive 

system, and overall growth. In a 2008 paper in the Journal of the American Medical Association 

(JAMA), it was demonstrated that people with CF who are exposed to any SHS in the home have worse 

lung function than people who were not exposed. In addition it is observed that certain genetic variants of 

an inflammatory gene (TGF beta1) can drastically accelerate the decline in lung function from SHS. 

Demonstration that genetically defined subsets of patients with CF exposed to SHS in the home have a 

substantial lifetime reduction in lung function provides potent justification for eradication of SHS exposure 

for all individuals with this life-limiting disorder. 

Currently, the research is focusing on examining the effect of SHS on lung function compared to other 

environmental modifiers of CF lung disease, such as air pollution, climate, access to healthcare, and socioeconomic 

status. Preliminary analyses suggest that SHS remains one of the most detrimental factors to 

affect lung function. They are also examining whether certain environmental conditions act with SHS in a 

multiplicative fashion to worsen lung disease. Finally, genetic data for study population have been collected 

and in the process of conducting genome-wide analyses to look for genetic variants that may ameliorate or 

worsen the effects of SHS. Preliminary analyses suggest gene-SHS interactions exist. Knowledge of these 

interactions may enable the prediction of which individuals (with or without CF) may be more susceptible 

to the effects of SHS. 

P A G E 5 5


Collaco JM, Vanscoy L, Bremer L, McDougal K, Blackman SM, Bowers A, Naughton K, Jennings J, Ellen 

J, Cutting GR. Interactions between secondhand smoke and genes that affect cystic fibrosis lung disease. 

JAMA 2008;299:417-424. 

AIRWAY DISEASES 

Completed Research 

SMOKE AND SUSCEPTIBILTIY TO RESPIRATORY INFECTION 

Lester Kobzik, MD; Harvard University; CIA, 2002 

Dr. Kobzik investigated whether cigarette smoke downregulates levels of class A receptors, such as 

macrophage receptor with collagenous structure (MARCO), mediators of initial binding of unopsonized 

bacteria and environmental particles, on human alveolar macrophages. He also determined if cigarette 

smoke-mediated decreased expression of MARCO resulted in a decreased ability to bind and kill bacteria 

and if the effect of cigarette smoke particulates on MARCO levels is mediated by oxidant-mediated pathways 

that can be ameliorated by antioxidants, providing theoretical grounds for potential therapeutic interventions. 

Sidestream and mainstream smoke showed decreases in expression of one of the major scavenger 

receptors on human alveolar macrophages and demonstrated a decrease in bacterial ingestion in human 

alveolar macrophages. 

PASSIVE SMOKE EXPOSURE IN ASTHMATICS: RELATIONSHIP TO MATRIX METALLOPROTEASES 

Jeanine M. D’Armiento, MD, PhD; Columbia University; CIA 2004 

The hypothesis of this research is that asthmatic patients exposed to active tobacco smoke or SHS have 

more severe airway inflammation and remodeling compared to asthmatics not exposed. The specific aims 

included 1) measurement and comparison of biomarkers of airway remodeling such as metalloproteinases 

and their inhibitors with inflammation (cytokine levels) in the induced sputum of mild and moderate asthmatic 

patients exposed to SHS, active tobacco smoke, and no smoke; and 2) comparison of airflow 

obstruction reversibility, hyperresponsiveness, and asthma quality of life among asthmatics exposed to passive 

smoking, active smoking, and no smoking. Subsequent study changes added two new study groups, 

nonasthmatics without active tobacco smoke exposure, and those without SHS exposure. Twenty individuals 

were recruited for each of the five groups. 


Foronjy R, Mercer B, Maxfield M, Okada Y, Powell C, D’Armiento J. Structural emphysema does not correlate 

with lung compliance: lessons from the mouse smoking model. Exp Lung Res 2005;31:547-562. 

Foronjy R, Mirochnitchenko O, Propokenko O, Lemaitre V, Jia Y, Inouye M, Okada Y, D’Armiento J. 

Superoxide dismutase expression attenuates cigarette smoke or elastase generated emphysema in mice. 

Am J Resp Crit Care Med 2005;173:623-631. 

Foronjy RF, Mirochnitchenko O, Propokenko O, Lemaitre V, Jia Y, Inouye M, Okada Y, D’Armiento JM. 

Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice. 

Am J Respir Crit Care Med 2006; 173:623-631. 

SMOKE-INDUCED DYSREGULATION OF AIRWAY AQUAPORINS 

Landon S. King, MD; The Johns Hopkins University; CIA 2004 

Aquaporins, water specific membrane channel proteins that determine water permeability in a number of 

tissues, specifically aquaporin 5 (AQP5), have been shown to be dynamically regulated by pathophysiologically 

relevant stimuli. The hypothesis of this research states that cigarette smoke alters the expression and 

distribution of AQP5 in lung epithelium, contributing to altered secretions and pathogenesis of chronic 

bronchitis. The specific aims included 1) exposing the lung epithelial cell lines to cigarette smoke and 

examination of AQP5 abundance; 2) determination of the effects of cigarette smoke condensate on AQP5 

subcellular distribution in cultured cells via immunofluorescence; and 3) assessment of differential gene 

expression via genomic arrays in tracheal cells from wild-type and AQP5-null mice exposed to cigarette 

smoke. Preliminary findings showed that the expression of several proteins predicted to contribute to the 

generation and biophysical properties of the lung surface airway layer is altered within a few hours of cigarette 

smoke extract exposure. 

5 6 P A G E

IMPACT OF SECOND HAND TOBACCO SMOKE ON RESPIRATORY HEALTH OF NON-SMOKING ADULTS 

Archana Mishra, MD, MS; State University of New York at Buffalo; YCSA 2002 

The PI investigated the relationship between SHS and respiratory health in adult non-smokers using 

data from two cross-sectional studies. Prevalence of self-reported SHS exposure at work and home was 

compared with self-reported exposure during an initial 16- year-old survey in adult non-smokers, and the 

validity of questionnaires were determined in indicating SHS exposure by assessing the relationship 

between self-reported measures and urinary cotinine adjusted for creatinine. Further, the PI determined 

the association between SHS exposure and pulmonary function tests in the adult population and the association 

between SHS exposure and respiratory symptoms. Analysis of the association between SHS exposure 

and self-report of obstructive airway disease in non-smoking adults and comparing gender differences 

in reported respiratory symptoms and pulmonary function measures in individuals exposed to SHS was 

performed. Lifetime SHS exposure places adults at risk for respiratory symptoms. An additive deleterious 

effect of SHS on lung function was seen by a decline in forced expiratory volume (FEV1) in current smokers 

with high versus low SHS exposure. 

ARTHRITIS 

Current Research 

TOBACCO-CAUSED RHEUMATOID ARTHRITIS; GENES, MECHANISMS, AND SPECIFIC THERAPY 

Lars Klareskog, MD, PhD; Karolinska Institutet; CIA 2004 

A large case-control study of recent rheumatoid arthritis patients will be used to determine the risk of 

arthritis development secondary to exposure to cigarette smoke in a potential dose-dependent manner. A 

recent addition to the epidemiological portion of the study will include data on SHS. The investigators 

also plan to use animal models to describe the molecular pathways that are triggered by cigarette smoke 

exposure, which may be involved in the etiology of arthritis. 


Klareskog L, Alfredsson L, Rantapaa-Dahlqvist S, Berglin E, Stolt P, Padyukov L. What precedes development 

of rheumatoid arthritis? [review]. Ann Rheum Dis 2004;63(Suppl2):ii28-ii31. 

Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, 

Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology 

of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to 

autoantigens modified by citrullination. Arthritis Rheum 2006;54:38-46. 

Lundberg K, Nijenhuis S, Vossenaar E, Palmblad K, van Venrooij WJ, Klareskog L, Zendman AJW, 

Erlandsson HH. Citrullinated proteins have increased immunogenicity and arthritogenicity and their 

presence in arthritic joints correlates with disease severity. Arthritis Res Ther 2005;7:R458-R467. 

Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking 

and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis 

Rheum 2004;50:3085-3092. 

CANCER, ANGIOGENESIS 


REGULATION OF TUMOR ANGIOGENESIS BY COMBOSTATIN 

Sudhakar Akulapalli, PhD; Boys Town National Research Hospital; YCSA 2007 

Dr. Akulapalli has continued studies with a fusion protein that his laboratory group developed. This protein, 

called combostatin, comprises the functional regions from three known antiangiogenic molecules: 

endostatin (type XVIII collagen noncollagenous (NC1) domain) and a1 and a3 type IV collagen NC1 

domains. It was found that combostatin displays more antitumor activity than any of its parent molecules. 

As an anti-angiogenic molecule, combostatin blocks formation of new blood vessels in solid tumors, a prerequisite 

for tumor growth. Combostatin inhibits the important pro-inflammatory molecule, cyclo-oxygenase 

(COX-2), and inhibits activation of metalloproteinase-2 (MMP-2). A number of studies using one of 

the parent molecules of combostatin, (a3(IV)NC1) were carried out, and showed that regulation of COX- 

2 is dependent on integrin a3b1. Recently efforts have focused on understanding the in-depth functional 

nature of the parent molecules by in vitro and in vivo studies. Understanding the precise signaling mecha- 

P A G E 5 7

nisms of combostatin and its parent molecules will offer additional clues for controlling and treating cancer. 

In future studies, the PI will continue to address the following: 1) investigation of inhibition of tumor 

angiogenesis and regulation of MMP activation by combostatin; 2) identification of interactions with cell 

surface integrins and associated cytoskeletal disorganization triggered by combostatin; and 3) identification 

of the signaling mechanism by which combostatin regulates COX-2 and associated factors. Some of the 

comparative studies on combostatin with its parent molecules have been submitted for publication and are 

currently under revision in peer-reviewed journals. 


Boosani CS and Sudhakar A. Molecular cloning and functional characterization of mouse a3(IV)NC1. 

Clinical Medicine: Oncology 2008;2;73-81. 

Boosani CS, Mannam AP, Cosgrove D, Silva R., Hodivala-Dilke KM, Keshamouni GV, Sudhakar A. 

Regulation of COX-2 mediated signaling by a3 type IV non-collagenous domain in tumor angiogenesis. 

Blood 2007;110(4),1168-1177. 

Nyberg, P, Xie, L, Sugimoto, H, Colorado, P, Sund, M, Holthaus, K, Sudhakar, A, Salo, T, Kalluri, R. 

Characterization of the anti-angiogenic properties of arresten, an a1b1 integrin dependent collagen 

derived tumor suppressor. Exp Cell Res 2008 Nov 1;314(18):3292-305. 

Sudhakar, A, Boosani, CS. Signaling mechanisms of endogenous angiogenesis inhibitors derived from type 

IV collagen. Gene Regulation and System Biology 2007; 1, 217-226. 

Sudhakar, A, Boosani, CS. Inhibition of tumor angiogenesis by Tumstatin: Insights into mechanisms and 

implication in cancer regression. Pharm Res 2008 Dec;25(12):2731-9. 

Sudhakar, A. Signaling mechanisms of collagen derived endogenous angiogenesis inhibitors. Sterling Life 

Sciences Journal August 2007;1-9. 

CANCER, CHEMOTHERAPEUTIC AGENTS 


THE ROLE OF CDK5 IN CANCER AND METASTASIS 

Barry Nelkin, PhD; The Johns Hopkins University; CIA 2006 

Dr. Nelkin has shown that CDK5, a kinase heretofore thought to be active mainly in neuronal lineages, 

is active in SCLC, and in several other types of cancer. Inhibition of CDK5 activity resulted in loss of cell 

motility and invasion, and a 79% decline in spontaneous metastasis. This finding strongly suggests that 

inhibition of CDK5 could be therapeutically beneficial in limiting metastasis in cancers such as SCLC, 

which is caused by smoke exposure. Dr. Nelkin will directly examine the steps of metastasis affected by 

CDK5 activity, in a xenograft model in vivo, using intravital imaging and experimental metastasis. Dr. 

Nelkin and his team will also explore whether CDK5 activity is required for the cellular response to the 

clinically relevant motility-inducing factors HGF/SF and CXCL12/SDF-1, which promote metastasis. 

They hypothesize that inhibition of CDK5, by altering normal cytoskeletal function, can sensitize cancer 

cells to chemotherapeutic agents; this will be examined in SCLC cells, using chemotherapeutic agents 

(etoposide, cisplatin, topotecan, gemcitabine) commonly employed clinically to treat SCLC. Finally, the 

investigators hypothesize that NNK, an important component of cigarette smoke that has been shown to 

activate cell motility and invasion, acts through a CDK5-dependent pathway. They will attempt to define 

the molecular pathway, by which NNK may promote metastasis. In these experiments, Dr. Nelkin will 

examine whether inhibition of CDK5 can block NNK-induced SCLC cell migration and invasion, and 

whether NNK treatment results in increased CDK5 activity in SCLC cells. These experiments may define 

CDK5 as a potential therapeutic target in cancer, and may implicate cigarette smoke exposure in the activation 

of CDK5. Since small molecule inhibitors of CDK5 already exist, clinical development, if warranted, 

could be rapid. 

CANCER, BLADDER 


THE GPI TRANSAMIDASE COMPLEX SUBUNITS AS ONCOGENES IN BLADDER CANCER 

Barry Trink, PhD; The Johns Hopkins University; CIA 2003, CIA 2007 

Dr. Trink recently cloned and characterized PIG-U, a novel human oncogene for human bladder cancer, 

5 8 P A G E

and implicated for the first time the glycosylphosphatidylinositol (GPI) anchoring pathway in the development 

of human cancers. PIG-U is one of five subunits making up the transamidase complex involved in 

the GPI anchoring pathway. The team has shown that at least three of these subunits can be oncogenic. 

The investigators will continue to study their activation in the progression of transitional cell carcinoma 

(TCC) in bladder cancer which will help elucidate the role of these subunits of the GPI anchoring complex 

in bladder cancer. Aerolysin, (a cytolytic toxin), binds to GPI-anchored proteins on the target cells. It 

becomes active upon proteolysis and causes cell lysis. The investigators have shown that cells overexpressing 

the subunits have increased sensitivity to proaerolysin. With this in mind, the team will test whether 

this toxin might be used for therapeutic purposes and evaluate the toxicity of proaerolysin in non-tumor 

bearing mice and orthotopic bladder tumor-bearing mice to establish whether a therapeutic index can be 

achieved. Finally, human bladder cells will be subjected to tobacco smoke and the expression of these subunits 

in those cells will be measured in order to determine the relationship between tobacco exposure and 

the oncogenic potential of these subunits in bladder cancer. Some results of the activation of the subunits 

in bladder cancer through microarray analysis and immunohistochemistry (IHC) have been obtained. 


Nagpal JK, Dasgupta S, Jadallah S, Chae YK, Ratovitski EA, Toubaji A, Nissan A, Netto GJ, Sidransky D, 

Trink B. Profiling the expression pattern of GPI transamidase complex subunits in human cancer. Mod 

Pathol 2009;21(8): 979-991. 

FUNCTIONAL ROLE OF CDC91L1-CONTAINING COMPLEX IN HUMAN BLADDER CANCERS 

Edward Ratovitski, PhD; The Johns Hopkins University; CIA 2005, 2009 

Dr. Ratovitski and his collaborators have recently discovered that the expression of the gene for 

CDC91L1 is affected by a common genomic amplification in bladder cancer at 20q11-13. This gene, 

CDC91L1, phosphatidylinositol glycan anchor biosynthesis, class U (PIG-U), is a part of the glycosylphosphatidylinositol 

(GPI)-anchoring complex, which modifies other membranal proteins. The GPI complex 

consists of several proteins, PIG-U, phosphatidylinositol glycan anchor biosynthesis, class T (PIG-T), glycosylphosphatidylinositol 

anchor attachment protein 1 homolog (GPAA1), and others, contributing to its 

functional activity. Dr. Ratovitski has proposed further evaluation of the protein-protein interactions caused 

by overexpression of the GPI proteins (PIG-U) PIG-T and GPAA1, to determine their roles in tumor formation, 

apoptosis, and cell proliferation of human cancer cells (e.g., bladder and breast). PIG-U was found 

to form several different protein-protein complexes with paxillin, mitogen-activated protein kinase kinase 6 

(MEK6), or human leukocyte antigen B-associated transcript 3 (BAT-3) in bladder and breast cancer cells. 

It also plays an important role in tumorigenesis, cell adhesion, and apoptosis. Future studies will 1) examine 

PIG-U (PIG-T, GPAA1) modifications (serine/threonine phosphorylation) mediated by association of 

PIG-U with MEK6; 2) study interactions between PIG-U (PIG-T, GPAA1) and paxillin and its effect on 

cell migration; and 3) examine the association of PIG-U (PIG-T, GPAA1) with BAT-3 and its effect on 

BAT-3-mediated apoptosis. 


Jiang WW, Zahurak M, Zhou ZT, Park HL, Guo ZM, Wu GJ, Sidransky D, Trink B, Califano JA. 

Alterations of GPI transamidase subunits in head and neck squamous carcinoma. Mol Cancer 2007;6:74- 

81. 

Shen YJ, Ye DW, Yao XD, Trink B, Zhou XY, Zhang SL, Dai B, Zhang HL, Zhu Y, Guo Z, Wu G, 

Nagpal J. Overexpression of CDC91L1 (PIG-U) in bladder urothelial cell carcinoma: correlation with 

clinical variables and prognostic significance. BJU Intl 2008;101(1):113-9. 

Wu G, Guo Z, Chatterjee A, Huang X, Rubin E, Wu F, Mambo E, Chang X, Osada M, Sook Kim M, 

Moon C, Califano JA, Ratovitski EA, Gollin SM, Sukumar S, Sidransky D, Trink B. Overexpression of 

glycosylphosphatidylinositol (GPI) transamidase subunits phosphatidylinositol glycan class T and/or GPI 

anchor attachment 1 induces tumorigenesis and contributes to invasion in human breast cancer. Cancer 

Res 2006;66: 9829-9836. 

DEVELOPING DMAPT, A NF-KAPPA B INHIBITOR FOR BLADDER CANCER 

Harikrishna Nakshatri, PhD; Indiana University; CIA 2006 

Bladder cancer is the fifth most prevalent cancer with primary and SHS exposure implicated as the major 

etiologic factor. Approximately 80% of patients present with superficial disease confined to the mucosa. 

Recurrence is common with invasion into muscle or even distant metastasis with fatal consequences. 

P A G E 5 9

Bladder cancer progression involves activation of specific oncogenic pathways and/or inactivation of tumor 

suppressor genes through mutations or epigenetic mechanisms. The major tumor suppressor pathways 

inactivated include p53, retinoblastoma, RASSF1A, RUNX3, and p16INK4. Inactivation of these pathways 

leads to reduced expression of the cell cycle inhibitor p21. Epigenetic mechanisms of gene silencing appear 

to be dominant during bladder cancer progression; at least 50 genes are reported to undergo epigenetic 

modification. This mechanism of gene silencing involves specific post-translational modifications of histones, 

particularly histones H3 and H4. Therefore, drugs that can reverse cancer-enriched histone modifications 

should be effective in not only treating invasive bladder cancer but also in preventing progression 

from superficial to invasive lesions. Dr. Nakshatri has developed a compound called LC-1, which inhibits 

bladder cancer cell growth both in vivo and in vitro. Although this drug was originally developed as an 

inhibitor of the transcription factor NF-kB, the investigators observed key proteins involved in epigenetic 

gene silencing as its additional targets. LC-1 reduced the levels of “bad” epigenetic regulators such as 

polycomb protein EZH2, histone deacetylase HDAC1, and CtBP-1. It also increased histone H4lys20 

trimethylation. Loss of histone H4lys20 trimethylation is a hallmark of a variety of cancers and this observation 

may be the first demonstration of a drug that has the capacity to reverse this loss. LC-1 increased 

the levels of histone demethylase JMJD2A, which correlated with reduced levels of Histone H3K9 methylation. 

Histone H3K9 trimethylation is associated with repressive chromatin and this modification is often 

observed in cancers. LC-1-treated cells displayed elevated levels of p21, possibly due to epigenetic changes. 

The results of these experiments have immediate translational potential because LC-1 is now in a Phase I 

clinical trial for leukemia. A successful leukemia trial could provide the justification for a bladder cancer 

chemoprevention trial for patients with superficial bladder lesions. 

BLADDER CANCER ASSOCIATED GENE EXPRESSION SIGNATURES IDENTIFIED BY PROFILING OF EXFOLIATED 

UROTHELIA 

Charles J. Rosser, MD; University of Florida; CIA 2008 

Bladder cancer is the fifth most commonly diagnosed malignancy in the United States and one of the 

most prevalent worldwide. It has a probability of recurrence of approximately 50%; thus rigorous, longterm 

surveillance of patients is advocated. Flexible cystoscopy coupled with voided urine cytology (VUC) 

is the primary diagnostic approach, but cystoscopy is an uncomfortable, invasive procedure, and the sensitivity 

of VUC is poor in all but high-grade tumors. Thus, improvements in non-invasive urinalysis assessment 

strategies would benefit patients. Dr. Rosser has applied gene expression microarray analysis to exfoliated 

urothelia recovered from bladder washes obtained prospectively from 46 patients with subsequently 

confirmed presence or absence of bladder cancer. Data from microarrays containing 56,000 targets was 

subjected to a panel of statistical analyses to identify bladder cancer-associated gene signatures. Hierarchical 

clustering and supervised learning algorithms were used to classify samples on the basis of tumor burden. 

A differentially expressed gene set of 319 gene probes was associated with the presence of bladder cancer, 

and visualization of protein interaction networks revealed vascular endothelial growth factor (VEGF) and 

angiotensin (AGT) as pivotal factors in tumor cells. Supervised machine learning and a cross-validation 

approach were used to build a 14-gene molecular classifier that was able to classify patients with and without 

bladder cancer with an overall accuracy of 76%. The investigators have shown that it is possible to 

achieve a high level of detection of bladder cancer using molecular signatures present in exfoliated tumor 

urothelia. Further investigation and validation of the cancer-associated profiles may reveal important biomarkers 

for the non-invasive detection and surveillance of bladder cancer. 

CIGARETTE SMOKE IMPAIRMENT OF BLADDER CANCER TREATMENT 

Warren D. W. Heston, PhD; Cleveland Clinic; CIA 2008 

Smoking increases recurrence and progression of bladder cancer in patients undergoing surveillance following 

treatment; however, there has never been a clear demonstration of direct association. Dr. Heston 

has established a bladder cancer mouse model that will allow investigators to test the effects of SHS on 

current treatment regimens used in humans as well as novel treatments. They have demonstrated cure rates 

in mice with bladder cancer, using intravesical gene therapy with IL2, that are equivalent to those seen 

using Bacillus Calmette–Guérin (BCG, the current standard of care in humans). This approach has the 

advantage of yielding prolonged immunological memory that protects the cured mice from re-challenge of 

the tumor, which BCG does not. IL-2 treatment, however, is limited in the percentage cures observed 

because it has the propensity to adversely increase immunosuppressive cells. A similar suppression is 

observed with smoking. Sunitinib, an anti-angiogenic agent, has been shown to reverse immune suppression. 

Therefore, the investigators hypothesize that SHS has a deleterious effect on current treatments for 

6 0 P A G E

ladder cancer and that combining novel treatments may overcome that effect. 

Based on these observations, the PI proposes three specific aims. In aim-1 the investigators will examine 

the role of SHS on the response of bladder cancer to BCG treatment; in aim-2, they will investigate the 

role of cytokine gene therapy alone and with sunitinib; and in aim-3, they will test these treatments in 

combination with SHS. 

The investigators have obtained baseline measurements of tumor response to single agents. The malignant 

bladder tumor-2 (MBT-2) is inhibited in a dose response fashion to sunitinib in vitro and is growth 

inhibited in vivo as well. Studies examining the response of the tumor to BCG and SHS are currently 

underway. Reports based on these initial findings have been accepted for presentation at the 100th Annual 

Meeting of the American Association for Cancer Research. 


Patel A, et al., Quantification of the antitumor effects of sunitinib maleate in a localized orthotopic bladder 

cancer model. Presented at the Annual Meeting of the American Association for Cancer Research, April 

2009. 

HEDGEHOG SIGNALING LINKS CANCER AND INJURY REPAIR IN BLADDER EPITHELIUM 

Sunil S. Karhadkar, MBBS; The Johns Hopkins University; YCSA 2004 

In this research, Dr. Karhadkar continues to investigate the roles of the gene sonic hedgehog (Hh) signaling 

in the repair of chemical injury to the bladder. He hopes to be able to estimate the number of bladder 

cancer patients who could benefit from anti-Hh signaling drug therapy. His results have demonstrated 

a loss of urothelial bladder function after cyclophosphamide (CPX) therapy, but showed that the barrier 

function returns to baseline within 4 weeks of the injury, establishing an important endpoint for the study. 

The investigators also found that CPX injury induces stromal and urothelial expression of an Hh pathway 

target. Since the Hh pathway has been shown to promote malignant transformation in a number of different 

types of epithelial cells, the injury finding supports the central hypothesis that Hh signaling links 

urothelial injury and carcinogenesis. Dr. Karhadkar proposes three research aims which are to 1) investigate 

the role of Hh signals in repairing bladder injury; 2) estimate the number of bladder cancer patients that 

might benefit from therapy with drugs that block Hh signaling; and 3) test the ability of such therapy to 

treat bladder cancer. Significant progress has been made in completing aims 1 and 2. Progress has yielded a 

working model to study the return of urothelial barrier function, an important measure of the efficacy of 

repair. Exciting new data show localization of induction of Hh signaling in response to bladder injury. 

Moreover, xenographs have been established from 15 primary human bladder cancers resected at The 

Johns Hopkins Hospital and Dr. Karhadkar has characterized the Hh pathway activity in eight of them, to 

date. 


Beachy PA, Karhadkar SS, Berman DM. Mending and malignancy. Nature 2004;431:402. 

Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis [review]. 

Nature 2004;432:324-331. 

Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada 

Y, Eshleman JR, Watkins DN, Beachy PA. Widespread requirement for Hedgehog ligand stimulation in 

growth of digestive tract tumors. Nature 2003 Oct 23;425(6960):846-51. 

MARKERS OF RESPONSE TO INTRAVESICAL BLADDER CANCER THERAPY 

Ashish Kamat, MD; University of Texas M. D. Anderson Cancer Center; YCSA 2005 

Dr. Kamat’s hypothesis is that the presence of cytogenetically abnormal cells 3 months after initiation of 

intravesicular immunotherapy (molecular recurrence) predicts clinical tumor recurrence. At present, clinicians 

use frequent cystoscopy and cytology to detect recurrences (at 3 month intervals for the first 24 

months) but there is no reliable predictor of response to therapy. Dr. Kamat’s specific aims are to 1) determine 

whether molecular recurrence, as defined by the presence of cytogenetically abnormal cells on fluorescence 

in situ hybridization (FISH) 3 months after initiation of intravesical immunotherapy, predicts clinical 

tumor recurrence within 24 months after initial diagnosis; and 2) determine whether urinary interleukin 

(IL)-2, IL-8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) measured at predefined 

time points, correlate with tumor recurrence and progression. The investigators have enrolled 68% 

of their goal of 150 patients. Data analysis shows that the negative predictive value (NPV) using the FISH 

test is 72% or greater when evaluating results independently at baseline (n = 29, NPV = 72%), 6 weeks (n = 

P A G E 6 1

45, NPV = 8%), 3 months (n = 42, NPV = 79%), and 6 months (n = 46, NPV = 91%) post-induction. The 

NPV increases to 88% when combining results from baseline and 6 weeks (n=16) and 92% when combining 

baseline, 6 weeks and 3 months (n = 13). When reviewing results independently for positive predictive 

value (PPV) at baseline, 6 weeks, 3 months, and 6 months, the results respectively are 35% (n = 66), 47% 

(n = 43), 47% (n = 43), and 43% (n = 21). When combining baseline and 6 week results there is a PPV of 

39% (n = 38); and combining baseline, 6 week and 3 month results gives a PPV of 52% (n = 23). A negative 

FISH at baseline and 6 weeks after induction of therapy predicts tumor-free status although further 

follow-up is required before definitive conclusions can be drawn. 


Fomenkov A, Zangen R, Huang Y-P, Osada M, Guo Z, Fomenkov T, Trink B, Sidransky D, Ratovitski 

EA. RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous 

cell carcinoma cells upon DNA damage. Cell Cycle 2004;3:1285-1295. 

Guo Z, Linn JF, Wu G, Anzick SL, Eisenberger CF, Halachmi S, Cohen Y, Fomenkov A, Hoque MO, 

Okami K, Steiner G, Engles JM, Osada M, Moon C, Ratovitski E, Trent JM, Meltzer PS, Westra WH, 

Kiemeney LA, Schoenberg MP, Sidransky D, Trink B. CDC91L1 (PIG-U) is a newly discovered oncogene 

in human bladder cancer. Nat Med 2004;10:374-381. 

Huang YP, Kim Y, Li Z, Fomenkov T, Fomenkov A, Ratovitski E. AEC-associated p63 mutations lead to 

alternative splicing/protein stabilization of p63 and modulation of notch signaling. Cell Cycle 

2005;4:1440-1447. 

Huang YP, Wu G, Guo Z, Osada M, Fomenkov T, Park HL, Trink B, Fomenkov A, Ratovitski EA. 

Altered sumoylation of p63a contributes to the split-hand/foot malformation phenotype. Cell Cycle 

2004;3:1587-1596. 

Wu G, Osada M, Guo Z, Fomenkov A, Begum S, Zhao M, Upadhyay S, Xing M, Wu F, Moon C, Westra 

WH, Koch WM, Mantovani R, Califano JA, Ratovitski E, Sidransky D, Trink B. DeltaNp63alpha upregulates 

the Hsp70 gene in human cancer. Cancer Res 2005;65:758-766. 

GENETIC AND EPIGENETIC ALTERATIONS IN BLADDER CANCER BY TOBACCO SMOKE 

Mohammad O. Hoque, DDS, PhD; The Johns Hopkins University; YCSA 2006 

Many of the toxins that enter the body after inhalation of cigarette smoke are absorbed into the bloodstream 

and excreted by the kidneys into the urine. Because urine stays in the bladder for hours before it is 

expelled, the bladder epithelium is exposed to prolonged contact with carcinogens absorbed from smoke. 

Recent evidence indicates that methylation and allelic deletion occur more frequently in cancers from 

smokers than non-smokers. These observations suggest that a useful tobacco signature could emerge from 

distinctive patterns of methylation and deletion. The objective of this study is to determine whether there 

are distinct patterns of chromosomal loss and methylation in smokers and non-smokers. The discovery of 

such patterns would be useful in the identification of bladder cancer-associated tumor suppressor genes. 

Additionally, these genes can be used for overall clinical management of bladder cancer patients such as initial 

diagnosis and monitoring of disease using urine sediment. To date, Dr. Hoque has been able to 

demonstrate that methylation of a panel of genes can be used for diagnosis of bladder cancer, using urine 

sediment. He also reported that stratification of tumor stage could be possible by profiling methylation 

markers. By a multivariate analysis, Dr. Hoque reported that tissue inhibitor of metalloproteinases-3 

methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p 

= 0.001 and 0.02, respectively). An integrated genetic and epigenetic approach will be continued for the 

discovery of new genes, which should provide important insights into the pathogenesis of this tobaccorelated 

cancer, and will provide information to develop strategies for early detection and treatment. 


Hoque MO, Kim MS, Ostrow KL, Liu J, Wisman BA, Park HL, Poeta ML, Jeronimo C, Henrique R, 

Lendvai A, Schuuring ED, Begum S, Rosenbaum R, Ongenaert M, Yamashita K, Califano J, Westra 

WH, Zee VD, Criekinge WV, Sidransky D. Genome-wide promoter analysis uncovers portions of the 

cancer methylome. Cancer Res 2008;68(8):2661-70. 

Dasgupta S, Hoque MO, Upadhyay S, Sidransky D. Mitochondria encoded cytochrome B mutation promotes 

tumor growth in bladder cancer through NFkB2 activation. Cancer Res 2008;68:700-706. 

Hoque MO, Begum S, Brait M, Jeronimo C, Ostrow K, Trock B, Westra WH, Schoenberg M, Sidransky 

D. TIMP3 promoter methylation is an independent prognostic factor for bladder cancer. J Urol 

2008;179(2):743-7. 

6 2 P A G E

Brait M, Begum S, Carvalho AL, Dasgupta S, Vettore AL, Czerniak B, Caballero OL, Westra WH, 

Sidransky D, Hoque MO. Aberrant promoter methylation of multiple genes during pathogenesis of 

bladder cancer. Cancer Epidemiol Biomarkers Prev 2008;17(10):2786-2794. 

Ostrow K, Park H, Hoque MO, Kim MS, Liu JW, Argani P, Westra WH, Criekinge WV, Sidransky D. 

Pharmacologic unmasking of epigenetically silenced genes in breast. Cancer Clin Cancer Res 

2009;15(4):1184-91. 

Bernert H, Brait M, Ostrow KL, Loyo M, Dasgupta S, Sidransky D, Trink B, Hoque MO. Promoter 

hypermethylation of candidate tumor suppressor genes in bladder and prostate cancer. Presented at the 

Annual Meeting of the American Association for Cancer Research. Apr 2008. 

Hoque MO, Myong S. Kim MS, Kim, Ostrow K, Liu J, Bea G, Wisman A, Jeronimo C, Rui H, Straub J, 

Lui HP, Poeta L, Begum S, Rosenbaum E, Yamashita K, Califano J, Westra W, Van der Zee GJ, 

Criekinge WV, Sidransky D. Genome-wide promoter analysis uncovers portions of the cancer 

“Methylome” in primary tumors and cell lines. Presented at the Annual Meeting of the American 

Association for Cancer Research, April 2007. 

Dasgupta S, Mambo E, Hoque MO, Chatterjee A, Upadhyay S, Sidransky D. Mitochondria encoded 

Cytochrome B gene mutation contributes to enhanced tumor growth in bladder cancer. Presented at the 

Annual Meeting of the American Association for Cancer Research. April 2007. 

Papaiahgari S , Ford JG, Lee M, Brait M, Loyo M, Begum S, Hoque MO. Promoter Methylation of 

Prostate Cancer Specific Genes in low-income African American Adults Cancer Epidemiology Biomarkers 

& Prevention 2008;17:460-4653. 

Papaiahgari S. Promoter Hypermethylation of Multiple Genes Detected in Germ Cell Tumors. Presented 

at the Annual Meeting of the American Society of Preventive Oncology, March 2008. 

Netto GJ, Brait M, Begum S, Wehle D, Tavora F, Sidransky D, Hoque MO. The United States and 

Canadian Academy of Pathology Annual Meeting, March 2008. 

Hoque MO, Brait M, Begum S, Dasgupta S, Zahurak M, Carvalho AL, Kim MS, Califano J, Westra WH, 

Sidransky D. Molecular analysis of serum/plasma DNA for the detection of lung cancer. Presented at 

the 5th Early Detection Research Network (EDRN) Scientific Workshop Meeting, Mar 2008. 

Demokan S, Chang X, Chuang A, Brait M, Hoque MO, Sidransky D, Koch W, Califano J. Methylation of 

the KIF1A and EDNRB genes is a frequent event in head and neck cancer. Presented at the Annual 

Meeting of the American Association for Cancer Research. April 2008. 

Begum S, Rosenbaum E, Brait M, Zahurak M, Ostrow K, Dasgupta S, Sidransky D, Westra WH, Hoque, 

MO. AIM1 Promoter hypermethylation as an independent prognostic factor for relapse in patients with 

prostate cancer following radical prostatectomy. Presented at the Annual Meeting of the American 


Ostrow KL, Park HL, Hoque MO, Kim MS, Liu J, Westra W, Criekinge WK, Sidransky D. Pharmacologic 

unmasking of epigenetically silenced genes in breast cancer. Presented at the Annual Meeting of the 

American Association for Cancer Research, April 2008. 

Loyo M, Brait M, Ostrow K, Begum S, Tao Q, Lung M, Ford JG, Hoque MO, Sidransky D. Novel gene 

promoter hypermethylation in nasopharyngeal carcinoma. Presented at the Annual Meeting of the 

American Association for Cancer research, April 2008. 

Bernert H, Brait M, Ostrow KL, Loyo M, Dasgupta S, Sidransky D, Trink B, Hoque MO. Promoter 

hypermethylation of candidate tumor suppressor genes in bladder and prostate cancer. Presented at the 

Annual Meeting of the American Association for Cancer Research. April 2008. 

Rosenbaum E, Brait M, Ostrow K, Loyo M, Papagerakis S, Markova A, Zahurak M, Goodman S, 

Sidransky S, Zeiger M, Hoque MO, Umbricht CB. Quantitative assessment of promoter methylation 

profiles in thyroid tumors. Presented at the Annual Meeting of the American Association for Cancer 

Research. April 2008. 

Prencipe M, Hoque MO, Poeta ML, Gallo A, Valori VM, Maiello E, Murgo R, Bisceglia M, Tommasi S, 

Paradiso A, Sidransky D, Fazio VM, Parrella P. Changes in CpG islands methylation patterns during 

ductal breast carcinoma progression. Presented at the Annual Meeting of the American Association for 

Cancer research, April 2008. 

Brait M, Begum S, Wehle D, Tavora FF, Loyo M, Sidransky D, Hoque MO. Methylation profiling of multiple 

genes in germ cell tumors. Presented at the Cancer Epigenetics Meeting. May 2008. 

P A G E 6 3

THE EFFECT OF ADENYLATE KINASE 3 ON TOBACCO SMOKE-INDUCED CISPLATIN RESISTANCE 

IN BLADDER CELLS 

Aditi Chatterjee, PhD: The Johns Hopkins University;YCSA 2008 

The major established etiologic risk factor for bladder cancer is cigarette smoking. Exposure to SHS 

increases the chances for offspring to develop bladder cancer. One of the most commonly used antineoplastic 

agents for the treatment of advanced bladder cancer is cisplatin but the development of resistance to 

cisplatin during treatment is common and constitutes a major obstacle to the treatment. Cellular mechanisms 

of cisplatin resistance are multifactorial and contribute to severe limitations in the use of this drug in 

clinics. In this study, Dr. Chatterjee will study the role of adenylate kinase 3 in bladder cancer and SHSrelated 

cisplatin resistance. A major goal will be to establish a relationship between tobacco exposure and 

cisplatin resistance in bladder cells. These studies will yield a new insight into the therapeutic potential for 

the treatment of bladder cancer when associated with cisplatin resistance, and further increase the understanding 

of the role of tobacco smoke in human bladder cancer etiology. 

CANCER, BLADDER 


ADENOVIRAL BLADDER CANCER GENE THERAPY 

Ronald Rodriguez, MD, PhD; The Johns Hopkins University; CIA 2002 

Dr. Rodriguez discovered that bladder cancer cells downregulate the expression of the adenoviral receptor. 

This downregulation was reversed by histone deacetylase inhibitor (HDACI) and it was determined 

that HDACI has an impact on bladder cancer. 

A MARKER FOR BLADDER CANCER IN INVOLUNTARY SMOKERS 

Robert H. Getzenberg, PhD; The Johns Hopkins University; CIA 2005 

Voluntary smoking is a well-known risk factor for developing bladder cancer, and there is mounting evidence 

suggesting that SHS exposure produces an increased risk as well. Dr. Getzenberg hypothesizes that 

the presence of a bladder cancer-specific nuclear matrix protein, BLCA-4, is sensitive and specific for the 

diagnosis of early bladder cancer and has potential as a screening tool in high-risk populations such as 

SHS-exposed individuals and smokers. His research aims were to: 1) determine if urine BLCA-4 correlates 

with the presence of bladder cancer in SHS-exposed individuals in a highly sensitive and specific fashion; 

and 2) determine whether smoking confounds the measurement of BLCA-4 in urine. Current screening 

methods lack the sensitivity to detect the low-grade tumors that characterize the majority of all bladder 

cancers. Cystoscopy, the gold standard for diagnosis, is expensive, highly invasive, and can result in urethra 

stricture, making this technique less than ideal for the life-long monitoring that bladder cancer patients 

must undergo. Exposure to cigarette smoke increases the risk for developing bladder cancer but the survival 

rate is high if the tumors are detected early. Consequently, the ability to screen high-risk populations 

for the presence of low-grade bladder tumors has potential to improve the health management of this population 

group. 

CANCER, BREAST 


TRANSLATIONAL CONTROL AND BREAST CANCER DEVELOPMENT 

Ronald B. Gartenhaus, MD; University of Maryland; CIA 2008 

Breast cancer is a serious health problem worldwide with over 1.1 million new cases diagnosed annually 

and is one of the leading causes of mortality in Western countries. There are a number of risk factors for 

breast cancer including SHS exposure. The molecular mechanisms of breast cancer initiation and 

progression are still poorly understood, limiting our ability to develop targeted therapeutic approaches. Dr. 

Gartenhaus previously analyzed the novel oncogene multiple copies in a T cell malignancy (MCT-1) 

expression in breast cancer cells and found significantly higher MCT-1 protein levels in estrogen receptor 

(ER)-negative breast cancer compared with ER-positive breast cancer. Dr. Gartenhaus has shown that 

MCT-1 can both transform immortalized breast epithelial cells as well as increase the tumor forming ability 

of MCF7 cells in nude mice. There is often a poor correlation observed between protein and RNA in 

eukaryotic systems, supporting the emerging paradigm that many of the abnormalities in a cancer cell’s 

6 4 P A G E

proteome may be achieved by differential recruitment of messenger RNAs (mRNAs) to polysomes referred 

to as the translational profile. Dr. Gartenhaus has previously demonstrated that increased levels of MCT-1 

are able to modify a cell’s translational profile. He plans to examine alterations in translational control 

exploiting the previously established cellular model of breast cancer transition from immortalization to 

transformation/progression in order to identify the repertoire of translated mRNAs required for in vivo 

transformation and progression. The MCT-1 protein modifies mRNA translational profiles through its 

interaction with DENR, a cell density regulated protein containing an SUI1 domain involved in 

recognition of the translation initiation codon. Dr. Gartenhaus has demonstrated that two RNA-binding 

proteins, HuR and AUF1, both bind to the 3’ untranslated region of DENR. The identification of 

structurally related mRNAs associated with ribonucleoprotein (RNP) complexes may provide insight into 

structural and functional relationships among translated protein products involved in tumor development 

and progression. He wishes to examine the effect of these interactions on the translation of the DENR 

transcript as well as identifying and profiling endogenously clustered mRNAs associated with HuR and 

AUF1. This analysis will provide insight into functional relationships among translated protein products 

involved in tumor development. He designed experiments in order to gain mechanistic insight into how 

MCT-1 impacts the cancer cell phenotype. Dr. Gartenhaus hypothesizes that 1) examining the altered 

translational profiles using his established breast cancer transformation/progression model will identify 

relevant proteins required for in vivo transformation and progression; and 2) identifying and profiling 

endogenously clustered mRNAs associated with RNP complexes will provide insight into functional 

relationships among translated protein products involved in transformation and tumor progression. 

ACTIVATION OF DDX3 BY BENZO[A]PYRENE DIOL EPOXIDE, A COMPONENT OF SECOND HAND TOBACCO 

SMOKE IN TRANSFORMATION OF HUMAN BREAST CELLS: A POTENTIAL MECHANISM FOR NEOPLASTIC 

TRANSFORMATION 

Venu Raman, PhD; The Johns Hopkins University; CIA 2003, 2006 

The evolution of cancer has been associated with a myriad of causative agents both at the genetic level 

(predisposition) and to the exposure of potent carcinogens over a period of time. Although active exposure 

still contributes to the majority of cancer development, there has been a preponderance of evidence to 

indicate that passive exposure like SHS inflicts serious damage to visceral organs. In this continuing 

research effort to understand the effects of SHS on breast cancer formation, Dr. Raman has identified a 

key molecule that plays a pivotal role in transforming normal mammary epithelial cells to its associated 

tumor phenotype. This gene was identified by the ability of a component present in SHS to induce its 

expression in normal mammary epithelial cells. The importance of this finding is underscored by its functional 

role in altering normal mammary epithelial cells to an invasive phenotype. An extension of this finding 

can be applied to the vast number of people who have been exposed to long periods of SHS that may 

now predispose them to breast tumor formation. The gene is referred to as the DEAD-box protein 3 

(DDX3), and it belongs to a family of RNA helicases. Very little is known about the functions of this gene 

in mammalian system. Recently, it has been demonstrated that over-expression of this gene contributes to 

hepatocellular carcinoma and is also important in facilitating human immunodeficiency virus (HIV) replication. 

Its primary function in lower eukaryotes has been demonstrated in the area of RNA biogenesis resulting 

in the appropriate protein product. The induction of DDX3 in normal mammary epithelial cells by 

benzo[a]pyrene diol epoxide (BP[a]DE), a component present in SHS, led the research team to explore 

the functions of this gene in mammalian system. They have now demonstrated that the over-expression of 

this gene in normal mammary epithelial cells can augment cellular motility and invasive properties. The 

acquisition of these properties is a hallmark for metastatic potential for these cells. In addition, over-expression 

of this gene transforms normal cells to phenotypically resemble highly invasive breast carcinomas. 

Based on the data accrued, it is possible that over-expression of DDX3 plays an important role in breast 

carcinogenesis. Further characterization of this gene’s functions will provide information to its multifaceted 

role in cancer development, especially to initiate or trigger breast cancer formation following exposure 

to SHS. Finally, detection of this gene product can be used as a prognostic marker for breast cancers 

and can be targeted for therapy by novel chemotherapeutic agents. 

MECHANISMS OF SHS INDUCED BREAST CARCINOGENESIS 

Satya Narayan, PhD; University of Florida; CIA 2003 

Second hand tobacco smoke is estimated to cause an average 68% increase in the breast cancer risk of 

women younger than 50. Women who have not reached menopause have as much as a 120% higher risk, 

according to a California Air Resources Board decision approving a California Environmental Protection 

P A G E 6 5

Agency report in 2006 (ftp://ftp.arb.ca.gov/carbis/regact/ets2006/ app3part%20b.pdf). However, the 

link between SHS and an increased risk of breast cancer is still controversial. Identification of the mechanisms 

that potentially link SHS and breast cancer would be a key factor in resolving this controversy. Early 

laboratory studies, based on analysis of the effects of single chemicals of the 4,000 found in cigarette 

smoke, indicated only weak correlations between smoking and breast cancer risk. These findings are now 

being challenged by studies that analyze the effects of simultaneous exposure to several of the chemical 

components and the use of cigarette smoke condensate (CSC), a surrogate for cigarette smoke that contains 

all of these compounds. The compounds in cigarette smoke damage the DNA and specifically cause 

particular types of lesions that would normally be repaired by a process known as base-excision repair 

(BER). It has been estimated that BER can repair 10,000 lesions per cell per day under normal circumstances. 

An inability of cells to respond effectively to the DNA damage incurred on exposure to cigarette 

smoke, i.e., either by complete repair of the lesions or elimination of the cells bearing the lesions, can 

result in the survival of cells carrying mutations and the acquisition of these cells of malignant properties. 

In a series of studies, Dr. Narayan established that the activity of BER can be compromised by the activity 

of the adenomatous polyposis coli (APC) protein and that carcinogens can enhance the levels of expression 

of this protein. This concept is highly innovative. Although it is well established that mutations of APC 

play a role in some cancers, the potential contribution of the levels of APC to carcinogenesis had not been 

recognized previously. 

Dr. Narayan has preliminary data that exposure to CSC results in the transformation of normal human 

breast epithelial cells into tumor cells. Moreover, Dr. Narayan has evidence that CSC compromises the 

ability of the cells to repair by blocking BER. He and his colleagues propose to test the hypothesis that 

APC-mediated blockage of BER is a principal mechanism for CSC-induced transformation of normal 

breast epithelial cells. They will determine whether exposure of normal breast epithelial cells to CSC results 

in an APC-mediated blockage of BER activity that results in an accumulation of mutations in the cells, 

with an emphasis on mutations associated with the Pol-beta mutator phenotype that has been associated 

with the development of breast cancer. In independent experiments, Dr. Narayan and colleagues will determine 

whether the APC-mediated blockage of BER causes transformation of normal breast epithelial cells 

exposed to CSC using both in vitro and in vivo approaches. Finally, they will establish the effects of CSC 

on the invasive behavior of normal breast epithelial cells in culture with the goal of establishing the factors 

that determine susceptibility to the development of more aggressive tumors. The data generated through 

these studies are of relevance to both sexes and all ethnic groups and should identify a mechanistic link 

that will permit direct testing of the association between SHS and breast cancer. Moreover, the results of 

the studies will provide a framework for the development of chemopreventive and chemotherapeutic agents 

to combat this deadly disease. 


Kumar SK, Williams SA, Isaacs JT, Denmeade SR, Khan SR. Modulating paclitaxel bioavailability for targeting 

prostate cancer. Bioorg Med Chem 2007;15:4973-4984. 

Kundu CN, Balusu R, Jaiswal AS, Gairola CG, Narayan S. Cigarette smoke condensate-induced level of 

adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells. Oncogene 

2007;26:1428-1438. 

Narayan S, Jaiswal A, Kang D, Srivastava P, Das GM, Gairola C. Cigarette smoke condensate-induced 

transformation of normal human breast epithelial cells in vitro. Oncogene 2004;23:5880-5889. 

Narayan S, Jaiswal AS, Balusu R. Tumor suppressor APC blocks DNA polymerase beta-dependent stranddisplacement 

synthesis and increases sensitivity to DNA methylation. J Biol Chem 2005;280:6942-6949. 

MECHANISM OF SECOND HAND CIGARETTE SMOKE-INDUCED TRANSFORMATION OF NORMAL HUMAN 

BREAST EPITHELIAL CELLS 

Satya Narayan, PhD; University of Florida; CIA 2008 

The goal of this study is to determine the mechanism by which SHS promotes breast carcinogenesis. 

Building on a previous FAMRI study, Dr. Narayan has obtained preliminary data indicating that exposure 

of a spontaneously immortalized normal human breast epithelial cell line in culture to CSC both blocks 

Pol-beta-directed BER and results in transformation of the cells. Dr. Narayan proposes to test the 

hypothesis that APC-mediated blockage of BER is a principal mechanism for CSC-induced transformation 

of normal breast epithelial cells. Dr. Narayan and colleagues paln to determine whether 1) APC-mediated 

blockage of Pol-beta activity causes accumulation of mutations in normal breast epithelial cells exposed to 

CSC- and B[a]P and stimulates a mutator phenotype in conjunction with Pol-beta mutations; 2) the APC- 

6 6 P A G E

mediated blockage of Pol-beta activity causes transformation of normal breast epithelial cells exposed to 

CSC and B[a]P as indicated by anchorage-independent growth and xeongraft assays; and 3) the invasive 

characteristics of CSC- and B[a]P-transformed normal breast epithelial cells are increased in culture and 

associated with the expression of NFkappaB. The feasibility of the studies is supported by the innovative 

strategies and novel reagents that Dr. Narayan and colleagues have developed. The studies are of relevance 

to both sexes and all ethnic groups. In addition to potentially identifying an etiologic basis for SHSinduced 

breast carcinogenesis, they may pinpoint the events that lead to the development of more 

aggressive tumors and indicate novel chemopreventive and chemotherapeutic agents. 


Balusu R, Armas ML, Jaiswal AS, Kundu CN, Narayan S. Structural basis of interaction of adenomatous 

polyposis coli (APC) with DNA polymerase beta and its implications for base excision repair [abstract 

1961]. Proc Am Assoc Cancer Res 2007. 

Balusu R, Jaiswal AS, Armas ML, Bloom LB, Narayan S. Structure/function analysis of the interaction of 

adenomatous polyposis coli (APC) with DNA polymerase beta and its implications for base excision 

repair. Biochemistry 2007;46:13961-13974. 

Connors SK, Balusu R, Kundu CN, Jaiswal AS, Gairola CG, Narayan S. C/EBPb-mediated transcriptional 

regulation of bcl-xl gene expression in human breast epithelial cells in response to cigarette smoke condensate. 

Oncogene 2009;28:921-932. 

Connors SK, Basulu R, Kundu CN, Jaiswal AS, Gairola CG, Narayan S. C/EBPb regulates bcl-xl gene 

expression in human breast epithelial cells after treatment with cigarette smoke condensate. Proc Am 

Assoc Cancer Res 2008;72A. 

Connors SK, Basulu R, Kundu CN, Jaiswal AS, Narayan S. Upregulation of bcl-xl in cigarette smoke condensate-treated 

spontaneously immortalized human breast epithelial cells [abstract 1859]. Presented at 

the 47th Annual Meeting of American Society for Cell Biology. 2007. 

Jaiswal AS, Aneja A, Multani AS, Connors SK, Joshi HC, Pathak P, Narayan S. Treatment of 9-bromonoscapine 

induces irreversible mitotic arrest and apoptosis in cigarette smoke condensate-transformed 

human breast epithelial cells. Proc Am Assoc Cancer Res 2008 [abstract 2243]. 

Jaiswal AS, Aneja R, Connors SK, Joshi HC, Multani AS, Pathak S, Narayan S. 9-Bromonoscapine-induced 

mitotic arrest of cigarette smoke condensate-transformed breast epithelial cells. J Cell Biochem 2009 Feb 

19 [Epub ahead of print]. 

Jaiswal AS, Balusu R, Armas ML, Kundu CN, Narayan S. Adenomatous polyposis coli (APC) interacts 

with flap endonuclease 1 (Fen-1) and blocks its cleavage activity in base excision repair [abstract 1068]. 

Proc Am Assoc Cancer Res 2006;47. 

Jaiswal AS, Balusu R, Kundu CN, Armas ML, Narayan S. Mechanism of adenomatous polyposis coli-mediated 

blockage of long-patch base excision repair. Biochemistry 2006;45:15903-15914. 

Jaiswal AS, Narayan S. A novel function of adenomatous polyposis coli (APC) in DNA repair. Cancer Lett 

2008;271:272-280. 

Jaiswal AS, Narayan S. Role of APC in colorectal carcinogenesis (invited review). Front Biosci 

2005;10:1118-1134. 

Kundu CN, Balusu R, Jaiswal AS, Gairola CG, Narayan S. Cigarette smoke condensate-induced levels of 

adenomatous polyposis coli (APC) block long-patch base excision repair in breast epithelial cells. 

Oncogene 2007;26:1428-1438. 

Kundu CN, Balusu R, Jaiswal AS, Narayan S. Adenomatous polyposis coli-mediated hypersensitivity of 

mouse embryonic fibroblast cell lines to methylmethane sulfonate treatment: implication of base excision 

repair pathways. Carcinogenesis 2007;28:2089-2095. 

Narayan S, Jaiswal AS, Balusu R. A novel role of adenomatous polyposis coli (APC) in DNA repair and 

carcinogenesis [abstract 1627]. Proc Am Assoc Cancer Res 2005;46. 

Narayan S, Jaiswal AS, Balusu R. Tumor suppressor APC blocks DNA polymerase b-dependent strand-displacement 

synthesis and increases sensitivity to DNA methylation. J Biol Chem 2005;280:6942-6949. 

Narayan S, Jaiswal AS, Kang D, Srivastava P, Das GM, Gairola CG. Transformation of normal human 

breast epithelial cells by cigarette smoke condensate. Oncogene 2004;23:5880-5889. 

Narayan S, Jaiswal AS, Kang D, Srivastava P, Das GM, Gairola CG. Selective growth advantage of normal 

human breast epithelial cells after exposure with cigarette smoke condensate. Proc Am Assoc Cancer Res 

2004;45:7Abstract. 

Narayan S, Jaiswal AS. Novel approach for chemotherapeutic intervention of colorectal carcinogenesis 

[abstract 90]. Ind J Clin Biochem 2007;22(suppl.). 

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Narayan S, Jaiswal AS. Structure-based drug design for chemotherapy of colorectal cancer. Proceedings of 

the 95th Indian Science Congress, Part II (abstract and symposia), 2008;4-5Abstract. 

Narayan S, Roy D. Role of APC and DNA mismatch repair genes in the development of colorectal cancers. 

Mol Cancer 2003;2:41-55. 

Ye CJ, Stevens JB, Liu G, Bremer SW, Jaiswal AS, Ye KJ, Lin MF, Lawrenson L, Lancaster WD, Kurkinen 

M, Liao JD, Gairola CG, Shekhar MPV, Narayan S, Miller FR, Heng HH. Genome based cell population 

heterogeneity promotes tumorigenicity: the evolutionary mechanism of cancer. J Cell Physiol 2008 

[Epub ahead of print]. 

ESTROGEN RECEPTOR SIGNALING IN NORMAL AND CANCEROUS BREAST EPITHELIAL CELLS 

Ben-Ho Park, MD, PhD; The Johns Hopkins University; YCSA 2003 

Dr. Park’s study focuses on clarifying the mediators of estrogen receptor (ER) signaling as related to 

breast carcinogenesis. This in turn will allow for the identification of pathways involved with SHS and 

breast cancer, as the risk of increased breast cancer and SHS is primarily seen in premenopausal women. A 

normal breast epithelial line was engineered to overexpress ER alpha to create a hormonally-responsive ER 

positive nontumorigenic breast cell line. Contrary to most other studies, these results showed that over 

expression of ER in normal human breast epithelial cells lead to an agonistic response to estrogen that can 

be blocked by antiestrogen compounds such as tamoxifen. Moreover, somatic cell deletion of the p21 gene 

reversed the response of tamoxifen from antagonistic to agonistic. As loss of p21 expression can be found 

in many early breast cancer lesions, not only can abnormal estrogen signaling cause breast cancer, current 

hormonal preventive drugs may have a harmful effect on early cancerous breast tissues. Isogenic p21 

knockout cell lines have now been used to isolate drugs that can overcome this form of tamoxifen resistance 

with the hope of bringing these compounds into early phase clinical trials. 


Abukhdeir AM, Blair BG, Brenner K, Karakas B, Konishi H, Lim J, Sahasranaman V, Huang Y, Keen J, 

Davidson N, Vitolo MI, Bachman KE, Park BH. Physiologic estrogen receptor alpha signaling in nontumorigenic 

human mammary epithelial cells. Breast Cancer Res Treat 2006;99(1):23-33. 

Abukhdeir A, Vitolo M, Argani P, De Marzo AM, Karakas B, Konishi H, Gustin J, Lauring J, Garay J, 

Pendleton C, Konishi Y, Blair BG, Brenner K, Garrett-Mayer E, Carraway H, Bachman KE, Park BH. 

Tamoxifen stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci USA 

2008;105(1):288-293. 

Bachman KE , Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, 

Peters BA, Velculescu VE, Park BH. The PIK3CA gene is mutated with high frequency in human breast 

cancers. Cancer Biol Ther 2004;3:772-775. 

Bachman KE, Blair BG, Brenner K, Bardelli A, Arena S, Zhou S, Hicks J, De Marzo AM, Argani P, Park 

BH. p21 mediates the growth response to TGF beta in human epithelial cells. Cancer Biol Ther 

2004;3:221-225. 

Bachman KE, Sager J, Cheong I, Catto M, Bardelli A, Park BH, Vogelstein B, Carotti A, Kinzler KW, 

Lengauer C. Identification of compounds that inhibit growth of PhIP resistant cancer cells. Mol Cancer 

Ther 2005;4(6):1026-1030. 

Huang Y, Keen JC, Pledgie A, Marton LJ, Zhu T, Sukumar S, Park BH, Blair B, Brenner K, Casero RA Jr, 

Davidson NE. Polyamine analogues down-regulate estrogen receptor alpha expression in human breast 

cancer cells. J Biol Chem 2006;281(28):19055-19063. 

Karakas B, Weeraratna A, Abukhdeir A, Blair BG, Konishi H, Arena S, Becker K, Wood W, Argani P, De 

Marzo AM, Bachman KE, Park BH. Interleukin-1 alpha mediates the growth proliferative effects of 

transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells. Oncogene 

2006;25(40):5561-5569. 

Karakas B, Weeraratna A, Abukhdeir A, Konishi H, Gustin J, Vitolo MI, Bachman KE, Park BH. p21 gene 

knock down does not identify genetic effectors seen with gene knock out. Cancer Biol Ther 2007;6(7). 

Keen JC, Zhou Q, Park BH, Pettit C, Mack KM, Blair B, Brenner K, Davidson NE. Protein phosphatase 

2A (PP2A) regulates estrogen receptor alpha (ER) expression through modulation of ER mRNA stability. 

J Biol Chem 2005;280(33):29519-29524. 

Konishi H, Karakas B, Abukhdeir AM, Lauring J, Gustin JP, Garay JP, Konishi Y, Gallmeier Y, Bachman 

KE, Park BH. Knock in of mutant K-ras in non-tumorigenic human epithelial cells as a new model for 

studying K-ras mediated transformation. Cancer Res 2007;67(18):8460-8467. 

Konishi H, Lauring J, Garay JP, Karakas B, Abukhdeir AM, Gustin JP, Konishi Y, Park BH. A PCR-based 

6 8 P A G E

high-throughput screen with multi-round sample pooling: application to somatic cell gene targeting. 

Nat Protoc 2007;2(11):2865-2874. 

Lauring J, Abukhdeir AM, Konishi H, Garay JP, Gustin JP, Wang Q, Arceci RJ, Matsui M, Park BH. The 

multiple myeloma-associated MMSET gene contributes to cellular adhesion, clonogenic growth, and 

tumorigenicity. Blood 2008;111(2):856-864. 

Leary R, Lin J, Cummins J, Boca S, Wood L, Parsons D, Jones S, Sjoblom T, Park BH, Parsons R, Willis 

J, Dawson D, Willson J, Nikolskaya T, Nikolsky Y, Kopelovich L, Papadopoulos N, Pennacchio L, Wang 

TL, Markowitz S, Parmigiani G, Kinzler K, Vogelstein B, Velculescu V. Dramatic changes in copy number 

are a major mechanism for gene activation and inactivation in breast and colorectal cancers. Proc 

Natl Acad Sci USA 2008;105(42):16224-16229. 

Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, 

Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, 

Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler 

KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science 

2006;314(5797):268-274. 

Sui M, Huang Y, Park BH, Davidson NE, Fan W. Estrogen Receptor a Mediates Breast Cancer Cells 

Resistance to Paclitaxel through Inhibition of Apoptotic Cell Death. Cancer Res 2007;67(11):5337- 

5344. 

Weiss MB, Vitolo MI, Baerenfaller K, Marra G, Park BH, Bachman KE. Persistent mismatch repair deficiency 

following targeted correction of hMLH1. Cancer Gene Ther 2007;14(1):98-104. 

Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman 

N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, 

Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, 

Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, 

Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. The genomic 

landscapes of human breast and colorectal cancers. Science 2007;318(5853):1108-1113. 

ACTIVATION OF CUBGP1 IN BREAST BY SECOND HAND TOBACCO SMOKE 

Cynthia Zahnow, PhD; The Johns Hopkins University; CIA 2004 

Research studies have shown that tobacco carcinogens in cigarette smoke reach breast tissue and form 

DNA adducts. Furthermore, treatment of cultured mammary epithelial cells with the same tobacco carcinogens 

has been shown to lead to transformation. Although mounting scientific evidence suggests that 

cigarette smoke increases the risk of breast cancer, epidemiological studies thus far have been inconclusive 

at validating the link between cigarette smoke and breast cancer. Some large prospective studies show no 

association, while case control studies show both a strong or weak association between breast cancer and 

cigarette smoke. Of interest however, are several studies that show that smokers have an increased rate of 

death from breast cancer and that this increased mortality is due to increased metastasis of breast cancer 

cells to the lungs. Dr. Zahnow’s data support these published results, and have demonstrated that treatment 

of mammary epithelial cells with cigarette smoke leads to anchorage-independent growth, an increase 

in migration and invasion, elevated expression of genes associated with tumorigenesis, and a switch to a 

more mesenchymal-like, invasive phenotype. Dr. Zahnow‘s objective demonstrated that exposure to cigarette 

smoke leads to cumulative changes in gene expression profiles that can lead to the transformation of 

non-malignant mammary epithelial cells and result in a more aggressive and metastatic phenotype in breast 

cancer cells. Dr. Zahnow and colleagues hypothesize that exposure to cigarette smoke leads to an increase 

in the malignant progression and metastatic potential of mammary epithelial cells via regulation of epithelial-mesenchymal 

transition (EMT). 

Dr. Zahnow and colleagues have developed a cell culture model that permits analysis of the progressive, 

molecular changes that occur in mammary epithelial cells as they are temporally transformed by treatment 

with cigarette smoke. Normal mammary epithelial cells (MCF10A, MCF12A) and breast cancer cells 

(MCF7) were continuously cultured for 50 weeks with either 0.5% or 1% aqueous extracts of main stream 

cigarette smoke (CSE) or 10ug/ml or 25ug/ml organic suspensions of particulate matter (PM) from SHS. 

After every 2-week treatment of CSE or PM, a fraction of the treated cells and vehicle control cells were 

cryopreserved for later analysis and another fraction were transferred to soft agar to assess anchorage-independent 

growth. At 13 and 50 weeks of treatment cells were analyzed for migratory behavior and induction 

of molecular changes associated with EMT via quantitative PCR. Soft agar colonies were observed 

after 7 weeks of treatment with either CSE or PM, and significant numbers of colonies were observed after 

15 weeks of treatment and thereafter up to 40 weeks. Colony number was found to grow with an increase 

P A G E 6 9

in the duration of the cigarette smoke treatment. Cigarette smoke treatment also led to an increase in the 

migratory potential and invasive potential of all three cells lines tested as well as a more spindle-like appearance. 

Microarray analysis after 21 weeks of 0.5% CSE treatment revealed that the MCF10A cells had 

undergone changes in gene expression that are representative of EMT, including increases in vimentin, N- 

cadherin, snail, transforming growth factor beta, and decreases in E-cadherin. Removal of these cells from 

0.5% CSE followed by culture without CSE for an additional 20 weeks demonstrated that the EMT gene 

expression profile is not easily reversed as these cells retained many of the EMT changes that were initially 

observed in the array analysis. This EMT expression profile was validated by quantitative PCR at both 13 

and 50 weeks of treatment. Non-EMT changes include an increase in the expression of the RNA binding 

protein, CUGBP1, and increases in expression of the oncogenic transcription factor, C/EBP beta-LIP. 

Studies are underway in mice to validate tumor formation and metastasis. Dr. Zahnow has demonstrated 

that mammary epithelial cells treated with either mainstream cigarette smoke extract (CSE) or SHS PM, 

show evidence of anchorage-independent growth, increased migration, increased invasiveness, elevated 

expression of genes associated with tumorigenesis, and changes in gene expression that are associated with 

epithelial to mesenchymal transition (EMT). During EMT, epithelial cells lose cell-cell contacts and undergo 

cytoskeletal changes that permit them to become more motile and invasive. These results suggest that 

breast cancers arising in smokers or those subjected to SHS will become more invasive and metastatic than 

tumors from women who are not exposed to cigarette smoke. These data support Dr. Zahnow’s hypothesis 

that exposure to cigarette smoke increases a woman’s risk of developing metastatic breast cancer. 

SECOND HAND SMOKE AND ITS ROLE IN BREAST CANCER 

Cynthia Zahnow, PhD; The Johns Hopkins University; CIA 2008 

Smoking and exposure to SHS leads to cumulative changes in gene expression profiles that over time 

increase a woman’s risk of developing breast cancer. Dr. Zahnow hypothesizes that exposure of mammary 

epithelial cells to cigarette smoke leads to tumorigenesis via regulation of epithelial-mesenchymal transition 

(EMT), Wnt signaling, and cancer stem cell activity. She also hypothesizes that gene silencing, caused by 

aberrant epigenetic regulation, plays a role in both the early and late stages of cigarette smoke-induced 

transformation. To confirm these hypotheses and to identify the molecular mechanisms involved, Dr. 

Zahnow and colleagues have developed a cell culture model that will allow them to study the progressive, 

transforming effects of cigarette smoke on mammary epithelial cell behavior and to assess the impact of 

chronic cigarette smoke exposure on tumorigenesis and breast cancer. The specific aims are to 1) demonstrate 

using in vitro and in vivo models that both SHS and main stream cigarette smoke can transform 

human mammary epithelial cells and lead to tumorigenesis; and 2) characterize progressive, epigenetic 

changes in human mammary epithelial cells chronically exposed to both SHS and main stream cigarette 

smoke and to correlate these changes with transformation. Experiments will include culture of cigarette 

smoke treated cells in soft agar assays to test for anchorage independent growth, transmembrane assays of 

migration and invasion, and in xenograft studies to assess tumorigenic and metastatic potential in mice. 

Molecular markers for EMT will be validated by PCR, immunocytochemistry, and western blot analysis. 

Epigenetic changes in Wnt signaling and other regulatory genes will be conducted using PCR and methylation 

specific PCR. Dr. Zahnow has developed a cell culture model that permits analysis of the progressive 

molecular changes that occur in mammary epithelial cells as they are slowly transformed by many weeks of 

treatment with cigarette smoke. Her preliminary data suggest that chronic exposure of mammary epithelial 

cells to cigarette smoke leads to EMT, anchorage independent growth, regulation of Wnt signaling, and an 

increase in the cancer stem cell population. Dr. Zahnow’s research will identify new epigenetic targets and 

silenced gene expression profiles in critical, transformed populations that are therapeutically relevant for 

those individuals exposed to cigarette smoke and at increased risk for developing breast cancer. 

Additionally, the results from this study will have wide-ranging impact on the clinical assessment of breast 

cancer risk, the early detection of cancer, and the improvement of existing strategies. 

EPOXYGENASE MECHANISMS OF BREAST CANCER PROGRESSION 

David A. Potter, MD, PhD; University of Minnesota Twin Cities; CIA 2005 

Epoxygenases have been linked to human cancer. Dr. Potter and colleagues discovered that inhibition of 

epoxygenases inhibits the growth of breast cancer xenografts in nude mice. Dr. Potter’s research seeks to 

determine if epoxygenases are potential therapeutic targets in breast cancer. The research is based on the 

hypothesis that epoxygenase activation promotes breast cancer progression by promoting protein kinase B 

(Akt) phosphorylation and cancer cell survival. Akt is a protein that, when activated, promotes resistance to 

cell death, and thereby is a major regulator of cancer survival. 

7 0 P A G E

Overexpression of the transmembrane tyrosine kinase insulin-like growth factor 1 receptor (IGF-IR) or 

its ligands (e.g., IGF1) correlate with cancer development and progression. For example, activation of the 

IGF-IR signaling pathway in estrogen receptor (ER) positive breast cancer has anti-apoptotic effects and 

targeting IGF-IR in ER-negative breast cancer cells decreases metastasis. The mechanism of action of IGF- 

1R in breast cancer still needs to be elucidated in order to better develop effective and efficient cancer 

therapies by targeting this pathway. Dr. Potter proposes a novel mechanism of action for IGF-IR in breast 

cancer progression by which cytochrome P450 1A1 (CYP1A1) metabolizes dietary essential omega-3 fatty 

acids into the eicosanoid 17(18)-epoxyeicosatetraenoic acid (17,18-EpETE). Specifically Dr. Potter 

hypothesizes that IGF-IR/IGF1 induces expression of CYP1A1 which will produce 17,18-EpETE, thereby 

promoting breast cancer proliferation and survival. CYP1A1 has previously been of particular interest due 

to its roles metabolizing exogenous compounds (e.g., polycyclic aromatic hydrocarbons) into carcinogenic 

compounds and metabolizing endogenous compounds such as estrogen. CYP1A1 is also responsible of 

selectively oxygenating eicosapentaenoic acid (EPA, an omega-3 essential fatty acid commonly found in 

fish oil) into 17,18-EpETE. Small interfering RNA was utilized to knock down CYP1A1 in breast cancer 

lines. A liquid chromatography electrospray ionization tandem mass spectrometric (LC/ESI.MS/MS) 

method was developed to measure 17,18-EpETE levels. CYP1A1 knockdown suggested a role for this 

CYP in breast cancer cell proliferation. Measurement of IGF1 effects on gene expression in the T47D 

breast cancer line indicates that IGF1 induces CYP1A1 expression by more than 10-fold. In vitro incubation 

of EPA with human CYP1A1 expressed in baculovirus extracts results in NADPH (the reduced form 

of nicotinamide adenine dinucleotide phosphate)-dependent synthesis of 17,18-EpETE. Furthermore, 

MCF7 and MDA-MB-231 cells contain endogenous 17,18-EpETE, as assayed by the novel LC-ESI- 

MS/MS method. A MTT proliferation assay demonstrated that exogenous 17,18-EpETE significantly promotes 

MCF7, T47D, and MDA-MB-231 cell proliferation under serum starvation conditions (P-value < 

0.05), exhibiting a threshold for inducing proliferation between 100 nM and 1 microM concentration. 

Taken together, these results suggest that IGF-IR plays a role in breast cancer progression, in part, by 

inducing CYP1A1 and associated 17,18-EpETE production, a potential mitogenic and pro-survival 

eicosanoid. 

Dr. Potter has also developed a method for detection of passive smoke exposure in children and adults 

using oral based rapid test technology. The epoxyeicosatrienoic acids (EETs) are signaling molecules 

formed by cytochrome P450 epoxygenase catalyzed epoxidation of arachidonic acid. These nonclassic 

eicosanoids have been implicated in diverse biological activities in a variety of systems. EETs enhance 

proliferation, motility and survival of breast cancer cells. An accurate and sensitive bioanalytical method 

that quantifies the levels of EETs in cancer cells and tumor tissue would help delineate the mechanisms of 

activity. Therefore, a liquid chromatography electrospray ionization tandem mass spectrometric (LC-ESI- 

MS/MS) method was developed to quantitatively measure the content of three EET regioisomers— 

(±)8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoic acid [(±)8,9-EET], (±)11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic 

acid [(±)11,12-EET], and (±)14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoic acid [(±)14,15-EET]—in biological 

samples such as cultured cells and plasma. Using synthetic standards, the lower limit of detection under 

multiple reaction monitoring (MRM) scan mode was 20 pg for all three regioisomers. This method has 

been successfully used in the preliminary study of the effect of estradiol on the level of EETs in MCF7 

estrogen receptor (ER)-positive breast cancer cells, which is of interest because EETs have been reported 

to promote breast cancer cell motility, while estradiol is inhibitory. The result indicates that the presence of 

exogenous estradiol (1 nM) reduces the total amount of all the three EET regioisomers (p=0.009, 0.006, 

and 0.026 for (±)8,9-EET, (±)11,12-EET, and (±)14,15-EET, respectively). These results suggest that 

estradiol could reduce motility in ER + breast cancer and possibly affect the balance between proliferation 

and motility, in part due to reduction of EETs. 


Srirangam A, Mitra R, Wang M, Gorski JC, Badve S, Baldridge LA, Hamilton J, Kishimoto H, Hawes J, 

Li L, Blum JS, Donner DB, Sledge GW, Nakshatri H, Potter DA. Effects of HIV protease inhibitor ritonavir 

on Akt-regulated cell proliferation in breast cancer. Clin Cancer Res 2006;12:1883-1896. 

Yamoutpour F, Bodempudi V, Park SE, Mauzy MJ, Dudek A, Kratzke RA, Woo RA, Potter D, 

O’Rourke DM, Tindall DJ, Farassati F. Gene silencing for epidermal growth factor receptor variant III 

induces cell-specific cytotoxicity. Mol Cancer Ther 2008;7(11):3586-3597. 

P A G E 7 1

ENVIRONMENTAL AND GENETIC RISK FACTORS OF BREAST CANCER 

Yun-Ling Zheng, PhD, MPH; Georgetown University; CIA 2005 

The high incidences of breast cancer, together with the fact that more than half of breast cancer cases 

remain unexplained, emphasize the need to identify risk factors for breast cancer. Tobacco smoking is 

among the leading preventable risk factors for cancer in general. Despite considerable research, the association 

between tobacco smoking and breast cancer risk remains controversial. Several studies suggest that 

active smoking and SHS increase the risk of breast cancer in subgroups of susceptible women. Mutagen 

sensitivity has been shown to identify subgroup of population at risk for tobacco-induced cancers, such as 

lung, head and neck, and bladder cancers. A breast cancer case-control study (150 cases and 176 controls) 

was conducted to investigate the associations between bleomycin-induced chromosomal breaks and risk of 

breast cancer and to evaluate the effect of interactions between bleomycin sensitivity and tobacco smoking 

on breast cancer risk in the general population. The bleomycin sensitivity was determined by the mutagen 

sensitivity assay (MSA) that quantifies the frequency of chromosomal breaks induced by bleomycin in cultured 

lymphocytes. The MSA is a phenotypic biomarker that measures the combined effects of individual’s 

sensitivity to carcinogens, DNA repair capacity and/or function of cell cycle checkpoints. Dr. Zheng found 

that bleomycin-induced chromosomal breaks were significantly higher in breast cancer patients compared 

with healthy women controls. Defining women who had more than 0.64 breaks per cell (the median value 

in controls) as bleomysin sensitive, women who expressed bleomycin sensitive phenotype had a significantly 

2.7-fold (95% CI = 1.68 to 4.51) increased risk of breast cancer compared with women who expressed 

bleomycin resistant phenotype. When the bleomycin-induced chromosomal breaks were divided into quartiles, 

a significant dose-response relationship between bleomycin sensitivity and breast cancer risk was 

observed compared with women in the 1st quartile. Dr. Zheng also observed a significant interaction 

between bleomycin sensitivity and tobacco smoking (P = 0.03). Women who had bleomycin sensitive phenotype 

and smoked cigarettes were at significant 3.9-fold increased risk of breast cancer compared with 

women who had bleomycin resistant phenotype and were non-smokers. The data suggests that bleomycin 

sensitivity is significantly associated with breast cancer risk, and tobacco smoking increases risk of breast 

cancer among women who are sensitive to tobacco carcinogens. 

NICOTINE: SIGNALING AND MITOGENESIS IN THE BREAST 

Chang-Yan Chen, MD, PhD; Harvard University; CIA 2007 

Although cigarette smoke is directly correlated with carcinogenesis of various types of cancers, the 

mechanisms of cancer induced by SHS exposure (especially that of breast cancer), are undefined. Nicotine 

is a major component in cigarettes and can be measured at high concentrations in the bloodstream of 

smokers. It has been shown that nicotine binds to the nicotine acetylcholine receptor (nAChR), resulting 

in activation of several mitogen-related signals and of pro-survival pathways in various types of normal cells 

as well as cancer cells. Dr. Chen and colleagues are investigating the signaling pathways by which nicotine 

potentiates tumorigenesis in human mammary epithelial-like or cancerous cell line. Demonstration that 

human breast epithelia-like MCF10A and cancer MCF7 cells both express four subunits of nAChR has 

been made. The treatment of these cells with nicotine enhances the activity of protein kinase C (PKC). 

Nicotine also stimulates incorporation of [ 3 H] thymidine into the genome of the cells and forces serumstarved 

cells to enter S phase of the cell cycle. Importantly, upon nicotine treatment, the mobility of 

MCF10A and MCF7 cells increases. Experiments with small interfering RNA or ectopic expression of 

nAChR demonstrated that cdc42, a downstream effector of PKC, functions as a key player in nicotinemediated 

migratory activity in the cells. The data suggest that nicotine interacts with the nACh receptor, 

initiates a signaling cascade (involving PKC and cdc42), and augments migration of mammary epithelial or 

tumor cells. Continuation of the investigation will provide a better understanding of nicotinemediated 

signaling in breast cancer. 

Epidermal growth factor receptor (EGFR) is a major mitogenic-related receptor on the surface of cells 

and belongs to the family of tyrosine kinase receptors. Ligation of EGFR activates various intracellular 

signaling pathways through protein phosphorylation cascades. Nicotine treatment has been shown to 

promote cell survival in different types of human or murine normal or cancer cells. Dr. Chen has 

demonstrated that nicotine, via binding to its receptor, activates protein kinase C (PKC)/cdc42 to 

promote cell migration and invasion in normal mammary epithelial MCF10A and breast cancer MCF7 

cells. However, the mechanisms of nicotine in regulation of non-neuronal cell growth or survival remain 

undefined. In this study, Dr. Chen examined various signaling pathways in response to nicotine exposure. 

Two hours after adding nicotine, the level of EGFR was dramatically reduced in MCF10A and MCF7 

cells, which suggest that the receptor is activated and further internalized, as that observed in response to 

7 2 P A G E

mitogenic stimuli. After the same treatment, Raf/extracellular signal-regulated kinase (ERK), PKC, and 

Akt pathways were transiently activated and c-Src was phophorylated at tyrosine residues. However, the 

treatment with mecamylamine hydrochloride (MCA), which is a nicotine inhibitor, blocked nicotinemediated 

activation of all these pathways. In contrast, the addition of CL-6 (an EGFR inhibitor) 

suppressed the activation of Raf/ERK, PKC, and Akt pathways, but had no effect on c-Src 

phosphorylation. A neutralizing anti-EGFR antibody that only blocks the binding of the receptor without 

affecting the function of its transmembrane or intracellular domains plays no role in nicotine-mediated 

activation. But, knockdown of c-Src with the small hairpin RNA abolished EGFR internalization as well as 

activation of Raf/ERK, PKC, or Akt. Thus, the results reveal a crosstalk between nicotine and EGFRmediated 

intracellular signaling pathways and that c-Src plays as an intermediator to link the actions 

governed by nicotine receptor and EGFR to promote mammary epithelial or breast cancer cell growth. 


Guo J, Ibaragi S, Zhu T, Luo LY, Hu GF, Huppi PS, Chen CY. Nicotine promotes mammary tumor 

migration via a signaling cascade involving protein kinase C and cdc42. Chen Cancer Res 2008;68:8473- 

8481 [Press Release]. 

NICOTINE INDUCED SRC SIGNALING IN LUNG METASTASIS 

Hong-Gang Wang, PhD; The Pennsylvania State University; CIA 2007 

Breast cancer is the most common cancer diagnosed in women and, even with early detection and treatment; 

these cancers still metastasize at a high rate. Approximately 30% of women initially diagnosed with 

earlier stages of breast cancer eventually develop metastatic disease. Metastases are a hallmark of aggressive 

and refractory cancers and are the cause for 90% of the mortalities attributable to cancer. Exposure to 

smoking has been shown to promote metastasis from the breast to the lungs, but the underlying mechanism 

has not been established. Anoikis is an inherent mechanism that induces apoptosis by activating the 

death effector Bax in cells detached from their normal extracellular matrix environment and therefore plays 

an inhibitory role in metastatic dissemination of cancers. Nicotine, a major component in tobacco smoke, 

is known to activate the tyrosine kinase Src. Activated Src has been shown to inhibit anoikis, but the 

molecular mechanisms of this control have not been thoroughly explored. Dr. Wang has recently identified 

the stabilization of Mcl-1 and suppression of Bim as critical events during Src-mediated suppression of 

anoikis. Specific targeting of Src with the small molecule inhibitor dasatinib promotes normal anoikis 

response through restoration of Bim induction and Mcl-1 degradation. The objectives of this study are to 

provide a greater understanding of metastatic spread caused by cigarette smoke exposure and to explore 

the possible chemotherapeutic benefits of dasatinib in the prevention of SHS-induced breast cancer metastasis 

to the lungs. 


Woods NT, Yamaguchi H, Lee FY, Bhalla KN, Wang HG. Anoikis, initiated by Mcl-1 degradation and 

Bim induction, is deregulated during oncogenesis. Cancer Res 2007;67:10744-10752. 

Yamaguchi H, Woods NT, Dorsey JF, Takahashi Y, Gjertsen NR, Yeatman T, Wu J, Wang HG. Src directly 

phosphorylates Bif-1 and prevents its interaction with Bax and the initiation of anoikis. J Biol Chem 

2008;283:19112-19118. 

Yamaguchi H, Woods NT, Piluso LG, Lee HH, Chen J, Bhalla KN, Monteiro A, Liu X, Hung MC, Wang 

HG. p53 acetylation is crucial for its transcription-independent pro-apoptotic functions. J Biol Chem 

2009; Epub March 5. 

TARGETING THE SRC ONCOGENE IN BREAST CANCER THERAPY 

Joyce Slingerland, MD, PhD; University of Miami; CIA 2007 

Breast cancer is the second highest cause of cancer mortality in women, and tobacco smoke is causally 

implicated in breast cancer. Exposure to tobacco smoke increases breast cancer risk. Dr. Slingerland’s team 

is investigating novel mechanisms underlying the pathogenesis of cancer and how activation of the Src 

oncogene promotes cell cycle progression by inactivating a key cell cycle inhibitor, p27. Potential therapeutic 

applications by using a novel Src inhibitor drug, AZD0530, to oppose resistance to antiestrogen drugs 

have been tested. While up to 70% of breast cancers express the estrogen receptor (ER), only 60-70% 

responds to the antiestrogen tamoxifen and responders often acquire resistance. Antiestrogens cause G1 

cell cycle arrest. p27 is a cell cycle inhibitor that critically regulates breast cell proliferation. Dr. Slingerland 

showed that p27 is often reduced in association with a poor prognosis in primary human breast cancers. 

P A G E 7 3

Estrogen activates the cell cycle by triggering p27 degradation. Prior work showed that p27 is required for 

therapeutic efficacy of tamoxifen. Dr. Slingerland recently demonstrated that Src binds and phosphorylates 

p27, promoting p27 destruction. The Src signaling kinase binds epidermal growth factor receptor (EGFR) 

family members to synergistically stimulate cell proliferation, motility, and survival. Src and EGFR/Her2 

family members are over-expressed in up to 70% of primary human breast cancers. Src is also activated by 

estrogen. When estrogen binds the ER, it recruits and activates Src signaling to promote mitogenesis. 

Overexpression of Her2 and Src in ER positive breast cancer cells alters p27 phosphorylation, impairs 

p27’s cdk inhibitor action, and causes antiestrogen resistance. The hypothesis is that Src promotes p27 

degradation and loss of function, leading to antiestrogen resistance. ER positive breast cancers with high 

Src activity may show reduced p27 protein and be resistant to antiestrogen therapy. In the last year, Dr. 

Slingerland obtained xenograft data showing that the Src inhibitor, AZD0530, acts synergistically with 

anastrozole to inhibit the growth of ER positive breast cancer xenograft tumors in vivo, and thus may prevent 

or delay resistance to antiestrogens. Moreover, the Src inhibitor caused a greater increase in p27 levels 

and a greater reduction in the proliferation marker Ki67 in these xenograft tumors than either drug when 

given alone. Thus, restoration of p27 function restores the efficacy of analstrozole to impair breast cancer 

cell proliferation. Another goal was to further investigate how Src mediated phosphorylation influences 

cyclin-Cdk action. Current data indicate that Src-mediated tyrosine phosphorylation of p27 bound to 

cyclin D-Cdk complexes are essential for catalytic activation of these complexes. Further work is underway 

to determine how PI3K effectors and Src influence the assembly of p27-cyclin-Cdk complexes, their 

nuclear import, and their activation. Xenograft experiments are underway to test if AZD0530 and ER 

blockade by selective ER modulators, such as faslodex and IOS5974, can delay or prevent resistance to 

faslodex in ER positive breast cancer xenografts. The data may support clinical trials of Src inhibitors to 

prevent or delay the development of antiestrogen resistance in ER positive breast cancer and expedite the 

clinical implementation of Src inhibitors in breast cancer therapy. 

ROLE OF SECOND TOBACCO HAND SMOKE IN BREAST CANCER ANGIOGENESIS AND METASTASIS 

Shalom Avraham, MD, PhD; Harvard University; CIA 2007 

SHS is classified as a known human carcinogen which causes atherosclerosis and cancer. Recent studies 

have strongly suggested that breast cancer has a nexus with passive and active smoking. Dr. Avraham examined 

the effect of nicotine exposure on breast cancer cell proliferation, survival, and apoptosis. The results 

show that breast cancer cells exposed to nicotine had decreased extracellular signal-regulated kinase (ERK) 

activation and enhanced activation of protein kinase B (AKT). Nicotine had no effects on vascular 

endothelial growth factor (VEGF) secretion from breast cancer cells but it enhanced the transmigration of 

breast cancer cells. As a result, nicotine increases the cell survival of breast cancer cells through the activation 

of the phosphatidyl-inositol-3-kinase (PI3K)-AKT pathway and acts as a chemotaxis agent to induce 

invasion and migration of breast cancer cells. Further, nicotine induced changes in genes are indicative for 

the process of epithelial to mesenchymal transition (EMT), as characterized by decrease in E-cadherin and 

ZO-1 expression. Thus, nicotine is able to induce invasion and EMT of breast cancer cells, contributing to 

breast cancer progression. 

HOW SECOND-HAND TOBACCO SMOKE AFFECTS BREAST TUMOR DORMANCY IN THE LUNG 

Stuart S. Martin, PhD; University of Maryland; CIA 2007 

Nearly 90% of all human solid tumors arise from a class of cells known as epithelial cells. When these 

tumor cells begin to spread through the bloodstream, they cannot easily fit through capillaries due to their 

large size, thus often becoming trapped in the first capillary bed they encounter, which is generally in the 

lung. A further understanding of how circulating tumor cells invade the lung could improve the understanding 

of the risks posed by exposure to SHS. In recent publications, Dr. Martin has noted that circulating 

tumor cells generate novel extensions, that he has named microtentacles. These microtentacles are supported 

by a unique coordination of microtubules and vimentin intermediate filaments. Importantly, these 

microtentacles are restrained by polymerized actin that provides a barrier at the cell surface. Cigarette 

smoke has been shown to disrupt polymerized actin and could therefore increase microtentacles. As recommended 

by FAMRI grantee Dr. Jeff Wolf, Dr. Martin obtained cigarette smoke condensate and tested 

its effects on breast tumor cells. In the weakly aggressive Zr-75-1 cell line, which has low levels of microtentacles, 

cigarette smoke condensate significantly increased microtentacles. These results pose the question 

of whether exposure to cigarette smoke can increase the aggressive actions of circulating breast tumor cells. 

Since the lung is such an important site of primary metastasis, the question of how SHS affects circulating 

tumor cells is particularly relevant. It is now possible to use light emission from firefly luciferase to track 

7 4 P A G E

circulating tumor cells in living mice. This method can be used to determine how cigarette smoke affects 

tumor cell trapping and recurrence in living mice. 


Whipple, RA, Balzer EM, Cho EH, Matrone MA, Yoon JR, Martin SS. Vimentin filaments support extension 

of tubulin-based microtentacles in detached breast tumor cells. Cancer Res 2008;68(14):5678- 

5688. 

ROLE OF PBRS IN BREAST CANCER INDUCED BY SECOND HAND TOBACCO SMOKE 

Salil K. Das, ScD, DSc; Meharry Medical College; CIA 2007 

Dr. Das’ hypothesis is that SHS causes breast cancer initiation or progression by increasing the 

messenger RNA (mRNA) expression of a novel gene encoding a protein, peripheral benzodiazepine 

receptor (PBR), nuclear localization of PBR, and PBR-mediated cholesterol transport into the nucleus. To 

achieve this goal, Dr. Das has developed a modified version of the CULTEX cell culture smoke exposure 

model system to expose human breast cell lines to both direct and SHS and study whether smoke exposure 

causes an increase in PBR gene expression associated with an increase in cell proliferation. Three different 

normal breast cell lines (MCF-10, MCF-12A, and MCF-12F) were grown in a complete culture media 

(DMEM/F-12) and exposed to both direct SHS generated from 1R3F cigarettes in a THRI MS-SS smoke 

exposure system in a time- and dose-dependent manner. A sham control group was also used where cells 

were exposed to the same environmental condition without smoke exposure. The cells showed an increase 

in proliferation rate and morphological changes when exposed to low levels of either direct (MS) or SHS 

(SS) exposure than sham control (SH). Proliferative index, as assessed by Ki-67 immunochemistry, was 

significantly higher in both MS and SS groups than SH group. MS and SS exposed cells showed increased 

level of cell cycle protein cyclin D1 and cell differentiation marker of proliferating-cell nuclear antigen 

(PCNA) than SH. However, at higher levels of smoke exposure, these cells showed evidence of apoptosis. 

Furthermore, exposure to both direct and SHS caused an activation of AP-1 signaling as evident by an 

increase in the levels of c-Fos, Fos B, and c-Jun. Immunohistochemical, western blot, and PCR analysis 

revealed a significant increase in PBR protein and mRNA levels in these cells and in particular in the nuclei 

due to both direct and SHS exposure. Dr. Das and his team are now investigating whether smoke-induced 

increase in nuclear PBR is associated with an increase in the nuclear cholesterol uptake. Furthermore, Dr. 

Das and colleagues want to know which phase of the cell cycle is affected by smoke-induced increase in 

cellular proliferation. These studies will provide insights into future therapeutic strategies to counteract 

smoke-induced breast cancer. 


Das SK. Peripheral benzodiazepine receptor, a biomarker for breast cancer. Presented at the 96th Indian 

Science Congress. Shillong, Meghalaya, India, Jan 3-7, 2009. 

Das SK. Role of peripheral benzodiazepine receptors in breast cancer induced by secondhand smoke. 

Presented at the Annual FAMRI meeting. Boston, MA, May 12-14, 2008. 

Das SK. Role of peripheral benzodiazepine receptors in breast cancer induced by secondhand smoke. 

Presented at the Annual FAMRI Meeting. Miami, FL, May 14-16, 2007. 

Miller L, Mukherjee S, Das SK. Effect of cigarette smoke exposure on the binding characteristics of 

dopamine receptors and transporter in guinea pig brain. Presented at a FASEB Meeting. San Diego, CA, 

April 4-9, 2008. 

Miller LR, Mukherjee S, Ansah TA, Das SK. Cigarette smoke and dopaminergic system. J Biochem. Mol 

Toxicol 2007;21:325-335. 

Miller LR, Das SK. Cigarette smoking and Parkinson’s disease. EXCLI Journal 2007;6:93-99. 

Mukherjee S, Das SK. Development of methods for exposure of cultured cells to direct and secondhand 

cigarette smoke. Presented at a FASEB Meeting. San Diego, CA, April 5-9, 2008. 

Mukhopadhyay S, Guillory B, Mukherjee S, Das SK. Control of Proliferation, migration and invasion of 

rat breast tumor cells by PK11195, an antagonist of peripheral benzodiazepine receptors. Presented at 

the 5th Annual Era of Hope Meeting. Baltimore, MD, June 25-28, 2008. 

Mukhopadhyay S, Mukherjee S, Das SK. Inhibition of AP-1 activation in DMBA-induced rat breast 

tumors by soy protein. Presented at the Annual FASEB Meeting. Washington, DC, Apr 28-May 2, 

2007. 

Mukhopadhyay S, Rajaratnam V, Mukherjee S, Das SK. Control of peripheral benzodiazepine receptormediated 

breast cancer in rats by soy protein. Mol Carcinog 2008;47:310-319. 

P A G E 7 5

Schaeffer MW, Sinha Roy S, Mukherjee S, Das SK. Identification of lutein, a dietary antioxidant carotenoid 

in guinea pig tissues. Biochem Biophys Res Commun 2008; 374:378-381. 

Schaeffer MW, Sinha Roy S, Mukherjee S, Das SK. Improved high-performance liquid chromatography 

method with diode array detection for simultaneous analysis of retinoic acid isomers, retinol, retinyl 

esters, vitamin E, and selected carotenoids in guinea pig tissues. Presented at a FASEB Meeting. San 

Diego, CA, Apr 5-9, 2008. 

Sinha Roy S, Mukherjee S, Das SK. Beneficial effect of whey protein on dimethylbenz[a]anthraceneinduced 

breast cancer in female rats. Presented at a FASEB Meeting. Washington, DC, Apr 28-May 2, 

2007. 

Sinha Roy S, Mukhopadhyay S, Mukherjee S, Das SK. Breast cancer is associated with an increase in the 

activity and expression of cholinephosphotransferase in rats. Life Sci 2008;83:661-665. 

TELOMERE DYSFUNCTION AND BREAST CANCER DETECTION 

David P. Gilley, PhD; Indiana University; CIA 2008 

Telomere dysfunction is a key driving force behind the genomic instability observed in early cancer 

lesions. Since genomic instability is one of the earliest neoplastic changes known to occur in tumorigenesis, 

determining its cause(s) is critical for understanding the etiology of cancer for early detection and therapeutic 

purposes. Several recent reports support the concept that defects in telomere maintenance initiate 

genomic instability, eventually resulting in the development of breast cancer and other cancers. There are 

two major causes of telomere dysfunction leading to genomic assault and subsequent disease: replicative 

aging and environmental assaults. Aging has long been recognized as a source for telomere dysfunction 

through increasing numbers of cell divisions in the absence of sufficient telomerase activity. Environmental 

assaults, including passive and active smoking, that correlate with telomere shortening are beginning to be 

identified and recognized. Several recent reports suggest that smoking can significantly decrease telomere 

length, thereby increase the chance of telomere dysfunction potentially leading to cancer. This study focuses 

on an innovative method for detecting telomere dysfunction markers in breast tumor tissue and corresponding 

circulating DNA for early breast cancer detection. Dr. Gilley has developed a PCR-based method 

to detect and analyze chromosome fusions from isolated genomic DNA initially using cell lines with 

known percentages of end-to-end chromosome fusions. Importantly, his team has discovered recently that 

there are relatively short fragments of previously identified fragile DNA sites and other non-telomeric 

DNA within these telomere-to-telomere fusion junctions. The discovery of these DNA sequences at chromosome 

fusion junctions provides important clues regarding the mechanisms responsible for generating 

these junctions. Additionally, using this detection assay, Dr. Gilley and colleagues have found that these 

chromosome fusions are present in over 90% of tumor tissue tested, very early during breast tumorigenesis. 

Dr. Gilley’s research will determine the prevalence of telomere dysfunction in breast tumor tissue samples 

and corresponding circulating DNA. Based upon their preliminary results, Dr. Gilley and colleagues anticipate 

that they will be able to develop a simple, accessible clinical test for very early detection of breast cancer. 

By using their method to identify these molecular markers (chromosome fusion junctions) in the early 

stages of breast tumorigenesis, they will provide an immensely useful diagnostic tool for detection, prevention, 

and treatment of breast cancer. 

ROLE OF TRANSCRIPTION FACTOR TBX2 IN BREAST CANCER 

Karoline J. Briegel, PhD; University of Miami Miller School of Medicine; CIA 2008 

Gene amplification of T box transcription factor 2 (TBX2) occurs in many human cancers, including 

invasive and hereditary cancers of the breast. TBX2 is a key regulator of embryonic development involved 

in cell specification and morphogenesis. Published in vitro studies have suggested that TBX2 may also play 

an important role in tumorigenesis. TBX2 represses ADP-ribosylation factor (ARF) and p21, two major 

growth control genes in the p53 tumor suppressor pathway and thereby abrogates p53-induced cellular 

senescence. However, the in vivo role of TBX2 in breast cancer has remained elusive. By generating a 

mouse model for TBX2 deregulation in breast cancer (MMTV-Tbx2 transgenics), Dr. Briegel has obtained 

the first provocative evidence that abnormal TBX2 expression in mammary epithelial cells causes breast 

tumor formation. In addition, MMTV-TBX2 transgenic mice exhibit defects in mammary gland development 

similar to pre-neoplastic lesions found in breast cancer patients. These defects are suggestive of that 

both p53-dependent as well as p53-independent mechanisms were perturbed by TBX2 overexpression. 

Moreover, Dr. Briegel’s work has uncovered a previously unappreciated function of TBX2 in breast metastasis. 

Ectopic expression of Tbx2 in normal HC11 mammary epithelial cells results in down regulation of 

E-cadherin, an epithelial adhesion molecule whose loss has been implicated in metastasis. Conversely, RNA 

7 6 P A G E

interference-mediated knockdown of TBX2 in the metastatic MDA-MB435 human breast carcinoma cell 

line reduces the invasiveness of these tumor cells in vitro. Together, these studies provide important novel 

insights into the molecular mechanisms underlying breast cancer development, and will be essential in further 

evaluating to what extent TBX2 can be used as a biomarker and therapeutic target for the prevention 

and therapy of metastatic breast disease. 

PROMOTER HYPERMETHYLATION AS A MOLECULAR MARKER FOR BREAST CANCER 

Hetty E. Carraway, MD; The Johns Hopkins University; YCSA 2004 

Dr. Carraway’s hypothesis is that molecular evidence of lymph node cancer involvement exists in some 

women with histologically negative nodes, and may be detected in DNA by methylation-specific PCR of 

hypermethylated CpG islands (regions of high density of C followed by G). Her goal is to develop methods 

to detect tumor-specific DNA methylation changes and to examine sentinel lymph node biopsies for 

tumor-specific methylation changes that can be clinically prognostic. Results show that methylation found 

in sentinel lymph nodes is abnormal, and the study has been expanded to establish testing that shows lack 

of abnormal methylation in normal lymph nodes. By examining the methylation pattern in histologically 

negative nodes from breast cancer patients, which patients are likely to suffer a breast cancer recurrence 

will be predicted. 

HDGF, A NEW POTENTIAL TARGET FOR BREAST CANCER THERAPY 

Jun Yang, PhD; The Johns Hopkins University; YCSA 2005 

Dr. Yang and collaborators have identified hepatoma-derived growth factor (HDGF) as a nuclear-targeted 

mitogen over expressed in human breast cancer. Their goal is to determine the importance of HDGF as 

a new target for breast cancer therapy. Using viral delivery techniques to silence the HDGF gene, they 

found HDGF is necessary for tumor cell growth both in vitro and in nude mouse model. Additionally, the 

migration ability of a breast tumor cell line was decreased dramatically when the HDGF protein level was 

knocked down, implying that HDGF plays an important role in breast tumor metastasis. Given the observation 

that women smokers have decreased serum estrogen levels and more importantly, estrogen receptor 

negative breast tumors usually have increased HDGF expression levels, they discovered that estrogen 

receptors directly regulate HDGF gene expression. Using chromatin immunoprecipitation, reporter gene 

assay, and electromobility shift assay, they provided evidence that different estrogen receptor isoforms play 

different roles on HDGF gene expression. Currently, Dr. Yang is generating an animal model to overexpress 

HDGF in mammary tissue to determine whether HDGF is essential for breast tumor formation and 

for further novel therapy testing. Taken together, a smoking related protein HDGF is a valuable target for 

breast cancer therapy. 


Yang J, Everett AD. Hepatoma-derived growth factor binds DNA through the N-terminal PWWP domain. 

BMC Mol Biol 2007;8:101. 

Yang J, Everett AD. Hepatoma derived growth factor represses SET and MYND domain containing 1 

gene expression through interaction with C-terminal binding protein. J Mol Biol 2009;386:938-950. 

TARGETING THE TROP-2 RECEPTOR PATHWAY IN CANCER 

Loren Michel, MD; Washington University; 2006 YCSA 

Tumor cells frequently produce receptors on the surface of cells at higher levels than normal tissues. This 

increased production often means that the tumor has become dependent on the receptor for its ability to 

grow and invade. Due to this dependency, targeting tumor cells with monoclonal antibodies that bind to 

receptors on the cell surface is emerging as a major approach to treating cancer. Treating cancers with 

monoclonal antibody therapy has been shown to reduce recurrence rates and extend life, depending on the 

tumor type. Additionally, examining the level of production of some of these receptors on the tumor cell 

has proven to be predictive of the prognosis of the cancer. Dr. Michel and colleagues have identified an 

essential role for a poorly characterized receptor, Trop-2, in tumor formation and invasion. Tumor cells in 

which Trop-2 production is blocked by RNA interference are no longer able to grow as tumors. This suggests 

that targeting Trop-2 can be effective in treating cancer. Some tumor cells, including those from 

breast and lung cancer, exhibit high levels of Trop-2 production. The objectives of this project are to 

determine the frequency of increased Trop-2 production in breast cancers and whether Trop-2 expression 

portends a poor prognosis. Antibodies will be generated that can assist in the analysis of Trop-2 protein 

levels in tumors. During 2007, it was found that Trop-2 is expressed in approximately one-third of primary 

P A G E 7 7

east tumors. When breast cancer cells based on high versus low levels of Trop-2 expression have been 

purified, it is found that only cells expressing high levels are tumorigenic and invasive. Consistent with 

these observations, it has been reported that polyclonal antibodies against Trop-2 can block tumor cell 

invasion. Importantly, there is now a monoclonal antibody against Trop-2 that has antitumor properties. 

When human tumor cell xenografts growing in mice are treated with this antibody, tumors either decrease 

or fail to increase in size. Further work is aimed at the definitive preclinical development of these antibodies 

to lay the foundation for clinical trials against Trop-2 using a humanized monoclonal antibody. 

SECOND HAND TOBACCO SMOKE AND HMG-IY IN BREAST CANCER 

Francescopaolo Di Cello, PhD; The Johns Hopkins University; YCSA 2007 

Breast cancer is a common lethal malignancy that occurs in one in eight women. SHS exposure is causal 

with an increased risk of breast cancer, particularly in younger women with more aggressive disease. SHS 

produces toxins that can act as estrogen agonists and stimulate gene expression and cellular proliferation. It 

is hypothesized that this process activates molecular pathways that promote the development of breast cancer. 

Dr. Di Cello is studying molecular pathways induced by SHS in breast cancer, with the long-term goal 

of designing better therapy. The focus is the high mobility group A (HMGA) gene family, which encodes 

chromatin binding proteins that regulate gene expression. Since the HMG-I gene is induced by estrogen, 

Dr. Di Cello hypothesizes that it can be induced by SHS. It has been already demonstrated that HMGA 

genes are overexpressed in metastatic breast cancer cells and high-grade lung cancers. HMGA genes are 

oncogenic in cultured cells derived from normal breast or lung tissue and if HMGA genes are inhibited 

then the transformed phenotype in breast and other cancer cells is blocked. Based on these findings, Dr. Di 

Cello proposes to 1) determine if HMGA expression and SHS exposure correlate with more aggressive 

breast cancer; 2) determine if inhibiting HMGA genes blocks breast cancer growth; and 3) identify molecular 

pathways activated by HMGA genes in breast cancer with emphasis on those that can be blocked 

pharmacologically. These studies will enhance the understanding of breast cancer associated with SHS 

exposure and should lead to the discovery of novel therapies 


Di Cello F, Hillion J, Hristov A, Wood LJ, Mukherjee M, Schuldenfrei A, Kowalski J, Bhattacharya R, 

Ashfaq R, Resar LMS. HMGA2 participates in transformation in human lung cancer. Mol Cancer Res 

2008;6:743-750. 

Di Cello F, Hillion J, Kowalski J, Ronnet BM, Aderinto A, Huso D, Resar LMS. COX-2 inhibitors block 

uterine tumorigenesis in HMGA1a transgenic mice and human cancer xenografts. Molecular Cancer 

Ther 2008;7:2090-2095. 

CHEMICAL GENETIC VALIDATION OF POLO-LIKE KINASE-1 AS A BREAST CANCER DRUG TARGET 

Mark E. Burkard, MD, PhD; University of Wisconsin; YCSA 2007 

Breast cancer is a tobacco-related illness that affects 180,000 American women annually. Polo-like kinase 

1 (Plk1) is an enzyme that is required for division of human cells, including cancer cells. Basic research has 

suggested that Plk1 may be a useful target for treating hormone resistant or refractory breast cancer, based 

on its Taxol-like effects. The goal of this project is to develop cell-based assays and model systems to 

understand the biologic functions of Plk1 and assess the value of targeting Plk1 for breast cancer therapy. 

Since kinase-targeted drugs often affect many cellular enzymes, it is important to identify which targets 

mediate their effects. Recently, Dr. Burkard has developed human cell lines containing modified Plk1 that 

is resistant to drug inhibition. This has allowed Dr. Burkard to 1) distinguish effects due to specific Plk1 

inhibition from off-target effects; 2) evaluate the relative specificities of several proposed therapeutic 

agents; and 3) uncover previously unknown functions of Plk1 and establish potential therapeutic implications. 

These provide a platform for validating Plk1-targeted therapy in breast cancer and a general 

approach to understanding the potential therapeutic effect of kinase-targeted therapies using genetic rescue. 


Randall CL, Burkard ME, Jallepalli PV. Polo kinase and cytokinesis initiation in mammalian cells: harnessing 

the awesome power of chemical genetics. Cell Cycle 2007; 6:1713-1717. 

Burkard ME, Randall CL, Larochelle S, Zhang C, Shokat KM, Fisher RP, Jallepalli PV. Chemical genetics 

reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in 

human cells. Proc Natl Acad Sci U S A 2007;104:4383-4388. 

7 8 P A G E

TARGETING NRF2/ARE BY HDAC INHIBITION IN BREAST CANCER 

Qun Zhou, MD, PhD; University of Maryland; YCSA 2008 

Breast cancer is a leading cause of death among women in the U.S. despite recent advancements in 

cancer research. Estrogen is a risk factor for the development of breast cancer. The nuclear factor erythoid- 

2 related factor (Nrf2)-dependent genes encode phase II enzymes, which mediate detoxification and 

antioxidant functions thereby protecting cells from genotoxic damage. Disruption of the Nrf2 pathway by 

estrogen increases DNA adducts and DNA mutations, which greatly predispose to breast cancer formation. 

Because of its essential role in the development of breast cancer, the Nrf2 pathway is being targeted by 

certain anticancer agents as a means to enhance the effectiveness of chemotherapy, and promote 

elimination of chemical carcinogens. For this study Dr. Zhou and colleagues will select estrogen receptor 

(ER)alpha-negative breast cancer cells and treat them with clinic relevant histone deacetylase (HDAC) 

inhibitors to reexpress the silenced ER alpha gene. Using this strategy, Dr. Zhou and colleagues will 

demonstrate that reexpression of functional ER alpha by pharmacological HDAC inhibitors restores 

antiestrogen induction of phase II enzymes and prevents DNA damage. Moreover, they will utilize a highthroughput 

proteomic technology to identify that HDAC inhibitors can induce hyperacetylation of 

SQSTM1, an activator of the Nrf2/antioxidant response element (ARE) pathway. By defining the precise 

roles of ER alpha and SQSTM1 in activation of the Nrf2/ARE pathway, Dr. Zhou believes that his study 

will discover previously unrecognized benefits of HDAC inhibitors in chemotherapeutic and 

chemoprevention of SHS related breast cancer. 

Cancer chemoprevention may be achieved through induction of phase II detoxifying enzymes, a process 

mediated by the antioxidant response element (ARE) in the promoter region of these genes. A key 

transcription factor involved in induction of phase II enzymes is nuclear factor erythoid-2 related factor 

(Nrf2). Although the cellular functions of Nrf2-Keap1 pathway in human carcinogenesis have been 

extensively investigated, the majority of these studies focus on the negative regulator Keap1, which is 

responsible for cytoplasmic retention of the Keap1-Nrf2 complex, thereby preventing Nrf2-mediated gene 

transcription. Given the critical role of lysine acetylation in regulating diverse cellular pathways, Dr. Zhou 

and colleagues use clinically relevant histone deacetylase (HDAC) inhibitors to explore novel mechanisms 

that govern Nrf2/ARE pathway. By a global proteomic survey, Dr. Zhou has learned that the HDAC 

inhibitor, SAHA (vorinostat), induces lysine acetylation of 73 proteins in MDA-MB-231 human breast 

cancer cells. These proteins include chromatin-associated proteins, transcriptional factors, transcriptional 

regulators, chaperone proteins, DNA repair enzymes, structural proteins, and kinase mediators. Among 

these proteins, SQSTM1 is of particular interest as a recent study has confirmed its critical function in 

activation of the Nrf2/ARE pathway. Dr. Zhou’s work shows that SAHA elevates protein expression of 

Nrf2 and NQO1. He and his colleagues have also shown that acetylated SQSTM1 is associated with 

regulation of NQO1 transcription. Furthermore, induction of Nrf2 by SAHA is mediated through 

SQSTM1 as depletion of SQSTM1 by small interfering RNA diminishes the effect of SAHA on Nrf2 and 

NQO1. These findings suggest that therapeutic HDAC inhibitors may be useful as chemopreventive 

agents for breast cancer and support work to elucidate the roles of lysine acetylation in the Nrf2/ARE 

dependent gene transcription as an underlying mechanism. 


Zhou Q, Shaw PG, Davidson NE. Inhibition of histone deacetylase suppresses EGF signaling pathways by 

destabilizing EGFR mRNA in ER-negative Human Breast Cancer Cells. Breast Cancer Res Treat 2008 


Zhou Q, Chaerkady R, Shaw PG, Kensler TW, Pandey A, Davidson NE. Targeting Nrf2/ARE pathway by 

inhibition of HDAC in breast cancer prevention Presented at the 7th Annual American Associaton for 

Cander Research International Conference on Frontiers in Cancer Prevention Research. Washington, 

DC, Nov 16-19, 2008 (abstract number #B104). 

DISCOVERY AND CHARACTERIZATION OF NOVEL TUMOR SUPPRESSOR GENES IN BREAST CANCER USING 

GENOME-WIDE GENETIC AND EPIGENETIC ANALYSIS 

Timothy A. Chan, MD, PhD; Memorial Sloan-Kettering Cancer Center; YCSA 2008 

The discovery and analysis of tumor suppressor genes has provided insight into the processes underlying 

cancer development and has proven useful for the development of new therapeutic and diagnostic modalities 

for cancer. The complete sequencing of the human genome has enabled the genome-wide analysis of 

genetic alterations in cancer. To date, efforts to sequence the cancer genome have cataloged somatic mutations 

in a large number of genes in breast and colon cancer. However, identification of the key subset of 

these mutations that drive cancer development remains a challenge. The long-term objective of this study 

P A G E 7 9

is to identify and characterize key, novel tumor suppressor genes in breast cancer, and to study the utility 

of these genes for diagnostic and therapeutic use. Tumor suppressor genes crucial for oncogenesis are often 

targeted by multiple mechanisms of inactivation including mutation and promoter hypermethylation. Dr. 

Chan and colleagues hypothesize that tumor suppressors that are key to the development of cancer can be 

discovered by identifying common targets of multiple modes of inactivation. As such, the specific aims are 

to 1) use combined global mutation and methylation analysis to identify common gene targets of mutation 

and hypermethylation; 2) determine whether decreased expression of these “common target” genes predicts 

for poor clinical prognosis in breast cancer and evaluate the use of these genes as biomarkers for outcome 

in high risk breast cancer patients such as those with tobacco smoke exposure; and 3) determine the 

function of the most promising candidate gene and evaluate this candidate as a tumor suppressor and 

potential target of epigenetic therapy. 

To this end, Dr. Chan and colleagues have developed a microarray approach that enables rapid and accurate 

identification of genes silenced by hypermethylation in cancer. They used this technique to identify 

genes silenced by hypermethylation in breast cancer. This dataset was then compared to the genes newly 

discovered to be mutated in breast cancer (CAN genes). In all, 11 genes were found to be subject to both 

mutation and cancer-specific methylation, and will be studied further. The relative roles played by mutation 

versus methylation in disrupting gene function in cancer for these genes will be examined. Expression levels 

of these 11 common target genes will be analyzed using well-annotated expression microarray datasets 

from breast cancers to identify useful biomarkers for diagnosis and prognosis. As tobacco exposure is a 

strong risk factor for poor outcome in patients with breast cancer, the use of these new genes as prognostic 

biomarkers will be evaluated in breast cancer patients with this risk factor. This information may clarify the 

use of adjuvant therapy for this group of high-risk breast cancer patients. Lastly, the molecular details of 

the tumor suppressive function of the most promising and clinically significant gene (PTPRD) will be studied 

using gene overexpression, RNA interference studies, and biochemical analysis. This study will allow 

the discovery of novel cancer genes and explore the utility of these genes as useful predictors of clinical 

prognosis and targets for therapy. 


Chan TA, Glockner S, Mi Yi J, Chen W, Van Neste L, Cope L, Herman JG, Schuebel KE, Ahuja N, Baylin 

SB. Convergence of mutation and epigenetic alterations identified common genes in cancer that predict 

for poor prognosis. PLoS Med 2008;5(5):823-838. 

Wong J, Armour E, Kazandies P, Iordachita I, Tryggestad E, Deng H, Matinfar M, Kennedy C, Liu Z, 

Chan T, Gray O, Verhaegen F, McNutt T, Ford E, DeWeese TL. High-resolution, small animal 

radiation research platform with x- ray tomographic guidance capabilities. Int J Radiat Oncol Biol Phys 

2008;71:1591-1599. 

CANCER, BREAST 

COMPLETED RESEARCH 

THE ROLE OF LYSINE HISTONE METHYLTRANSFERASE SET 7/9 IN BREAST CANCER 

Nickolai A. Barlev, PhD; Tufts-New England Medical Center Hospitals; CIA 2005 

Dr. Barlev and collaborators discovered a novel mechanism of p53 regulation, through lysine 

methylation, by which p53 is upregulated in response to DNA damage. They investigated the molecular 

mechanisms of p53 activation by lysine methylation in response to SHS, using a mammary cell model 

system. In addition, they found that lysine methylation is not only required for activation of p53, but is 

also necessary for global DNA repair. Elucidation of new downstream targets or effectors of this process 

are important. 


Morgunkova A., and Barlev, N.A. Lysine methylation goes global. Cell Cycle 5:pp. 1308-12; (2006) 

Ivanov, G., Ivanova T., Kurash J.K.A, Ivanov, S., Gizzatullin F., Chuikov, F., Rauscher, D., Reinberg, and 

Barlev, N.A. DNA damage activates p53 through a methylation-acetylation cascade. Mol Cell Biol (2008) 

AN MVA VACCINE TARGETING p53 IN BREAST CANCER 

Joshua Ellenhorn, MD; City of Hope; CIA 2005 

The prupose of this project was to develop a vaccine against p53 antigen using an attenuated poxvirus, 

modified vaccine Ankara (MVA) as a carrier vehicle to express p53 (MVAp53). The animal model used is a 

8 0 P A G E

human p53 knock-in (Hupki) mouse that is tolerant to human p53. Efficacay of the MVAp53 vaccine was 

tested in the Hupki mouse. The rationale behind the study was that the intracellular concentration of 

non-mutated p53 is normally very low, and cells expressing wild type p53 at low levels escape autoimmune 

attack by an enhanced immune response to over-expressed mutant p53. For this purposes p53-specific 

cytotoxic T-cells that are able to lyse p53-overexpressing tumors can be generated from the peripheral 

blood of cancer patients. The PI explored potential of an MVAp53 vaccine for patients with malignancy 

and identified appropriate laboratory links of p53-specific immunity. Based on this evidence the PI was 

able to show that stimulation with MVAp53 resulting in p53-specific immunity can overcome the tolerance 

to p53. 


Mojica P, Smith D, Ellenhorn JDI. Adjuvant radiation therapy is associated with improved survival for gallbladder 

carcinoma with regional metastatic disease. J Surg Oncol 2007;96:8-13. 

Mojica-Manosa P, Smith D, Ellenhorn JDI. Adjuvant radiation therapy is associated with improved survival 

in Merkel cell carcinoma of the skin. Am J Clin Oncol 2007;25:1043-1047. 

Podnos YD, Smith D, Wagman LD, Ellenhorn JDI. Radioactive iodine offers survival improvement in 

patients with follicular carcinoma of the thyroid. Surgery 2005;138:1072-1077. 

Podnos YD, Smith DD, Wagman LD, Ellenhorn JDI. Survival in patients with papillary thyroid cancer is 

not affected by the use of radioactive isotope. J Surg Oncol 2007;96:3-7. 

Podnos YD, Tsai NC, Smith D, Ellenhorn JDI. Factors affecting survival in patients with anal melanoma. 

Am Surg 2006;72:917-920. 

Podnos YD, Smith D, Wagman LD, Ellenhorn JDI. The implication of lymph node metastasis on survival 

in patients with well-differentiated thyroid cancer. Am Surg 2005;71:731-734. 

Roberts M, Maghami E, Kandeel F, Yamauchi D, Ellenhorn HL, Ellenhorn JDI. The role of positron 

emission tomography scanning in patients with radioactive iodine scan-negative, recurrent differentiated 

thyroid cancer. Am Surg 2007;73:1052-1056. 

Song GY, Gibson G, Haq W, Huang ECC, Srivasta T, Hollstein M, Daftarian P, Wang Z, Diamond D, 

Ellenhorn JDI. An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer 

Immunol Immunother 2007;56:1193-1205. 

ONCOGENIC ROLE OF RHBDF1 IN BREAST CANCER 

Luyuan Li, PhD: University of Pittsburgh; CIA 2005 

The rhomboid family of genes carries out a wide range of important functions in a variety of organisms, 

but little is known about the function of the human rhomboid family-1 gene (RHBDF1). The studies have 

shown that the RHBDF1 gene expression level is significantly elevated in clinical specimens of invasive 

ductal carcinoma of the breast, and the protein is readily detectable in human breast cancer or head and 

neck cancer cell lines. The RHBDF1 gene was silenced with short interfering RNA (siRNA) results in 

breast cancer cell-line MDA-MB-435 cells and head and neck squamous cell cancer cell-line 1483 cells. 

The treatment caused apoptosis to the former and autophagy to the latter. The treatment also led to 

down-modulation of activated AKT and extracellular signal-regulated kinases. Diminished strength of these 

critical growth signals may be the key attributes of the induction of apoptosis or autophagy. Furthermore, 

the RHBDF1 gene in established MDA-MB-435 or 1483 xenograft tumors have been silenced by using 

intravenously administered histidine-lysine polymer nanoparticle-encapsulated siRNA. The treatment 

resulted in marked inhibition of tumor growth in both cases. The findings indicate that RHBDF1 has a 

pivotal role in sustaining growth signals in epithelial cancer cells, and thus may serve as a therapeutic target 

for treating epithelial cancers. 

THE ROLE OF WT1 IN THE PATHOGENESIS OF BREAST CANCER 

David M. Loeb MD, PhD; The Johns Hopkins University; YCSA 2002 

The hypothesis of the project is that Wilms’ tumor protein (WT1), a transcription factor aberrantly 

expressed in breast cancer. His aims were to identify new WT1 target genes important for proliferation and 

cell death, to determine the effect of expressing WT1 in mammary epithelial cells, and to utilize a breast 

tumor bank to correlate WT1 expression with expression of putative target genes and with clinical outcome. 

Results have demonstrated that different forms of WT1 have distinct effects on mammary epithelial 

cells, and one form promotes changes typically seen in cancer cells. Dr. Loeb and colleagues have also 

identified a number of new potential WT1 target genes, including ribosomal protein S6 kinase, vascularendothelial 

growth factor, and the cell survival-promoting gene, Bfl-1. Ongoing work will determine which 

P A G E 8 1

of these target genes are regulated by WT1 in primary tumor samples and correlate these findings with 

prognosis. 

NOVEL DRUG DEVELOPMENT FOR BREAST CANCER 

Saeed R. Khan, PhD; The Johns Hopkins University; YCSA 2003 

The human homolog to the mouse double minute 2 (MDM2) oncogene is a potential target for breast 

cancer therapy. This oncogene is amplified or over expressed in human breast cancer, and high levels are 

associated with a poor prognosis. MDM2 exerts influence by both p53-dependent and -independent 

mechanisms. This study investigated the value of MDM2 as a drug target for breast cancer therapy by 

using boronic-chalcone analogs to inhibit its expression. Results demonstrated that certain chalcones preferentially 

inhibit growth of human breast cancer cell lines compared to normal epithelial cells. Structurefunction 

relationship studies of these compounds are continuing. 


Gallmeier E, Winter JM, Cunningham SC, Khan SR, Kern SE. Novel genotoxicity assays identify norethindrone 

to activate p53 and phosphorylate H2AX. Carcinogenesis 2005;26:1811-1820. 

Gurulingappa H, Amador ML, Zhao M, Rudek MA, Hidelgo M, Khan SR. Synthesis and antitumor evaluation 

of benzoylphenylurea analogs. Bioorg Med Chem Lett 2004;14:2213-2216. 

Gurulingappa H, Buckhalts P, Kinzler KW, Vogelstein B, Khan SR. Synthesis and evaluation of aminophosphinic 

acid derivatives as inhibitors of renal dipeptidase. Bioorg Med Chem Lett 2004;14:3531-3533. 

Khan SR, assignee. Novel boronic chalcones derivatives and uses thereof [patent]. United States, 2003. 

Khan SR, Kumar SK, Farquhar D. Bis(carbamoyloxymethyl) esters of 2’,3’-ideoxyuridine 5’- monophosphate 

(ddUMP) as potential ddUMP prodrugs. Pharm Res 2005;22:390-396. 

Khan SR, Nowak B, Plunkett W, Farquhar D. Bis(pivaloyloxymethyl) thymidine 5’-phosphate is a cell 

membrane-permeable precursor of thymidine 5’-phosphate in thymidine kinase deficient CCRFCEM 

cells. Biochem Pharmacol 2005;69:1307-1313. 

Kumar SK, Amador M, Hidalgo M, Bhat SV, Khan SR. Design, synthesis and biological evaluation of 

novel riccardiphenol analogs. Bioorg Med Chem 2005;13:2873-2880. 

Kumar SK, Hager E, Pettit C, Gurulingappa H, Davidson NE, Khan SR. Design, synthesis and evaluation 

of novel boronic-chalcone derivatives as antitumor agents. J Med Chem 2003;46:2813-2815. 

Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P, Khan SR. Anticancer activities of novel 

chalcone and bis-chalcone derivatives. Bioorg Med Chem 2006 [Epub ahead of print]. 

Modzelewska A, Sur S, Kumar SK, Khan SR. Sesquiterpenes: natural products that decrease cancer growth. 

Curr Med Chem Anticancer Agents 2005;5:477-500. 

Rudek MA, Zhao M, Smith NF, Robey RW, He P, Khan S, Hidalgo M, Jimeno A, Colevas AD, 

Messersmith WA, Wolff AC, Baker SD. In vitro and in vivo metabolism of BPU, a novel oral tubulininteractive 

agent. Clin Can Res 2005;11:8503-8511. 

CANCER, CERVICAL 


SYNERGY OF HPVS AND TOBACCO SMOKE IN CERVICAL CANCER 

Hans-Ulrich Bernard, PhD, MSc; University of California, Irvine; CIA 2007 

The objectives of this research are to 1) analyze the mechanisms that confer an increased risk of anogenital 

cancer in human papillomavirus (HPV)-infected patients who have been exposed to tobacco smoke; and 

2) improve the clinical diagnosis of these lesions to provide patients with earlier access to treatment. The 

investigators have detected by reverse transcription PCR that cervical cancer cells express 11 different subunits 

of several nicotinic acetylcholine receptors. This finding was further supported by western blots and 

immunofluorescence that showed that cervical cancer cells contain several different nicotinic acetylcholine 

receptors that stimulate the proliferation of these cancers slowly in response to the natural transmitter 

acetylcholine, but strongly in response to tobacco smoke. Similar receptors on normal cervical cells were 

found, which suggest that cervical cancer is initiated by HPV infection and progresses through the stimulation 

by nicotine. The investigators are uncovering more details about how methylation of the HPV L1 

gene serves as biomarker of cancer progression. HPV genomes exist as circular episomes after infection, 

but become integrated into cellular chromosomes in cancer - more efficiently in the presence than in the 

absence of tobacco smoke. Detection of integration in cancer precursors is a desirable diagnosis, but there 

8 2 P A G E

are no powerful techniques yet to achieve it. HPV DNA methylation fills this gap, because it results from 

integration. The investigators have confirmed that HPV DNA methylation is relevant in cervical, penile, 

and oral cancer, and detection of it is apparently the most powerful diagnosis of lesions that are not yet 

malignant but have the highest probability of progressing toward malignancy. 


Calleja-Macias IE, Kalantari M, Bernard HU. Cholinergic signaling through nicotinic acetylcholine receptors 

stimulates the proliferation of cervical cancer cells: an explanation for the molecular role of tobacco 

smoking in cervical carcinogenesis? Int J Cancer 2009;124:1090-1096. 

Kalantari M, Villa LL, Calleja-Macias IE, Bernard HU. Human papillomavirus-16 and -18 in penile carcinomas: 

DNA methylation, chromosomal recombination, and genomic variation. Int J Cancer 

2008;123:1832-1840. 

CANCER, CERVICAL 


GENETIC SUSCEPTIBITLITY TO CERVICAL CANCER IN SECOND HAND TOBACCO SMOKERS 

Ramin Mirhashemi, MD; Torrance Memorial Medical Center; CIA 2003 

Cervical cancer propensity is the function of a differential bioactivation of environmental carcinogens in 

the population, and that women with invasive cervical cancer share certain xenobiotic metabolism gene 

polymorphisms not present in healthy women. SHS-exposed individuals are at higher risk for developing 

cervical cancer, provided they carry specific polymorphisms in xenobiotic genes. Specific genes were identified 

that play a role in the pathogenesis of invasive cervical cancer. 

ENHANCING CISPLATIN EFFICIENCY WITH A COPPER CHELATOR 

Douglas Hanahan, PhD; University of California, San Francisco; CIA 2005 

Dr. Hanahan’s project is focused on assessing a provocative hypothesis, that cervical cancer therapy 

involving the pharmacological agent tetrathiomolybdate (TM), which reduces systemic copper levels, will 

increase the transport of cisplatin into tumors, thereby improving antitumor efficacy, while reducing the 

dose (and attendant toxicity) required for maximal efficacy. The PI predicts that modulating copper levels 

will improve cisplatin responses with less toxicity in cervical and other cancers where SHS is causally linked, 

and that modulating copper levels with TM may, in addition, inhibit the tumor-related angiogenesis that 

sustains cervical and other forms of human cancer. Preliminary results in the laboratory from Dr. Seiko 

Ishida, lead scientist on the FAMRI-supported project, indicate that TM treatment both reduces systemic 

copper levels in mice (with antiangiogenic effects) and increases cisplatin transport into mouse cervical cancers, 

but not into normal tissues. The therapeutic benefit of combining TM and cisplatin in a preclinical 

model of cervical cancer is currently being assessed. 

DEVELOPMENT OF NOVEL HUMAN IMMUNOLOGY ASSAYS FOR HPV VACCINE TRIALS 

Chien-Fu Hung, PhD; The Johns Hopkins University; YCSA 2003 

Dr. Hung hypothesizes that human patients receiving an increased number of human papillomavirus 

(HPV) DNA vaccinations will exhibit greater HPV-specific cluster of differentiation 8 (CD8)+T cell activity 

and a rapid expansion of HPV-specific CD8+T cells, which may lead to a stronger therapeutic effect 

against cervical cancer. Dr. Hung also hypothesizes that patients with different immunological genetics 

may generate different HPV-specific CD8+ T cell immune responses after DNA vaccination. Using blood 

samples taken at three different stages from patients receiving the HPV DNA vaccine regimen as part of an 

ongoing clinical trial, Dr. Hung is characterizing the quantitative and qualitative differences among the T 

cells from patients with different immunological genetics using four immunological assays. Dr. Hung plans 

to correlate the data gathered in the immunologic analysis with the therapeutic outcome of the clinical 

trial. 

P A G E 8 3

CANCER, GASTRIC 


GASTRIC CANCER: MOLECULAR PATHOGENESIS AND BIOMARKER DISCOVERY 

Florin M. Selaru, MD; The Johns Hopkins University; YCSA 2008 

Gastric cancer (GC) places second in terms of worldwide cancer-related deaths, claiming more than one 

half-million lives every year. Previous studies have shown that smoking increases the risk of GC by approximately 

1.8-fold, but the specific carcinogenic pathways induced by cigarette smoking are not clearly 

defined. To shed light on these pathways, Dr. Selaru and colleagues performed microRNA (miR) arrays on 

gastric tissues from smokers with gastric cancer (GC-smk), non-smokers with gastric cancer (GC-nsmk), 

smokers with normal stomach (NS-smk) and non-smokers with normal stomach (NS-nsmk). Analysis of 

the microarrays was used to choose differentially expressed miRs and TargetScan was employed to identify 

mRNA targets for the selected miRs. Multiple miRs were found differentially expressed between GC and 

normal gastric (NL) specimens; specifically, miR-21 was found to be overexpressed in GC when compared 

to NL. Interestingly, NS-smk appeared to express more miR-21 than NS-nsmk, suggesting that smoking 

may induce miR-21 levels. Also of note, miR-21 was also upregulated in GC-smk vs. GC-nsmk, although 

the difference was of lesser magnitude. The upregulation of miR-21 was verified in gastric tissue specimens 

from smokers vs. non-smokers. The MNK28 gastric cell line was transfected with a miR-21 inhibitor and 

with a miR non-specific inhibitor and western blotting demonstrated that tissue inhibitor of metalloproteinases 

3 (TIMP3) was upregulated in miR-21 inhibitor-treated cells. These findings suggest that miR-21 

may exert its oncogenic properties in gastric cancer cells in part through TIMP3 inhibition. The miR array 

experiments allowed the research team to identify miR species differentially expressed in GC vs. NL and to 

show that miR-21 is generally overexpressed in GC. Moreover, the data show that the levels of miR-21 are 

higher in smokers than in non-smokers. Taken together the data suggest that smoking may increase the 

risk of gastric cancer in part by regulating previously unknown miR networks. TIMP3 was identified as a 

possible downstream target of miR-21 in GC. 

CANCER, HEAD AND NECK 


TOBACCO-INDUCED MITOCHONDRIAL ALTERATIONS IN UPPER AERODIGESTIVE MUCOSA 

Joseph A. Califano, MD; The Johns Hopkins University; CIA 2002 

Mitochondria serve as the power plant of the cell. However, these structures are also intimately involved 

with control over cellular death, a process commonly altered in solid cancers. Dr. Califano’s project builds 

upon data that suggest that alterations in mitochondria and the DNA contained within mitochondria are 

part of the process by which cells become cancerous. Alterations in mitochondria have been shown to 

reflect exposure to tobacco smoke in cells shed in saliva. The project specifically examined the connection 

between tobacco exposure, including SHS exposure and primary smoking, and changes in mitochondrial 

DNA, and the ability of mitochondria to control cell death in cancer and in normal cells in the mouth and 

throat from smokers and those with SHS exposure. 

FAMRI Supported Research 

Jiang WW, Masayesva B, Zahurak M, Carvalho AL, Rosenbaum E, Mambo E, Zhou S, Minhas K, Benoit 

N, Westra WH, Alberg A, Sidransky D, Koch W, Califano J. Increased mitochondrial DNA content in 

saliva associated with head and neck cancer. Clin Cancer Res 2005;11:2486-2491. 



saliva associated with head and neck cancer. Clin Cancer Res 2005;11:2486-2491. Kim MM, Glazer CA, 

Mambo E, Chatterjee A, Zhao M, Sidransky D, Califano JA. Head and neck cancer cell lines exhibit differential 

mitochondrial repair deficiency in response to 4NQO. Oral Oncol 2006;42:201-207. 

Masayesva B, Ha P, Garrett-Mayer E, Pilkington T, Mao R, Pevsner J, Benoit N, Moon C, Sidransky D, 

Westra W, Califano J. Gene expression alterations over large chromosomal regions in cancers include 

multiple genes unrelated to malignant progression. Proc Natl Acad Sci USA 2004;101:8715-8720. 


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OZhao M, Rosenbaum E, Carvalho AL, Koch W, Jiang W, Sidransky D, Califano J. Feasibility of quantitative 

PCR-based saliva rinse screening of HPV for head and neck cancer. Int J Cancer 2005;117:605- 

610. 

Sirianni NM, Ha PK, Oelke M, Califano J, Gooding W, Westra W, Whiteside TL, Koch WM, Schneck JP, 

DeLeo A, Ferris RL. Effect of human papillomavirus-16 infection on CD8+ T cell recognition of a wild 

type sequence p53264-272 peptide in head and neck cancer patients. Clin Can Res 2004;10:6929- 

6937. 




Xing M, Westra WH, Tufano RP, Rosenbaum E, Cohen Y, Rhoden KJ, Carson KA, Vasko V, Larin A, 

Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, 

Ringel MD, Zeiger MA, Sidransky D, Ladenson PW. BRAF mutation predicts a poorer clinical prognosis 

for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373-6379. 

APOPTOSIS OF EFFECTOR T CELLS IN CANCER: IMPLICATIONS FOR IMMUNE THERAPY 

Robert L. Ferris, PhD; University of Pittsburgh; YCSA 2003 

Based on evidence that HNSCC has been shown to interfere with T cell survival and function, Dr. Ferris 

hypothesizes that tumor antigen-specific T cells are preferentially targeted for early apoptosis, leading to 

host tolerance to the tumor. This investigation will include a mechanistic study of the dynamic basis for T 

cell depletion in patients with HNSCC, its in vivo kinetics, and therapeutic strategies for preventing early 

death of circulating immune cells in a prospective series of patients. Results thus far suggest abnormally 

high T-lymphocyte apoptosis in cancer. For further documentation, the investigators are initiating a Phase 

1 clinical trial where they will directly label T cells from HNSCC patients with deuterated water to compare 

cell life to the T cell lifespan in healthy controls. Biomarker analyses from accrued patients and healthy 

controls are currently being conducted. 


Albers A, Abe K, Hunt J, Wang J, Lopez-Albaitero A, Schaefer C, Gooding W, Whiteside TL, Ferrone 

S, DeLeo A, Ferris RL. Antitumor activity of human papillomavirus type 16 E7-specific T cells against 

virally infected squamous cell carcinoma of the head and neck. Cancer Res 2005;65:11146-11155. 

Albers AE, Ferris RL, Kim GG, Chikamatsu K, DeLeo AB, Whiteside TL. Immune responses to p53 in 

patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory CD4+CD25+ T 

cells at tumor sites. Cancer Immunol Immunother 2005;54:1072-1081. 

Kim J, Ferris RL, Whiteside TL. CCR7 protects T lymphocytes from apoptotic cell death in patients 

with head and neck cancer. Clin Cancer Res 2005;11:7901-7910. 

Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL. Decreased absolute counts of T lymphocyte 

subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Can Res 

2004;10:3755-3762. 

Kuss I, Schaefer C, Godfrey TE, Ferris RL, Harris JM, Gooding W, Whiteside TL. Recent thymic 

emigrants and subsets of naive and memory T cells in the circulation of patients with head and neck 

cancer. Clin Immunol 2005;116:27-36. 

Lopez-Albaitero A, Nayak JV, Ogino T, Machandia A, Gooding W, DeLeo AB, Ferrone S, Ferris RL. 

Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and 

neck cells to recognition by CTL. J Immunol 2006;176:3402-3409. 

Sirianni NM, Ha PK, Oelke M, Califano J, Gooding W, Westra W, Whiteside TL, Koch WM, Schneck 

JP, DeLeo A, Ferris RL. Effect of human papillomavirus-16 infection on CD8+ T cell recognition of a wild 

type sequence p53264-272 peptide in head and neck cancer patients. Clin Can Res 2004;10:6929-6937. 

P A G E 8 5



CHRONIC CIGARETTE SMOKE EXTRACT TREATMENT SELECTS FOR APOPTOTIC DYSFUNCTION AND MITOCHON- 

DRIAL MUTATIONS IN MINIMALLY TRANSFORMED ORAL KERATINOCYTES 


Cigarette smoke demonstrates a carcinogenic effect through chronic exposure, not acute exposures. 

However, current cell line models study only the acute effects of cigarette smoke. Using a cell line model, 

Dr. Califano and colleagues compared the effects of acute versus chronic cigarette-smoke-extract (CSE) on 

mitochondria in minimally-transformed oral keratinocytes (OKF6). 

OKF6 cells were treated with varying concentrations of CSE for 6-months. Cells were analyzed monthly 

by flow cytometry for mitochondrial-membrane-potential (MMP), cytochrome-c release, caspase-3 

activation, and viability after CSE-exposure. At each time point the same assays were performed after 24 

hours of valinomycin (MMP depolarizing agent) treatment. The mitochondrial-DNA of chronically CSEtreated 

cells was sequenced. 

After 6-months of CSE-treatment, the cells were increasingly resistant to CSE-mediated and valinomycin 

induced cell death. In addition, chronic CSE-treatment caused chronic depolarization of MMP, 

cytochrome c release, and caspase activation. Cells grown in the presence of the only CSE vapor also 

exhibited the same resistance and chronic baseline apoptotic activation. Mitochondrial DNA sequencing 

found that chronic CSE treated cells had more amino acid changing mitochondrial mutations than acutely 

treated cells. 

CSE treatment of normal cells selects for apoptotic dysfunction as well as mitochondrial mutations. 

Therefore, chronic tobacco exposure induces carcinogenesis via selection of apoptosis resistance and 

mitochondrial mutation in addition to previously known genotoxic effects that were found by acute 

treatments. Chronic models of tobacco exposure on upper aerodigestive epithelia are more insightful than 

models of acute exposure in studying head and neck carcinogenesis. 

MOLECULAR DISRUPTION OF RAD50 SENSITIZES TUMOR CELLS TO CISPLATIN-BASED CHEMOTHERAPY 

Daqing Li, MD; University of Pennsylvania; YCSA 2002 

Platinum-based drugs are commonly used first-line chemotherapy agents for testicular, bladder, head and 

neck, lung, esophageal, stomach and ovarian cancers. The therapeutic efficacy of these agents, including 

cisplatin, is often limited by the inherent resistance of tumors to DNA damage. Enhanced DNA repair and 

telomere maintenance by the Mre11/Rad50/Nbs1 (MRN) complex is critical in driving this chemoresistance. 

Dr. Li and colleagues hypothesized that targeted impairment of native cellular MRN function could 

sensitize tumor cells to cisplatin. They designed a novel dominant negative vector containing a mutant 

Rad50 gene that significantly downregulates MRN expression and disrupts MRN function. Combination 

cisplatin and mutant Rad50 therapy produced significant tumor cytotoxicity in vitro with a corresponding 

increase in DNA damage and telomere shortening. In cisplatin-resistant human squamous cell cancer 

xenografts, combination therapy caused dramatic tumor regression with increased apoptosis. These findings 

support the use of targeted Rad50 disruption as a novel chemosensitizing approach for cancer therapy 

in the context of chemoresistance. This strategy has the potential to be cross-applicable to several types of 

malignant tumors demonstrating chemoresistance and may positively impact the treatment of these 

patients. 


Abuzeid W, Khan K, Jiang X, Cao X, O’Malley BW, Li D. DNA damage signaling pathway as a treatment 

target for HNSCC. Presented at the American Academy of Otolaryngol Head Neck Surg Meeting. San 

Diego, CA, 2007. 

Abuzeid W, Khan K, Paulson DP, Jiang X, Araki K, Reddy N, Jungreis DB, Zhang J, Lapidus RG, 

O’Malley BW, Li D. Dual disruption” therapy for head and neck cancer: targeting DNA repair pathways 

to induce cancer cell death. Presented at the American Head and Neck Surgery Society. San Francisco, 

CA, 2008. 

Abuzeid W, Khan K, Paulson DP, Jiang X, Araki K, Reddy Ni, Jungreis DB, Zhang J, Lapidus RG, 

O’Malley BW, Li D. Disruption of DNA repair pathways: chemoradiation-free treatment for cancer. 

Presented at the American Association of Cancer Research Meeting. San Diego, CA 2008. 

Abuzeid W, Shi G, Rhee J, Carney J, O’Malley BW, Li D. Mutant Rad50-mediated cisplatin chemosensitization 

for the treatment of human head and neck cancer. Presented at the American Association of 

8 6 P A G E

Cancer Research Meeting. Los Angeles, CA, 2007. 

Araki K, Abuzeid W, Khan K, Wang J, O’Malley BW, Li D. Cisplatin chemosensitization for head and neck 

cancer. Presented at the American Academy of Otolaryngology Head Neck Surgery Meeting. San Diego, 

CA, 2007. 

Araki K, Ahmad S, Li G, Bray D, Wirtz U, Sreedharan S, O’Malley BW, Li D. Retinoblastoma RB94 

enhances radiation treatment of head and neck squamous cell carcinoma. Clin Cancer Res 

2008;14:3514-3519. 

Araki K, Ahmad SM, Abuzeid W, Wang D, Katime E, O’Malley BW, Li D. FGF2-retargeted adenoviral 

gene therapy for mrn disruption induces cisplatin chemosensitization for head and neck cancer. 

Presented at the American Head and Neck Surgery Society. San Francisco, CA, 2008. 

Araki K, Ghandehari H, O’Malley BW, Li D. A novel delivery system for adenoviral HSV-thymidine Kinase 

gene therapy against head and neck squamous cell carcinoma. Presented at the Combined 

Otolaryngology Spring Meeting (First Place Award from Triology Society Meeting). San Diego, CA, 

2007. 

Guang W, O’Malley BW, Li D. Cisplatin-based chemoresistance resulted from enhanced DNA repair in 

human head and neck squamous cell carcinoma. American Association of Cancer Research. Los Angeles, 

CA, 2005. 

Guang W, O’Malley BW, Li D. Increased expression level of MRN and cisplatin chemoresistant in the head 

& neck cancer. Presented at the American Academy of Otolaryngol Head Neck Surg Meeting. Los 

Angeles, CA, 2005. 

Hao T, Shi G, Li G, O’Malley BW, Li D. Mutant NBS-1 expression enhances cisplatin-induced cellular 

DNA damage and cytotoxicity in human head and neck squamous cell carcinoma. Presented at the 

American Academy of Otolaryngol Head Neck Surg Meeting. Orlando FL, 2003. (First Place Award for 

basic science research, American Academy of Otolaryngol Head Neck Surg.) 

Khan K, Abuzeid W, Cao X, Jiang X, Li D, O’Malley BW. Double DNA repair hits:chemoradiation-free 

therapy for HNSCC. Presented at the Europe Academy of Otolaryngology-Head & Neck Surgery. 

Vienna Austria, 2007. 

Li D, Guang W, O’Malley BW. MRN-targeted chemosensitization in combination with FGF retargeting 

for head and neck squamous cell carcinoma. Presented at the American Association of Cancer Research 

Meeting. Los Angeles CA, 2005. 

Li D, Guang, Abuzeid W, Roy S, Gao G-P, Sauk JJ, O’Malley BW. A novel adenoviral gene delivery system 

targeted against head and neck cancer. Laryngoscope 2008;118:650-658. 

Li D, Li G, Shi G, Van Echo DA, Wirtz U, Sreedharan S, O’Malley BW. FGF2-targeted adenovirus-mediated 

rb94 gene therapy in combination with cisplatin for head and neck squamous cell carcinoma. 

Presented at the American Association of Cancer Research Meeting. Washington DC, 2003. 

Li D, Li G, Van Echo DA, Wirtz U, Sreedharan S, O’Malley BW. Targeted adenovirus-mediated rb94 and 

cisplatin approach for head and neck cancer. Presented at the American Academy of Otolaryngol Head 

Neck Surg Meeting. Orlando FL, 2003. 

O’Malley BW, Li D. Mutant Rad50 sensitizes cisplatin-based chemotherapy for human head and neck cancer. 

American Academy of Otolaryngol Head Neck Surg Meeting. Los Angeles CA, 2005. 

Qie W, Quang W, O’Malley BW, Li D. A novel tumor-targeted adenoviral system for head and neck squamous 

cell carcinoma. Presented at the American Association of Cancer Research Meeting. Washington 

DC, 2006. 

Reddy, Araki K, Jiang X, Xu, Liu T, Wang H, O’Malley BW, Li D.A novel orthotopic mouse model of 

head and neck cancer detected by noninvasive optical imaging. Presented at the American Association of 

Cancer Research Meeting. Denver CO, 2009. 

Rhee J, Li D, Suntharalingam M, Guo C, O’Malley BW, Carney J. Radiosensitization of head/neck squamous 

cell carcinoma by adenovirus-mediated expression of the Nbs1 protein. Int J Radiat Oncol Biol 

Phys 2007;67:273-278, 

Saito K, Khan K, Sosnowski B, Li D. (co-correspondence author), O’Malley BW. Cytotoxicity and antiangiogenesis 

by fgf2-targeted ad-tk cancer gene therapy. laryngoscope, 2009;Epub ahead of print. 

Saito K, Khan K, Yu S-Z, Ronson S, Rhee J, Li G, Van Echo D, Suntharalingam M, O’Malley BW, , Li D. 

The predictive and therapeutic value of thymidine phosphorylase and dihydropyrimidine dehydrogenase 

in capecitabine (Xeloda)-based chemotherapy for head and neck cancer. Laryngoscope 2008;119:82-88, 

Shi G, Li G, Lang, Yu S, O’Malley BW, Li D. Dominant negative effect of mutant rad50 sensitizes cisplatin-based 

hemotherapy for human head and neck cancer, Presented at the American Society of Gene 

Therapy Meeting. Washington DC, 2003. 

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Tran HM, Shi G, Li G, Carney JP, O’Malley BW, Li D. Mutant Nbs1 enhances cisplatin-induced DNA 

damage and cytotoxicity in head and neck cancer. Otolaryngol Head Neck Surg 2004;131:478-484. 

Wobb J, Araki K, Xu L, Li D, O’Malley BW. FGF-targeted chemosensitization of head and neck squamous 

cell carcinoma. Presented at the American Association of Cancer Research Meeting. Denver CO, 2009. 

DETECTION OF PREMALIGNANT LESIONS IN THE ORAL CAVITY INDUCED BY TOBACCO RELATED CARCINOGENS 

WITH REPLICATION-COMPETENT, HERPES SIMPLEX VIRUS, NV1066, AND PREVENTION OF ITS DEVELOPMENT 

INTO CANCER. 

Yuman Fong, MD; Memorial Sloan-Kettering Cancer Center; CIA 2007 

Numerous chemical compounds in tobacco smoke lead to the development of oral, esophageal, bladder, 

and lung cancers. While early detection of cancer provides hope of cure with traditional anticancer strategies 

including chemotherapy, radiation, and surgery, these treatments are only palliative against cancers that 

have progressed to advanced stages. In previous studies, Dr. Fong’s group and other investigators have discovered 

that certain genetically engineered herpes simplex viruses (HSVs) selectively infect and kill many 

different types of cancers while sparing normal tissues. The objective of Dr. Fong’s current research is to 

determine if one such virus (NV1066) carrying the gene for the green fluorescent protein that turns 

infected cells fluorescent, can be used to identify and kill premalignant lesions caused by tobacco-related 

carcinogens before they progress to invasive cancers. Specifically, they aim 1) to determine if NV1066 can 

identify premalignant lesions for early biopsy and excision; 2) to demonstrate that NV1066 will selectively 

replicate in and lyse premalignant cells preventing their progression to invasive carcinomas; and 3) to 

determine what cellular change in the process of malignant transformation allows this selective infection of 

premalignant cells. 

To address these aims, the research team will use an animal model that mainfests progressive carcinogenesis 

in the oral cavity; sensitivity to carcinogenesis (SENCAR) mice. Tobacco-related carcinogens will be 

applied to the buccal, palatal, and tongue mucosa of these mice promoting the development of dysplasia 

and ultimately squamous cell carcinoma. The ability for the herpes virus to infect tumors at all stages from 

benign to malignant phenotype will be assessed. The ability for such infection to retard and arrest the 

transformation process will be assessed. Correlation will be made to cellular changes to determine the alterations 

in the cellular environment responsible for the selective infection by the herpes virus. These studies 

are meant to elucidate the mechanism underlying the interesting phenomenon that certain engineered herpes 

viruses selectively infect and kill a wide variety of cancers, and to determine when in the transformation 

process this selectively occurs. More importantly, these studies will amass preclinical data to determine if 

use of these oncolytic herpes viruses would be a reasonable strategy in human disease for early diagnosis of 

this specific tobacco-related cancer and as a definitive treatment of these lesions. Furthermore, once the 

principle of the study is validated, these viruses will have the potential to assist in the detection of other 

tobacco-related precancers such as in the esophagus, lung, and bladder. 


Gil Z, Kelly KJ, Brader P, Shah JP, Fong Y, Wong RJ. Utility of a herpes oncolytic virus for the detection 

of neural invasion by cancer. Neoplasia 2008 Apr;10(4):347-53. 

Kelly K, Brader P, Rein A, Shah JP, Wong RJ, Fong Y, Gil Z. Attenuated multimutated herpes simplex 

virus-1 effectively treats prostate carcinomas with neural invasion while preserving nerve function. 

FASEB J 2008 Jun;22(6):1839-48. Epub 2008 Jan 30. 

Kelly KJ, Brader P, Woo Y, Li S, Chen N, Yu YA, Szalay AA, Fong Y. Real-time intraoperative detection of 

melanoma lymph node metastases using recombinant vaccinia virus GLV-1h68 in an immunocompetent 

animal model. Int J Cancer 2009 Feb 15;124(4):911-8. 

Kelly KJ, Woo Y, Brader P, Yu Z, Riedl C, Lin SF, Chen N, Yu YA, Rusch VW, Szalay AA, Fong Y. Novel 

oncolytic agent GLV-1h68 is effective against malignant pleural mesothelioma. Hum Gene Ther 2008 

Aug;19(8):774-82. 

Lin SF, Gao SP, Price DL, Li S, Chou TC, Singh P, Huang YY, Fong Y, Wong RJ. Synergy of a herpes 

oncolytic virus and paclitaxel for anaplastic thyroid cancer. Clin Cancer Res 2008 Mar 1;14(5):1519- 

1528. 

Lin SF, Price DL, Chen CH, Brader P, Li S, Gonzalez L, Zhang Q, Yu YA, Chen N, Szalay AA, Fong Y, 

Wong RJ. Oncolytic Vaccinia Virotherapy of Anaplastic Thyroid Cancer In vivo. J Clin Endocrinol Metab 

2008 Nov;93(11):4403-4407. 

Woo Y, Kelly KJ, Stanford MM, Galanis C, Shin Chun Y, Fong Y, McFadden G. Myxoma Virus Is 

Oncolytic for Human Pancreatic Adenocarcinoma Cells. Ann Surg Oncol 2008 Aug;15(8):2329-35. 

8 8 P A G E

Yu YA, Galanis C, Woo Y, Chen N, Zhang Q, Fong Y, Szalay AA. Regression of human pancreatic tumor 

xenografts in mice after a single systemic injection of recombinant vaccinia virus GLV-1h68. Mol Cancer 

Ther 2009 Jan;8(1):141-151. 

Yu Z, Li S, Huang YY, Lin SF, Fong Y, Wong RJ. Sensitivity of squamous cell carcinoma lymph node 

metastases to herpes oncolytic therapy. Clin Cancer Res 2008 Mar 15;14(6):1897-904. 

TARGETING THE INK4A/ARF LOCUS IN HEAD AND NECK CANCERS 

James W. Rocco, MD, PhD; Harvard University; CIA 2004 

The majority of smoking related head and neck cancer (squamous cell carcinoma) has lost the Ink4a/Arf 

locus early in the progression of normal epithelium to invasive cancer. Expression of the p16INK4A tumor 

suppressor protein (p16; also known as MTS1 and CDKN2A) prevents inappropriate division of a stressed 

cell, often leading to permanent exit from the cell cycle into senescence. This critical tumor-suppressive 

role of pl6 comes at a significant cost to the organism; decreased replicative potential of stem cells crucial 

for the normal regeneration of many tissues. Dr. Rocco has shown that the C-terminal binding protein 

(CtBP), a physiologically regulated transcriptional co-repressor that dimerizes to hold together repressive 

complexes, controls p16 expression and senescence in primary human cells. If expression of CtBP-mediated 

repression is disrupted, p16 mRNA and protein expression are turned on, resulting in accelerated cellular 

senescence. If CtBP-mediated repression is enhanced by growing cells at low oxygen conditions that 

mimic those found in solid tumors, reduced expression of p16 is observed. Stresses and stimuli such as cigarette 

smoke exposure reduce CtBP-mediated repression and are associated with increased p16. The p53 

family member p63 plays an essential role in the developing epithelium, and overexpression of the 

DeltaNp63alpha isoform is frequently observed in human squamous cell carcinomas (SCCs). These findings 

suggest that DeltaNp63alpha might function as an oncogene within squamous epithelial cells. Data 

from mouse models implies that the p63 locus might function as a tumor suppressor in these same tissues. 

A study using RNA interference in human SCC-derived cell lines shows that DeltaNp63alpha mediates an 

essential survival function in human SCC cells by virtue of its ability to suppress the pro-apoptotic function 

of the related p53 family member p73. These findings support an oncogenic role for DeltaNp63alpha and 

they demonstrate the existence of critical physical and functional interactions between endogenous p53 

family members in human cancer. Specific agents and targeted approaches may be able to exploit this pathway 

to therapeutic advantage. 

ERYTHROPOIETIN SIGNALING IN HEAD AND NECK CANCER 

Stephen Y. Lai, MD, PhD; MD Anderson Cancer Center; YCSA 2005 

Dr. Lai and collaborators have shown that erythropoietin (EPO) and its receptor (EPOR) are expressed 

in HNSCC cell lines and tissue specimens. EPO/EPOR expression levels are increased in metastatic 

HNSCC specimens as compared to paired primary HNSCC specimens. Signaling through the 

EPO/EPOR complex in HNSCC also promotes tumor invasion and metastasis. Dr. Lai’s current work is 

focused upon defining the regulation of signaling pathways activated by EPO/EPOR and investigating the 

relationship between EPOR expression and patient prognosis. Given the use of EPO in cancer and treatment-associated 

anemia, the characterization of EPO/EPOR expression and signaling in HNSCC has 

direct patient care impact. Additionally, characterization of the EPO/EPOR complex in solid tumors has 

led to major changes in patient care guidelines from the FDA, the European Medicines Agency (EMEA), 

and the National Comprehensive Cancer Network (NCCN). Understanding the role of EPO/EPOR in 

HNSCC may alter the clinical use of EPO and lead to the development of novel molecular targeted therapies. 


Bennett CL, Silver S, Djulbegovic B, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, 

McKoy JM, Edwards BJ, Tigue CC, Samaras A, Raisch DW, Yarnold PR, Dorr D, Kuzel T, Tallman 

MS, West DP, Lai SY, Henke M. Venous thromboembolism and mortality associated with recombinant 

erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 

2008;299:914-924. 

Lai SY, Childs EE, Xi S, Coppelli FM, Gooding WE, Wells A, Ferris RL, Grandis JR: Erythropoietinmediated 

activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous 

cell carcinoma. Oncogene 2005;24:4442-4449. 

P A G E 8 9

ANALYSIS OF SERUM PEPTIDES ASSOCIATED WITH SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK 

(HNSCC) 

Radoslav Goldman, PhD; Georgetown University; CIA 2006 

Early detection of squamous cell carcinoma of the head and neck (HNSCC) improves patient prognosis 

and survival. Stage I disease is successfully treated in 90% of cases; stage IV disease has a greater than 50% 

mortality. Large numbers of smokers, ex-smokers, and people exposed to SHS in the population underlies 

the necessity for improved early detection and treatment. Clinical biomarker tests for detection of HNSCC 

or its recurrence are not yet available. Dr. Goldman and collaborators hypothesize that serum of patients 

contains a set of peptides that identifies HNSCC with high sensitivity and specificity, and thus have the 

potential to serve as novel markers of the disease. The research team’s goal is to identify peptides associated 

with HNSCC in a case-control study and evaluate their behavior following therapeutic intervention. To 

this end, Dr. Goldman’s laboratory developed methods for enrichment of the low molecular weight fraction 

of serum. The method allows high-throughput analysis of peptides by matrix assisted laser desorption 

ionization-time of flight (MALDI-TOF/TOF) mass spectrometry (MS). This approach allows screening of 

peptide biomarker candidates and their identification by TOF/TOF sequencing. Similar MS methods can 

be applied to the analysis of glycans, a common peptide modification. The analysis of peptides and glycans 

is facilitated by newly developed computational methods for selection of the best combination of biomarkers 

for disease classification as demonstrated in a study of hepatocellular carcinoma. To further improve the 

depth of coverage, the investigators are using high temperature fractionation of the enriched peptides prior 

to MS analysis and adding this to the methods for discovery of marker candidates for early detection of 

HNSCC. An optimal protocol will be established by analyzing blood samples collected from patients after 

treatment and will be used to examine newly diagnosed HNSCC cases and controls matched on age, gender, 

and smoking. Samples collected sequentially from the same person should establish how the marker 

candidates change with the treatment. Peptides and glycans will be sequenced by MALDI-TOF/TOF and 

complementary chromatographic/ MS methods. This pilot study will fill an important gap in the ability to 

identify HNSCC at an early and treatable stage. Defining peptides associated with HNSCC and clinical 

tests for their quantification has potentially far-reaching consequences for disease management and patient 

health. The biomarkers could be used to screen high-risk populations for early signs of disease, to design 

and test improved chemoprevention strategies, to identify an aggressive subset of the disease, and to follow 

disease progression after treatment. Identification of the peptides is expected to generate new hypotheses 

for targeted disease management. 

ROLES OF DNA PROMOTER HYPERMETHYLATION IN HEAD AND NECK CANCER CISPLATIN RESISTANCE 

Zhongmin Guo, MD, PhD; Indiana University; YCSA 2007 

Head and neck cancer is one of the most common cancers related to smoking and SHS exposure. 

Cisplatin-based chemotherapy is an important approach for combined treatment of head and neck cancer, 

especially for patients at late stages. However, intrinsic and acquired resistance of cancer cells to cisplatinbased 

drugs is responsible for more than one third of chemotherapy failures and is the major limitation of its 

clinical application. Dr. Guo’s long term goal is to elucidate the role of epigenetic mechanisms in cisplatinbased 

chemoresistance and establish tissue and serum methylation markers that will be predictive for 

chemoresistance in head and neck cancer. He has performed genome-wide scanning of hypermethylated 

genes in two isogenic cisplatin-resistant cell models, HN17B/HN17Bcp and SCC25/SCC25cp, and identified 

a panel of candidate genes whose methylation may associate with cisplatin resistance in head and neck 

cancer. A subset of these candidates is members of several important pathways associated with cell proliferation, 

apoptosis, transcription regulation, and oxidative stress response. The first candidate that was characterized 

further was glutathione peroxidase 3 (Gpx3), an important antioxidant enzyme that protects cells 

against reactive oxidative species (ROS)-induced DNA damage. Since ROS is an important mediator for cisplatin 

induced cell death, alterations of Gpx3 might have a critical impact on cisplatin resistance. To test this 

hypothesis, a thorough analysis of Gpx3 methylation, expression, and function in head and neck cancer cisplatin 

resistance was performed. The PI found that Gpx3 methylation predominantly occurred in cisplatin 

resistant cell lines and strongly correlated with chemoresistance in head and neck cancer patients. In addition, 

he showed that Gpx3 methylation is a strong predictor for patient survival in head and neck cancer. 

Interestingly, up-regulation of Gpx3 protein expression was associated with promoter hypermethylation in 

both cell lines and tumors. Further functional experiments demonstrated that forced expression of the Gpx3 

protein significantly enhances the resistance of cells to cisplatin. The current results show that Gpx3 alteration 

is an important mechanism for head and neck cancer chemoresistance and Gpx3 methylation is a 

strong candidate marker that is predictive of chemoresistance and patient survival in head and neck cancer. 

9 0 P A G E

SECOND HAND TOBACCO SMOKE AND ALCOHOL IN HEAD AND NECK CANCER 

Michael McClean, ScD; Boston University; YCSA 2007 

HNSCC is the tenth most common cancer in the US and the sixth most common cancer worldwide. 

While it is widely accepted that active smoking and alcohol consumption synergistically increase the risk of 

HNSCC, the role of SHS is considerably less clear. There is a sizable literature demonstrating that lung 

cancer is caused by exposure to SHS, but little is known about the role of SHS in HNSCC. Accordingly, 

the PI is investigating the main effect of SHS and the potential synergistic effect of SHS exposure and 

alcohol consumption in a large case-control study of HNSCC. The first phase of the study included the 

recruitment of 705 cases and 815 controls in the greater Boston metropolitan area from 1999 to 2003, 

and the second phase of participant recruitment will target a final sample size of 1300 cases and 1300 controls. 

The process of entering and validating all collected data is nearly complete, and preliminary data 

analyses have started. The analysis of SHS exposure and alcohol consumption as HNSCC risk factors are 

being conducted using multiple logistic regression models and smoothing techniques (penalized splines). 

Additionally, polynomial distributed lag models will be used to examine the SHS-related risks at different 

points in life, potentially yielding insight into the mechanism of action of SHS exposure (i.e., age-specific 

risks and latency). 

ROLE OF EGR3 IN SMOKING INDUCED CANCER 

Sanjai Sharma, MD; West Los Angeles VA Medical Center; YCSA 2007 

The aim of the project is to study genes that are downregulated in smoking induced cancer. One of the 

genes targeted by Dr. Sharma is the early growth response 3 gene (egr3), located on chromosome 8p. 

Previous data have shown that this region of the chromosome is frequently deleted in head and neck cancer 

cell lines. The egr3 gene product has a zinc finger (C2H2) domain that possibly confers a role as a 

transcription factor. Recent studies have shown a downregulation of C2H2 expression in head and neck 

cancer cell lines. The PI is investigating this in primary human tissues. The other candidate gene is the E- 

cadherin gene, a well known tumor suppressor gene in head and neck cancer. Dr. Sharma and colleagues 

found that the E-cadherin gene is often upregulated by inhibition of the nonsense-mediated decay (NMD) 

pathway. This is because exon 11 can be aberrantly spliced in a number of transcripts that as a result have a 

premature termination codon and are targeted for the NMD pathway. This aberrantly spliced transcript is 

more frequent in tumor cell lines than in non-malignant controls. Further studies demonstrate that the 

exon-intron junctions harbor no mutations, thus this is aberrant splicing is due to a splicing factor which is 

differentially expressed in tumor cells. Tumor suppressor inactivation by increased aberrant or non-functional 

splicing is a novel mechanism of gene inactivation. 


Sharma S, Nemeth E, Chen Y-H, Goodnough J, Huston A, Roodman GD, Ganz T, Lichtenstein A. 

Involvement of hepcidin in the anemia of muliple myeloma. Clin Cancer Res 2008;14(11):3262-3267. 

Sharma S, Lichtenstein A. Dexamethasone induced apoptotic mechanisms in myeloma cells by analysis of 

mutant glucocorticoid receptors. Blood 2008 Aug 15;112(4):1338-45. 

EPIGENETIC ALTERATIONS IN PROGRESSION OF ESOPHOGEAL SQUAMOUS CELL CARCINOMA BY TOBACCO 

SMOKING 

Myoung Sook Kim, PhD; The Johns Hopkins University; YCSA 2007 

Esophageal cancer is a malignant tumor of the esophagus. In the United States, a major cause of this 

disease is exposure to tobacco smoke. Carcinogens in tobacco smoke damage important genes that control 

the growth of cells, causing them to grow abnormally or to reproduce too rapidly. Evidence indicates that 

promoter methylation of tumor suppressor genes (TSGs) occurs more frequently in cancers from smokers 

than non-smokers, suggesting that a tobacco signature could emerge from distinctive patterns of gene promoter 

methylation. The purpose of Dr. Kim’s study is to identify TSGs that are methylated due to exposure 

to cigarette smoke. 

SMOKING-GENE-ENVIRONMENT INTERACTIONS IN ESOPHAGEAL ADENOCARCINOMA 

Rihong Zhai, MD, PhD; Harvard University; YCSA 2007 

Esophageal adenocarcinoma (EA) has the fastest rising incidence of all solid tumors in the United States 

and in Europe; the annual incidence has more than tripled in North America over the past four decades. 

The rapid rise in EA incidence in a relatively short period of time suggests that environmental influences 

dominate the etiology. Identified risk factors include mainstream smoking (MSS), Barrett’s esophagus 

P A G E 9 1

(BE), gastroesophageal reflux disease (GERD), and obesity. Since no single risk factor can explain the rising 

prevalence of EA, it is plausible to hypothesize that other risk factors, such as SHS exposure, certain 

genetic polymorphisms, and particularly, interactions among multiple risk factors, play important roles in 

EA development. The objective of Dr. Zhai’s research is to investigate the roles of SHS, MSS, functional 

genetic polymorphisms, obesity, and particularly the joint effects of multiple factors in the development of 

EA. The ultimate goal of this study is to gain a deeper insight into the mechanisms underlying the etiology 

of EA and to develop better prevention, screening, and treatment strategies. 


Asomaning K, Reid AE, Zhou W, Heist RS, Zhai R, Su L, Kwak EL, Blaszkowsky L, Zhu AX, Ryan DP, 

Christiani DC, Liu G. MDM2 promoter polymorphism and pancreatic cancer risk and prognosis. Clin 

Cancer Res 2008;14:4010-40155. 

Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA, Crowell RE, 

Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, 

Weidhaas JB. A SNP in a let-7 microRNA complementary site in the KRAS 3’ untranslated region 

increases non-small cell lung cancer risk. Cancer Res 2008;68:8535-8540. 

Currier PF, Gong MN, Zhai R, Pothier LJ, Boyce PD, Xu L, Yu CL, Thompson BT, Christiani DC. 

Surfactant protein-B polymorphisms and mortality in the acute respiratory distress syndrome. Crit Care 

Med 2008;36:2511-2516. 

Fru’h M, Zhou W, Zhai R, Su L, Heist RS, Wain JC, Nishioka NS, Lynch TJ, Shepherd FA, Christiani 

DC, Liu G. Polymorphisms of inflammatory and metalloproteinase genes, Helicobacter pylori infection 

and the risk of oesophageal adenocarcinoma. Br J Cancer 2008;98:689-692. 

Heist RS, Zhai R, Liu G, Zhou W, Lin X, Su L, Asomaning K, Lynch TJ, Wain JC, Christiani DC. VEGF 

polymorphisms and survival in early-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 856-862. 

Lanuti M, Liu G, Goodwin JM, Zhai R, Fuchs BC, Asomaning K, Su L, Nishioka NS, Tanabe KK, 

Christiani DC. A functional epidermal growth factor (EGF) polymorphism, EGF serum levels, and 

esophageal adenocarcinoma risk and outcome. Clin Cancer Res 2008; 14:3216-3222. 

Sheu CC, Zhai R, Su L, Tejera P, Gong MN, Thompson BT, Chen F, Christiani DC. Gender-specific 

association of Epidermal Growth Factor gene polymorphisms with ARDS. Eur Respir J 2008; Nov 14. 

Ter-Minassian M, Zhai R, Asomaning K, Su L, Zhou W, Liu G, Heist RS, Lynch TJ, Wain JC, Lin X, 

Devivo I, Christiani DC. Apoptosis gene polymorphisms, age, smoking and the risk of non-small cell 

lung cancer. Carcinogenesis 2008;29:2147-2152. 

Wheatley-Price P, Asomaning K, Reid A, Zhai R, Su L, Zhou W, Zhu A, Ryan DP, Christiani DC, Liu G. 

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of 

developing pancreatic adenocarcinoma. Cancer 2008; 112:1037-1042. 

Zhai R, Liu G, Asomaning K, Su L, Kulke MH, Heist RS, Nishioka NS, Lynch TJ, Wain JC, Lin X, 

Christiani DC. Genetic polymorphisms of VEGF, interactions with cigarette smoking exposure and 

esophageal adenocarcinoma risk. Carcinogenesis 2008;29: 2330-4. 

Zhai R, Liu G, Zhou W, Su L, Heist RS, Lynch TJ, Wain JC, Asomaning K, Lin X, Christiani DC. 

Vascular endothelial growth factor genotypes, haplotypes, gender, and the risk of non-small cell lung 

cancer. Clin Cancer Res 2008;14: 612-617. 

Zhai R, Liu G, Zhou W, Su L, Heist RS, Lynch TJ, Wain JC, Asomaning K, Lin X, Christiani DC. 

Vascular endothelial growth factor genotypes, haplotypes, gender, and the risk of non-small cell lung 

cancer. Clin Cancer Res 2008;14: 612-617. 

OPTIMIZING FUSION HYBRIDS FOR CANCER IMMUNOTHERAPY 

Walter T. Lee, MD; Duke University; YCSA 2007 

Advanced stage HNSCC patients continue to have significant mortality despite advances in surgery, radiation, 

and chemotherapy modalities. Dr. Lee seeks to develop an immunotherapy vaccine based on dendritic 

cell (DC) - tumor fusion hybrids. Although therapeutic responses from DC-tumor hybrids in animal 

tumor models have been demonstrated, clinical use of autologous tumors has been problematic. Issues 

include insufficient tumor cells and difficulties associated with establishing permanent cell lines. Since it is 

known that tumor cells of the same histological origin share tumor-associated antigens (TAA), one potential 

solution is to use defined and established HNSCC cell lines. Dr. Lee hypothesizes that vaccination with 

these allogeneic tumor-DC fusion hybrids will be effective against autologous tumors expressing shared 

TAAs. He seeks to optimize the components of DC-tumor fusion hybrids and provide an immune environment 

resulting in improved immunotherapy and clinical applicability. The following aims will be addressed: 

9 2 P A G E

1) to investigate methods that will skew DC maturation in vivo using toll-like receptor (TLR) agonists for 

effective immunotherapy; and 2) to develop an allogeneic tumor-DC fusion model targeting shared TAAs. 

In vivo results supporting the use of TLR agonists with fusion cells have already been observed and in 

vitro studies to further analyze their effects are being conducted. Experiments using allogeneic tumor-DC 

fusion vaccines have immune responses against subsequent tumors sharing target antigens; this will be used 

to further investigate the objectives of Aim 2. 

USE OF PDE5 INHIBITORS FOR THE IMMUNE THERAPY OF HNSCC 

Paolo Serafini, PhD; University of Miami Miller School of Medicine; YCSA 2008 

Frequently associated with tobacco products, alcohol use, and a genetic predisposition, HNSCC is a 

disease that, despite the advances in multimodality treatment and the improvements in mortality rates, is 

still associated with a significant morbity and mortality. Although immunotherapy is an interesting 

alternative its efficacy is dramatically compromised by the immune suppressive environment associated with 

this disease. Dr. Serafini and collegues previously demonstrated that the two major immune suppressive 

host cell populations, myeloid derived suppressor cells (MDSC) and regulatory T cells (Treg) associated 

with this cancer can be inhibited by the use of phosphodiesterase type 5 (PDE5) inhibitors sildenafil 

(Viagra) or tadalafil (Cialis). In murine models, PDE5 inhibition is sufficient to enhance intra-tumoral T 

cell infiltration and activation, to reduce tumor outgrowth, and to prime a spontaneous anti-tumor 

response. Furthermore, in vitro T cell proliferation when sildenafil is added to the otherwise anergic 

peripheral blood mononuclear cells (PBMCs) from HNSCC patients. With the current study Dr. Serafini 

and collegues are verifying if a preoperative tadalafil administration can modulate the anti-tumor immune 

response in HNSCC patients. Briefly, patients with HNSCC of the oral cavity, oropharynx, and nasal 

cavity, whose initial treatment is definitive surgical resection, are treated with tadalafil or placebo for 20 

days before surgery. Blood and tumor specimens are examined before and after drug administration to 

delineate the degree of immunosuppression and the presence of an anti-tumor immune response. 

Specifically, MDSC and Treg presence and function will be analyzed in two distinct immunological districts 

(blood and tumor) to determine if PDE5 inhibition is sufficient to revert tumor induced 

immunosuppressive mechanisms. These studies are designed to: 1) provide novel data in the complex 

relationship between immune system and tumor, and 2) provide direction for new and powerful 

approaches in which reversal of tumor-induced immunosuppression could be coupled with additional 

strategies including anti-tumor vaccination or adoptive cell transfer. 

DEVELOPMENT OF PKC EPSILON INHIBITORS FOR TREATING HEAD AND NECK CANCER 

Quintin Pan, PhD; Ohio State University; YCSA 2008 

HNSCC is the sixth most frequent cancer worldwide, comprising almost 50% of all malignancies in some 

developing nations. Dr. Pan’s recent work identified protein kinase Ce (PKCe) as a critical and causative 

player in establishing an aggressive phenotype in HNSCC. Dr. Pan investigated the specificity and efficacy 

of HN1-PKCe, a novel bi-functional HNSCC homing PKCe inhibitory peptide as a treatment for 

HNSCC. A specific HN1-PKCe peptide was designed by merging two separate technologies and synthesized 

as a capped peptide with two functional motifs, HN1 (HNSCC cell homing) and PKCe (specific 

PKCe inhibitory), connected by a novel linker motif. HN1-PKCe preferentially internalized in cells of two 

HNSCC cell lines, UMSCC1 and UMSCC36, when compared to oral epithelial cells. In addition, HN1- 

PKCe penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro 

observations, systemic injection of HN1-PKCe resulted in selective delivery of HN1-PKCe into UMSCC1 

xenografts in nude mice. HN1-PKCe blocked the translocation of active PKCe in UMSCC1 cells confirming 

HN1-PKCe as a PKCe inhibitor. HN1-PKCe inhibited cell invasion by 72 ± 2% (p



TOBACCO-INDUCED MITOCHONDRIAL ALTERATIONS IN UPPER AERODIGESTIVE MUCOSA 


Mitochondria serve as the power plant of the cell. However, these structures are also intimately involved 

with control over cellular death, a process commonly altered in solid cancers. Dr. Califano’s project builds 

upon data that suggest that alterations in mitochondria and the DNA contained within mitochondria are 

part of the process by which cells become cancerous. Alterations in mitochondria have been shown to 

reflect exposure to tobacco smoke in cells shed in saliva. The project specifically examined the connection 

between tobacco exposure, including SHS exposure and primary smoking, and changes in mitochondrial 

DNA, and the ability of mitochondria to control cell death in cancer and in normal cells in the mouth and 

throat from smokers and those with SHS exposure. 

FAMRI Supported Research 



saliva associated with head and neck cancer. Clin Cancer Res 2005;11:2486-2491. 



saliva associated with head and neck cancer. Clin Cancer Res 2005;11:2486-2491. Kim MM, Glazer CA, 

Mambo E, Chatterjee A, Zhao M, Sidransky D, Califano JA. Head and neck cancer cell lines exhibit differential 

mitochondrial repair deficiency in response to 4NQO. Oral Oncol 2006;42:201-207. 









OZhao M, Rosenbaum E, Carvalho AL, Koch W, Jiang W, Sidransky D, Califano J. Feasibility of quantitative 

PCR-based saliva rinse screening of HPV for head and neck cancer. Int J Cancer 2005;117:605- 

610. 




6937. 








APOPTOSIS OF EFFECTOR T CELLS IN CANCER: IMPLICATIONS FOR IMMUNE THERAPY 

Robert L. Ferris, PhD; University of Pittsburgh; YCSA 2003 

Based on evidence that HNSCC has been shown to interfere with T cell survival and function, Dr. Ferris 

hypothesizes that tumor antigen-specific T cells are preferentially targeted for early apoptosis, leading to 

host tolerance to the tumor. This investigation will include a mechanistic study of the dynamic basis for T 

cell depletion in patients with HNSCC, its in vivo kinetics, and therapeutic strategies for preventing early 

death of circulating immune cells in a prospective series of patients. Results thus far suggest abnormally 

high T-lymphocyte apoptosis in cancer. For further documentation, the investigators are initiating a Phase 

1 clinical trial where they will directly label T cells from HNSCC patients with deuterated water to compare 

cell life to the T cell lifespan in healthy controls. Biomarker analyses from accrued patients and healthy 

controls are currently being conducted. 

9 4 P A G E


Albers A, Abe K, Hunt J, Wang J, Lopez-Albaitero A, Schaefer C, Gooding W, Whiteside TL, Ferrone S, 

DeLeo A, Ferris RL. Antitumor activity of human papillomavirus type 16 E7-specific T cells against 

virally infected squamous cell carcinoma of the head and neck. Cancer Res 2005;65:11146-11155. 

Albers AE, Ferris RL, Kim GG, Chikamatsu K, DeLeo AB, Whiteside TL. Immune responses to p53 in 

patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory CD4+CD25+ 

T cells at tumor sites. Cancer Immunol Immunother 2005;54:1072-1081. 

Kim J, Ferris RL, Whiteside TL. CCR7 protects T lymphocytes from apoptotic cell death in patients with 

head and neck cancer. Clin Cancer Res 2005;11:7901-7910. 

Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL. Decreased absolute counts of T lymphocyte 

subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Can Res 

2004;10:3755-3762. 

Kuss I, Schaefer C, Godfrey TE, Ferris RL, Harris JM, Gooding W, Whiteside TL. Recent thymic 

emigrants and subsets of naive and memory T cells in the circulation of patients with head and neck 

cancer. Clin Immunol 2005;116:27-36. 

Lopez-Albaitero A, Nayak JV, Ogino T, Machandia A, Gooding W, DeLeo AB, Ferrone S, Ferris RL. Role 

of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and 

neck cells to recognition by CTL. J Immunol 2006;176:3402-3409. 




6937. 

PKC-EPSILON EXPRESSION ON THE OUTCOME OF CHEMOTHERAPY 

Lei Xiao, PhD; University of Florida; CIA 2002 

Dr. Xiao investigated the relationship between expression of a protein kinase C (PKC)-epsilon isoform 

and patient response to lung cancer chemotherapy. The difference in the regulation of PKC-epsilon expression 

may be important with respect to the cellular response to lung cancer chemotherapy. Results suggest 

that PKC-epsilon-negative lung cancer patients may have a better prognosis. 

ADENOVIRAL GENE TRANSFER OF FRNK AND P53 FOR TREATMENT OF HEAD AND NECK CANCER: IN VITRO 

STUDIES 

Lori J. Kornberg, PhD; University of Florida; CIA 2003 

Dr. Kornberg has shown that focal adhesion kinase (FAK), a tyrosine kinase that mediates intracellular 

signals produced by the integrin family of adhesion receptors, is overexpressed in oral and laryngeal cancers. 

The PI produced an epithelial line that overexpresses FAK-related non-kinase (FRNK), an FAK 

inhibitor, for study of these cancers. Her data suggest that expression of p53 and FRNK render cancer cells 

exquisitely sensitive to anticancer drugs. 


Kornberg LJ, Villaret D, Popp M, Lu L, McLaren R, Brown H, Cohen D, Yun J, McFadden M. Gene 

expression profiling in squamous cell carcinoma of the oral cavity shows abnormalities in several signaling 

pathways. Laryngoscope 2005;115:690-698. 

Kornberg LJ. Adenovirus-mediated transfer of FRNK augments drug-induced cytotoxicity in cultured 

SCCHN cells. Anticancer Res 2005;25:4349-4356. 

ROLE OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AND ITS DOWNSTREAM TARGETS IN HEAD AND 

NECK CANCERS OF SMOKING PATIENTS 

Alexey Fomenkov, PhD; The Johns Hopkins University; CIA 2003 

Dr. Fomenkov found that HNSCC from patients affected by both primary smoking and second-hand 

smoke exposure displayed induced tyrosine autophosphorylation of the epithelial growth factor receptor 

(EGFR) tyrosine and activated the phosphoinositol 3- kinase/protein kinase B (P3IK/Akt) signaling pathway. 

Profiling analysis of genes induced and downregulated in human tumor samples of primary smokers 

and those exposed to second hand tobacco revealed that the p63 gene was dramatically induced. Dr. 

Fomenkov showed that p63, which is a transcriptional regulator of epithelial stratification, is one of the 

major downstream targets of EGFR and its expression is specifically modulated by the PI3K/Akt pathway 

rather than by Ras/ErkIMAPK pathway. The expression pattern of ANp63a, which is a major p63 isotype 

P A G E 9 5

in normal epithelia, was shown to be associated with the highly proliferative compartment of the basal cell 

layer. However the expression was shifted to the suprabasal layer during progression of HNSCC. p63 was 

shown to regulate transcription of numerous genes specifically involved in cell adhesion, which code for 

proteins that are critical components of hemidesmosomes that define epithelial stratification and mediate 

cell-cell junctions. p63 was also shown to associate with components of the RNA transcription/splicing 

machinery. Further, p63 function is regulated by a specific proteasome dependent degradation mechanism 

through association with stratifin and the receptor for activated C-kinase-1 (RACK1), required for phosphorylation 

and sumoylation of p63 and contribute to normal stratified epithelial differentiation. 

Environmental stimuli that induce DNA damage also enhanced p63 protein modifications leading to selective 

degradation of p63. Cisplatin is a major treatment of head and neck tumors. ANp63c is downregulated 

in response to cisplatin treatment in HNSCC cell lines and DNA damage caused by it will induce 

degradation of the ANp63 protein. These observations suggested a way to determine resistance of cancer 

cells to platinum treatment. 


Fomenkov A, Zangen R., Huang Y-P., Osada M, Guo Z., Fomenkov T, Trink B, Sidransky D, Ratovitski 

EA. RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous 

cell carcinoma cells upon DNA damage. Cell Cycle 2004;3:1285-1295. 

Guo Z, Linn J, Wu G, Anzick S, Eisenberger C, Halachmi S, Cohen Y, Fomenkov A, Hoque O, Okami K, 

Steiner G, Engles J, Osada M, Moon C, Ratovitski E, Trent J, Meltzer P, Westra W, Kiemeney L, 

Schoenberg M, Sidransky D, Trink B. CDC91L1 (PIG-U) is a newly discovered oncogene in human 

bladder cancer. Nat Med 2004;10:374-381 

Huang YP, Kim Y, Li Z, Fomenkov T, Fomenkov A, Ratovitski E. AEC-associated p63 mutations lead to 

alternative splicing/protein stabilization of p63 and modulation of notch signaling. Cell Cycle 

2005;4:1440-1447. 

Huang YP, Wu G, Guo Z, Osada M, Fomenkov T, Park HL, Trink B. SD, Fomenkov A, Ratovitski EA. 

Altered sumoylation of p63a contributes to the split-hand/foot malformation phenotype. Cell Cycle 

2004;3:1587-1596. 

Osada M, Nagakawa Y, Park HL, Yamashita K, Wu G, Kim MS, Fomenkov A, Trink B, Sidransky D. P63- 

specific activation of the BPAG-1e promoter. J Invest Dermatol 2005;125:52-60. 

Osada M, Park HL, Nagakawa Y, Yamashita K, Fomenkov A, Kim MS, Wu G, Nomoto S, Trink B, 

Sidransky D. Differential recognition of response elements determines target gene specificity for p53 and 

p63. Mol Cell Biol 2005;14:6077-6089. 

Wu G, Osada M, Guo Z, Fomenkov A, Begum S, Zhao M, Upadhyay S, Xing M, Wu F, Moon C, 

WestraWH, Koch WM, Mantovani R, Califano JA, Ratovitski E, Sidransky D, Trink B. DeltaNp63alpha 

up-regulates the Hsp70 gene in human cancer. Cancer Res 2005;65:758-766. 

MARKERS AND MECHANISMS FOR HEAD AND NECK CANCER 

Elizabeth Franzmann, MD; University of Miami; YCSA 2002 

Dr. Franzmann established molecular markers that identify HNSCCs at an early stage and the role these 

molecules play in tumor growth and metastases. Studies in other tissues have shown that CD44 antigen is 

a useful tumor marker. Preliminary analysis has been done on salivary soluble CD44 expression via an 

ELISA in HNSCC patients and normal controls to determine its potential as a screening tool. The data 

revealed that soluble CD44 levels were significantly elevated in HNSCC patients compared to controls, 

suggesting that soluble CD44 could be used as a marker for early HNSCC. Further work has established 

that this marker can distinguish HNSCC from benign diseases of the mouth, nose, and throat. The marker 

also appears to detect lesions that are precancerous. Since precancer is a reversible state, the marker will be 

particularly useful for the early detection of HNSCC. Additional work in Dr. Franzmann’s laboratory has 

shown that certain members of the CD44 family of proteins are expressed at high levels in HNSCC tissues 

compared to controls. Such over expression of these isoforms in cell lines result in increased tumor cell 

growth and migration. Thus, these CD44 proteins will also be useful as targets for therapy. 


Franzmann EJ, Reategui EP, Carraway K, Goodwin WJ. Salivary soluble CD44 test: a potential tool for 

head and neck cancer screening [abstract]. Proc Amer Assoc Cancer Res 2005;46:4849. 

Franzmann EJ, Reategui EP, Carraway KL, Hamilton KL, Weed DT, Goodwin WJ. Salivary soluble CD44: 

a potential molecular marker for head and neck cancer. Cancer Epidemiol. Biomarkers Prev 

9 6 P A G E

2005;14:735-739. 

Reategui E, Goodwin WJ, Franzmann E. Characterization of CD44 variant 3-containing isoforms in head 

and neck cancer [abstract]. Proceedings of the 6th International Conference on Head and Neck Cancer 

Final Program and Abstract Book. 2004:p.65. 

Reategui E, Goodwin WJ, Weed DT, Hamilton K, Carraway K, Franzmann E. Salivary soluble CD44: a 

potential molecular marker for head and neck cancer [abstract]. Proc Amer Assoc Cancer Res. 

2004;45:92. 

Zito JR, Reategui E, Weed DT, Astor FC, Franzmann EJ. Differential expression of CD44 isoforms in 

head and neck squamous cell carcinoma [poster]. Otolaryngol Head Neck Surg 2004;131:P178. 

CANCER, KIDNEY 


TUMOR VACCINE AFTER MYELOABLATIVE ALLOGENIC STEM CELL TRANSPLANTATION FOR KIDNEY CANCER 

Ephraim J. Fuchs, MD; The Johns Hopkins University; CIA 2003 

Dr. Fuchs and collaborators found that significant anti-tumor responses can be obtained by the infusion 

of allogenic T cells following the administration of high dose cyclophosphamide, with or without tumor 

cell vaccine. Based on these results, it seemed reasonable that a transient graft-versus-host reaction, mediated 

by donor CD4+ T cells, would be sufficient to unmask functional anti-tumor immunity among host T 

cells. His research involved a trial of cyclophosphamide administration followed by the infusion of purified 

CD4+ T cells from a partially human leukocyte antigen (HLA) mismatched donor to treat locally advanced 

or metastatic kidney cancer to determine the maximally tolerated dose of semi-unified CD4+ T cells 

administered one day after cyclophosphamide treatment. 

EARLY DETECTION OF BLADDER AND RENAL CELL CANCER BY HYPERMETHYLATION 

Paul Cairns, PhD; Fox Chase Cancer Center; YCSA 2002 

Genetic alterations are promising markers for cancer diagnoses because they precede obvious cancer, are 

highly specific, and can be detected by extremely sensitive methylation-specific PCR methods. 

Hypermethylation is an epigenetic phenomenon in which a methyl group is added to certain nucleotides in 

the DNA. Tumor suppressor genes can be silenced if the DNA in the promoter sequence of the gene is 

hypermethylated. Using methylation-specific PCR (MSP), Dr. Cairns screened matched tumor and 

sediment DNA from urine specimens taken from 50 kidney cancer patients for hypermethylation status of 

six normally unmethylated tumor suppressor genes. Results revealed hypermethylation of at least one gene 

in all 50 tumor DNA samples and an identical pattern in the matched urine DNA from 44 out of 50 

patients. Also of interest was the difference in suppressor gene hypermethylation patterns between clear cell 

and nonclear cell tumors, suggesting that this panel of suppressor genes may be useful in differential 

kidney cell cancer diagnosis. This study provides evidence that MSP will lead to an early, noninvasive urine 

diagnostic test for renal cancer. Hypermethylation of at least one out of three suppressor genes was found 

in all 45 bladder cancers. Additionally, gene hypermethylation was detected in the matched urine DNA of 

39 out of 45 patients, including 16 specimens with negative cytology. Panel gene hypermethylation was 

not found in normal transitional cell DNA or DNA from normal healthy individuals or patients with 

cystitis. An unmethylated gene in the tumor DNA was found to be unmethylated in the matched urine 

DNA. Dr. Cairns concluded that MSP may enhance early detection of bladder cancer via a noninvasive 

urine test. Dr. Cairns used the promoter methylation status of 10 tumor suppressor and cancer genes in 

100 kidney cancers of various pathologic types. Hypermethylation was found in 93 out of 100 tumors. 

Thirty-three percent of kidney tumors had hypermethylation in 1 gene, 35% in 2 genes, 14% in 3 genes, 

and 11% in 4 or more genes. No hypermethylation was noted in 15 samples from normal kidney or 

ureteral tissue. Hypermethylation of the tumor suppressor gene VHL was found to be specific for clear cell 

tumors. Dr. Cairns concluded that promoter hypermethylation likely plays an important part in kidney 

tumor genesis and that the hypermethylation profile may provide molecular markers for diagnostic and 

prognostic approaches to renal cancer. 


Al-Saleem T, Cairns P, Dulaimai E, Feder M, Testa J, Uzzo R. The genetics of renal oncocytosis: a possible 

model for neoplastic progression. Cancer Genet Cytogenet 2004 July; 152(1); 23-28. 

Battagli C, Uzzo R, Dulaimi E, Ibanez I, Krassenstein R, Al-Saleem T, Greenberg RE, Cairns P. 

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Commentary: Bonn, D. Urine test for renal-cell carcinoma. Lancet Oncol 2004;5:72. 

Battagli C, Uzzo R, Dulaimi E, Ibanez I, Krassenstein R, Al-Saleem T, Greenberg RE, Cairns P. Promoter 

hypermethylation of tumor suppressor genes in urine from kidney cancer patients. Cancer Res 

2003;63:8695-8699. 

Cairns, P. Detection of promoter hypermethylation of tumor suppressor genes in urine from kidney cancer 

patients. Ann NY Acad Sci 2004;1022:40-43 

Dulaimi E, de Caceres I, Uzzo R, Al-Saheem T, Greenberg R, Polascik T, Babb J, Grizzle W, Cairns P. 

Promotor hypermethylation profile of kidney cancer. Clin Cancer Res 2004;0: 3972-3979. 

Dulaimi E, Uzzo R, Greenberg R, Al-Saheem T, Cairns P. Detection of bladder cancer in urine by a tumor 

suppressor gene hypermethylation panel. Clin Cancer Res 2004 March; 10:1887-1893. 

CANCER, LUNG 


DEVELOPMENT OF STRUCTURE-BASED SMALL MOLECULE ANTI-LUNG CANCER DRUG(S) BY TARGETING BAX 

Xingming Deng, MD, PhD; University of Florida; CIA 2002, 2005 

Lung cancer is a major SHS-related cancer and one of the leading causes of cancer death worldwide. 

Most patients with lung cancer have a poor prognosis because of chemoresistance. Thus, development of 

new and more effective drugs to overcome chemoresistance is critical to improve the prognosis of patients 

with lung cancer. Dr. Deng’s group recently discovered that nicotine-activated AKT phosphorylates Bax at 

its serine (Ser) 184 site, which abolishes the proapoptotic activity of Bax. In contrast, protein phosphatase 

2A-mediated dephosphorylation of Bax at Ser184 activates its proapoptotic function, suggesting that the 

Ser184 site is critical in regulating the proapoptotic activity of Bax. Therefore, the group chose the Ser184 

residue as a docking site for screening of small molecules that may activate Bax using the computerized 

DOCK suite of programs (version 6.1) and a database of 300,000 small molecules from the National 

Cancer Institute (NCI) filtered to follow the Lipinski rules. Thirty-six of the compounds determined to 

have the highest affinity for the Bax Ser184 site were obtained from the NCI and their effects were tested 

on apoptosis. Preliminary data indicate that three of the thirty six compounds potently induce apoptosis of 

various human lung cancer cells. Dr. Deng and collegues named these three compounds as small molecule 

Bax activators (i.e. SMBA1, SMBA2 and SMBA3). Treatment of lung cancer cells with SMBA1, SMBA2 

or SMBA3 blocks nicotine-induced Bax phosphorylation in association with enhanced apoptotic cell death. 

Importantly, a combination of SMBA1, 2, or 3 with a chemotherapeutic drug (i.e. cisplatin) significantly 

enhances chemosensitivity of lung cancer cells as compared to chemotherapeutic drug alone. They 

hypothesize that SMBA(s) may activate the proapoptotic function of Bax by binding to the Ser184 site, 

which leads to apoptosis. Based on their apoptotic effects, SMBA(s) may have potent anti-tumor effect in 

vivo. To critically test these hypotheses, the team has proposed two specific aims. The first is to determine 

the mechanism(s) by which SMBA(s) induces apoptosis of human lung cancer cells. These studies will test 

whether SMBA(s) displays synergism with chemotherapeutics in inducing apoptosis of various lung cancer 

cells. The second is to determine whether SMBA(s) suppresses nicotine-or SHS-induced growth of lung 

tumors in SCID mice. These studies will evaluate the anti-tumor efficacy of SMBA(s) in vivo. From the 

results, it is expected that these small molecules can be developed as novel anti-lung cancer drugs that 

activate the proapoptotic function of Bax in tumor cells. 


(see below) 

MCL-1 IS A NICOTINE TARGET IN LUNG CANCER CELLS 

Xingming Deng, MD, PhD; University of Florida; CIA 2008 

Growing evidence indicates that therapeutic response and prognosis of lung cancer are closely linked to 

the Bcl-2 family proteins. Mcl-1, a major antiapoptotic protein of the Bcl-2 family, is extensively expressed 

in both SCLC and NSCLC cells, suggesting that Mcl-1 may be a therapeutic target of patients with lung 

cancer. Since Mcl-1 has a short half-life (~2-4 hours), the mechanism(s) to prolong its half-life is critical for 

its long-term survival function. Dr. Deng’s preliminary data indicate that nicotine-induced Mcl-1 

phosphorylation at threonine163 (T163) enhances Mcl-1’s antiapoptotic activity, indicating that the T163 

site is a key site in regulating Mcl-1 function. Dr. Deng and colleagues have identified two small molecule 

Mcl-1 inhibitors (SMMI-1 and -2) through the in silico screening of the NCI compound database. They 

9 8 P A G E

found that two compounds not only block nicotine-stimulated Mcl-1 phosphorylation at T163 but also 

potently induce apoptosis of lung cancer cells. Additionally, nicotine can also induce Stat3 phosphorylation 

in association with up-regulation of Mcl-1. The team’s hypothesis is that nicotine-enhanced survival and 

chemoresistance of human lung cancer cells occurs through functional regulation of Mcl-1 at both the 

transcriptional and post-translational (i.e. phosphorylation) levels. SMMI-1 and -2 may have potent antitumor 

effect through induction of apoptosis. To critically test these hypotheses, the group identified three 

specific aims. The first is to determine whether nicotine-induced Mcl-1 phosphorylation regulates Mcl-1 

protein turnover and its survival function, leading to chemoresistance of human lung cancer cells. Studies 

will determine whether inhibition of Mcl-1 phosphorylation by SMMI or PD98059 affects Mcl-1’s 

stability and antiapoptotic activity. The second is to determine whether nicotine-activated Stat3 regulates 

Mcl-1 transcription in nicotine-induced survival signaling, and the third is to determine whether SMMI 

represses lung tumor growth in the xenograft animal models. Studies will evaluate the anti-lung cancer 

efficiency of SMMI in vivo. The results are expected to fill fundamental gaps in the knowledge regarding 

the signaling mechanism by which nicotine regulates survival and/or chemoresistance of human lung 

cancers expressing Mcl-1. It is expected that more efficient novel anti-lung cancer strategies that target 

Mcl-1 will be developed based on the results. 


Hou Y, Gao F, Wang Q, Zhao J, Flagg T, Zhang Y, Deng X. Bcl2 impedes DNA mismatch repair by 

directly regulating the hMSH2-hMSH6 heterodimeric complex. J Biol Chem 2007;282:9279-9287. 

Jin Z, Gao F, Flagg T, Deng X. Nicotine induces multisite phosphorylation of Bad in association with 

suppression of apoptosis. J Biol Chem 2004;279:23837-23844. 

Jin Z, Gao F, Flagg T, Deng X. Tobacco-specific nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1- 

butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating 

cell survival and proliferation. J Biol Chem 2004;279:40209-40219. 

Jin Z, May WS, Gao F, Flagg T, Deng X. Bcl2 suppresses DNA repair by enhancing c-Myc transcriptional 

activity. J Biol Chem 2006;281:14446-14456. 

Jin Z, Xin M, Deng X. Survival function of protein kinase Ci as a novel nitrosamine 4- 

(methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated Bad kinase. J Biol Chem 2005;280:16045- 

16052. 

Mai H, May WS, Gao F, Jin Z, Deng X. A functional role for nicotine in Bcl2 phosphorylation and 

suppression of apoptosis. J Biol Chem 2003;278:1886-1891. 

Wang Q , Gao F, May WS, Flagg T, Zhang Y, Deng X. Bcl2 negatively regulates DNA double-strand 

break repair through a non-homologous end joining pathway. Molecular Cell 2008;29:488-498. 

Xin M, Deng X. Nicotine inactivation of Bax’s proapoptotic function through phosphorylation. J Biol 

Chem 2005;280:10781-10789. 

Xin M, Deng X. Protein phosphatase 2A enhances the proapoptotic function of Bax through 

dephosphorylation. J Biol Chem 2006;281:18859-18867. 

Xin M, Gao F, May WS, Flagg T, Deng X. Protein kinase C abrogates the proapoptotic function of Bax 

through phosphorylation. J Biol Chem 2007;282:21268-21277. 

Xu L, Deng X. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces 

phosphorylation of m- and m- calpains in association with increased secretion, cell migration and 

invasion. J Biol Chem 2004;279:53683-53690. 

Xu L, Deng X. Protein kinase CI promotes nicotine-induced migration and invasion of cancer cells via 

phosphorylation of µ- and m-calpains. J Biol Chem 2006;281:4457-4466. 

Xu L, Deng X. Suppression of cancer cell migration and invasion by protein phosphatase 2A through 

dephosphorylation of µ- and m-calpains. J Biol Chem 2006;281:35567-35575. 

Zhao J, Gao F, Zhang Y, We K, Liu Y, Deng X. Bcl2 inhibits abasic site repair by down-regulating APE1 

endonuclease activity. J Biol Chem 2008;283:9925-9932. 

LUNG CANCER SUSCEPTIBILITY AND CHEMOPREVENTION 

Shyam Biswal, PhD; The Johns Hopkins University; YCSA 2002, CIA 2008 

Gene-environment interactions that regulate inflammation and oxidative stress play an important role in 

determining susceptibility to lung diseases. Dr. Biswal’s research focuses on understanding the role of the 

basic leucine zipper (bZIP) transcription factor, Nrf2 that regulates host stress response to environmental 

factors and oxidative stress. His studies using mouse models have indicated that Nrf2-directed host 

response may be critically involved in various pulmonary diseases such as chronic obstructive pulmonary 

P A G E 9 9

disease (COPD), innate immune dysfunction and acute lung injury (ALI), asthma, and cancer. Ongoing 

projects are focused on understanding the Nrf2-dependent regulation of host stress response, which critically 

determines the initiation, progression, and pathophysiology of these diseases. Strategies based on targeting 

Nrf2 for intervention of these diseases are being developed. 


Biswal S, Maxwell T, Rangasamy T, Kehrer JP. Modulation of benzo[a]pyrene-induced p53 DNA activity 

by acrolein. Carcinogenesis 2003;24:1401-1406. 

McGrath-Morrow S, Rangasamy T, Cho C, Susson T, Neptune E, Wise R, Tuder RM, Biswal S. 

Impaired lung homeostasis in neonatal mice exposed to cigarette smoke. 2 Am J Respir Cell Mol Biol. 

008;38(4):393-400. 

Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma S, Kensler TW, Yamamoto M, Petrache I, 

Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema 

in mice. J Clin Invest 2004;114:1248-1259. 

Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder 

RM, Georas SN, Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and 

asthma in mice. J Exp Med 2005;202:47-59. 

Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman, JG, Baylin SB, Sidransky 

D, Gabrielson E, Brock MV, Biswal S. Dysfunctional KEAP1 Nrf2 interaction in non-small-cell lung cancer. 

PLoS Medicine 2006;3(10): e420. 

Singh A, Rangasamy T, Thimmulappa RK, Lee H, Osburn WO, Brigelius-Flohe R, Kensler TW, 

Yamamoto M, Biswal S. glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in 

lungs is regulated by Nrf2. Am J Respir Cell Mol Biol 2006;35(6):639-50. 

Thimmulappa RK, Lee H, Rangasamy T, Kensler TW, Yamamoto M, Reddy SP, and Biswal S. Nrf2 is a 

critical regulator of innate immune response and survival during experimental sepsis. J Clin Invest 

2006;116(4):984-995. 

Thimmulappa RK, Scollick C, Trarore K, Yates M, Trush MA, Liby KT, Spoorn M, Yamamoto M, 

Kensler TW and Biswal S. Nrf2 dependent protection from LPS induced inflammatory response and mortality 

by CDDO-Imidazolide. Biochem Biophys Res Commun 2006;351(4):883-889. 

REGULATION OF NON-SMALL CELL LUNG CANCER BY NOTCH 

Douglas W. Ball, MD; The Johns Hopkins University; CIA 2003, 2007 

The capacity of individual cancer cells within a tumor to initiate new tumors is frequently 

heterogeneous, reflecting different stages of renewal and differentiation. Dr. Ball’s data for both SCLC and 

NSCLC have illustrated this heterogeneity, using direct xenograft models. For SCLC, the investigators 

have identified two key markers of enhanced tumor-initiating capacity, CD133/prominin 1 and aldehdye 

dehdrogenase (ALDH1A1). Both of these markers are positively regulated by the neuroendocrine bHLH 

transcription factor ASCL1 (achaete-scute homolog 1), as identified by microarray and confirmed by 

quantiative PCR, fluorescence activated cell sorting (FACS) analysis and chromatin immunprecipitation. 

ASCL1 expression and action are antagonized by the Notch signaling pathway. The group finds high levels 

of Notch pathway signaling activity in a spectrum of NSCLC cell lines and NSCLC tumors using tissue 

microarrays. In NSCLC direct xenograft tumor models, they find a broad range of Notch pathway activity 

which is concordant with expression of both CD133 and ALDH1A1. Studies are underway to determine 

whether Notch activity is itself a determinant of tumorigenicity in these direct xenograft systems. To 

approach the question of whether Notch is activated in the earliest stages of airway epithelial injury by 

tobacco carcinogens, the group, in collaboration with FAMRI grantee Cindy Zahnow, studied expression 

of downstream Notch effectors in cultured normal human bronchial epithelial cells (NHBE) incubated 

with graded doses of tobacco smoke condensate. They did not identify any evidence for Notch pathway 

activation as a response to this early in vitro injury model. 

In summary, Dr. Ball and colleagues have strong evidence that the bHLH transcription factor ASCL1 

promotes tumor initiating capacity in SCLC. Conversely in NSCLC, high levels of Notch pathway 

signaling effectively silence ASCL1. Higher levels of Notch activity correlate with markers of tumor 

initiating capacity such as CD133. 


Ball DW. Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer. Cancer 

Lett 2004;204:159-169. 

1 0 0 P A G E

Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancer [review]. Semin Cancer 

Biol 2004;14:357-364. 

Jiang T, Collins BJ, Jin N, Watkins DN, Brock MV, Matsui W, Nelkin BD, Ball DW. Achaete-scute 

complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res 

2009 Feb 1;69(3):845-54. 

MODULATION OF STEREOTACTIC BODY RADIATION THERAPY TO IMPROVE THERAPEUTIC RATIO 

Debabrata Saha, PhD; University of Texas Southwestern; YCSA 2003, CIA 2008 

Stereotactic body radiation therapy (SBRT), also known as stereotactic radiosurgery, is a non-invasive 

treatment in which high dose radiation beams are delivered to a tumor in a concentrated, precise manner. 

With stereotactic radiosurgery, often more than 100 beams of radiation coming from different directions 

are utilized. Each of these is relatively weak and therefore causes minimal entry damage. However, when 

all the beams converge, their cumulative effect adds up to an extremely potent dose aimed at destroying 

the target cells with great precision. This is different from conventionally fractionated radiotherapy 

(CFRT). Despite high rates of local tumor control with SBRT, it is not effecaceous as a treatment for 

tumors near the center of organs next to ducts, airways, vascular pedicles, and bowels because the danger 

of damage to these essential structures. Dr. Saha’s objective is to overcome barriers to the effective use of 

SBRT by modulating the dose using a radiosensitizer. 

To begin, Dr. Saha will systematically describe the survival characteristics relating to dose response and 

fractionation to find the transition points between the high tumor control with SBRT with serious toxicity 

and poor control with CFRT with acceptable toxicity. Dr. Saha will use this information to analyze the 

particular mechanisms of tissue response, injury, and repair to SBRT treatments. By understanding the true 

mechanisms of tissue response, directed strategies for modulating these effects by a variety of means can be 

formulated, which will ultimately allow SBRT treatments to be carried out in serially functioning 

hilar/central organ regions. Potential radiosensitizers (cdk inhibitors) will be tested in combination with 

SBRT regimen to reduce the tumoricidal dose in order to prevent serious tissue toxicity. With this 

accomplished, cancer patients will be afforded a treatment option with significantly higher control and cure 

rates than currently available. 

EARLY DETECTION OF LUNG CANCER IN AFRICAN AMERICANS EXPOSED TO SECOND HAND SMOKE 

Feng Jiang, MD, PhD; University of Maryland; CIA 2008 

Lung cancer is the number one cancer killer in the USA. It is particularly problematic for African 

Americans, because they have the highest rates of exposure to SHS and incidence and death for lung 

cancer among all racial and ethnic groups. Given the poor prognosis associated with advanced stage lung 

cancer, early detection of the disease will reduce the mortality. CT plays an important role in diagnosis of 

lung cancer, however has been limited by uncertain diagnostic rates for early stages of NSCLC, particularly 

central tumors. Genetic analysis of sputum has proven to be useful in diagnosis of NSCLC. Dr. Jiang and 

colleagues are evaluating the efficacy of combing CT and genetic analysis of sputum for noninvasive 

diagnosis of stage I NSCLC in African American non-smokers exposed to SHS. Genomic copy changes of 

a panel of lung cancer-related genes, HYAL2, FHIT, p16, and SP-A were analyzed by a mini-chip in 

sputum from 23 patients with stage I NSCLC.The controls were samples from 26 cancer-free individuals. 

The genetic and CT diagnoses were compared with surgical-pathologic stage. CT had higher sensitivity 

(86%) in detection of lung cancer compared with the mini-chip (71%), while there was no significant 

difference in specificity between the two tests (89 vs. 93%). Similarly, CT showed considerably higher 

sensitivity (93%) in identifying peripheral tumors than did the mini-chip (65%), whereas there was no 

difference in specificity between them (98 vs. 97%,). However, in detecting central tumors, CT had lower 

specificity (91%) compared with the mini-chip (99%), although its sensitivity (80%) was higher than that of 

the mini-chip (72%). Combining both tests resulted in higher sensitivity (91%) than did any single one 

(86%, 71%), while still keeping 92% sensitivity. In particular, this combined approach yielded higher 

sensitivity, specificity, and accuracy for diagnosing central cancers compared with CT alone. The integration 

of the genetic assay with CT led to improvements in noninvasive diagnosis of stage I NSCLCs, especially 

central tumors among African American non-smokers exposed to SHS. 

TETRAVALENT VACCINE AGAINST SCLC: A PILOT TRIAL 

Lee M. Krug, MD; Memorial Sloan-Kettering Cancer Center; CIA 2008 

SCLCs constitute 15% of lung cancers and are essentially all linked to active or passive cigarette smoke 

exposure. Dr. Krug is performing a pilot clinical trial of an antibody-inducing tetravalent vaccine against 

P A G E 1 0 1

SCLC. The foundation for this approach comes from 30 years of studies. During this time interval the 

following advances were made: 1) vaccine design for optimal antibody responses against cancer cell surface 

antigens was determined; 2) the benefit of immunization was demonstrated in preclinical studies in the 

minimal disease setting where circulating tumor cells, micro-metastases, and partially treated metastases 

were the primary targets; 3) the cell surface antigens expressed by the common cancers were defined and 

the four antigens most relevant for a SCLC vaccine were identified; and 4) the safety, immunogenicity, and 

optimal dose of monovalent vaccines against each of these four antigens was confirmed. In this pilot trial, 

ten patients with limited or extensive stage SCLC and a complete response (CR) or or partial response 

(PR) after first-line chemotherapy and radiation therapy will be enrolled. The patients will receive six 

injections with a tetravalent vaccine. The primary endpoints are safety and immunogenicity. Because the 

individual conjugates in this tetravalent vaccine were prepared under contract by good manufacturing 

practice (GMP) facilities or in the new MSKCC clinical grade production facility instead of in research labs 

at MSKCC as in the past, and will be vialed and administered together rather than individually, this initial 

pilot trial is necessary. If the GMP grade tetravalent vaccine proves safe and immunogenic, support will be 

sought for a randomized, placebo-controlled, Phase 2 trial. If antibodies of sufficient titer can be induced 

against these antigens that are capable of eliminating tumor cells from the blood or inhibiting growth of 

early metastasis, this would offer an effective adjuvant therapy to add to standard SCLC chemotherapy, 

which could lengthen time to progression or even confer survival in patients with SCLC. 

SMOKING, POLYMORPHISMS, AND LUNG CANCER PROGNOSIS 

Zhaoxi (Michael) Wang, MD, PhD; Harvard School of Public Health; CIA 2008 

Lung cancer is the leading cause of cancer death in the US. Although diagnostic techniques and 

treatment modalities have improved over that past several decades, the overall prognosis for this disease 

remains poor, with about 13% survival at 5 years for all stages. Little is known about the role of cigarette 

smoking, especially SHS, in lung cancer survival. Building on previous work, Dr. Wang plans to explore 

the roles of SHS exposure and genetic polymorphisms in the survival of lung cancer patients. Dr. Wang 

and colleagues will investigate whether SHS exposure (before diagnosis and continuous SHS exposure after 

diagnosis) are associated with shorter survival in a large population of lung cancer patients. In addition, 

they will investigate whether genetic polymorphisms of genes involved in several biological pathways, such 

as tobacco smoke metabolism, DNA repair, cell cycle regulation, etc., will modify the association between 

smoking and the survival of lung cancer patients. The data on SHS exposure will be obtained using 

questionnaires, and the genetic polymorphisms of candidate genes will be genotyped using state-of-art 

high throughput technologies. The research team will use various statistical techniques to adjust for 

important covariates that have been shown to be associated with lung cancer survival, including clinical 

stage and performance status. This study should result in a better idea of how the combination of SHS 

exposure and constitutive host factors influence the effect of cancer therapy. It will provide easily 

measurable markers for clinicians to help in planning patient-specific therapy. 


Ksomaning K, Miller DP, Liu G, Wain JC, Lynch TJ, Su L, Christiani DC. Second hand smoke, age of 

exposure and lung cancer risk. Lung Cancer 2008 Jul;61(1):13-20. Epub 2008 Jan 8. 

ROLE OF IRF-5 AS A TUMOR SUPPRESSOR IN A NON-SMALL CELL LUNG CANCER 

Betsy J. Barnes, PhD; UMDNJ-New Jersey Medical School; YCSA 2003 

The objective of Dr. Barnes’ research is to investigate the relationship between interferon regulatory 

factor 5 (IRF-5) expression and the tumor suppressor gene, p53, in human NSCLC to illuminate novel 

IRF-5-based therapies for lung cancer. The majority of NSCLC expresses mutant, non-functional p53 or 

are lacking in IRF-5 expression. The specific aims are: 1) to examine expression of IRF-5 and p53 in 

multiple human cancers; 2) to investigate the IRF-5 tumor suppression potential in the growth regulation 

of lung cancers where IRF-5 and/or p53 are not expressed; and 3) to discover the mechanism through 

which IRF-5 induces tumor cell growth arrest, apoptosis, and/or necrosis. 


Barnes BJ, Richards J, Mancl ME, Hanash S, Beretta L, Pitha PM. Global and specific targets of IRF-5 

and IRF-7 during innate response to viral infection. J Biol Chem 2004;279:45194-45207. 

Hu G, Mancl ME, Barnes BJ. Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to 

DNA damage-induced apoptosis and cell death. Cancer Res 2005;65:7403-7412. 

1 0 2 P A G E

Mancl ME, Hu G, Sangster-Guity N, Olshalsky SL, Hoops K, Fitzgerald-Bocarsly P, Pitha PM, Pinder K, 

Barnes BJ. Two discrete promoters regulate the alternative-spliced human interferon regulatory factor-5 

isoforms: Multiple isoforms with distinct cell type-specific expression, localization, regulation and 

function. J Biol Chem 2005;280:21078-21090. 

EXPRESSION PROFILING OF BLOOD IN LUNG CANCER CHEMOPREVENTION 

Christopher D. Coldren, PhD; University of Colorado; YCSA 2004 

Dr. Coldren and colleagues are demonstrating that that the gene expression profiles from circulating 

peripheral blood mononuclear cells (PBMCs) can provide important biomarkers for the development of 

lung cancer as an adjunct to an ongoing clinical trial testing iloprost (a prostacyclin analog) for prevention 

of lung cancer in high-risk current and former smokers. The specific aims are: 1) to collect PBMC gene 

expression data on the upper and lower quartile of Iloprost trial enrollees prior to medication 

administration; and 2) to use the data and gene expression profiles collected during the follow-up period 

to identify biomarkers for the early detection of lung cancer. Patient recruitment and sample collection 

have been concluded. Sample collections occurred over the period from April 2003 through February 

2009. Dr. Coldren and colleagues have a nearly complete set of RNA samples, and will choose from 

among 51 subjects with two PBMC samples each. They will construct a cohort for the final array 

experiment based on the degree of dysplasia change. This information, as well as the drug/placebo status 

of each subject will soon be released by the iloprost trial group. When the final cohort is assembled the 

group will collect all of the microarray data in a single batch in order to minimize nuisance effects. 

The investigators have recently been granted funds from the American Cancer Society to expand this 

study in an additional cohort of individuals with newly identified lung nodules. These nodules will be 

biopsied and a diagnosis of lung cancer or no cancer will be assigned. The team will compare PBMC gene 

expression between individuals with these two diagnoses, and this will be interpreted in light of the 

FAMRI studies on PBMC gene expression in Iloprost trial subjects. 


Bull TM, Coldren CD, Moore M, Sotto-Santiago SM, Pham DV, Nana-Sinkam SP, Voelkel NF, Geraci 

MW. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension, Am J Respir 

Crit Care Med 2004;170: 911-919. 

Nick JA, Coldren CD, Geraci MW, Poch KR, Fouty BW, O’Brien J, Gruber M, Zarini S, Murphy RC, 

Kuhn K, Richter D, Kast KR, Abraham E. Recombinant human activated protein C reduces human 

endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 

2004;104:3878-3885. 

Bull TM, Coldren CD, Nana-Sinkam P, Sotto-Santiago SM, Moore M, Voelkel NF, Geraci MW. 

Microarray analysis of peripheral blood cells in pulmonary arterial hypertension, surrogate to biopsy. 

Chest 2005;128:584S. 

Coldren CD, Nick JA, Poch KR, Woolum MD, Fouty BW, O’Brien JM, Gruber MP, Zamora MR, 

Svetkauskaite D, Richter DA, He Q, Park JS, Overdier KH, Abraham E, Geraci MW. Functional and 

genomic changes induced by alveolar transmigration in human neutrophils. Am J Physiol Lung Cell Mol 

Physiol 2006;291:1267-1276. 

Coldren CD, Helfrich BA, Witta SE, Sugita M, Lapadat R, Zeng C, Baron A, Franklin WA, Hirsch FR, 

Geraci MW, Bunn PA Jr. Baseline gene expression predicts sensitivity to gefitinib in non-small cell lung 

cancer cell lines. Mol Cancer Res 2006;4:521-528. 

Coldren CD, Lai Z, Shragg P, Rossi E, Glidewell SC, Zuffardi O, Mattina T, Ivy DD, Curfs LM, Mattson 

SN, Riley EP, Treier M, Grossfeld PD. Chromosomal microarray mapping suggests a role for BSX and 

neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen 

syndrome). Neurogenetics 2008; Oct15:[Epub ahead of print]. 

Geraci MW, Bull TM, Voelkel NF, Coldren CD. Diagnosis of disease and monitoring of therapy using 

gene expression analysis of peripheral blood cells. US Patent Application No.:US 2006/0019272 A1, 

Jan 26, 2006. 

Helfrich BA, Raben D, Varella-Garcia M, Gustafson D, Chan DC, Bemis L, Coldren CD, Baron A, Zeng 

C, Franklin WA, Hirsch FR, Gazdar A, Minna J, Bunn PA. Antitumor activity of the epidermal growth 

factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in non-small cell lung cancer 

cell lines correlates with gene copy number and EGFR mutations but not EGFR protein levels. Clin 

Cancer Res 2006;12:7117-7125. 

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Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, Helfrich B, Dziadziuszko R, 

Chan DC, Sugita M, Chan Z, Baron A, Franklin W, Drabkin HA, Girard L, Gazdar AF, Minna J, Bunn 

PA. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors 

in lung cancer cell lines. Cancer Res 2006;66: 944-950. 

Bull TM, Coldren CD, Geraci MW, Voelkel NF. Gene expression profiling in pulmonary hypertension. 

Proc Am Thorac Soc 2007;4:117-120. 

Frederick BA, Helfrich BA, Coldren CD, Zheng D, Chan D, Bunn PA, Raben D. Epithelial to 

mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell 

carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 2007;6:1683-1691. 

Silva E, Arcaroli J, He Q, Svetkauskaite D, Coldren CD, Nick JA, Poch K, Park JS, Banerjee A, Abraham 

E. HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from 

patients with sepsis-induced acute lung injury. Intensive Care Med 2007;33:1829-1839. 

Bull TM, Meadows CA, Coldren CD, Moore M, Sotto-Santiago, SM, Nana-Sinkam SP, Campbell TB, 

Geraci MW. Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. Am J 

Respir Cell Mol Biol 2008;39(6):706-716. 

Saavedra MT, Hughes GJ, Sanders LA, Carr M, Rodman DM, Coldren CD, Geraci MW, Sagel SD, 

Accurso FJ, West J, Nick JA. Circulating RNA transcripts identify therapeutic response in cystic fibrosis 

lung disease, Am J Respir Cell Mol Biol 2008;178(9):929-38. 

Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, McDermott LA, Coldren CD, 

Nemenoff RA, Merrick DT, Helfrich BA, Bunn PA, Heasley LE. Fibroblast growth factor (FGF) and 

FGF receptor-mediated autocrine signaling in non-small cell lung cancer cells. Mol Pharmacol 

2009;75(1):196-207. 

*Coldren CD, *Lai Z, Shragg P, Rossi E, Glidewell SC, Zuffardi O, Mattina T, Ivy DD, Curfs LM, 

Mattson SN, Riley EP, Treier M, Grossfeld PD. Chromosomal microarray mapping suggests a role for 

BSX and neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder 

(Jacobsen syndrome). Neurogenetics 2008; Oct15:(Epub ahead of print). 

Yang H, Harrington CA, Vartanian K, Coldren CD, Hall R, Churchill GA. Randomization in laboratory 

procedure is key to obtaining reproducible microarray results, PLoS ONE 2008;3:e3724. 

DEVELOPMENT OF STEM CELL MODEL SYSTEMS OF LUNG CANCER AND TOBACCO-DAMAGED 

AIRWAY EPITHELIUM 

Balazs Halmos, MD, MS; Case Western Reserve University; YCSA 2004 

Dr. Balazs Halmos’ work is based on the prior recognition that cancers comprise a heterogeneous 

population of cells, only a small fraction of which have the power of long-term self-renewal and clonogenic 

ability. Dr. Halmos is establishing progenitor cell line models from normal as well as tobacco-damaged 

airway epithelial cells to identify proliferative capacity differences, with the goal of providing novel models 

for lung cancer study and novel markers for lung cancer prevention and treatment. Epidermal growth 

factor receptor (EGFR) is a member of the family of receptor tyrosine kinases, and is often overexpressed 

and implicated in the pathogenesis of NSCLC. A certain percentage of NSCLC patients carry oncogenic 

EGFR gene mutations, predictive of a dramatic response to small-molecule tyrosine kinase inhibitors, such 

as gefitinib or erlotinib. Patients who respond to these drugs unfortunately often relapse. Dr. Halmos’ 

research group has identified that the mechanism of resistance in the majority of patients is due to 

secondary mutations of EGFR, such as the key mutations EGFR threonine 790 methonine (T790M). His 

investigations also revealed that a specific and irreversible anilinoquinazoline EGFR inhibitor, CL-387,785, 

was able to overcome the clinical resistance caused by the T790M mutation. The research team established 

a novel random mutagenesis-based strategy to predict what potential resistance mechanisms will be 

encountered in the clinic with the use of the new class of irreversible EGFR inhibitors. They revealed a 

number of potential new research mechanisms and defined alternative targeted therapies, such as cyclindependent 

kinase 4 inhibition as ways to overcome resistance. Other goals of this research include: 1) 

indentifying the functional role of the ERK-inhibitory dual-specificity phosphatase family in the 

suppression of the oncogenic effects of EGFR signaling; 2) developing cell-based model systems for the 

discovery of novel resistance mechanisms to EGFR-targeted agents; 3) determining the frequency of 

EGFR pathway abnormalities in African American patients; and 4) developing primary cell lines from 

patients with malignant pleural effusions for the fractionation of progenitor cell populations and the 

assessment of EGFR signaling in stem cell maintenance. 

1 0 4 P A G E


Basseres D, Levantini E, Ji H, Monti S, Elf S, Dayaram T, Fenyus M, Kocher O, Goulb T, Wong KK, 

Halmos B, Tenen DG. Respiratory failure due to differentiation arrest and expansion of alveolar cells 

following lung-specific loss of the transcription factor C/EBP-alpha in mice. Mol Cell Biol 

2006;26:1109-1123. 

Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, Tenen DG, Kobayashi S. BIM 

mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR 

mutations. PLoS Med 2007;4:1669-1679; discussion 1680. 

Costa DB, Nguyen KSH, Cho BC, Sequist LV, Jackman DM, Riely GJ, Yeap BY, Halmos B, Kim JH, 

Janne PA, Huberman MS, Pao W, Tenen DG, Kobayashi S. Effects of erlotinib in EGFR mutated nonsmall 

cell lung cancers with resistance to gefitinib. Clin Cancer Res 2008;14:7060-7067. 

Dowlati A, Kluge A, Nethery D, Halmos B, Kern JE. SCH66336, Inhibitor of Protein Farnesylation, 

Blocks STAT3 Signaling in lung cancer and interacts with a small molecule inhibitor of EGFR/HER2. 

Anticancer Drugs 2008;19:9-16. 

Huang G, Yan M Monti S, Lawrence E, Walbroehl J, Lowenberg E, Golub T, Merchan J, Tenen DG, 

Markowitz S, Halmos B. 15-hydroxyprostaglandin dehydrogenase is a target gene of hepatocyte nuclear 

factor 3 beta and a candidate tumor suppressor in human lung cancer. Cancer Res 2008;68:5040-5048. 

Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen 

DG, Halmos B. Emergence of a drug-resistance causing mutation in the epidermal growth factor 

receptor gene in gefitinib-responsive non-small cell lung cancer. N Engl J Med 2005;352:786-792. 

Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, Halmos B. An alternative inhibitor 

overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 

2005;65:7096-7101. 

Kobayashi S, Shimamura T, Monti S, Steidl U, Hetherington CJ, Lowell AM, Golub T, Meyerson M, 

Tenen DG, Shapiro GI, Halmos B. Transcriptional profiling identifies cyclin D1 as a critical downstream 

effector of mutant epidermal growth factor receptor signaling. Cancer Res 2006;66:11389-98. 

Koschmieder S, Halmos B (shared first authorship), Levantini E, Tenen DG. Dysregulation of the 

C/EBPalpha differentiation pathway in cancer. J Clin Oncol 2009;27:619-628.. 

Kumar A, Petri E, Halmos B, Boggon TJ. The structure and clinical relevance of the EGF receptor in 

human cancer. J Clin Oncol 2008;26:1742-1752. 

Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, Halmos B, Pearlberg J, 

Tsuchihashi Z, Cantley LC, Tenen DG, Johnson BE, Janne PA. Differential effects of gefitinib and 

cetuximab on non-small cell lung cancers bearing epidermal growth factor receptor mutations. J Natl 

Cancer Inst 2005;97:1185-1194. 

Tang Z, Du R, Jiang S, Wu C, Barkauskas DS, Richey J, Molter J, Lam M, Flask C, Gerson S, Dowlati A, 

Liu L, Lee Z, Halmos B, Wang Y, Kern JA, Ma PC. Dual MET-EGFR combinatorial inhibition against 

T790M-EGFR mediated erlotinib-resistant lung cancer. Br J Cancer 2008;99:911-922. 

Tang Z, Jiang S, Du R, Dietrich S, Boggon T, Halmos B, Kern JA, Ma PC. Disruption of a conserved ion 

pair in EGFR differentially alters kinase inhibitor sensitivity. Oncogene 2008;28:518-533. 

Yu Z, Boggon TJ, Kobayashi S, Jin C, Ma PC, Dowlati A, Kern JA, Tenen DG, Halmos B. Resistance to 

an irreversible epidermal growth factor receptor (EGFR) inhibitor in EGFR-mutant lung cancer reveals 

novel treatment strategies. Cancer Res 2007;67:10417-10427. 

TARGETING MYC FOR THE TREATMENT OF LUNG CANCER 

Catherine M. Shachaf, PhD; Stanford University; YCSA 2004 

A large number of lung cancers caused by tobacco smoke exposure express high levels of the MYC gene, 

known to cause different types of cancer in humans. Dr. Shachaf and collaborators hypothesize that 

targeting MYC may be effective in the treatment of lung cancer caused by tobacco smoke. Her study 

employs genetically-altered mice, in which MYC expression can be activated or inactivated using a genetic 

switch. The PI has demonstrated in an in vivo transgenic model that atorvastatin reverses and prevents the 

onset of MYC-induced tumorigenesis, but fails to reverse or prevent tumorigenesis in the presence of 

constitutively activated K-Ras (G12D). Utilizing phospho-protein fluorescence-activated cell sorting 

(FACS) analysis, atorvastatin treatment was found to result in the inactivation of the Ras and extracellular 

signal-regulated kinase (ERK)1/2 signaling pathways associated with the dephosphorylation and 

inactivation of MYC. Correspondingly, tumors with a constitutively activated K-Ras (G12D) did not 

exhibit dephosphorylation of ERK1/2 and MYC. Thus, atorvastatin, by inhibiting 3-hydroxy-3-methylglutaryl-CoA 

(HMG-CoA) reductase, induces changes in phosphoprotein signaling that in turn prevent 

P A G E 1 0 5

MYC-induced lymphomagenesis. It will be interesting to investigate the preventive effect of atorvastatin 

and other statins among the flight attendants. 

MYC is likely to contribute to tumorigenesis by its effects on global gene expression. The investigators 

have demonstrated that there is a precise threshold level of MYC expression required for maintaining the 

tumor phenotype, whereupon there is a switch from a gene expression program of proliferation to a state 

of proliferative arrest and apoptosis. The investigators have defined the gene and protein expression 

changes required to maintain tumorigenesis. Critical changes in gene expression occurred at or near the 

MYC threshold, including genes implicated in the regulation of the Gap 1/Synthesis, Gap 2/ mitosis cell 

cycle checkpoints, and death receptor/apoptosis signaling. The researchers used two-dimensional (2D) 

protein analysis followed by mass spectrometry, phospho-flow FACS, and antibody arrays to establish 

changes at the protein level that contributed to MYC-dependent tumor regression cell cycle checkpoints, 

halt protein translation, and promote apoptosis. These findings will be useful in determining targets for 

therapeutic use. 

To better understand the processes occurring in abnormal cells compared to normal cells, there is an 

urgent need to improve the technology for simultaneous detection of multiple events in a single cell. To 

better characterize several different events that occur in a single cell at a given time, it is necessary to 

accurately detect and analyze several nodes concurrently. Dr. Shachaf has developed “composite organicinorganic 

nanoparticles” (COINs), which are Raman nanoparticles for immunodetection assays of extraand 

intracellular proteins in single cells. COINs are surface-enhanced Raman scattering (SERS) silver 

particle clusters with incorporated Raman labels. Each COIN has a unique Raman spectral fingerprint, 

which allows higher levels of multiplexing. The ability of antibody-conjugated COINs to detect surface 

antigens was tested by the ability to recognize the CD54 antigen. CD8-expressing T cells were identified 

from among a heterogeneous population of primary human peripheral blood mononuclear cells. COINs 

were also used to measure intracellular phosphorylation in cells. U937 cells were treated with IFN-gamma 

and IL-4 cytokines and changes in Stat1 (Y701) and Stat6 (Y641) phosphorylation were measured. The 

Raman signals measured are comparable to the fluorescence signals measured by flow cytometry. The 

utility of COINs in a multiplex assay was confirmed by simultaneous detection of pStat1 and pStat6 in 

single cells. Dr. Shachaf has demonstrated the feasibility and practicality of using COINs for cell surface 

marker analysis and for measuring changes in intracellular phosphorylation. The COIN Raman 

nanoparticles offer new possibilities to expand on the current fluorescent technology used for 

immunoassays in single cells. 

To better identify cancer cells, a unique method to detect DNA amplifications and deletions in single 

cells by FACS has been developed. These single cell FACS assays detect amplifications in the genes for 

EGFR, MYC, BCL2, PDGF, and 20 base pair DNA deletions. By identifying genomic alterations at the 

single cell level it will be possible to distinguish among different tumor cell clones. This will make it 

possible to distinguish how the different cell populations respond to therapy. For instance, in patients with 

recurrent tumors, it will be possible which specific tumor cell populations in a primary tumor was resistant 

to therapy. 


Koh AL, Shachaf CM, Elchuri S, Nolan GP, Sinclair R. Electron microscopy localization and 

characterization of functionalized composite organic-inorganic SERS nanoparticles on leukemia cells. 

Ultramicroscopy 2008;109(1):111-121. 

Shachaf CM, Felsher DW. Tumor dormancy and MYC inactivation: pushing cancer to the brink of 

normalcy. Cancer Res 2005;65:4471-4474. 

Shachaf CM, Gentles A, Elchuri S, Sahoo D, Gentles A, Soen Y, Sharpe O, Perez OD, Chang M, Mitchel 

D, Amati B, Dill D, Nolan GP, Plevritis SK and Felsher DW. Systematic molecular analysis of a MYC 

overexpressing tumor cell following MYC inactivation. Cancer Res 2008;68(13):5132-42. 

Shachaf CM, Perez OD, Youssef S, Fan AC, Elchuri S, Goldstein MJ, Shirer AE, Sharpe O, Chen J, 

Mitchell DJ, Chang M, Nolan GP, Steinman L, Felsher DW. Inhibition of HMGcoA reductase by 

atorvastatin prevents and reverses MYC-induced lymphomagenesis. Blood 2007;110:2674-84. 

Shachaf SM, Felsher DW. Rehabilitation of cancer through oncogene inactivation. Trends Mol Med 

2005;11:316-321. 

Tran PT, Lin J, Bendapudi P, Koh S, Komatsubara K, Horng G, Chen J, Shachaf C, Paik D, Felsher D.W. 

2007. Predictive modeling of tumor regression kinetics using a murine model of oncogene-addicted 

lung cancers. Int J Radiat Oncol Biol Phys 2007;69(3)(Supplement1)S596-S597. 

1 0 6 P A G E

TRANSCRIPTIONAL REGULATION OF PUMA IN LUNG CANCER 

Jian Yu, PhD; University of Pittsburgh; YCSA 2004 

Dr. Yu and colleagues have identified a novel p53 target and B-cell lymphoma 2 (Bcl-2) family protein, 

p53 upregulated modulator of apoptosis (PUMA), which induces profound apoptosis in cancer cells. The 

study objectives are to establish the role and regulation of PUMA in the induction of apoptosis of human 

lung cancer cells, as well as to determine its role in chemo-and radiosensitization of these cells The plan 

also involves developing cell-based and high throughput assays to identify small molecules that can 

potentially activate PUMA in the absence of p53. Using lung cancer lines and gene-targeted cancer cell 

lines, Dr. Yu’ s group demonstrated that p53-mediated PUMA transcription is essential for apoptosis 

induced by commonly used chemotherapeutic drugs and radiation. Reintroduction of PUMA results in 

extensive apoptosis, growth suppression, and chemosensitization in cancer cells derived from lung, 

esophageal, and head and neck in vitro and in vivo. Several transcription factors were recently found to 

regulate PUMA induction in p53- deficient cancer cells in response to targeted cancer therapies, including 

selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. These findings are being 

translated into cell-based assays for small molecule compound library screening, and additional mechanistic 

studies are on-going. 


Bank A, Wang P, Du C, Yu J, Zhang L. SMAC mimetics sensitize nonsteroidal anti-inflammatory 

druginduced apoptosis by promoting caspase-3-mediated cytochrome c release. Cancer Res 

2008;68:276-284. 

Ding WX, Ni HM, Chen X, Yu J, Zhang L, Yin XM. A coordinated action of Bax, PUMA, and p53 

promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Mol Cancer Ther 

2007;6:1062-1069. 

Dudgeon C, Yu J. Green Tea and PUMA: A deadly combination? Cancer Biol Ther 2008;7(6)909-910. 

Garrison, SP, Jeffers JR, Yang C, Nilsson JA, Hall M, Rehg JE, Yue W, Yu J, Zhang L, Onciu M, Sample 

JT, Cleveland JL, and Zambetti GP. Selection against PUMA gene expression in Myc-driven B cell 

lymphomagenesis. Mol Cell Biol 2008;28(17):5391-5402 

Hu CA, Donald SP, Yu J, Lin WW, Liu Z, Steel G, Obie C, Valle D, Phang JM. Overexpression of proline 

oxidase induces proline-dependent and mitochondria-mediated apoptosis. Mol Cell Biochem 

2007;295:85- 92. 

Jiang M, Wei Q, Wang J, Du Q, Yu J, Zhang L, Dong Z. Regulation of PUMA-alpha by p53 in cisplatininduced 

renal cell apoptosis. Oncogene 2006;25:4056-4066. 

Kohli M, Yu J, Seaman C, Bardelli A, Kinzler KW, Vogelstein B, Lengauer C, Zhang L. 

SMAC/Diablodependent apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in 

colon cancer cells. Proc Natl Acad Sci 2004;101:16897-16902. 

Liu Z, Lu H, Shi H, Du Y, Yu J, Gu S, Chen X, Liu K, Hu CA. PUMA over expression induces reactive 

oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells. 

Cancer Res 2005;65:1647-1654. 

Luo W, Liu J, Li J, Zhang D, Liu M, Addo JA, Patil S, Zhang L, Yu J, Buolamwini JK, Chen J, Huang C. 

Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent, and 

p53-independent pathway. J Biol Chem 2008. 

Ming L, Sakaida T, Yue W, Jha A, Zhang L, and Yu J. Sp1 and p73 activate PUMA following serum 

starvation. Carcinogenesis 2008;29(10):1878-1884. 

Ming L, Wang P, Bank A, Yu J, Zhang L. PUMA Dissociates Bax and Bcl-X(L) to induce apoptosis in 

colon cancer cells. J Biol Chem 2006;281:16034-16042. 

Qiu W, Carson-Walter EB, Liu H, Epperly M, Greenberger JS, Zambetti, GP, Zhang L, Yu J. PUMA 

regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell 

2008;2(6):576-583. 

Sun Q, Sakaida T, Yue W, Gollin SM, Yu J. Chemosensitization of head and neck cancer cells by PUMA. 

Mol Cancer Ther 2007;6:3180-3188. 

Wang H, Qian H, Yu J, Zhang X, Zhang L, Fu M, Liang X, Zhan Q, Lin C. Administration of PUMA 

adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs. Cancer Biol Ther 

2006;5:[Epub ahead of print]. 

Wang P, Yu J, Zhang L. The nuclear function of p53 is required for PUMA-mediated apoptosis induced 

by DNA damage. Proc Natl Acad Sci USA 2007;104:4054-4059. 

Wu B, Qiu W, Wang P, Yu H, Cheng T, Zambetti GP, Zhang L, Yu J. p53-independent Induction of 

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PUMA Mediates Intestinal Apoptosis in Response to Ischemia Reperfusion. Gut 2007;56(5):645-54. 

Yu J, Wang P, Ming L, Wood MA, Zhang L. SMAC/Diablo mediates the proapoptotic function of PUMA 

by regulating PUMA-induced mitochondrial events. Oncogene 2007;26(29):4189-4198. 

Yu J, Yue W, Wu B, Zhang L. PUMA sensitizes lung cancer cells to chemotherapeutic agents and 

irradiation. Clin Cancer Res 2006;12:2928-2936. 

Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun 

2005;331:851-858. 

Yue W, Dacic S, Sun Q, Landreneau R, Guo M, Zhou W, Siegfried JM, Yu J, Zhang L. Frequent 

inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clin Cancer 

Res 2007;13:4336-4344. 

Zhang L, Ming L, Yu J. BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist 

Updat 2007;10:207-217. 

TARGETING THE ESTROGEN RECEPTOR AND EPITHELIAL GROWTH FACTOR RECEPTOR FOR LUNG CANCER 

THERAPY 

Laura A. Stabile, PhD; University of Pittsburgh; YCSA 2004 

Dr. Stabile and her colleagues are interested in targeting both the estrogen receptor (ER) pathway and 

the epidermal growth factor receptor (EGFR) pathway in lung cancer cells. The EGFR pathway appears to 

be turned on when estrogen is depleted in lung cancer cells. The overall goal of the study is to determine 

if a combination of drugs that target these two signaling pathways might decrease lung cancer growth in 

vitro and in vivo, and to identify the signaling pathways involved. Results from an in vivo lung tumor 

mouse model treated with a pure antiestrogen, fulvestrant, and an EGFR tyrosine kinase inhibitor, 

gefitinib, demonstrate a drug combination decrease in tumor size compared to either drug alone. Distinct 

histological changes within the tumors themselves are also observed. These results have been duplicated 

with a more clinically-relevant drug, erlotinib, which is also a selective EGFR tyrosine kinase inhibitor but 

shows superior survival benefits in lung cancer patients. 

Dr. Stabile and colleagues have demonstrated that estrogen can increase vascular endothelial growth 

factor (VEGF) secretion in lung cancer cells. Use of a dual EGFR/VEGFR inhibitor, AZD6474, in 

combination with fulvestrant showed very promising anti-carcinogenic effects in the in vivo tumor model. 

The signaling pathways between these two receptors have been further elucidated to aid in the 

understanding of this important cross talk. Src is an important mediator in this cross talk and the Src 

inhibitor, dasatinib, is currently being tested in combination with various estrogen and EGFR signaling 

pathway inhibitors to determine optimal drug combination therapies. This work has directly resulted in the 

establishment of patient clinical trials for women patients with lung cancer. A Phase 1 clinical trial to 

examine the safety of fulvestrant and gefitinib has been completed and no major adverse effects were 

observed. A Phase 2 clinical trial of fulvestrant and erlotinib is currently underway. Dr. Stabile has more 

recently shown that ER beta is the subtype of ER that is responsible for both the genomic and nongenomic 

actions of estrogen in the lung. The PI has also shown that GPR30, a newly identified 

nonnuclear ER, is highly expressed in the lung and may be responsible for some of the actions of estrogen. 

Interestingly, GPR30 appears to be more highly expressed in cells derived from non-smoking lung cancer 

patients compared to those from smokers. Currently, patient tissue specimens are being examined for 

expression of ER beta, GPR30, and EGFR to determine if there is any relationship between amount of 

protein present and any clinical parameters, including patient survival, as well as any interactions between 

the receptors. By more accurately identifying the estrogen signaling pathways and receptors involved in 

lung tumor growth, better-targeted therapies may be developed. 


Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM. Combined targeting of the estrogen 

receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced 

antiproliferative effects. Cancer Res 2005;65:1459-1470. 

SECOND HAND TOBACCO SMOKE AND LUNG CANCER RISK 

Olga Y. Gorlova, PhD; M. D. Anderson Cancer Center; YCSA 2004 

Dr. Gorlova’s hypothesis is that lifetime risk of developing lung cancer in SHS-exposed individuals 

depends on genetic background, in particular on the polymorphisms in the insulin-like growth factor 

pathway, as well as on diet and certain other chemical and dust exposures. Her research so far has 

identified several lung cancer risk factors for never smokers, including overall and workplace SHS exposure, 

1 0 8 P A G E

dust exposure, and family history of young-onset cancer (age less than 50), while hay fever occurring 

without asthma was associated with decreased lung cancer risk. In addition, a significantly elevated risk of 

overall cancer, young-onset lung cancer, breast, and testicular cancer was demonstrated among the firstdegree 

relatives of never smokers with lung cancer. It was found that in never smokers, suboptimal DNA 

repair capacity (DRC) conferred a significantly increased lung cancer risk, also demonstrating a clear doseresponse 

pattern and exacerbating the effect of SHS exposure. An almost four-fold lung cancer risk was 

observed in SHS-exposed individuals with suboptimal DRC. Notably, relatives of cases and controls with 

lowest DRC (below the first quartile) were almost three times more likely to be diagnosed with lung 

cancer, compared to relatives of probands with the most proficient DRC (above the third quartile). Female 

relatives of probands with suboptimal (below the control median) versus proficient DRC also had an 

earlier age at diagnosis with lung cancer (55.4 versus 67.7 years). 


Gorlova O, Zhang Y, Amos C, Spitz M. Aggregation of cancer among relatives of never smoking lung 

cancer patients Presented at the American Association for Cancer Res. Washington, DC, 2005. 

Gorlova OY, Zhang Y, Schabath MB, Lei L, Zhang Q, Amos CI, Spitz MR. Never smokers and lung 

cancer risk: A case-control analysis of epidemiological and environmental factors. Int J Cancer 

2006;118:1798-1804. 

Wu X, Lin J, Etzel CJ, Schabath MB, Gorlova OY, Zhang Q, Dong Q, Amos CI, Spitz MR. Interplay 

between mutagen sensitivity and epidemiological factors in modulating lung cancer risk. Abstract 

presented at American Association for Cancer Res, 97th Annual Meeting Washington, DC, 2006. 

PPAR-GAMMA IN TUMOROGENESIS AND THERAPY OF NON-SMALL CELL LUNG CANCER 

Venkateshwar Keshamouni, PhD; University of Michigan; YCSA 2004 

Preliminary studies have shown that agonists of peroxisome proliferator-activated receptor gamma 

(PPAR-g), a critical regulator of cellular differentiation, inhibit the growth of lung cancer cells in vitro and 

in vivo. Dr. Keshamouni is investigating the role of PPAR-g in the initiation and progression of NSCLC 

tumors and is developing new strategies to target PPAR-g for therapy. As part of this research program, 

Dr. Keshamouni demonstrated that chemotherapeutic drugs induce PPAR-g expression and synergize with 

PPAR-g ligands in the treatment of lung cancer. In 2008, Dr. Keshamouni secured NCI/NIH R01 

funding for his research program investigating TGF-beta regulation of macrophage function in the tumor 

microenvironment. In January 2009 he was awarded a Research Scholar Grant from the American Cancer 

Society for his proposal on “Targeting tumor stromal interactions by PPAR-g activation”, which is a direct 

extension of the FAMRI YCSA award. Both of these would not have been possible without the generous 

support of FAMRI through this YCSA award, which came at very critical juncture in Dr. Keshamouni’s 

career. 


Boosani CS, Mannam AP, Cosgrove D, Silva R, Hodivala-Dilke KM, Keshamouni VG, Sudhakar A. 

Regulation of COX-2 mediated signaling by alpha3 type IV noncollagenous domain in tumor 

angiogenesis. Blood 2007;110:1168-77. 

Keshamouni VG, Jagtap P, Michailidis G, Strahler JR, Kuick R, Papoulias P, Krishnapuram R, Srirangam A, 

Standiford TJ, Andrews PC, Omenn GS. Temporal quantitative proteomics by iTRAQ 2D-LC-MS/MS 

and corresponding mRNA expression analysis identify post-transcriptional modulation of actincytoskeleton 

regulators during TGF-b-induced epithelial-mesenchymal transition. J Proteome Research 

2008;8(1):35-47. 

Keshamouni VG, Michailidis G, Grasso CS, Anthwal S, Strahler JR, Walker A, Arenberg DA, Reddy RC, 

Akulapalli S, Thannickal VJ, Standiford TJ, Andrews PC, Omenn GS. Differential protein expression 

profiling by iTRAQ-2DLC-MS/MS of lung cancer cells undergoing epithelial-mesenchymal transition 

reveals a migratory/invasive phenotype. J Proteome Res 2006;5(5):1143-54. 

Keshamouni VG, Arenberg DA, Reddy RC, Newstead MJ, Anthwal S, Standiford TJ. PPAR-gamma 

activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung 

cancer. Neoplasia 2005;7(3):294-301. 

Keshamouni VG, Han SW, Roman J. Peroxisome proliferator activated receptors (PPARs) in lung cancer. 

PPAR Research 2007;2007:90289 

Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM, Standiford TJ, Thannickal 

VJ, Reddy RC. PPAR-g agonists inhibit pro-fibrotic phenotypes in human lung fibroblasts and 

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leomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2007;294(5):L891-901. 

Reddy RC, Narala VR, Keshamouni VG, Milam JE, Newstead MW, Standiford TJ. Sepsis-induced 

inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated 

receptor-g. Blood 2008 Jun 5 [Epub ahead of print]. 

Reddy RC, Srirangam A, Reddy K, Chen J, Gangireddy S, Kalemkerian G, Standiford TJ, and Keshamouni 

VG. Chemotherapeutic drugs induce PPAR-g expression and synergise with PPAR-g ligands in the 

treatment of non-small cell lung cancer. Neoplasia 2008;10(6):597-603. 

Standiford TJ, Keshamouni VG, Reddy RC. Peroxisome proliferator-activated receptor-gamma as a 

regulator of lung inflammation and repair. Proc Am Thorac Soc 2005;2(3):226-231. 

Sudhakar A, Nyberg P, Keshamouni VG, Mannam AP, Li J, Sugimoto H, Cosgrove D, Kalluri R. Human 

alpha type IV collagen NCI domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 

integrin. J Clin Invest 2005;115(10):2801-2810. 

SMOKING, POLYMORPHISMS, AND LUNG CANCER PROGNOSIS 

Wei Zhou, MD, PhD; Harvard University; YCSA 2004 

In this study, Dr. Zhou investigates the interactive roles of SHS and mainstream smoke (MSS) with a 

number of genetic polymorphisms in clinical outcomes of patients with NSCLC. In a large prospective 

study, a cohort of NSCLC patients is being studied to investigate whether SHS and MSS are associated 

with poorer prognosis in both earlier and more advanced stages of cancer. The investigators are examining 

whether polymorphisms of interest might modify the association between SHS and MSS and NSCLC 

prognosis. The ultimate goal is to assess the potential for various constitutive prognostic markers to be 

used to individualize therapies. Results thus far demonstrate that smoking cessation is associated with 

improved survival in early stage NSCLC, and the longer the duration since smoking cessation, the better 

the survival outcome. Recent results show SHS exposure before diagnosis results in poorer survival in early 

stage NSCLC patients. 


Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Boyce P, Christiani DC. 308GA and TNFB 

polymorphisms in acute respiratory distress syndrome. Eur Respir J 2005;26:382-389. 

Hang J, Zhou W, Wang X, Zhang H, Sun B, Dai H, Su L, Christiani DC. Microsomal epoxide hydrolase, 

endotoxin, and lung function decline in cotton textile workers. Am J Respir Crit Care Med 

2005;171:165-170. 

Liu G, Zhou W, Miller DP, Thurston SW, Xu LL, Wain JC, Lynch TJ, Su L, Christiani DC. MPO and 

MnSOD polymorphisms, gender, and the risk of non-small cell lung carcinoma. Cancer Lett 

2004;214:69-79. 

Liu G, Zhou W, Park S, Wang LI, Miller DP, Wain JC, Lynch TJ, Su L, Christiani DC. The SOD2 

Val/Val genotype enhances the risk of non-small cell lung carcinoma by p53 and XRCC1 

polymorphisms. Cancer 2004;101:2802-2808. 

Miller DP, Park S, Gitin E, Zhou W, Liu G, Wain JC, Lynch TJ, Christiani DC. DNA repair 

polymorphisms, second hand tobacco smoke and lung cancer risk. Presented at the Annual Meeting of 


Miller DP, Park S, Gitin E, Zhou W, Liu G, Wang Z. ERCC2 Asp312Asn polymorphism modifies the 

association between second hand tobacco smoke and lung cancer risk. Presented at the Annual Meeting 

of the American Association for Cancer Research, April 2004. 

Park S, Miller DP, Gitin E, Zhou W, Liu G, Wain JC, Lynch TJ, Christiani DC. A new metric for second 

hand tobacco smoke and its association with lung cancer risk. Presented at the AnnualMeeting of the 


Su L, Zhou W, Asomaning K, Lin X, Wain JC, Lynch TJ, Liu G, Christiani DC. Genotypes and haplotypes 

of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. Carcinogenesis 2005;Epub 

ahead of print: Nov 25, 2005. 

Su L, Zhou W, Park S, Wain JC, Lynch TJ, Liu G, Christiani DC. Matrix metalloproteinase-1 promoter 

polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2005:567-570. 

Yue W, Dacic S, Sun Q, Landreneau R, Guo M, Zhou W, Siegfried JM, Yu J, Zhang L. Frequent 

inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clin Cancer 

Res 2007;13:4336-44. 

Zhou W, Heist R, Liu G, Miller DP, Neuberg DS, Asomaning K, Wain JC, Lynch TJ, Christiani D. 

Second hand tobacco smoke exposure and survival in early stage non-small cell lung cancer patients. 

1 1 0 P A G E

Presented at the Annual Meeting of the American Association for Cancer Research, April 2006. 

Zhou W, Heist RS, Liu G, Neuberg DS, Asomaning K, Su L, Wain JC, Lynch TJ, Giovannucci E, 

Christiani DC. Polymorphisms of vitamin D receptor and survival in early-stage non-small cell lung 

cancer patients. Cancer Epidemiol Biomarkers Prev 2006;15:2239-45. 

Zhou W, Heist RS, Liu G, Park S, Neuberg DS, Asomaning K, Wain JC, Lynch TJ, Christiani DC. 

Smoking cessation before diagnosis and survival in early stage non-small cell lung cancer patients. Lung 

Cancer 2006;53:375-80. 

Zhou W, Liu G, Park S, Wang Z, Wain JC, Lynch TJ, Su L, Christiani DC. Gene-smoking interaction 

associations for the ERCC1 polymorphisms in the risk of lung cancer. Cancer Epidemiol Biomarkers Prev 

2005;14:491-496. 

Zhou W, Park S, Liu G, Miller DP, Wang LI, Pothier L, Wain JC, Lynch TJ, Giovannucci E, Christiani 

DC. Dietary iron, zinc, and calcium and the risk of lung cancer. Epidemiology 2005;16:772-779. 

Zhou W, Suk R, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Giovannucci E, Christiani DC. Vitamin 

D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer 


THE ROLE OF THE TRANSCRIPTION FACTOR C/EBP ALPHA IN NORMAL LUNG DEVELOPMENT AND IN MURINE 

MODELS OF LUNG CANCER AND TOBACCO-DAMAGED AIRWAY EPITHELIUM 

Elena Levantini, PhD; Harvard University; YCSA 2006 

Lung cancer is the principal cause of worldwide cancer mortality. Advances in lung cancer therapy 

require a greater understanding of its molecular pathogenesis. Previously, Dr. Levantini showed that the 

transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) is downregulated in NSCLC 

patients. Furthermore, using a mouse model where excision of C/EBPa is under the control of the 

Surfactant Protein C (SPC) promoter (C/EBPa SPC-deleted) mice, Dr. Levantini showed that this 

transcription factor regulates alveolar type II cell differentiation. Subsequently she investigated the effects 

of C/EBPa downregulation in predisposing the mouse lung epithelium to tumorigenesis and 

demonstrated that the C/EBPa SPC-deleted mouse lung epithelium displays increased numbers of 

proliferating cells and decreased numbers of apoptotic cells. The PI also identified potential target genes 

that may elucidate the mechanisms by which C/EBPa acts. For example, the cell survival gene Gli-1, a 

transcription factor downstream of sonic hedgehog signaling, is upregulated and its contribution in 

promoting the malignant phenotype promises to be important biologically and therapeutically. Therefore, 

Dr Levantini and collaborators hypothesized that loss of C/EBPa in the adult lung epithelium is a 

transforming event. Consistently, their data indicate that C/EBPa is detected at the level of 

bronchoalveolar stem cells, a pulmonary population that has been recently linked to adenocarcinoma 

initiation. Moreover, Dr Levantini has data from two different lung conditional models [SPC and Clara 

Cell (CC10)-driven excision] that supports her hypothesis that C/EBPa is a lung tumor suppressor, in that 

they develop adenocarcinoma. Furthermore, their data indicate that Gli-1, a transcriptional effector of the 

sonic hedgehog pathway, is highly active only in C/EBPa-deleted pulmonary cells that, according to her 

hypothesis, represent the cells of origin of the lung adenocarcinomas found in her murine models. Gli-1 

expression peaks in the lung stem cells, it is reduced in progenitor cells, but it is still active in the 

adenocarcinoma. Overall, Dr Levantini’s data show that loss of C/EBPa might increase the susceptibility 

to lung cancer development and supports the hypothesis that C/EBPa acts as a tumor suppressor for lung 

cancer in vivo. 


Basseres D, Levantini E, Ji H, Monti S, Elf S, Dayaram T, Fenyus M, Kocher O, Golub T, Wong KK, 

Halmos B, Tenen DG. Respiratory failure due to differentiation arrest and expansion of alveolar cells 

following lung-specific loss of the transcription factor C/EBP-alpha in mice. Mol Cell Biol 

2006;26:1109- 1123. 

Koschmieder S, D’Alo F, Radomska H, Schoneich C, Chang JS, Konopleva M, Kobayashi S, Levantini E, 

Suh N, DiRuscio A, Voso MT, Watt JC, Santhanam R, Sargin B, Kantarijan H, Andreeff M, Sporn MB, 

Perrotti D, Berdel WE, Muller-Tidow C, Serve H, Tenen DG. CDDO induces granulocytic 

differentiation of myeloid leukemic blasts through translational upregulation of p42 CCAAT enhancer 

binding protein alpha. Blood 2007; 110(10):3695-705. 

Koschmieder S, Halmos B, Levantini E, Tenen DG. Dysregulation of the C/EBPa differentiation pathway 

in human cancer. Journal Clinical Oncology 2009;27(4):619-28. 

Kubo S, Levantini E., Kobayashi S, Kocher O, Halmos B, Tenen DG, Takahashi M. In vitro three- 

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dimensional magnetic resonance microscopy of pulmonary solitary tumors in transgenic mice. Magn 

Reson Med 2006;56(3):698-703. 

Peter Y, Comellas A, Levantini E, Ingenito EP, Shapiro SD. Epidermal growth factor receptor and claudin- 

2 participate in A549 permeability and remodeling: implications for non-small cell lung cancer. Mol 

Carcinog 2008 Oct 21 [EPub ahead of print]. 

DEVELOPING NRF2 INHIBITORS FOR CANCER CHEMOTHERAPY 

Anju Singh, PhD; The Johns Hopkins University; YCSA 2007 

Therapeutic resistance in cancer cells occurs as a result of genetic aberrations that confer tumorigenic 

potential and survival advantage against chemo- and radiotherapy. Nuclear factor erythroid-2-related factor 

2 (NRF2), is a redox-sensitive transcription factor that regulates the expression of antioxidants, xenobiotic 

detoxification enzymes, and efflux proteins. It also confers cytoprotection against a broad spectrum of 

drugs and electrophiles. Loss-of-function mutations in the NRF2 inhibitor, Kelch-like ECH-associated 

protein (KEAP1) result in gain of NRF2 function in NSCLC. The results indicate that gain of NRF2 

function in lung cancer cells results in therapeutic resistance by promoting tumorigenecity as well as 

chemo- and radioresistance. RNA interference (RNAi)-mediated targeting of NRF2 expression in lung 

cancer cells enhanced reactive oxygen species generation, suppressed tumor growth, and resulted in 

increased sensitivity to chemotherapeutic drug and radiation-induced cell death in vitro and in vivo. 

Intervening NRF2 expression in lung tumors using naked small interfering (siRNA) duplexes in 

combination with carboplatin and radiation significantly inhibited tumor growth in a subcutaneous model 

of lung cancer. Thus, targeting NRF2 activity in lung cancers, particularly those with KEAP1 mutations, 

could be a promising strategy to inhibit tumor growth and circumvent therapeutic resistance. The team 

has also screened a library of FDA-approved drugs to identify inhibitors of NRF2, and have identified 

several drugs as putative inhibitors. They are currently validating these drugs for NRF2 inhibitory activity 

using cell culture assay systems. 


Harvey CJ, Thimmulappa RK, Singh A, Blake DH, Ling G, Wakabayashi N, Fujii J, Myers AC, and Biswal 

S. Nrf2 regulated glutathione recycling independent of biosynthesis is critical for cell survival during 

oxidative stress. Free Radic Biol Med 2009;46(4)443-53. 

Malhotra D, Thimmulappa RK, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, 

Hogg J, Pare P, Tuder RM, Biswal S. Decline in NRF2 regulated antioxidants in COPD lungs due to 

loss of its positive regulator DJ-1. Am J Respir Crit Care Med 2008;178(6):592-604. 

Singh A, Boldin-Adamsky S ,Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman 

SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, and Biswal S. RNAi-mediated silencing of nuclear 

factor erythroid-2-related factor gene expression in non-small cell lung cancer inhibits tumor growth and 

increases efficacy of chemotherapy. Cancer Res 2008;68:(19):7975-84. 


TW, Watson WH, Biswal S. Nrf2 Dependent Sulfiredoxin-1 Expression Protects Against Cigarette 

Smoke induced Oxidative Stress in Lungs. Free Radic Biol Med 2009;1;46(3):376-386. 

USING NOVEL TUMOR MODELS AND NOVEL THERAPEUTICS TO DEFINE TUMOR PROGENITORS IN SMALL LUNG 

CANCER 

Christine L. Hann, MD, PhD; The Johns Hopkins University; YCSA 2007 

SCLC accounts for approximately 15% of all lung cancers and is exquisitely sensitive to cytotoxic 

chemotherapy. Despite initial responses to chemotherapy almost all SCLC patients will die of recurrent 

disease; the average survival for patients with extensive stage (ES) SCLC is less than one year. 

Recommended therapy for ES SCLC consists solely of cytotoxic chemotherapy, a treatment paradigm 

which has not changed significantly over the past two decades. Dr. Hann’s research group has been 

interested in characterizing and targeting apoptotic pathways in cancer cells. Bcl-2, a central apoptotic 

inhibitor, is markedly upregulated in up to 70-90% of SCLC cases, making it an attractive target for 

therapy. The investigators have demonstrated that treatment of traditional SCLC cell line xenografts with a 

small molecule inhibitor of Bcl-2, ABT-737, results in dramatic regressions. They have initiated studies 

using primary SCLC xenografts, a model system that has potential to better reflect patient tumor biology, 

developed by the project collaborator Dr. Neil Watkins. The group found that treatment with ABT-737 

caused a significant decrease in tumor growth in only one of the three primary xenografts; a result which is 

likely related to the relatively low expression of Bcl-2. Two primary SCLC xenografts with higher 

1 1 2 P A G E

expression levels of Bcl-2 are currently being investigated. To define mechanisms which may contribute to 

ABT-737 resistance, they have started to characterize an ABT-737-resistant derivative cell line. The 

findings show that both Bcl-2 expression and Bcl-2:BIM heterodimers were decreased in the resistant 

derivative. Expression profiling revealed 85 genes with changes in expression associated with acquired 

resistance. An oral form of ABT-737 is currently in Phase I/II clinical trials; thus, data on its efficacy in 

primary xenografts and mechanisms of resistance have implications for its clinical development. 

MEK-INDUCED GROWTH ARREST IN SMALL CELL LUNG CANCER CELLS 

Jong-In Park, PhD; Medical College of Wisconsin; YCSA 2007 

Lung cancer, the leading cause of cancer death, is predominantly caused by tobacco smoke. SCLC 

accounts for about 20% of lung cancers and currently no treatments are available to cure it. Identification 

of a tumor-specific growth-suppressive pathway has the potential to lead to the development of a novel 

therapeutic strategy. Aberrant Ras/Raf activation, detected in a large number of epithelial malignancies 

including NSCLC, is totally absent in SCLC. Indeed, sustained activation of the Ras/Raf/MEK/ERK 

pathway elicits cell cycle arrest in SCLC cells. Dr. Park hypothesizes that the ability of SCLC cells to arrest 

in response to Ras/Raf activation depends on a growth arrest-specific intracellular signaling complex of 

MEK/ERK, and that NSCLC cells, in which Ras/Raf has opposing effects, have lost the ability to form 

this complex. To evaluate this hypothesis, it is necessary to identify the components of growth arrestspecific 

MEK/ERK complexes. To this end, Dr. Park and colleagues have successfully generated tandem 

affinity-tagged functional MEK and ERK constructs in adenoviral and lentiviral vectors. Using these 

reagents, they are currently isolating the proteins that specifically interact with MEK and ERK in the 

context of Ras/Raf-induced growth arrest and cataloguing them using proteomics mass spectrometry 

techniques. In the upcoming year, they will evaluate the ability of these growth arrest-specific components 

to mediate the Ras/Raf-induced growth arrest in SCLC cells or to restore the growth arrest response in 

NSCLC cells by using RNA interference and viral vector-mediated overexpression techniques. 

TARGETING EPIGENETIC CHANGES IN METASTATIC LUNG CANCER 

Rosalyn Juergens, MD; The Johns Hopkins University; YCSA 2007 

NSCLC is the most common cause of cancer death in the U.S. Most NSCLC patients die of recurrent 

progressive disease after primary therapy. There are no available therapies for recurrent lung cancer 

associated with long-term disease-free survival. New therapies for NSCLC, particularly for recurrent 

disease, are a critical need. Epigenetic gene silencing mediated through aberrant DNA methylation and 

histone deacetylation is a key contributor to lung carcinogenesis. Studies by our group have shown that 

combined inhibition of DNA methyl transferases (DNMT) and of histone deacetylases (HDAC) 

synergistically induces re-expression of tumor suppressor genes that are epigenetically silenced in cancer. 

This research is designed to test the efficacy of combined epigenetic targeting in patients with advanced, 

recurrent NSCLC using the DNMT inhibitor, 5AC, and the HDAC inhibitor, entinostat, on a schedule 

shown to be well tolerated and associated with significant activity in patients with hematologic 

malignancies. Since receiving FAMRI funding the team has completed the Phase I portion of this clinical 

trial. At this point, toxicities have been mild and have included injection site reactions from the 5AC, 

nausea /vomiting, constipation, and mild lowering of the blood counts. One patient has been off therapy 

for over a year and is still disease free. Another patient has had stable disease on therapy for 18 months. 

Diseases in two other patients has stabilized for a shorter duration and continue on study. One of these 

patients does have tumor shrinkage and may eventually be categorized as another response. The 

investigators are near completion of the Phase II portion of the trial. An update on the Phase II trial will 

be presented in poster form at the American Society of Clinical Oncology (ASCO) meeting in June and 

will follow in a full-length publication this winter. The Phase I trial will be published in 2009. 


Juergens RA, Vendetti F, Coleman B, Sebree RS, Rudek MA, Belinsky SA, Brock MV, Herman JG, Baylin 

SB, Rudin CM. Phase I trial of 5-azacitidine (5AC) and SNDX-275 in advanced lung cancer (NSCLC). 

Presented at the Annual Meeting of the American Society of Clinical Oncology, May 2008. 

COMBINATION AD.P53-DC IMMUNOTHERAPY/CHEMOTHERAPY FOR SCLC 

Terri B. Hunter, PhD; H. Lee Moffitt Cancer Center; YCSA 2007 

This study builds on one previously conducted by the PI and her colleagues to conduct a clinical trial to 

test the safety and efficacy of a dendritic cell vaccine using p53 as a tumor antigen in SCLC patients. The 

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vaccine, Ad.p53-DC, was well tolerated and the majority of patients (57.1%) were observed to have p53- 

specific T cell responses and two patients demonstrated a clinical response to vaccination. A high rate 

(61.9%) of objective clinical responses to chemotherapy that immediately followed vaccination was 

observed and correlated positively with p53 responders. EphA2 receptor tyrosine kinase is frequently 

overexpressed in various human cancers, leading to the suggestion that it may be an oncoprotein. 

Surprisingly, recent studies from Dr. Hunter’s laboratory show that EphA2 is a novel tumor suppressor 

gene in mammalian lung, and is an attractive target for lung cancer therapy. Multiple lines of evidence 

from preliminary studies support this notion: 1) EphA2 homozygous knockout mice but not their wildtype 

littermates spontaneously develop lung tumors, and display markedly increased susceptibility to 

chemically induced lung carcinogenesis. 2) Intriguingly, unlike conventional tumor suppressor genes that 

are lost or mutated in tumors, EphA2 was consistently upregulated in tumors arising in wild-type mice. 

The overexpression is robust and occurs very early, even in preneoplastic lesions. However, the 

overexpressed EphA2 is poorly activated in mouse tumors, suggesting that tumor suppressor activities of 

EphA2 have been functionally silenced during tumorigenesis. Moreover, the investigators found that the 

loss of tumor suppressor activities of EphA2 was correlated with loss of ligand expression. Similar 

observations were also made in human lung cancer. 3) In human NSCLC cells in vitro, the latent tumor 

suppressor function of EphA2 can be reawakened by stimulation with ephrin-A1, a ligand for EphA2, 

which causes suppression of ERK1/2 and Akt kinase activities, and inhibition of cell migration and 

proliferation. 5) More importantly, the investigators demonstrated that systemic administration of ephrin- 

A1-Fc led to selective homing of the ligand to tumors that overexpress the dormant EphA2, and activated 

it. Over 160,000 men and women in the US died from lung cancer in 2007. A large majority of the cases 

are caused by first-hand and SHS. The overarching goal of Dr. Hunter’s project is to test if the intrinsic 

tumor suppressor activities of EphA2 kinase can be reawakened for use in lung cancer therapy, and whether 

the overexpressed EphA2 can be exploited for early detection of lung cancer. In Aim 1, ephrin-A1 is 

systemically administered to test its therapeutic efficacy against lung tumors by itself or in combination 

with other agents including rapamycin and Alimta. In Aim 2, the investigators are testing if the 

overexpressed EphA2 on lung tumors can be exploited as a marker for early detection of lung cancer. The 

proposed translational studies will lead to an innovative paradigm of exploiting innate tumor suppressor 

function of EphA2 kinase for therapeutic intervention and early detection. 

HEDGEHOG SIGNALING IN SMALL CELL LUNG CANCER STEM CELLS 

Craig D. Peacock, PhD; The Johns Hopkins University; YCSA 2008 

SCLC is an extremely aggressive malignancy strongly associated with tobacco exposure. Although 

initially very chemosensitive, the vast majority of patients die from SCLC within 2 years due to the rapid 

appearance of chemoresistant recurrent disease. Dr. Peacock contends that in SCLC, conventional 

chemotherapy effectively kills differentiated cancer cells, but spares the undifferentiated cancer stem cell. 

Cancer stem cells are capable of regenerating the entire tumor from a single cell, and represent the leading 

candidate population responsible for cancer recurrence. Hence there is a need to uncover and exploit 

therapeutic vulnerabilities within this compartment. 

All cancers must establish a pattern of aberrant self-renewal. Evidence from multiple laboratories, has 

revealed the Hedgehog (Hh) pathway as one of the most important in regulating progenitor cell fates in 

organ repair and cancer. The central hypothesis is that SCLC contains a sub-population of chemoresistant 

stem cells that is dependent on aberrant Hedgehog (Hh) signaling, which can be specifically targeted with 

Hh pathway inhibitors, resulting in terminal differentiation and loss of self-renewal capacity. The 

investigators’ earlier studies in multiple myeloma revealed that Hh signaling is markedly concentrated 

within tumor stem cells, and functions to maintain a population of undifferentiated, clonally competent 

progenitors. Conclusively demonstrating this phenomenon in SCLC will set the stage for an entirely 

different translational approach to Hh pathway inhibitors. 

Dr. Peacock’s data demonstrate active Hh pathway signaling in SCLC, which appears to be concentrated 

within a chemoresistant subset of cells. Moreover, the clonogenic capacity of SCLC cell lines declines in 

response to Hh pathway inhibition. Utilizing both tissue culture and mouse models, the investigators hope 

to prospectively identify a marker of SCLC stem cells and characterize the role of aberrant Hh signaling in 

this compartment. In addition, preclinical models are being employed to test the efficacy of novel Hh 

pathway antagonists, as inhibitors of the clonal growth and recurrence of chemosensitive SCLC in vivo. 

1 1 4 P A G E

THERAPEUTIC TARGETS IN K-RAS-INDUCED LUNG CANCER 

Daniela S. Basseres, PhD; University of North Carolina at Chapel Hill; YCSA 2008 

There is a fundamental gap in our understanding of how oncogenic mutations in the K-Ras protooncogene 

contribute to malignant transformation of lung epithelial cells. This is an important problem 

because lack of this knowledge precludes advances in treatment development for the 20-50% of lung 

cancer patients that carry these mutations. Dr. Basseres’ long-term goal is to increase the understanding of 

lung cancer pathogenesis and improve treatment of lung cancer. The overall objective of this project is to 

identify and test novel therapeutic targets in K-Ras-mediated lung cancer. The central hypothesis is that (1) 

a critical downstream effector of oncogenic K-Ras in lung cancer is the transcription factor Nuclear Factor 

B (NF-kB); and (2) NF-kB activation by K-Ras involves two important therapeutic targets: Aurora kinases 

and IkB kinase (IKK). The proposed research is relevant to FAMRI’s mission because of the wellestablished 

relationship between cigarette smoke exposure and K-Ras mutations. Dissecting the pathways 

by which K-Ras controls malignant transformation will have important implications for understanding the 

cancer-inducing mechanisms triggered by cigarette smoke exposure, both direct and second hand. Based 

upon their preliminary data, the investigators’ hypothesis will be tested by pursuing two specific aims: 1) 

determine the function and relative importance of NF-kB and its upstream regulators IKK and Aurora 

kinases in K-Ras-transformed human cells; and 2) determine the therapeutic efficacy of targeting of the 

IKK and Aurora kinase pathways in K-Ras-induced lung cancer in situ. Under the first aim, an already 

proven RNA interference approach will be used to inhibit expression of the p65 NF-kB subunit, IKK or 

Aurora kinases A and B, after which the transformed cells’ oncogenic properties, including the ability to 

grow tumors as xenografts and the ability to form pulmonary metastases in vivo, will be analyzed. Under 

the second aim, a K-Ras-induced lung cancer mouse model will be used to evaluate the effects of 

pharmacological inhibition of IKK and Aurora kinases on lung tumor growth and overall survival. This 

approach is innovative, because, not only does it aim at elucidating, for the first time, the role NF-kB plays 

in K-Ras-induced oncogenesis, but also because it aims at pre-clinically testing inhibition of novel NF-kBrelated 

targets for treatment of K-Ras lung tumors. The investigators expect to identify downstream targets 

of K-Ras in the lung that not only contribute to the oncogenic process, but also that are therapeutically 

relevant. This contribution is significant, because it is expected to provide the knowledge needed to 

develop novel pharmacologic strategies that will improve therapeutic outcome for lung cancer patients. 

Once such strategies become available to patients, it is expected that they will not only impact survival of 

lung cancer patients, but also survival of patients with other K-Ras-related malignancies. Furthermore, 

what is learned is expected to contribute to a broader understanding of how other Ras proteins can be 

targeted as an approach to cancer therapy. 

TOLERANCE OF TOBACCO SMOKE-INDUCED DNA DAMAGE IN LUNG 

Laura Barkley-Elliman, PhD; Galway University Foundation; YCSA 2008 

The broad long-term goal of this project is to determine the mechanisms by which cells are protected 

against mutagenic actions of the tobacco smoke carcinogen Benzo[a]pyrene (B[a]P). B[a]P is metabolized 

within cells generating benzo[a]pyrene diol epoxide (BPDE) which binds DNA covalently to form ‘bulky 

adducts’. This form of DNA damage can lead to mutagenesis and cancer. Therefore, BPDE and related 

adduct-forming genotoxins pose a serious threat to human health. DNA Polymerase kappa (Polk) is a 

trans-lesion synthesis (TLS) polymerase essential for accurate replication of BPDE adducts and suppression 

of BPDE-induced mutagenesis. Therefore, Polk is likely to play a key role in protecting humans against 

tobacco smoke-induced cancers. The mechanism by which Polk is recruited to replication forks at sites of 

DNA damage is not well understood, but involves mono-ubiquitination of the processivity factor PCNA 

by the E3 ligase Rad18. Dr. Barkley-Elliman’s preliminary data show that Rad18 is phosphorylated in 

response to BPDE-induced DNA damage. BPDE-induced Rad18 phosphorylation in vivo requires the 

checkpoint kinase, Chk1, and purified Chk1 phosphorylates the C-terminus of Rad18 in vitro. Therefore, 

the PI hypothesizes that Rad18 E3 ligase activity and subsequent Polk recruitment are regulated by Chk1. 

To test this hypothesis, Specific Aim 1 is designed to identify and mutate BPDE-induced Rad18 

phosphorylation sites. Specific Aim 2 is designed to test the consequences of Rad18 phosphorylation site 

mutations on TLS in BPDE-treated cells. The investigators will determine the effect of PSM on the subcellular 

localization of Rad18, PCNA-directed ubiquitination activity, interactions with TLS polymerases, 

and recovery from the S phase checkpoint. The results will provide a new paradigm for mechanisms that 

promote accurate replication of damaged DNA, genomic stability, and tumor suppression, in response to 

tobacco smoke carcinogens. A long-term goal is to determine whether Rad18 phosphorylation sites are 

mutated in lung cancer to give loss-of-function or gain-of-function phenotypes that perturb TLS. The 

P A G E 1 1 5

esults of these studies should also allow the investigators to broaden the scope of potential targets for 

drug intervention. Since they have shown that Rad18 deficiency sensitizes cells to killing by DNAdamaging 

agents, this work might identify Rad18 or other TLS components as therapeutic targets for 

cancer and other proliferative disorders. 

GENDER DIFFERENCES IN THE EFFICACY OF ANTIANGIOGENIC THERAPIES: THE ROLE OF EGFR/ESTROGEN 

RECEPTOR INTERACTIONS IN NSCLC 

Matthew H. Herynk, PhD; University of Texas M. D. Anderson Cancer Center; YCSA 2008 

NSCLC is the most common cause of cancer-related deaths in the US and worldwide. Recent clinical 

studies have established that agents targeting tumor angiogenesis and the vascular endothelial growth 

factor (VEGF) pathway, such as the monoclonal antibody bevacizumab and the tyrosine kinase inhibitor 

ZD6474, provide clinical benefit when used in combination with chemotherapy. Interestingly, there appear 

to be striking gender differences in the therapeutic efficacy of these angiogenesis inhibitors. These 

differences suggest that factors inherent in the male/female biology may have a significant impact in 

angiogenesis and its subsequent inhibition. Recent data suggest that estrogen and EGF can synergistically 

activate EGFR downstream effectors, including ERK1/2, and may impact critical angiogenic pathways 

including HIF1. Dr. Herynk proposes that the EGFR and ER pathways may cooperatively interact to 

increase angiogenesis and enhance EGFR dependence. He will evaluate this hypothesis by examining the 

role of estrogen and EGFR-mediated signaling in vitro in the production of cytokines and angiogenic 

factors in NSCLC cell lines and endothelial cells derived from normal lung and lung tumors. Using novel 

reverse phase protein arrays (RPPA) and multiplex bead analysis, the investigators will analyze differentially 

activated signal transduction pathways and secreted angiogenic factors following modulation of estrogen 

receptor signaling. Finally, by modulating estrogen signaling in an in vivo xenograft model of NSCLC, 

they will examine the role of estrogen signaling in the therapeutic efficacy of VEGF or dual 

EGFR/VEGFR inhibitors. These studies should reveal the molecular mechanisms underlying genderspecific 

differences in angiogenesis and the responsiveness to antiangiogenic therapies. The proposed 

strategy, while focused on estrogen receptor signaling, should allow identification of gender-specific factors 

independent of ER. This knowledge will have the potential to help in the selection of patients who are 

most likely to benefit from a given type of angiogenesis inhibitor and guide therapeutic strategies to 

enhance the efficacy of antiangiogenic therapies. 

Recent clinical trials in NSCLC have demonstrated therapeutic efficacy in a sex-specific manner from 

drugs such as bevacizumab and vandetanib. These differences suggest that factors inherent in the basic 

male/female biology may impact the growth and survival mechanisms of NSCLC tumors. In this study, 

Dr. Herynk proposes to identify secreted cytokine and angiogenic factors (CAFs) in NSCLC cell lines and 

patient samples. Thirty-five CAFs were measured by multiplex bead suspension arrays and ELISAs from 

pre-treatment plasma (N=123) and serum (N=151) collected from patients with stage IIIB/IV NSCLC 

participating in randomized Phase 2 trials of vandetanib alone or in combination with chemotherapy. 

Multiplex bead assays were used to measure the levels of 48 secreted cytokines and angiogenic factors in 

conditioned media from 36 NSCLC cell lines (female N=17, male N=19). Subconfluent cells were serum 

starved overnight and the media was changed; 24 hours later, conditioned media was collected and the 

cells were lysed. Measured CAF levels were normalized to total protein from whole-cell lysates. 

Univariate analysis of serum and plasma samples revealed eighteen statistically different CAFs between 

male and female patients, with most being upregulated in females including: IL-15 (mean 1193 vs. 291 

pg/ml; P =0.01), sIL-2R (mean 1413 vs. 577 pg/ml; P =0.01), MIG (CXCL-9) (mean 184 vs. 67 pg/ml; 

P =0.016), and macrophage inflammatory protein-1 (MIP-1alpha, CCL3) (mean 319 vs. 108 pg/ml; P 

=0.02) to name a few. Conditioned media from 36 NSCLC cell lines were analyzed for levels of secreted 

CAFs. Nine CAFs determined to be statistically significant in patient samples were also present in the cell 

line analyses, and two factors, MIP-1 alpha and intracellular adhesion molecule-1 (ICAM-1) also 

demonstrated increased levels in female versus male cell lines. While 18 CAFs were statistically significant 

in patient samples, no individual factors were statistically significant in conditioned media from cell lines. 

Subgroup analysis of female cell lines revealed an age association with 26 secreted CAFs in NSCLC cell 

lines. 

These data suggest an important role for age and sex in the secreted CAF profiles of NSCLC. Several 

secreted factors from these studies are common among the different analyses. Since EGFR inhibitors have 

shown preferential efficacy for females, hormone signaling varies between male and female populations, 

and in younger vs. older females. These secreted factors are involved in a number of signaling networks 

and thus, may contribute to a broad range of effects on tumor growth, metastases, and therapeutic efficacy 

1 1 6 P A G E

of angiogenesis inhibitors and other targeted agents. Dr. Herynk and his group will further investigate the 

contributions of EGFR and hormone signaling in these common secreted factors. 

ALLELIC IMBALANCE AND MIRNA REGULATION BY TOBACCO SMOKE IN NSCLC 

Shahnaz Begum, MBBS, PhD; The Johns Hopkins University; YCSA 2008 

Lung cancer is the leading cause of cancer death in the United States, with 160,390 deaths in 2007. 

However, lung cancer incidence is one fourth less common than breast, colorectal, and prostate carcinoma. 

In fact, the sum total of deaths attributable to these three more common cancers does not exceed the 

number of deaths attributable to lung cancer. The survival rate trend for lung cancer remains relatively flat 

and is currently 15%. Approximately, 80-90% of lung cancer in men and women is directly attributable to 

tobacco smoking, and many cases are believed to be due to exposure to second hand tobacco smoke, 

which contains over 300 chemicals, 40 of which are known to be potent carcinogens. 

Recent lung cancer research has been directed towards using molecular approaches to facilitate early 

diagnosis, to identify clinically relevant biological factors associated with histological heterogeneity, and to 

identify novel therapeutic agents. Dr. Begum’s research takes advantage of technical advances that allow 

rapid high-throughput assays to interrogate the genome, proteome, epigenome and miRNAome. His 

group has extensive experience in using expression microarrays and recently these investigators used a 

commercially available miRNA microarray for profiling primary lung cancer. In parallel, they have 

pioneered the use of single nucleotide polymorphism (SNP) arrays for analyzing allelic imbalance in cancer. 

Dr. Begum now proposes to determine whether there are distinct patterns of allelic imbalance that 

correspond to the deregulated miRNA expression, and to correlate these allelic imbalances and deregulated 

miRNA with smoking. The discovery of such patterns would help to validate adenocarcinoma classification 

and would be useful in the identification of lung cancer-associated deregulated genes (oncogenes and 

tumor suppressor genes). 

Specifically, the investigators propose the following aims: 1) to analyze patterns of chromosome allelic 

imbalance in lung adenocarcinoma in smokers, non-smokers and passive smokers, using SNP array 

hybridization for over 250K markers; 2) to generate a genome-wide map of LOH in these samples; and 3) 

to compare classification by allelic imbalance/LOH with classification by deregulated miRNA. 

Improvements in understanding the classification and pathogenesis of lung carcinoma are essential steps 

towards better diagnostic and treatment approaches. The combination of miRNA expression and allelotype 

classifications for lung adenocarcinoma will aid in fighting this deadly disease. 

LUNG CANCER CHEMOPREVENTION: THE ROLE OF ROSIGLITAZONE 

Saswati Hazra, PhD; University of California, Los Angeles; YCSA 2005 

Dr. Hazra’s studies are currently focused on the prevention of lung cancer. The successful advancement 

of clinical cancer chemoprevention requires identification of high-risk individuals and effective agents with 

limited toxicity. The possibility of an “individualized medicine” approach to chemoprevention targeted to 

the specific molecular abnormalities in the individual at risk has been suggested as a means to tailor 

prevention strategies (N Engl J Med. 2007;356:2195-8). Human lung cancer develops as a multi-step 

process, usually occurring because of years of smoking-related tobacco exposure that results in specific 

proto-oncogene (such as Kras) and tumor suppressor gene (such as p53) alterations in lung epithelial cells. 

There are approximately 45 million former smokers in the US who are at risk of lung cancer. 

Dr. Hazra reported on the effects of pioglitazone and rosiglitazone addition in NSCLC cells, and others 

have shown that rosiglitazone may lower the risk of lung cancer (J Clin Oncol, Vol 25, No 12, 

2007:1476-81). Based on the above findings, Dr. Hazra utilized human bronchial epithelial cell lines 

(HBECs) with genetic mutations relevant to the pathogenesis of lung cancer and common in individuals at 

high risk of lung cancer (with p53 knockdown, K-RasV12 and EGFR L858R mutations) to assess the 

potential role of rosiglitazone as a chemoprevention agent against these mutated HBECs. In this study, the 

investigators evaluated the impact of rosiglitazone on these HBECs by performing gene expression array, 

micro-RNA profiles and protein profiling. The data reveal specific patterns of alterations in gene 

expression, protein expression and micro-RNA profiles. The data indicate that not all high-risk individuals 

for lung cancer will respond the same way against a specific potential chemopreventive agent. Therefore, 

additional studies with other potential chemopreventive agents are needed in order to determine which will 

be ultimately beneficial for individuals with specific mutations who are at risk for lung cancer. 


Hazra S, Batra RK, Tai HH, Sharma S, Cui X, Dubinett SM. Pioglitazone and rosiglitazone decrease 

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prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin 

dehydrogenase. Mol Pharmacol 2007;71:1715-20. 

Hazra S, Dubinett SM. Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small 

cell lung cancer cells. Prostaglandins Leukot Essent Fatty Acids 2007;77:51-8. 

Hazra S, Kostyantyn K, Walser T, Gardner B, Lee G, Shay J, Minna J, Horvath S, Dubinett S. A systems 

approach to the preclinical evaluation of targeted chemoprevention for lung cancer. Cancer Prevention 

Research 1 (7 Supplement), A136, November 1, 2008). 

CANCER, LUNG 


METHYLATION ANALYSIS OF LUNG CANCERS FROM SMOKING AND NON-SMOKING WOMEN 

William P. Bennett, MD, MS; City of Hope; CIA 2004 

Tobacco carcinogens cause distinctive mutations in lung cancers. For example, the p53 “mutation 

signature” can discriminate groups of tumors from smokers and non-smokers, but it cannot classify 

individual tumors effectively, because informative mutations are sparse. Epigenetic changes occur more 

frequently than mutations, so Dr. Bennett and colleagues developed a “methylation signature” of 

incinerated tobacco. 

The group accomplished this goal by isolating genomic DNA from formalin-fixed, paraffin-embedded 

tissues, which was subsequently subjected to bisulfite modification, which converts unmethylated cytosines 

to uracils. Segments of CpG islands were amplified by PCR, and methylation was quantified by mass 

spectrometry (www.sequenom.com). The two principal advantages over other technologies were: 1) 

increased efficiency because many CpG sites are interrogated within a single PCR product; and 2) 

quantitative assessments because the methylated and unmethylated forms of a single CpG site are separated 

by mass differences that can be measured by mass spectrometry. 

The group analyzed the methylation status of 27 CpG units in promoter regions of the following genes: 

CDH13, p16/CDKN2A, and RassF1A from 30 smokers and 8 non-smokers. They found that: 1) 12 of 

30 (40%) tumors from smokers have more methylation in p16/CDKN2A and RassF1A than any of the 

eight non-smokers; 2) smokers have more moderate to high-level (30-100%) methylation than nonsmokers 

in p16/CDKN2A and RassF1A; 3) non-smokers have more low-level (1-10%) methylation than 

smokers; and 4) smokers and non-smokers have comparable amounts of methylation in CDH13. 

By developing a robust “tobacco signature” based on methylation rates at hotspot CpG sites lung 

cancers in non-smokers caused by exposure to SHS will be more readily identified. 


Bennett, WP, Larson G, Xiong W, Rivas G, Kernstine KH, Pfeifer GP. Methylation analysis of lung cancers 

from smoking and non-smoking women. Proc Am Assoc for Cancer Res 2008;49:7. 

TGF BETA SIGNALING IN LUNG CANCER: A THERAPEUTIC TARGET 

Pran Datta, PhD; Vanderbilt University; CIA 2005 

Dr. Datta’s hypothesis stated that loss of transforming growth factor-beta receptor type II (TGF 

betaRII) in NSCLC and SCLC is primarily due to the epigenetic change, histone deacetylation. This 

promotes unresponsiveness to transforming growth factor-beta (TGF- beta)-induced tumor suppressive 

effects, and restoration of this signaling may be a potential alternative or addition to radiation as a lung 

cancer treatment. The aims of the study were: 1) to determine the molecular mechanism of TGF beta RII 

downregulation in primary lung cancer; 2) to determine if restoration of TGF beta signaling re-establishes 

tumor suppressor function or tumor-promoting effects of TGF beta; and 3) to investigate the radiationsensitizing 

effects of the histone deacetylase inhibitor MS-275 in vitro and in vivo in human lung cancer 

preclinical models. Thus far, they have observed that TGF-beta-induced tumor suppressor function is 

restored in TGF beta-resistant lung cancer cells either by exogenous expression of TGF betaRII or by the 

treatment with histone deacetylase inhibitors (HDI). Dr. Datta’s group has identified a region of the TGF 

betaRII promoter required for its activation by HDI and proteins that are involved in the regulation of 

TGF betaRII expression using proteomics and biochemical methods. 


Anumanthan G, Halder SK, Friedman D, Datta PK. Oncogenic STRAP modulates the function of Ewing 

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sarcoma protein through a novel mechanism. Cancer Res 2006;66(22):10824-10832. 

Anumanthan G, Halder SK, Osada H, Takahashi K, Massion P, Carbone D , Datta PK. Restoration of 

TGF-beta-mediated tumor suppression function by stable expression of type II receptor in human lung 

cancer cells. Br J Cancer 2005;93:1157-1167. 

Datta PK, Mann JR. Transforming growth factor-beta signaling inhibitors in cancer therapy. In: TGF beta 

in Cancer Therapy. The Humana Press Inc., Vol II, 573-587, 2008. 

Halder SK, Anumanthan G, Maddula R, Mann J, Chytil A, Gonzalez A, Washington MK, Moses, HL, 

Beauchamp RD, Datta PK. Oncogenic function of a novel WD-domain protein STRAP in human 

carcinogenesis. Cancer Res 2006;66(12):6156-6166. 

Halder SK Rachakonda, G, Deane NG, Datta PK. Smad7 induces hepatic metastasis in colorectal cancer. 

Br J Cancer 2008;99: 957-965. 

Zhang B, Halder SK, Datta PK, Targeting transforming growth factor-beta signaling in liver metastasis of 

colorectal cancer. Cancer Lett 2009;277(1):114-120. 

NUCLEOLAR EXPRESSION OF PTHRP AND OUTCOME IN NON-SMALL CELL LUNG CANCER (NSCLC) 

Leonard Deftos, MD; VA San Diego Healthcare System; CIA 2002 

Dr. Deftos reported data suggesting that parathyroid-hormone-related protein (PTHrP), a growth factor 

produced by many lung cancers, may predispose lung cancer cells to apoptosis if transported to the cell 

nucleolus. PTHrP isoform 1-173 expression and nucleolar PTHrP were evaluated for their efficacy as 

favorable prognostic signs for NSCLC treatment in both patient and cell culture studies. PTHrP expression 

is present in two-thirds of cancer patients, and PTHrP immunoreactivity appears to be a positive prognostic 

factor for stage 1-2 lung cancer patients. 


Burton DW, Geller J, Yang M, Jiang P, Barken I, Hastings RH, Hoffman RM, Deftos LJ. Monitoring of 

skeletal progression of prostate cancer by GFP imaging, X-ray, and serum OPG and PTHrP. Prostate 

2005;62:275-281. 

Hastings RH, Araiza F, Burton DW, Deftos LJ. Role of parathyroid hormone-related protein in lung 

cancer cell survival. Chest 2004;125(5 Suppl):150S. 

Hastings RH, Araiza F, Burton DW, Zhang L, Bedley M, Deftos LJ. Parathyroid hormone-related protein 

ameliorates death receptor-mediated apoptosis in lung cancer cells. Am J Physiol Cell Physiol 

2003;285:C1429-C1436. 

Hastings RH, Folkesson HG, Matthay MA. Mechanisms of alveolar protein clearance in the intact lung. 

Am J Physiol Lung Cell Mol Physiol 2004;286:679-689. 

Hastings RH, Laux A, Casillas A, Xu R, Lukas Z, Ernstrom K, Deftos L. Sex-specific survival advantage 

with parathyroid hormone-related protein in non-small cell lung carcinoma patients. Clin Cancer Res 

2006;12:499-506. 

Hastings RH. Parathyroid hormone-related protein and lung biology. Respir Physiol Neurobiol 

2004;142:95-113. 

Pache JC, Burton DW, Deftos LJ, Hastings RH. A carboxyl leucine-rich region of parathyroid hormonerelated 

protein is critical for nuclear export. Endocrinology 2006;147:990-998. 

Tsigelny I, Burton DW, Sharikov Y, Hastings RH, Deftos LJ. Coherent expression chromosome cluster 

analysis reveals differential regulatory functions of amino-terminal and distal parathyroid hormonerelated 

protein domains in prostate carcinoma. J Biomed Biotechnol 2005;2005:353-363. 

LOH AND GENE EXPRESSION PROFILES IN LUNG CARCINOMA 

Matthew Meyerson, MD, PhD; Harvard University; CIA 2002 

Dr. Myerson observed loss of heterozygosity (LOH) and gene expression profiles in lung carcinoma. 

LOH is a common mechanism for tumor suppressor gene inactivation in human epithelial cells. The PI 

used single nucleotide polymorphism (SNP) arrays for analyzing LOH in tumors, to determine whether 

there are distinct patterns of LOH that correspond to gene expression-derived lung adenocarcinoma 

classes. This would help validate adenocarcinoma classification and be useful in identifying lung cancerassociated 

tumor suppressor genes. The combination of gene expression and allelotype classification for 

lung adenocarcinoma assists in developing better diagnostic and treatment approaches. Hybridization to 

SNP arrays is an efficient method for detection of genome-wide cancer LOH, and SCLC and NSCLC 

samples can be separated based on their LOH. Copy number alterations can also be detected in this way. 

DNA copy number changes contribute to cancer pathogenesis. In another study, tyrosine kinase genes 

P A G E 1 1 9

were sequenced from NSCLC tissue and matched normal tissue. Somatic mutations of the estrogen 

growth factor receptor (EGFR) gene were found in 15 out of 58 unselected tumors from Japan and 1 out 

of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib caused NSCLC 

regression more frequently in Japan, as well as in certain US cancer samples with EGFR gene mutations. 

The results suggested that EGFR gene mutations might predict sensitivity to gefitinib. It may be necessary 

to consider the power of clinical trials to identify differences within ethnic subgroups rather than assume 

equality in responses to drug therapies. 

ROLE OF ALDEHYDE DEHYDROGENASES IN THE PATHOGENESIS AND BIOLOGY OF LUNG CANCER 

Jan Moreb, MD; University of Florida; CIA 2003 

Dr. Moreb demonstrated that the enzymes aldehyde dehydrogenase (ALDH)1A1 and ALDH3A1 are 

highly expressed in squamous cell lung cancer (SCCA), adenocarcinoma (AdenoCA), and NSCLC, while 

very little expression can be detected in SCLC. Atypical pneumocytes demonstrated significantly higher 

levels of expression of ALDH-1A1 and ALDH-3A1 than normal pneumocytes, the normal counterpart of 

AdenoCA, which is suggestive of upregulation during malignant transformation to AdenoCA. On the 

other hand, similar levels of expression were observed in bronchial epithelium, the normal counterpart of 

SCCA. Cigarette smoking results in significantly increased expression of these enzymes in normal 

pneumocytes. Small interfering RNAs were shown to specifically inhibit ALDH-1A1 or ALDH-3A1 and 

result in increased 4-hydroperoxycyclophosphamide toxicity in the A549 lung cancer cell line. An Aldefluor 

assay was adapted successfully to measure ALDH activity in lung cancer cells and provided real-time 

changes in ALDH activity in viable cells treated with siRNA or chemotherapy. Lentiviral vectors had great 

efficacy and specificity in the inhibition of either enzyme. Differences in gene transcription were 

determined between wild-type A549 cells and lenti 1+3 cells and a number of genes were categorized that 

are either repressed or induced two-fold when compared with the wild-type cells. 


Moreb JS, Gabr A, Vartikar GR, Gowda S, Zucali JR, Mohuczy D. Retinoic acid down regulates aldehyde 

dehydrogenase and increases cytotoxicity of 4-hydroperoxycyclophosphamide and acetaldehyde. J 

Pharmacol Exp Ther 2005;312:339-345. 

IDENTIFICATION OF NEW MOLECULAR TARGETS IN LUNG CANCER 

Pierre P. Massion, MD; Vanderbilt University; CIA 2003 

Dr. Massion and collaborators identified molecular abnormalities in invasive and preinvasive lung 

cancers. Their aims were 1) to identify amplified and deleted genomic regions in invasive squamous, 

adeno, large, and small cell lung cancers using array-comparative genomic hybridization; 2) to identify 

potential targets in preinvasive lung cancer using matrix-assisted laser desorption/ionization mass 

spectrometry; and 3) to clinically validate candidate genes and proteins associated with lung cancer. They 

characterized eight tissue microarrays from a total of 360 lung cancers for validation of biomarkers in a 

high-throughput fashion. 


Gonzalez AL, Roberts RL, Massion PP, Olson SJ, Shyr Y, Shappell SB. 15-lipoxygenase-2 expression in 

benign and neoplastic lung: an immunohistochemical study and correlation with tumor grade and 

proliferation. Hum Pathol 2004;35:840-849. 

Massion PP, Taflan PM, Rahman SM, Yildiz P, Shyr Y, Edgerton MR, Westfall MD, Roberts JR, Pietenpol 

JA, Carbone DP, Gonzalez AL. Analysis of p63 in lung tumorigenesis. Cancer Res 2003;7113-7121. 

Massion PP, Taflan PM, Rahman SM, Yildiz P, Shyr Y, Carbone DP, Gonzalez AL. Role of p63 

amplification and overexpression in lung cancer development. Chest 2004;125 (5 Suppl):102S. 

Massion PP, Taflan PM, Shyr Y, Rahman SM, Yildiz P, Shakthour B, Edgerton ME, Ninan M, Andersen 

JJ, Gonzalez AL. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer 

progression. Am J Respir Crit Care Med 2004;170:1088-1094. 

Rahman SM, Shyr Y, Yildiz PB, Gonzalez AL, Li H, Zhang X, Chaurand P, Yanagisawa K, Slovis BS, 

Miller RF, Ninan M, Miller YE, Franklin WA, Caprioli RM, Carbone DP, Massion PP. Proteomic 

patterns of preinvasive bronchial lesions. Am J Respir Crit Care Med 2005;172:1556-1562. 

Wardwell NR, Massion PP. Novel strategies for the early detection and prevention of lung cancer. Semin 

Oncol 2005;32:259-268. 

1 2 0 P A G E

THE IMPLICATION OF POTENTIAL TUMOR SUPPRESSION FUNCTION OF DAXX IN C-MET-DEPENDENT LUNG 

MALIGNANCY 

Alexander M. Ishov, PhD: University of Florida; CIA 2004 

Death domain-associated protein (DAXX), a ubiquitous transcriptional modulator, is a potential tumor 

suppressor and an ideal target for study of the physiological regulation of c-Met (a member of the tyrosine 

kinase receptor group) in lung cancer progression. Dr. Ishov’s hypothesis is that DAXX may inhibit c-Met 

gene activation by recruiting negative regulators of gene expression. Downregulation or inactivation of 

DAXX can release this repression, leading to an increase in c-Met gene expression, resulting in oncogenic 

transformation of cells and lung tumor progression. Elucidation of ways to regulate c-Met protein 

production will lead to possible strategies for blocking lung malignancies. 


Morozov VM, Massoll NA, Vladimirova OV, Maul GG, Ishov AM. Regulation of c-met expression by 

transcription repressor Daxx. Oncogene 2007. 

THE SMALL MOLECULE INHIBITORS OF BCL-2 AS NOVEL THERAPEUTICS FOR LUNG CANCER 

Charles M. Rudin, MD, PhD; The Johns Hopkins University; CIA 2004 

Aberrant expression of B-cell lymphoma protein 2 (Bcl-2), an apoptotic inhibitor, is common in SCLC 

and NSCLCs (up to 90%), with a resulting increase in resistance to chemotherapy and radiation. Through 

the use of human lung cancer xenografts in mice, Dr. Rudin and colleagues explored the clinical 

development of a novel set of cytotoxic agents that function via inhibition of critical anti-apoptotic 

pathways upregulated in lung cancer and other malignancies. Potentially important results thus far have 

demonstrated that ABT-737, a very potent small molecule inhibitor of Bcl-2, is highly effective against 

SCLC in vitro and in vivo even in the absence of standard cytotoxic chemotherapy. 

A TRANSGENIC ANIMAL MODEL TO CONTROL THE ANGIOGENIC SWITCH IN LUNG CANCER 

Douglas A. Arenberg, MD; University of Michigan; CIA 2004 

Cytokine macrophage-produced migration inhibitory factor (MIF) is expressed in tumor cell lines and 

has been found to indirectly promote angiogenesis in lung cancer by an increase in expression of other 

angiogenic factors. MIF additionally antagonizes the tumor suppressor p53. Dr. Arenberg’s lab produced a 

transgenic mouse that permits precise control of the timing and nature of the angiogenic switch in the 

context of chemically induced lung cancer tumorigenesis. This transgenic model allowed testing of the 

hypothesis that during tumor development, evolution of a given angiogenic strategy suppresses the 

development of other angiogenic strategies, demonstrating that tumors use only one such strategy at a 

time. The results suggest that MIF expression during tumor growth accelerates tumor development and 

alters the angiogenic phenotype of the resulting tumors compared to control mice. These results will guide 

future therapeutic developments aimed at inhibiting tumor-related angiogenesis. 


Keshamouni VG, Arenberg DA, Reddy RC, Newstead MJ, Anthwal S, Standiford TJ. PPAR-gamma 

activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung 

cancer. Neoplasia 2005;7(3):294-301. 

McClelland M, Gray A, Carskadon S, Zhao L, Arenberg D. Angiogenic Strategies in Non-Small Cell Lung 

Cancer. Presented at the American Association for Cancer Research Conference: Molecular Pathogenesis 

of Lung Cancer. San Diego, CA, February 2005. 

McClelland M, Gray A, Carskadon S, Zhao L, Arenberg D. Macrophage migration inhibitory factor 

(MIF)-dependent induction of angiogenic CXC chemokines in an animal model of NSCLC Presented at 

the American Association for Cancer Research Conference: Molecular Pathogenesis of Lung Cancer. San 

Diego, CA, February 2005. 

McClelland MR, Carskadon SL, Zhao L, White ES, Beer DG, Orringer MB, Pickens A, Chang AC, 

Arenberg DA. Diversity of the Angiogenic Phenotype in Non-Small Cell Lung Cancer. Am J Respir Cell 

Mol Biol 2007;36:343-350. 

EPIGENETIC CONTROL OF HUMAN PROSTACYCLIN SYNTHASE 

Robert S. Stearman, PhD; University of Colorado; CIA 2004 

Prostacyclin synthase, the key enzyme responsible for producing the eicosanoid prostacyclin, is 

significantly decreased in human lung cancer. Murine studies have shown that high prostacyclin synthase 

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expression has a protective effect in various lung cancer models. Dr. Stearman’s study examines genetic and 

epigenetic mechanisms that could account for the deficiency of prostacyclin synthase in human lung cancer. 

His results suggest DNA methylation causes silencing and can significantly affect prostacyclin synthase 

expression. 

PATTERNS OF GENE EXPRESSION IN EARLY LUNG LESIONS 

Scott Wadler, MD (Maureen Lane, PhD); Weill-Cornell Medical Center; CIA 2004 

FAMRI regrets to report that Dr. Wadler passed away while this research was on-going. The studies 

were completed by Maureen Lane, PhD, who had been working with him. Drs. Wadler and Lane have 

shown that early lung lesions exhibit distinct genetic profiles and that these profiles cluster into distinct 

groups. These groups include, but are not limited to, normal, benign, three distinct subclasses of lung 

adenocarcinomas, and one subclass of metastatic adenocarcinomas. One of the three subgroups of 

adenocarcinomas exhibits a gender bias toward women. This will play a role in future treatment strategies 

for patients that express the genes associated with this group. Early lung samples obtained by guided fine 

needle aspirates (FNA) were profiled. This is a less invasive way to obtain individual molecular profiles on 

lung tumor patients. FNAs can be routinely used to obtain good quality specimens for molecular analysis 

using gene expression arrays. These data together with existing pathology parameters will lead to improved 

diagnostic criteria in lung cancer. Increased information on expression data that is associated with 

prognostic markers will be evaluated as follow-up data are collected. 



Hierarchical cluster analysis of pulmonary fine needle aspirates reveals distinct subgroups of 

adenocarcinomas Presented at the 12th International Conference on Screening for Lung Cancer. Nara, 

Japan, Apr, 2005. 

Lane WE, Yankelevitz DF, Henschke CI, Vazquez MF, Xiang Z, Kimmel M, Kramer A, Wadler S. Patterns 


Presented at the 11th International Conference on Screening for Lung Cancer. Rome, Italy, Oct, 2005. 


Pulmonary fine needle aspirates (FNA) with diverse radiographic appearances exhibit distinct patterns of 

gene expression. Proc Amer Assoc Cancer Res #876 2005. 

Lane ME, Yankelevitz DF, Henschke CI, Vazquez MF, Xiang Z, Kimmel M, Kramer A, Wadler S. Patterns 


exhibit distinct patterns of gene expression. Proc Amer Assoc Cancer Res, 45: 5589, 2004. 

THE MOLECULAR EPIDEMIOLOGY OF SECOND HAND TOBACCO SMOKE-ASSOCIATED LUNG CANCER 

David P. Miller, ScD, SM; Harvard University; YCSA 2002 

Dr. Miller collected samples and assessed the SHS exposure in a case control study comprising 

individuals with NSCLC and controls. Different genotypes were determined and genes, direct smoke 

exposure, and SHS exposure were correlated. The exposure to SHS in this population was not only 

associated with lung cancer, but exposure earlier than 25 years of age had a greater lung cancer risk than 

for those whose exposure occurred after they were 25. 


Liu G, Zhou W, Miller DP, Thurston SW, Xu LL, Wain JC, Lynch TJ, Su L, Christiani DC. MPO and 

MnSOD polymorphisms, gender, and the risk of non-small cell lung carcinoma. Cancer Lett 

2004;214:69-79. 

Liu G, Zhou W, Park S, Wang LI, Miller DP, Wain JC, Lynch TJ, Su L, Christiani DC. The SOD2 

Val/Val genotype enhances the risk of non-small cell lung carcinoma by p53 and XRCC1 


Miller DP, De Vivo I, Neuberg D, Wain JC, Lynch TJ, Su U, Christiani DC. Association between Self 

Reported Environmental Tobacco Smoke Exposure and Lung Cancer: Modification by GSTP1 

polymorphism. Int J Cancer 2003;104:758-763. 

Miller DP, Park S, Gitin E, Zhou W, Liu G, Wain JC, Lynch TJ, Christiani DC. DNA repair 

polymorphisms, second hand tobacco smoke and lung cancer risk Presented at the Annual Meeting of 


Miller DP, Park S, Gitin E, Zhou W, Liu G, Wang Z. ERCC2 Asp312Asn polymorphism modifies the 

1 2 2 P A G E

association between second hand tobacco smoke and lung cancer risk. Presented at the Annual Meeting 

of the American Association for Cancer Research, April 2004. 

Park S, Miller DP, Gitin E, Zhou W, Liu G, Wain JC, Lynch TJ, Christiani DC. A new metric for second 

hand tobacco smoke and its association with lung cancer risk. Presented at the Annual Meeting of the 


Zhou W, Heist R, Liu G, Miller DP, Neuberg DS, Asomaning K, Wain JC, Lynch TJ, Christiani D. 

Second hand tobacco smoke exposure and survival in early stage non-small cell lung cancer patients 

Presented at the Annual Meeting of the American Association for Cancer Research, April 2006. 

Zhou W, Heist RS, Liu G, Asomaning K, Miller DP, Neuberg DS, Wain JC, Lynch TJ, Christiani DC. 

Second hand smoke exposure and survival in early-stage non-small-cell lung cancer patients. Clin Cancer 

Res 2006;12:7187-7193. 

Zhou W, Park S, Liu G, Miller DP, Wang LI, Pothier L, Wain JC, Lynch TJ, Giovannucci E, Christiani 

DC. Dietary iron, zinc, and calcium and the risk of lung cancer. Epidemiology 2005;16:772-779. 

CYCLOPAMINE INHIBITS HEDGEHOG SIGNALING AND GROWTH IN LUNG CANCER CELLS 

D. Neil Watkins, MD, PhD; The Johns Hopkins University; YCSA 2002 

Dr. Watkins’ studies showed that the hedgehog (Hh) pathway activation is a frequent event in lung cancer, 

and follows two distinct paradigms. In Gorlin’s syndrome, mutations in the tumor suppressor patched 

(Ptch) cause medulloblastoma and basal cell carcinoma (BCC). These “Gorlin’s type” tumors manifest 

clonally deregulated Hh signaling and activation of the smoothened (Smo) protein in every cell in the 

tumor. This leads to activation of the Gli transcription factors and activation of Hh signaling. The data 

show that there are two distinct types of non-Gorlin’s tumors. In the SCLC group, both Hh ligands (Shh, 

Ihh), Ptch and Smo are expressed, and differential levels of Hh gene expression concentrate in the pathway 

in the tumor stem cell compartment. By contrast, NSCLCs express high levels of Hh ligands, but do not 

express Smo and do not demonstrate evidence of cell-autonomous pathway activation. In these types of 

tumors, tumor-stromal interactions mediated by Hh ligands promote tumor growth by non-cell 

autonomous mechanisms. These studies show how different mechanisms of Hh pathway activation in cancer 

can be therapeutically targeted in otherwise lethal cancers such as SCLC. 


Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada 

Y, Eshleman JR, Watkins DN, Beachy PA. Widespread requirement for Hedgehog ligand stimulation in 

growth of digestive tract tumors. Nature 2003;425(6960):846-851. 

Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, 

Huff CA, Beachy PA, Watkins DN, Matsui W. Hedgehog signaling maintains a tumor stem cell 

compartment in multiple myeloma. Proc Natl Acad Sci U S A 2007;104:4048-53. 

Peas JG, Janne PA, Lee JC, Tracy S, Greenish H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, 

Naoki K, Sasaki H, Fuji Y, Eck MJ, Sellers WR, Johnson BE, Watkins DN, Berman DM, Burkholder 

SG, Wang B, Beachy PA, Bailing SB. Hedgehog signaling within airway epithelial progenitors and in 

small cell lung cancer. Nature 2003;422:313-317. 

Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB. Hedgehog signaling within 

airway epithelial progenitors and in small cell lung cancer. Nature 2003;422:313-317. 

Watkins DN, Peacock CD. Hedgehog signaling in foregut malignancy. Biochem Pharmacol 2004;68:1055- 

1060. 

THE ROLE OF HMG-I/Y IN THE PATHOGENESIS OF LUNG CANCER 

Raka Bhattacharya, PhD; The Johns Hopkins University; YCSA 2002 

Lung cancer is currently the leading cause of cancer death worldwide. The major risk factor is associated 

with tobacco smoke exposure accounting for nearly 90% of the disease. While prevention strategies appear 

to have impacted the incidence of lung cancer, treatment strategies have failed to alter lung cancer 

mortality rates. In order to better understand the disease, Dr. Bhattacharya and colleagues definined the 

role of Id1, a family of helix-loop-helix transcription factors in lung cancer. Studies have demonstrated that 

over-expression of Id1 is associated with highly aggressive and less differentiated tumor types, with poor 

prognosis and a propensity for tumor metastasis. However, little data are available about the specific role of 

Id1 in lung cancer. Preliminary data show that patients with aggressive lung cancer, who have been 

exposed to tobacco smoke and treated at Johns Hopkins have elevated levels of Id1 when compared to the 

surrounding normal tissue, as shown by quantitative PCR. The investigators have also used qPCR to 

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evaluate the expression level of Id1 in primary lung cancer samples at various stages of malignant 

progression in order to determine whether Id1 expression in lung cancers is an early, intermediate, or late 

event. The data show that Id1 expression is found at an early stage of the disease with metastasis to the 

lymph nodes. The investigators have shown that most NSCLC cells as well as SCLC cells express elevated 

levels of Id1 when grown in media containing serum (fetal bovine serum). This serum responsiveness in 

many of the lung cancer cell lines suggests growth-factor dependent Id1 expression. The investigators are 

evaluating the functions of Id1 by downregulating its expression and are studying the specific effects of Id1 

loss of expression by using small interfering RNA in cell proliferation, migration, and metastasis in cells 

and mice. They would like to determine the potential role of Id1 in the development and progression of 

lung cancer, as well as establish whether Id1 expression correlates to the more aggressive forms of the 

disease by looking at various histopathologic subtypes and grades of lung cancer. Such studies should 

permit utilization of Id1 expression as a prognostic marker in lung cancers. Additional studies aimed at 

identifying Id1 target genes in primary cells will better define the molecular pathways altered by Id1 

expression in lung cancer. 

CANCER, LYMPHOMA 


FUNCTIONAL ANALYSIS OF THE MMSET ONCOGENE IN TRANSLOCATION 4;14 MULTIPLE MYELOMA 

Josh Lauring, MD, PhD; The Johns Hopkins University; YCSA 2007 

Dr. Lauring’s project concerns the function of the MMSET/REIIBP gene in translocation (4;14)+ multiple 

myeloma (MM), a tobacco smoke-related blood cell cancer that kills 12,000 people annually in the US 

alone. The chromosomal translocation t(4;14) juxtaposing the immunoglobulin heavy chain enhancer 

sequences with the MMSET and FGFR3 genes defines approximately 20% of MM cases and confers the 

worst prognosis of all MM subtypes. Research has been directed at targeting the aberrant overexpression of 

FGFR3, but approximately 30% of t(4;14) cases do not over-express FGFR3, suggesting that dysregulation 

of the MMSET locus is the primary and unifying oncogenic event in all t(4;14) MM cases. Using lentiviralmediated 

RNA interference and allele-specific gene knockout in MM cell lines, Dr. Lauring has demonstrated 

for the first time that translocation-mediated over-expression of MMSET is critical for the growth, 

adhesion, and tumorigenicity of these multiple myeloma cells. A number of adhesion proteins and growth 

factors are down regulated with loss of MMSET expression. These genes could represent MMSET target 

genes responsible for the pathogenesis and/or poor prognosis of this form of MM. The PI has established 

collaborations with other investigators to study the epigenetic regulation of potential MMSET target genes 

using chromatin immunoprecipitation-on-chip technology. Dr. Lauring has extended his research to focus 

on the recurrent, poor-prognosis 8p11-12 amplicon in breast, lung, and pancreatic cancer. Using small 

hairpin RNA loss-of-function analysis as well as modeling of this amplification event in non-tumorigenic 

breast epithelial cells using gene targeting techniques, he plans to identify “driver genes” in this amplicon 

that confer aggressive tumor behavior. WHSC1L1, a MMSET homolog located within the 8p11-12 amplicon 

and overexpressed in amplified tumors, is a good candidate driver gene and will be subjected to functional 

analysis. 


Abukhdeir AM, Vitolo MI, Argani P, De Marzo AM, Karakas B, Konishi H, Gustin JP, Lauring J, Garay 

JP, Pendleton C, Konishi Y, Blair BG, Brenner K, Garrett-Mayer E, Carraway H, Bachman KE, Park BH. 

Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci U S A 2008;105:288- 

293. 

Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi 

H, Konishi Y, Mohseni M, Wang G, Rosen DM, Denmeade SR, Higgins MJ, Vitolo MI, Bachman KE, 

Park BH. Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci U S A 

2009;106:2835-2840. 

Konishi H, Karakas B, Abukhdeir AM, Lauring J, Gustin JP, Garay JP, Konishi Y, Gallmeier E, Bachman 

KE, Park BH. Knock-in of mutant K-ras in nontumorigenic human epithelial cells as a new model for 

studying K-ras mediated transformation. Cancer Res 2007;67:8460-8467. 

Lauring J, Abukhdeir AM, Konishi H, Garay JP, Gustin JP, Wang Q, Arceci RJ, Matsui W, Park BH. 

The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and 

tumorigenicity. Blood 2008;111:856-864. 

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CANCER, LYMPHOMA 


TRANSFORMED FOLLICULAR LYMPHOMA: SMOKE RELATED? 

Ronald B. Gartenhaus, MD; University of Maryland; CIA 2002 

Several reports suggested a correlation of the incidence of follicular non-Hodgkin’s lymphoma (NHL) 

with cigarette smoking. In 40% of follicular lymphoma patients, the disease evolves into a diffuse large cell 

lymphoma often associated with genetic alterations, including mutations of the p53 tumor suppressor 

gene. Dr. Gartenhaus has made a comparison of p53 mutations in transformed follicular lymphoma from 

non-smokers and smokers and between the presence of a mutator phenotype in transformed follicular lymphoma 

from non-smokers and smokers. The results show no association between p53 status and smoking 

in transformed follicular lymphoma, but do show a trend towards a higher rate of mutation in a DNA 

repair mismatch enzyme (MLH-1) and in a gene associated with genetic instability in a hereditary form of 

colon cancer (MSH-2) in smokers as compared to non-smokers. 

CANCER, MULTIPLE 


ROLES OF THE CHECKPOINT KINASES IN THE RESPONSES OF HUMAN CANCER CELLS TO DNA DAMAGE 

Fred Bunz, MD, PhD; The Johns Hopkins University; YCSA 2002 

Dr. Bunz has recently identified and validated a new target for combination therapy of smoking-related 

cancers; the ataxia telangiectasia and Rad3-related protein (ATR) protein kinase. Current efforts in Dr. 

Bunz’s laboratory are directed at 1) evaluating the activation of the checkpoint kinase 1 by ATR; 2) examining 

the sensitivity of ATR-deficient cancer cells in a preclinical tumor model; and 3) identifying novel 

small molecule inhibitors of ATR that may serve as lead compounds for drug discovery. 


Bunz F. Regulation of cancer cell growth and death: evaluating new anticancer targets. Drug Discov Today 

2005;2:383-387. 

Dang DT, Chen F, Gardner LB, Cummins JM, Rago C, Bunz F, Kantsevoy SV, Dang LH. 

Hypoxiainducible factor-1 alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and 

xenografts. Cancer Res 2006;66:1684-1689. 

Hauguel T, Bunz F. Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in 

human cancer cells. Cancer Biol Ther 2003;2:679-684. 

Rago C, Vogelstein B, Bunz F. Genetic knockouts and knockins in human somatic cells. Nat Protoc 

2007;2:2734-2746. 

Topaloglu O, Hurley PJ, Yildirim O, Civin CI, Bunz F. Improved methods for the generation of human 

gene knockout and knockin cell lines. Nucleic Acids Res 2005;33:e158. 

TARGETING THE ATR KINASE IN SECOND HAND TOBACCO SMOKE-RELATED CANCERS 

Fred Bunz, MD, PhD; The Johns Hopkins University; CIA 2008 

Ionizing radiation can be used to treat almost every type of tumor. The majority of people with cancers 

caused by smoking or SHS are treated with radiation therapy, either used alone or in combination with 

chemotherapy or surgery. While radiation therapy is highly effective in many cancer patients, some types of 

tumors have proven to be resistant. Dr. Bunz’s efforts are focused on testing new molecular targets that 

may increase the sensitivity of cancer cells to ionizing radiation and DNA damaging drugs. 

One promising molecular target that has been identified by Dr. Bunz’s laboratory is the ataxia telangiectasia 

and Rad3-related protein (ATR) kinase. This DNA-damage induced enzyme is involved in the basic 

responses of all human cells to radiation and other forms of anticancer therapy. Unlike the related ataxia 

telangiectasia mutated (ATM) gene, ATR is required for the progression of damaged cells into S phase of 

the cell cycle. Importantly, ATR activity is not altered by cancer-associated mutations. In recently published 

studies that were funded by FAMRI, Dr. Bunz and colleagues have shown that the genetic inhibition of 

ATR kinase activity causes cancer cells to become highly sensitive to widely used therapeutic agents. The 

research plan is designed to follow up these informative in vitro studies. Dr. Bunz and colleagues will 1) 

test the effects of ATR and other DNA damage-response genes in a preclinical tumor model; and 2) identify 

small molecules that specifically inhibit ATR activity. They anticipate that these efforts will validate ATR 

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as a target for the sensitization of tumors to therapy and identify lead compounds for drug development. 


Bunz F. Thymidylate synthase and 5-fluorouracil: a cautionary tale. Cancer Biol Ther 2008;7:995-996. 

Bunz F. Principles of Cancer Genetics. Springer, 2008. 

Horowitz DP, Topaloglu O, Zhang Y, Bunz F. Deficiency of bloom syndrome helicase activity is 

radiomimetic. Cancer Biol Ther 2008; 7:1778-1781. 

Kim JS, Bonifant C, Bunz F, Lane W, Waldman T. Epitope tagging of endogenous genes in diverse human 

cell lines. Nucleic Acids Res 2008;36:e127. 

Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman 

SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, Biswal S. RNAi-mediated silencing of nuclear factor 

erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and 

increases efficacy of chemotherapy. Cancer Res 2008;68:7975-7984. 

Sur S, Pagliarini R, Bunz F, Rago C, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N. A panel of 

isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl 

Acad Sci U S A 2009;106:3964-3969. 

Wilsker D, Petermann E, Helleday T, Bunz F. Essential function of Chk1 can be uncoupled from DNA 

damage checkpoint and replication control. Proc Natl Acad Sci U S A 2008; 105:20752-20757. 

Wilsker D, Bunz F. Cell cycle defects and apoptosis in Ataxia-telangiectasia. In: Ahmad S, ed. Molecular 

Mechanisms of Ataxia-telangiectasia. Landes Bioscience 2008. 

SENSITIVITY OF TOBACCO-INDUCED CANCER TO HERPES VIRAL ONCOLYSIS 

Richard J. Wong, MD; Memorial Sloan-Kettering Cancer Center; CIA 2004, 2007 

Replication-competent, oncolytic herpes viruses have a remarkable ability to selectively infect tobaccoinduced 

cancers while preserving adjacent normal tissues. One factor to account for this selectivity is the 

differential expression of herpes viral receptors on cancer cells. Dr. Wong’s group has studied the expression 

by cancer cells of one particular receptor, nectin-1, and found the level of expression to be directly 

related to the susceptibility of these cancers to herpes infection and oncolysis. Modulation of nectin-1 leads 

to corresponding increases or decreases in herpes viral entry and oncolysis. Assessment of nectin-1 appears 

to be a useful tool for predicting response to therapy. Dr. Wong’s group has also demonstrated that the 

disruption of intercellular adherens junctions between cancer cells may enhance the availability of nectin-1 

to serve as a receptor for herpes oncolytic therapy. Ongoing goals include the evaluation of mechanisms of 

nectin-1 over expression by tobacco-induced cancers, elucidating the relationship of other surface adhesion 

molecules (such as E-cadherin) with nectin-1, and examining the influence of oncogenic signaling pathways 

that alter surface adhesion molecules on nectin-1 expression and oncolytic herpes viral sensitivity. 

These studies will elucidate mechanisms of natural susceptibility by tobacco-induced cancers to herpes 

oncolytic therapy, and may provide insights into strategies to enhance herpes therapeutic efficacy. 


Gil Z, Brader P, Shah JP, Fong Y, Wong RJ. Utility of a herpes oncolytic virus for the detection of neural 

invasion by cancer. Neoplasia 2008;10:347-353. 

Gil Z, Rein A, Brader P, Li S, Shah JP, Fong Y, Wong RJ. Nerve-sparing therapy with oncolytic herpes 

virus for cancers with neural invasion. Clin Cancer Res 2007;13:6479-6485. 

Huang YY, Yu Z, Lin SF, Li S, Fong Y, Wong RJ. Nectin-1 is a marker of thyroid cancer sensitivity to herpes 

oncolytic therapy. J Clin Endocrinol Metab 2007;92:1965-1967. 

Kelly K, Brader P, Rein A, Shah JP, Wong RJ, Fong Y, Gil Z. Attenuated multimutated herpes simplex 

virus-1 effectively treats prostate carcinomas with neural invasion while preserving nerve function. 

FASEB J 2008;22:1839-1848. 

Lin SF, Price DL, Chen CH, Brader P, Li S, Gonzalez L, Zhang Q, Yu YA, Chen N, Szalay AA, Fong Y, 

Wong RJ. Oncolytic vaccinia virotherapy of anaplastic thyroid cancer in vivo. J Clin Endocrinol Metab 

2008;93:4403-4407. 

Lin SF, Gao SP, Price DL, Li S, Chou TC, Singh P, Huang YY, Fong Y, Wong RJ. Synergy of a herpes 

oncolytic virus and paclitaxel for anaplastic thyroid cancer. Clin Cancer Res 2008;14:1519-1528. 

Lin SF, Yu Z, Riedl C, Woo Y, Zhang Q, Yu YA, Timiryasova T, Chen N, Shah JP, Szalay A, Fong Y, 

Wong RJ. Treatment of anaplastic thyroid cancer in vitro with a mutant vaccinia virus. Surgery 

2007;142:976-983. 

Reid V, Yu Z, Schuman T, Li S, Singh P, Fong Y, Wong RJ. Herpes oncolytic therapy of salivary gland carcinomas. 

Int J Cancer 2008;122:202-208. 

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Stiles BM, Adusumilli PS, Bhargava A, Stanziale SF, Kim TH, Chan MK, Huq R, Wong R, Rusch VW, 

Fong Y. Minimally invasive localization of oncolytic herpes simplex viral therapy of metastatic pleural 

cancer. Cancer Gene Ther 2006;13:53-64. 

Wong RJ, Patel SG, Kim SH, DeMatteo RP, Malhotra S, Bennett JJ, St-Louis M, Shah JP, Johnson PA, 

Fong Y. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. 

Hum Gene Ther 2001;12:253-265. 

Wong RJ, Kim SH, Joe JK, Shah JP, Johnson PA, Fong Y. Effective treatment of head and neck squamous 

cell carcinoma by an oncolytic herpes virus. J Am Coll Surg 2001;192:12-21. 

Wong RJ, Joe JK, Kim SH, Shah JP, Horsburgh B, Fong Y. Oncolytic herpesvirus effectively treats murine 

squamous cell carcinoma and spreads by natural lymphatics to treat sites of lymphatic metastases. Hum 

Gene Ther 2002;13:1213-1223. 

Wong RJ, Chan MK, Yu Z, Kim TH, Bhargava A, Stiles BM, Horsburgh BC, Shah JP, Ghossein RA, 

Singh B, Fong Y. Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes 

virus expressing IL-12. Clin Cancer Res 2004;10:251-259. 

Wong RJ, Chan MK, Yu Z, Ghossein RA, Ngai I, Adusumilli PS, Stiles BM, Shah JP, Singh B, Fong Y. 

Angiogenesis inhibition by an oncolytic herpes virus expressing IL-12. Clin Cancer Res 2004;10:4509- 

4516. 



2005;11:4889-4897. 

Yu Z, Adusumilli P, Eisenberg DP, Darr E, Ghossein RA, Li S, Liu S, Singh B, Shah JP, Fong Y, Wong RJ. 

Nectin-1 expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity. Mol Ther 

2007;15:103-113. 

Yu Z, Li S, Huang YY, Fong Y, Wong RJ. Calcium depletion enhances nectin-1 expression and herpes 

oncolytic therapy of squamous cell carcinoma. Cancer Gene Ther 2007;14:738-747. 

Yu Z, Li S, Huang YY, Lin SF, Fong Y, Wong RJ. Sensitivity of squamous cell carcinoma lymph node 

metastases to herpes oncolytic therapy. Clin Cancer Res 2008;14:1897-1904. 

EARLY DETECTION AND SCREENING OF SMOKING-RELATED CANCERS 

BY USE OF GREEN FLUORESCENT PROTEIN EXPRESSING HERPES SIMPLEX VIRUS 

Yuman Fong, MD; Memorial Sloan-Kettering Cancer Center; CIA 2003 

Tobacco and cigarette smoke lead to development of many malignancies including oral, lung, 

esophageal, pancreatic, and colon cancers. This cancer forming process involves a change from a normal 

cell to a dysplastic cell (abnormal cell but not yet truly cancerous), a carcinoma in situ (true cancer but not 

yet with metastatic potential), and then frank cancer. The laboratory is focused on development of viruses 

that very specifically infect and kill cancers. Some of the viruses being developed infect tumors and kill 

tumor cells within hours, and show no propensity for infecting normal, non-cancerous cells. The goals of 

this project have been to use viruses designed to infect and kill cancer for early detection of cancer and to 

see if these viruses can reverse the process of cancer formation. Using viruses that show green fluorescence 

upon infection of tumor cells, the investigators have demonstrated that this technique of fluorescenceassisted 

viral detection of cancer is possible and can be used to improve early diagnosis of cancer and its 

treatment. In animal and in human studies, they have been able to detect one tumor cell in the background 

of one million normal cells (50 times improvement over traditional cytology). The fluorescence 

that is indicative of cancer cells can be read by personnel with rudimentary training or by automated techniques. 

This can lead to rapid and high throughput detection of many cancers including lung, oral, pancreatic, 

and stomach. This technique also uses viruses that can be produced in a relatively inexpensive way. 

This may allow a new technique for cytologic screening of patients, even in rural areas of developing 

nations where cigarette smoking is still popular and produces cancer. This work has potentially immediate 

application in cancer screening worldwide. Ongoing studies will address the question of whether these 

viruses can reverse the development of cancer by killing cells that are committed to but have not yet 

become cancer. 


Adusumilli PS, Chan MK, Ben-Porat L, Mullerad M, Stiles BM, Tuorto S, Fong Y. Citation characteristics 

of basic science research publications in general surgical journals. J Surg Res 2005;128(2):168-173. 

Adusumilli PS, Chan MK, Chun YS, Hezel M, Chou TC, Rusch VW, Fong Y. Cisplatin-induced GADD34 

up regulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma. 

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Cancer Biol Ther 2006;5(1):48-53. 

Adusumilli PS, Chan MK, Hezel M, Yu Z, Stiles BM, Chou TC, Rusch VW, Fong Y. Radiation-induced 

cellular DNA damage repair response enhances viral gene therapy efficacy in the treatment of malignant 

pleural mesothelioma. Ann Surg Oncol 2007;14(1):258-269. 

Adusumilli PS, Eisenberg DP, Chun YS, Ryu KW, Ben-Porat L, Hendershott KJ, Chan MK, Huq R, Riedl 

CC, Fong Y. Virally directed fluorescent imaging improves diagnostic sensitivity in the detection of minimal 

residual disease after potentially curative cytoreductive surgery. J Gastrointest Surg 2005;9(8):1138- 

1147. 

Adusumilli PS, Eisenberg DP, Stiles BM, Hendershott KJ, Stanziale SF, Chan MK, Hezel M, Huq R, 

Rusch VW, Fong Y. Virally-directed fluorescent imaging (VFI) can facilitate endoscopic staging and minimally 

invasive cancer surgery. Surg Endosc 2006;13(1):53-64. 

Adusumilli PS, Stiles BM, Chan MK, Chou TC, Wong RJ, Rusch VW, Fong Y. Radiation therapy potentiates 

effective oncolytic viral therapy in the treatment of lung cancer. Ann Thorac Surg 2005;80(2):409- 

417. 

Adusumilli PS, Stiles BM, Chan MK, Eisenberg DP, Yu Z, Stanziale SF, Huq R, Wong RJ, Rusch VW, 

Fong Y. Real-time diagnostic imaging of tumors and metastases by use of a replication-competent herpes 

vector to facilitate minimally-invasive oncological surgery. FASEB J 2006;20(6):726-728. 

Adusumilli PS, Stiles BM, Chan MK, Mullerad M, Eisenberg DP, Ben-Porat L, Huq R, Rusch VW, Fong 

Y. Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex 

viruses. J Gene Med 2006;8(5):603-615. 

Chun YS, Adusumilli PS, Fong Y. Empoying tumor hypoxia for oncolytic therapy in breast cancer. J 

Mammary Gland Biol Neoplasia 2005;10(4):311-318. 

Eisenberg DP, Adusumilli PS, Hendershott KJ, Chung S, Yu Z, Chan MK, Hezel M, Wong RJ, Fong Y. 

Real-time intraoperative detection of breast cancer axillary lymph node metastases using a green fluorescent 

protein-expressing herpes virus. Ann Surg 2006;243(6):824-830. 

Eisenberg DP, Adusumilli PS, Hendershott KJ, Yu Z, Mullerad M, Chan MK, Chou TC, Fong Y. 5-fluoroururacil 

and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment 

of pancreatic cancer. J Gastrointest Surg 2005;9(8):1068-1079. 

Huang YY, Yu Z, Lin SF, Li S, Fong Y, Wong RJ. Nectin-1 is a marker of thyroid cancer sensitivity to herpes 

oncolytic therapy. J Clin Endocrinol Metab 2007;92(5):1965-1970. 

Mullerad M, Bochner BH, Adusumilli PS, Bhargava A, Kikuchi E, Hui-Ni C, Kattan MW, Chou TC, Fong 

Y. Herpes simplex virus-based gene therapy enhances the efficacy of mitomycin-c in the treatment of 

human bladder transitional cell carcinoma. J Urol 2005;174(2):741-746. 

Reid V, Yu Z, Schuman T, Li S, Singh P, Fong Y, Wong RJ. Herpes oncolytic therapy of salivary gland carcinomas. 

Int J Cancer 2008;122(1):202-208. 

Stiles BM, Adusumilli PS, Bhargava A, Stanziale SF, Kim TH, Chan MK, Huq R, Wong R, Rusch VW, 

Fong Y. Minimally invasive localization of oncolytic herpes simplex viral therapy of metastatic pleural 

cancer. Cancer Gene Ther 2006;13(1):53-64. 

Stiles BM, Adusumilli PS, Stanziale SF, Eisenberg DP, Bhargava A, Kim TH, Chan MK, Huq R, Gonen 

M, Fong Y. Estrogen enhances the efficacy of an oncolytic HSV-1 mutant in the treatment of estrogen 

receptor-positive breast cancer. Int J Oncol 2006;28(6):1429-1439. 

Yu Z, Adusumilli PS, Eisenberg DP, Darr E, Ghossein RA, Li S, Liu S, Singh B, Shah JP, Fong Y, Wong 

RJ. Nectin-1 expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity. Mol 

Ther 2007;15:103-113. 



2005;11:4889-4897. 

Yu Z, Li S, Huang YY, Fong Y, Wong RJ. Calcium depletion enhances nectin-1 expression and herpes 

oncolytic therapy of squamous cell carcinoma. Cancer Gene Ther 2007;14(8):738-747. 

THE IMPACT OF SWI/SNF COMPLEX IN CANCER 

David N. Reisman, MD, PhD; University of Michigan; CIA 2004 

Dr. Reisman’s hypothesis is that loss of the activity of the chromatin remodeling complex SWI/SNF is a 

pivotal event in development of smoking-related cancers. The loss not only abrogates key cellular growth 

controls such as the functions of tumor suppressor proteins Rb and p53, but it also negatively influences 

important signaling pathways that are targets for clinical intervention. The PI’s research aims are to determine 

1) the epigenetic mechanism underlying biological response modifier (BRM) suppression and identify 

1 2 8 P A G E

novel drugs that can restore BRM expression; and 2) the mechanism of brahma-related gene 1 (BRG1) 

loss, define how loss of BRM affects cancer development, and determine how loss of BRG1 can be used as 

a biomarker to guide clinical decision making. 


Glaros S, Cirrincione GM, Muchardt C, Kleer CG, Michael CW, Reisman D. The reversible epigeneticsilencing 

of BRM: implications for clinical targeted therapy. Oncogene 2007;26:7058-7066. 

SOMATIC CELL KNOCK-IN OF A MUTANT K-RAS GENE FOR UNDERSTANDING AND TARGETING RAS-INDUCED 

CANCERS RELATED TO SECOND HAND TOBACCO SMOKE 

Ben-Ho Park, MD, PhD; The Johns Hopkins University; YCSA 2006 

K-ras is an oncogene frequently mutated in a variety of human cancers related to SHS. Dr. Park recently 

took over this project from Dr. Konishi and plans to exploit this mutation to establish new cancer therapies. 

The PI and his colleagues have engineered human breast epithelial cells and created sibling cell clones 

that differ only by the presence or absence of a point mutation in the K-ras gene. These cell lines will be 

used in high-throughput drug screens to identify compounds that selectively target K-ras mutant cells 

without affecting their non-mutated counterparts. Such drugs will truly represent cancer-specific therapies. 

The investigators have already accomplished an extensive analysis of these K-ras engineered cell clones and 

found that the distinct biological and biochemical changes observed in conventional models are largely due 

to the overexpression of mutant K-ras, a condition not frequently seen in actual human cancer cells. In 

comparison, the mutant K-ras knock-in cells exhibited a significantly less pronounced, but reproducible 

phenotype. As these K-ras knock-in cell lines more closely recapitulate actual human cancers, the investigators 

believe that the use of these cells is advantageous for both gene functional analysis and drug screening 

over current existing cell models. In addition, investigators seek to introduce an activating point mutation 

of PIK3CA into the K-ras engineered cell clones. This approach enables the study of cooperative effects of 

two common oncogenes, and may provide an option to conduct drug discovery efforts in a condition closer 

to actual cancers. 


Abukhdeir AM, Blair BG, Brenner K, Karakas B, Konishi H, Lim J, Sahasranaman V, Huang Y, Keen J, 

Davidson N, Vitolo MI, Bachman KE, Park BH. Physiologic estrogen receptor alpha signaling in nontumorigenic 

human mammary epithelial cells. Breast Cancer Res Treat 2006;99:23-33. 

Abukhdeir AM, Vitolo MI, Argani P, De Marzo AM, Karakas B, Konishi H, Gustin JP, Lauring J, Garay 

JP, Pendleton C, Konishi Y, Blair BG, Brenner K, Garrett-Mayer E, Carraway H, Bachman KE, Park 

BH. Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci U S A 

2008;105:288-293. 

Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi H, 

Konishi Y, Mohseni M, Wang G, Rosen DM, Denmeade SR, Higgins MJ, Vitolo MI, Bachman KE, 

Park BH. Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci U S A 

2009;106:2835-2840. 

Karakas B, Weeraratna A, Abukhdeir A, Blair BG, Konishi H, Arena S, Becker K, Wood W, 3rd, Argani P, 

De Marzo AM, Bachman KE, Park BH. Interleukin-1 alpha mediates the growth proliferative effects of 

transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells. Oncogene 

2006;25:5561-5569. 

Karakas B, Weeraratna AT, Abukhdeir AM, Konishi H, Gustin JP, Vitolo MI, Bachman KE, Park BH. p21 

gene knock down does not identify genetic effectors seen with gene knock out. Cancer Biol Ther 

2007;6:1025-1030. 

Konishi H, Karakas B, Abukhdeir AM, Lauring J, Gustin JP, Garay JP, Konishi Y, Gallmeier E, Bachman 

KE, Park BH. Knock-in of mutant K-ras in nontumorigenic human epithelial cells as a new model for 

studying K-ras mediated transformation. Cancer Res 2007;67:8460-8467. 

Konishi H, Lauring J, Garay JP, Karakas B, Abukhdeir AM, Gustin JP, Konishi Y, Park BH. A PCR-based 

high-throughput screen with multi-round sample pooling: application to somatic cell gene targeting. 

Nat Protoc 2007;2:2865-2874. 

Lauring J, Abukhdeir AM, Konishi H, Garay JP, Gustin JP, Wang Q, Arceci RJ, Matsui W, Park BH. The 

multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and 

tumorigenicity. Blood 2008;111:856-864. 

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REGULATION OF TGF BETA SIGNALING IN PROSTATE CANCER 

Paula J. Hurley, PhD; The Johns Hopkins University; YCSA 2007 

Exposure to tobacco smoke has been positively correlated with metastatic prostate cancer (PCa). During 

this year, almost 200,000 new cases of PCa will be diagnosed and the disease will be associated with 

approximately 30,000 deaths. Developmental programs involved in prostate organogenesis have been 

linked to the pathogenesis of PCa. Prostate organogenesis is an excellent model system to study PCa as 

prostate development occurs when androgen signaling in the mesenchyme drives epithelial proliferation, 

invasion, and differentiation, events that are classic hallmarks of cancer. Recent evidence suggests that these 

developmental pathways are re-activated in benign and malignant prostatic growth. Dr. Hurley and colleagues 

have conducted a systematic genome wide screen for other androgen-regulated genes important in 

prostate development and have linked several of them to prostate cancer progression. 

Asporin is one such gene that is consistently androgen-regulated during prostate development and is disrupted 

in cancer. Asporin is an extracellular matrix protein known to regulate transforming growth factorb, 

a protein involved in both development and carcinogenesis. Recent studies have shown that asporin is 

significantly elevated in breast carcinomas further suggesting its involvement in hormonally regulated 

tumors. Understanding the function of asporin during development and in cancer will aid in the genesis of 

specific cancer therapies. 

CANCER, MULTIPLE 


ORGANISMAL EFFECT OF TOBACCO SMOKE ON TELOMERASE NULL MICE 

Kwok-Kin Wong, MD, PhD; Harvard University; CIA 2005 

Telomere maintenance has been proposed to play a crucial role in the processes of genomic stability, 

aging, organ homeostasis, and tumorigenesis. Dr. Wong’s research hypothesis states that when exposed to 

SHS, mice engineered to have critically short dysfunctional telomeres will be predisposed to accelerated 

organ failure and higher frequency of tumorigenesis in the lung and other organs. The PI proposes to 

chronically expose cohorts of wild-type mice, telomerase-null mice with long telomeres, and telomerasenull 

mice with shortened telomeres to SHS. These mice will be analyzed for level of inflammation, cell 

proliferation, and apoptosis in various organs. 


Basseres D, Levantini E, Ji H, Monti S, Elf S, Dayaram T, Fenyus M, Kocher O, Goulb T, Wong KK, Halmos 

B, Tenen DG. Respiratory failure due to differentiation arrest and expansion of alveolar cells following lungspecific 

loss of the transcription factor C/EBP-alpha in mice. Mol Cell Biol 2006;26:1109-1123. 

Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, 

Perera SA, Liang MC, Cai D, Naumov GN, Bao L, Contreras CM, Li D, Chen L, Krishnamurthy J, 

Koivunen J, Chirieac LR, Padera RF, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, 

Janne PA, Johnson BE, Meyerson M, Kwiatkowski DJ, Castrillon DH, Bardeesy N, Sharpless NE, Wong 

KK. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007;448:807-810. 

Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, Halmos B. An alternative inhibitor overcomes 

resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 

2005;65:7096-7101. 

INHIBITORS OF HISTONE ACETYLTRANSFERASE (HAT) AS NOVEL THERAPIES FOR HPV-ASSOCIATED MALIG- 

NANCIES 

Rhoda M. Alani, MD; The Johns Hopkins University; YCSA 2002 

Dr. Alani’s research objectives were to determine the role of histone acetyltransferase (HAT) in the 

development of human papillomavirus (HPV)-associated malignancies such as cervical and head and neck 

cancers and to develop HAT inhibitors (HATIs) as HPV-related tumor therapies. Dr. Alani’s specific aims 

were to 1) develop a series of HAT inhibitors that will inhibit oncogenic HPV activation of these enzymes 

with minimal toxicity; 2) determine the effects of HATIs on cell cycle progression and viability in HPVpositive 

and HPV-negative cell lines and identify HPV-specific cell inhibitors; and 3) determine the precise 

mechanism of action of HPV-specific HATIs and their ability to affect cell cycle regulatory proteins. Access 

to pure HATI compounds was facilitated by the novel chemistry therapy core of the Johns Hopkins 

Medical Institutions (JHMI) FAMRI Center of Excellence. 

1 3 0 P A G E


Alani RM, Silverthorn CF, Orosz K. Tumor angiogenesis in mice and men. Cancer Biol Ther 2004;3:41- 

42. 

Dunlap S, Yu X-B, Cheng L-Z, Civin CI, Alani RM. High-efficiency stable gene transduction in primary 

human melanocytes using a lentiviral expression system. J Investig Dermatol 2004;122:549-551. 

Govindarajan B, Shah A, Cohen C, Arnold RS, Schechner J, Chung J, Mercurio AM, Alani R, Ryu B, Fan 

CY, Cuezva JM, Martinez M, Arbiser JL. Malignant transformation of human cells by constitutive 

expression of platelet derived growth factor-BB (PDGF-BB). J Biol Chem 2005;280:13936-13943. 

Guidez F, Howell L, Isalan M, Cebrat M, Alani RM, Ivins S, Hormaeche I, McConnell MJ, Pierce S, Cole 

PA, Licht J, Zelent A. Histone acetyltransferase activity of p300 is required for transcriptional repression 

by the promyelocytic leukemia zinc finger protein. Mol Cell Biol 2005;25:5552-5566. 

Sikder HA, Dunlap SD, Devlin M, Ryu B, Alani RM. Id proteins in cell growth and tumorigenesis. Cancer 

Cell 2003;3:525-530. 

Sikder HA, Huso DL, Zhang H, Wang B, Ryu B, Hwang ST, Powell JD, Alani RM. Disruption of Id1 

reveals major differences in angiogenesis between transplanted and autochthonous tumors. Cancer Cell 

2003;4(4):291-299. 

Zheng Y, Karanam B, Cebrat M, Buck D, Devlin M, Zelent A, Alani RM, Cole PA. Synthesis and evaluation 

of a selective cell permeable p300 histone acetyltransferase inhibitor. J Am Chem Soc 

2005;127:17182-17183. 

Zheng Y, Thompson PR, Cebrat M, Wang L, Devlin MK, Alani RM, Cole PA. Selective HAT Inhibitors as 

Mechanistic Tools for Protein Acetylation. Methods in Enzymol 2004;376:188-199. 

CANCER, OVARIAN 


ANTIBODIES FOR SMOKING-RELATED MUCINOUS OVARIAN CANCER 

Shu-Wing Ng, PhD; Brigham and Women’s Hospital; CIA 2006 

Ovarian cancer is the most common cause of death among gynecological malignancies, with a dismal 5- 

year survival rate of 30%. Early detection and early intervention is critical for the prognosis and overall survival 

of ovarian cancer patients. Recent studies have suggested that the mucinous subtype of ovarian cancer, 

which currently has no detection markers, is smoking related. Emerging evidence has also shown that 

serum autoantibodies can serve as cancer biomarkers. The investigators aim to determine if the serum antibodies 

are indicators for mucinous ovarian cancer risk, and if active or passive smoking exposure affects 

cancer risk by changing the antibody levels. An innovative antibody array platform was applied to compare 

plasma autoantibodies between normal controls and a panel of mucinous tumor patients. Dr. Ng and colleagues 

have identified 35 autoantibodies that were significantly elevated in the cancer plasma samples 

compared with healthy controls, as well as six autoantibodies that segregated smoking and non-smoking 

patients. Functional annotation of the antibody targets has identified nine target antigens involved in integrin 

and Wnt signaling pathways. Immunohistochemistry of archived ovarian specimens showed significant 

overexpression of eight of the nine target antigens in mucinous ovarian tumor tissues. Dr. Ng and colleagues 

are currently devising methods to validate the autoantibody data and to understand the mechanisms 

by which immune system reacts to tobacco exposure and generates specific autoantibody biomarkers. 


Ehrlich JR, Tang L, Caiazzo RJ, Cramer DW, Ng SK, Ng SW, Liu BCS. The reverse capture autoantibody 

microarray: an innovative approach to profiling the autoantibody response to tissue-derived native antigens. 

In: Liu BCS, Ehrlich JR, ed. Tissue Proteomics - Pathways, Biomarkers, and Drug Discovery. 

Totowa, NJ: Humana Press 2008. 

CANCER, PROSTATE 


CIGARETTE SMOKE AND IMPAIRED SELENOPROTEIN PRODUCTION 

Charles B. Foster, MD; Cleveland Clinic; CIA 2007 

Low serum selenium levels are associated with an increased risk of prostate cancer (PCa), especially 

P A G E 1 3 1

among men exposed to cigarette smoke. Dr. Foster and colleagues hypothesize that cigarette smoke 

impairs the production of selenium containing proteins—called selenoproteins. The aim of their research is 

to characterize pathways that regulate selenoprotein production. Perhaps by augmenting selenoprotein 

production efficiency or by enhancing the stability of selenoprotein messenger RNAs it will be possible to 

increase the selenoprotein content of cells and afford protection against cellular sources of oxidative stress 

and toxins such as cigarette smoke. To characterize cellular signaling pathways regulating selenoprotein 

production and stability, their laboratory has developed two novel reporter assays. One reporter measures 

how efficiently the amino acid selenocysteine is incorporated into an artificial selenoprotein. The other 

reporter measures the stability of an artificial selenoprotein. Using these reporters, they have gained preliminary 

data that selenoprotein production efficiency is regulated by the phosphoinositide-3 kinase -protein 

kinase B (PI3K-AKT pathway). In the presence of selenium, inducers of the PI3K pathway, such as the 

cytokine IL-13, enhance L-seryl-tRNA (SEC) incorporation efficiency, increase the level of the antioxidant 

selenoprotein glutathione peroxidase 1, and protect HEK293 cells against hydrogen peroxide or cigarette 

smoke induced cell death. It is known that under selenium-limiting conditions that some selenoprotein 

messenger RNAs (mRNAs) are degraded by a cellular surveillance pathway called nonsense-mediated decay 

(NMD). To characterize the mechanisms by which GPX1 mRNA avoids NMD in the presence, but not in 

the absence of selenium, Dr. Foster and colleagues are using the second reporter to characterize signaling 

pathways that promote the degradation of selenoprotein mRNAs under conditions of selenium deficiency. 

In contrast to HEK293 cells, supplemental selenium does not afford PCa cells enhanced protection against 

inducers of oxidative stress. They will use their reporter assays and knowledge of the signaling pathways 

that regulate selenoprotein production to further characterize the mechanisms by which cigarette smoke 

contributes to PCa and to define whether selenoprotein production pathways are impaired in PCa cell 

lines. 

SMALL PEPTIDE THERAPY ON METASTATIC PROSTATE CANCER 

Jer-Tsong Hsieh, PhD; University of Texas Southwestern; CIA 2008 

Prostate cancer (PCa) is the most common type of cancer found in American men, other than skin cancer. 

Although smoking was unrelated to overall PCa incidence, a prospective study indicates that current 

smokers and recent quitters were at higher risk for distant metastatic PCa and fatal PCa. Currently, androgen 

ablation is the most effective regimen for distant metastatic PCa, over a period of time, the progression 

to life threatening androgen independent (AI) status is inevitable. For the AI disease, there are not 

many treatment options currently available with curative outcomes. Therefore, there is an immediate need 

to develop a new course of therapy that may hold significant promise for a better cancer control and 

improve the life qualities of patients with advanced diseases. 

The ultimate goal of this project is to design a combination molecular therapy. 

By employing biochemical techniques, Dr. Hsieh and colleagues intend to analyze the underlying mechanism 

of CPP specific uptake by PCa. In addition, they will further improve the stability of CPP by changing 

its chemical structure. Based on key functional motifs of several prominent tumor suppressor proteins, 

they will synthesize small peptides corresponding to these motifs and examine their effect using several preclinical 

animal models. 

The small peptide is considered much safer than synthetic chemicals. Moreover, the response of tumor 

can be detected by non-invasive molecular imaging techniques in a real-time manner. Thus, the outcome 

of this study has an immediate clinical application because the goal of this project is to combine new concept 

and state-of-art biotechnology to develop a comprehensive therapeutic regimen for AIPCa patients. 

INHIBITION OF HEDGEHOG SIGNALING BY CYCLOPAMINE PRODRUG FOR PROSTATE CANCER 

Anirban Maitra, MBBS; The Johns Hopkins University; CIA 2007 

Dr. Maitra assumed this project from Saeed R. Khan, PhD. The hedgehog (Hh) pathway plays a critical 

role in the development of prostate cancer. The Hh signaling pathway specifies patterns of cell growth and 

differentiation during embryogenesis in a wide range of tissues. A role for the Hh signaling in oncogenesis 

was first reported in subsets of brain tumors (medulloblastomas) and cutaneous basal cell carcinomas arising 

in the context of Gorlin’s syndrome, wherein inactivating mutations in the tumor suppressor gene 

PTCH result in constitutive activation of the pathway. Most recently Beachy et al described a new paradigm 

of Hh pathway activation in endoderm-derived tumors. It has been demonstrated that inhibition of 

Hh signaling by smoothened antagonist, cyclopamine suppresses Hh signaling, down-regulates cell invasiveness, 

and induces apoptosis. Thus, targeted inhibition of Hh signaling may have significant implications 

of prostate cancer (PCa) therapeutics. Currently there is no curative treatment for men with metastatic 

1 3 2 P A G E

PCa once they have failed androgen ablation. Androgen ablation therapy eventually fails because the 

metastatic PCa within an individual patient is heterogeneously composed of clones of both androgen 

dependent and independent cancer cells. Due to these androgen independent prostatic cancer cells, the 

patient is no longer curable using the numerous chemotherapeutic agents. Presently, standard treatments 

for metastatic PCa include estramustine in combination with vinca alkaloids, etoposide, or taxanes, and 

other regimens that include agents such as doxorubicin or cyclophosphamide. Unfortunately these treatments 

are associated with significant, often severe, toxicities. 

Cyclopamine has shown therapeutic efficacy for the management of human cancer. The cytotoxicity of 

this agent, however, is not PCa specific. Cyclopamine has proven to be a potent Hh signaling pathway 

inhibitor and induces apoptosis. Cyclopamine is associated with potential systemic toxicities and poor solubility 

in aqueous system that makes it difficult to formulate as an injectable dispersion. In this proposal, a 

PCa specific targeting strategy is outlined that will overcome this limitation. To achieve targeted cytotoxicity 

this compound will be converted to biologically inactive prodrugs by coupling to a peptide carrier or 

peptide linked with spacer group such that they can be efficiently converted back to active killing agents 

only upon proteolysis by the serine protease activity of a unique prostate-specific protein, prostate specific 

antigen (PSA). Within the male body, only normal and malignant PCa cells produce high levels of PSA. 

PSA is synthesized initially by the cells as a proenzyme; during the process of secretion into the extracellular 

fluid it is processed to an active chymotrypsin-like serine protease with unique substrate specificity. Thus 

the extracellular fluid around these cells contains a remarkably high level of enzymatically active PSA. Once 

PSA reaches the blood, its enzymatic activity is completely inhibited by the more than 1,000 fold molar 

excess of serum inhibitors. Therefore, the hypothesis is that the proteolytic activity of PSA, which is highly 

expressed only by normal malignant prostate cells, can be used to activate prodrugs delivered via the blood 

specifically to cytotoxic metabolites only in the extracellular fluid within sites of metastatic prostate cancer. 

Since PSA is expressed in high levels only by normal and malignant prostate cells and not in any significant 

amounts by other normal cell types, this approach should allow specific targeting of the killing ability of 

these agents to prostate cancer cells. 

Dr. Maitra and colleagues have prepared cyclopamine-peptide prodrugs that are activated by PSA. 

Specifically, they have coupled cyclopamine to two PSA specific peptide carriers. These are His-Ser-Ser-Lys- 

Leu-Gln, resulting in Mu- HSSKLQ-cyclopamine and Ac-Ser-Ser-Lys-Tyr-Gln, resulting in Mu-SSKYQcyclopamine. 

In Specific Aim 1, they will synthesize optimized copper peptide (CP) prodrugs and will 

characterize selectivity and efficiency of proteolysis of cyclopamine prodrugs in vitro, including determinating 

the rates of PSA proteolysis of cyclopamine prodrugs by high-performance liquid chromatography 

analysis, and stability in human plasma and serum. In Specific Aim 2, they will determine antitumor efficacy 

and selective cytotoxicity of cyclopamine prodrugs in vivo in xenograft models of prostate cancer. 

Prodrugs will be tested initially for hydrolysis by PSA. To determine specificity and selectivity of hydrolysis, 

prodrugs will be tested in vitro against PSA-producing LNCaP human PCa cell line and non-PSA producing 

DU145 human cancer cell line. Prodrugs will also be tested for stability in human and mouse plasma. 

From these studies, the lead prodrug(s) will be selected. These lead prodrug(s) will then be tested in vivo 

for activity in mice bearing PSA-producing human PCas. These studies will serve to identify the best candidate 

prodrugs of cyclopamine that will subsequently tested in clinical trials for the treatment of localized 

and the lead cyclopamine prodrug that will be tested as therapy for metastatic PCa. 

DNA METHYLATION BIOMARKERS IN PROSTATE CANCER AND TOWARDS A BETTER UNDERSTANDING AND 

TARGETING OF EPIGENETIC PROTEINS IN PROSTATE CANCER 

Joshi J. Alumkal, MD; Oregon Health and Sciences Center; YCSA 2005 

In the first project, Dr. Alumkal and colleagues are using a PCR based approach to validate a DNA 

methylation signature, which he identified previously is independently associated with an increased risk of 

prostate cancer (PCa) recurrence, in an independent cohort of patients treated with surgery. His group has 

also recently used DNA methylation microarrays to identify novel candidate diagnostic and prognostic 

markers in PCa. In the second project, Dr. Alumkal is studying the function of and targeting key epigenetic 

proteins in PCa cells including histone deacetylases, histone demethylases, and histone methyltransferases. 

The PI has shown that treatment of PCa cells with sulforaphane, a constituent of cruciferous vegetables 

whose high consumption is associated with a reduced risk of PCa, leads to attenuated androgen receptor 

signaling, the central player in PCa, through epigenetic mechanisms. This ongoing work has implications 

for PCa prevention and therapy. 

P A G E 1 3 3


Gibbs A, Schwartzman J, Deng V, Bagby G, Alumkal J. Sulforaphane destabilizes the androgen receptor 

and attenuates androgen receptor signaling in prostate cancer cells through inhibition of HDAC6. 

Presented at the 15th Annual Prostate Cancer Foundation Meeting. Incline Village, NV, Oct 15-18, 

2008. 

NDRG1 MODULATION TO DECREASE PROSTATE CANCER INVASION 

Sushant K. Kachhap, PhD; The Johns Hopkins University; YCSA 2007 

Increased tobacco smoke exposure positively correlates with an increased risk of metastasis, leading to a 

poor prognosis in a wide variety of cancers including those of lung, breast, and prostate cancer (PCa). 

Downregulation of the E-cadherin adhesion molecule is a common feature of a variety of metastatic 

epithelial tumors related to SHS. The N-myc downregulated gene 1 (NDRG1) is a known PCa metastasis 

suppressor gene. Apart from an alpha beta hydrolase motif the functionality of which remains questionable, 

NDRG1 lacks any known protein motif that can impart it a function. Dr. Kachhap and colleagues have 

recently elucidated the function of NDRG1 as a Rab4a effector protein that localizes to the trans Golgi 

network where it is involved with recycling of the E-cadherin molecule. Induction of NDRG1 leads to differentiation 

of PCa cells and decreases metastasis. Thus, it is hypothesized that the ability to pharmacologically 

control the expression of NDRG1 in PCa can potentially reduce invasion/metastasis of PCa. Their 

goal is to upregulate NDRG1 in PCa cells with small molecule compounds/drugs to decrease PCa invasion. 

Data from microarray analysis in PCA cells treated with histone deacetylase inhibitors (HDACi) indicated 

that NDRG1 upregulated by generic HDACis. They show that NDRG1 protein is expressed upon 

treatment of PCa cells DU-145 and LNCaP with generic HDACi. Using HDAC isotype-selective 

inhibitors supplied by MethylGene Inc., they further evaluated various histone deacetylases (HDACs) that 

regulate NDRG1 in these PCa cells. They found that NDRG1 is regulated specifically by an HDAC 1 and 

2 selective inhibitor and an HDAC 6 selective inhibitor, but not by an HDAC 8 selective inhibitor. By 

using small hairpin RNA for HDAC 1, HDAC 2, HDAC 4, HDAC 6, and HDAC 8 they have further 

confirmed that NDRG1 is specifically regulated by HDAC 1 and HDAC 6, and not other HDACs. They 

envisage NDRG1 as a pharmacologically anti-metastatic target that can be regulated for PCa. Knowledge 

pertinent to the role of specific HDAC isozymes regulating NDRG1 expression will help the rational 

development of such therapeutics, thereby decreasing PCa metastasis. 


Kortenhorst MS, Zahurak M, Shabbeer S, Kachhap S, Galloway N, Parmigiani G, Verheul HM, Carducci 

MA. A multiple-loop, double-cube microarray design applied to prostate cancer cell lines with variable 

sensitivity to histone deacetylase inhibitors. Clin Cancer Res 2008;14:6886-6894. 

Shabbeer S, Sobolewski M, Anchoori RK, Kachhap S, Davidson N, Carducci MA, Khan SR. Fenugreek: a 

naturally occurring edible spice as an anticancer agent. Cancer Biol Ther 2009;8 [Epub ahead of print]. 

CANCER, THYROID 


BRAF MUTATION AND OTHER COMMON GENETIC AND EPIGENETIC ALTERATIONS IN THYROID CANCER: RELA- 

TIONSHIP WITH SMOKING AND CLINICAL APPLICATIONS 

Michael M. Xing, MD, PhD; The Johns Hopkins University; CIA 2003 

The most common genetic and epigenetic alterations in thyroid cancer involve BRAF (Ras-regulated 

kinase) and Ras mutations and aberrant gene methylation. Smoking is linked with Ras mutation in other 

cancers, nodular goiter, and Grave’s disease. Both nodular goiter and Grave’s disease are associated with an 

increased risk of thyroid cancer. Dr. Xing and collaborators hypothesized that smoking may cause a higher 

incidence of certain genetic and epigenetic alterations, such as BRAF and Ras mutations and gene methylation 

in thyroid cancer leading to adverse pathological and clinical consequences. Aims of the study 

included 1) determining whether smoking causes a specific genetic/epigenetic alterations in thyroid cancer, 

such as BRAF and Ras mutations and gene methylation with predilection to a particular subtype and specific 

clinicopathological characters; and 2) applying genetic/epigenetic information to thyroid cancer diagnostic 

and prognostic evaluation. 

1 3 4 P A G E


Hu S, Ewertz M, Tufaro AP, Brait M, Carvalho AL, Tufano RP, Basaria S, Cooper DS, Sidransky D, 

Ladenson PW, Xing M. Detection of serum DNA methylation markers: a new diagnostic approach to 

thyroid cancer. J Clin Endocrinol Metab 2005;90:4688-4693. 

Liu D, Mambo E, Ladenson PW, Xing M. Letter re: uncommon mutation but common amplifications of 

the PIK3CA gene in thyroid tumors (amplification of PIK3CA gene in anaplastic thyroid cancer). J Clin 

Endocrinol Metab 2005;90:5509. 

Vasko V, Hu S, Larin A, Savchenko V, Xing M. High prevalence and possible de novo formation of BRAF 

mutation in lymph node metastasized thyroid cancer. J Clin Endocrinol Metab 2005;90:5265-5269. 

Wu G, Mambo E, Guo Z, Hu S, Trink B, Ladenson PW, Sidransky D, Xing M. Uncommon mutation but 

common amplification of the PIK3CA gene in thyroid tumors. J Endocrinol Metab 2005;90:4688-4693. 








Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer 2005;12:245-262. 

Xing M. BRAF mutation is not a germline mutation in familial papillary thyroid cancer. Clin Endocrinol 

2005;63:263-266. 

CARDIOVASCULAR 


THE RISK OF CORONARY HEART DISEASE AMONG WOMEN EXPOSED TO SECOND HAND SMOKE 

Wael K. Al-Delaimy, MD, PhD; University of California, San Diego; YCSA 2002, CIA 2009 

This study assesses the association between tobacco smoke exposure and coronary heart disease and lung 

cancer using toenail nicotine levels as a novel biomarker of exposure to tobacco. The aims of the study are: 

1) to assess the validity of using nicotine content in toenails as a biomarker of tobacco smoke exposure and 

compare it to questionnaire measures of tobacco smoke exposure; 2) to assess the dose-response 

association between tobacco smoke exposure using toenail nicotine levels and coronary heart disease 

incidence using the toenail markers and questionnaire measures; and 3) to assess the long-term 

independent additive effects of toenail nicotine levels on lung cancer development. The proposal is based 

on data collected from the large Nurses Health Study and Health Professionals follow up study. Aims 1 

and 2 have now been published (see publications below) and Aim 3 is at the statistical analysis stage. 

Toenail nicotine biomarkers have been shown to reflect additional risk for coronary heart disease not 

previously captured by questionnaires alone. Furthermore, toenail biomarkers were related to SHS 

exposure even after adjusting for other factors such as age age and active smoking. This provides the 

opportunity to use this novel biomarker in different aspects of tobacco related health research as well as 

tobacco control. Dr. Al-Delaimy will apply this biomarker in large population settings to assess its ability to 

predict SHS exposure in the general population. 


Al-Delaimy WK, Stampfer MJ, Manson JE, Willett WC. Toenail nicotine levels as predictors of coronary 

heart disease among women. Am J Epidemiol 2008;167:1342-1348. 

Al-Delaimy WK, Willett WC. Measurement of Tobacco Smoke exposure: comparison of toenail nicotine 

biomarkers and self-reports. Cancer Epidemiol Biomarkers Prev 2008;17:1255-1261. 

Repace JL, Al-Delaimy WK, Bernert JT. Correlating Atmospheric and Biological Markers in Studies of 

Secondhand Tobacco Smoke Exposure and Dose in Children and Adults. J Occup Environ Med 2006; 

48:181-194. 

CARBON MONOXIDE HYPOXIA IN TOBACCO SMOKE INDUCED DISEASE 

J. Timothy O’Neill, PhD; Uniformed Services University of the Health Sciences; CIA 2004 

Dr. O’Neill’s laboratory has utilized a model of chronic carbon monoxide (CO) hypoxia as a model of 

cigarette smoking in mice to examine cardiovascular adaptive changes. Mice have been exposed to 0, 100, 

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or 500 ppm CO for 30 days. Blood pressure dropped in the group with the highest CO and stayed lower 

than those with low CO or no CO. Weight of the 500 ppm group fell for the first week of exposure but 

returned to normal thereafter. At day 30, total hemoglobin was significantly elevated from 18.4 to 20.7 

and 30.0 gms % by 100 ppm and 500 ppm, respectively. Carboxyhemoglobin was also increased by CO 

from 4.5 to 17.2 and 53.4 %, respectively. Two hypoxia inducible factor 1 alpha-regulated proteins, 

vascular endothelial growth factor and erythropoietin, were also found to increase in brain and kidney with 

increased CO exposure. Data suggest that mice adapt to chronic CO hypoxia by increasing hemoglobin 

and microvascular proliferation rather than cardiac output to maintain tissue oxygenation. The increase in 

erythropoietin in the brain may be neuroprotective. 

LDL OXIDATION BY SECOND HAND TOBACCO SMOKE 

JeanClare Seagrave, PhD; Lovelace Respiratory Research Institute; CIA 2005 

Dr. Seagrave hypothesizes that exposure to second hand tobacco smoke increases oxidation of lowdensity 

lipoprotein (LDL), which is a candidate for linking cigarette smoke exposure (through oxidative 

stress) to cardiovascular disease. The specific aims are: 1) to determine the capacity of second hand tobacco 

smoke to oxidize LDL in the vascular compartment of a physiologically relevant in vitro model; 2) to 

determine the relationships among SHS exposure, increased levels of oxidized LDL, atherogenesis, and the 

potential for an antioxidant-rich diet to reduce LDL oxidation and progression of atherosclerotic lesions, 

using an atherosclerosis-susceptible strain of mice; and 3) to evaluate the oxidation of LDL in an isolatedperfused 

rat lung model. 

SECOND HAND TOBACCO SMOKE-INDUCED HEART AND BRAIN INJURY 

Mark S. Gold, MD; University of Florida; CIA 2005 

Due to institutional protocol, Dr. Gold acts as mentor and PI for Dr. Kevin Wang. SHS exposure has 

been shown to be a cause of preventable morbidity and death in America and around the world. It 

increases risk for cancer and cardiac problems, but little is known about its non-vascular effects on the 

brain. The hypothesis is that extended exposure to second hand tobacco smoke perturbs brain 

biochemistry resulting in CNS injury. Cigarette smoke contains large amounts of gaseous free-radicals 

(e.g., superoxide anions, nitrogen oxides, reactive aldehyde species, nitric oxide, and peroxynitrite) as well 

as neurotoxic heavy metals such as cadmium. Dr. Gold’s group has shown that SHS exposure promotes 

rapid protein regulation and modification and the over-activation of proteases by induced cellular oxidative 

stress, which leads to cell death in other tissues. They have shown that SHS induces a prominent increase 

in the glia marker glial fibrillary acidic protein (GFAP), suggesting increased reactive gliosis as an 

inflammatory response. This induction is coupled with an increased measure of the cell death marker 

alpha-II spectrin, suggesting that there is increased apoptosis and/or necrosis following exposure. Dr. 

Gold is analyzing body fluids including cerebrospinal fluid (CSF) and serum for neuronal markers (alpha-II 

spectrin and UCH-L1 proteins) that can serve as potential biomarkers for SHS exposure, using an 

advanced ELISA technique. Ultimately, the identification of these markers may be useful for characterizing 

putative brain injury consequent to chronic SHS exposure in clinical populations. 

REGULATION OF MATRIX METALLOPROTEINASE-1 BY CIGARETTE SMOKE IN AORTIC ENDOTHELIAL CELLS 

Vincent LeMaitre, PhD; Columbia University; CIA 2006 

Smoking is a major risk factor for heart disease, but the molecular mechanisms responsible for this 

susceptibility are still poorly understood. Studies on mouse models have demonstrated that matrix 

metalloproteinases (MMPs) are critical in atherosclerosis and aneurysm formation. In this study, Dr. 

LeMaitre examined the effect of cigarette smoke on the modulation of MMP-1 (interstitial collagenase) 

expression in human aortic endothelial cells (HAECs) in culture. Cigarette smoke extract (CSE), at 

concentrations from 0.5 to 5% v/v, significantly upregulated MMP-1 mRNA and protein expression in 

HAECs. At a concentration of 5% CSE (v/v) and after 24 hours, MMP-1 mRNA expression was increased 

25 times over that in non-treated cells (P

unaffected by the treatment with CSE. Treatment of HAECs with CSE resulted in decreased levels of 

phospho-p70S6K (Threonine 389), a specific target of the mTOR complex 1. Inhibition of mTOR in 

HAECs with rapamycin resulted in elevated MMP-1 mRNA expression and protein secretion. These data 

show that CSE upregulates MMP-1 expression in HAECs through inhibition of the mTOR pathway. 

Elevated MMP-1 in the endothelium of major arteries due to circulating cigarette smoke components 

result in extracellular matrix disruption, impaired angiogenesis, and vessel injury. 

ROLE OF HEAT SHOCK PROTEIN 90 IN TOBACCO SMOKE-INDUCED HEART DISEASE 

Kathleen L. Gabrielson, DVM, PhD; The Johns Hopkins University; CIA 2007 

Epidemiological studies demonstrate that tobacco smoke exposure (TSE) is associated with significant 

morbidity and mortality due to cardiovascular diseases. Identifying molecular pathways targeted by SHS 

exposure will allow translation into prevention strategies for TSE- induced cardiovascular disease. The heat 

shock protein 90/hypoxia-inducible factor-1 alpha-vascular endothelial growth factor receptor (HSP90/ 

HIF1 alpha-VEGFR) signaling pathway is one such pathway that may be inhibited by TSE, preventing 

growth of new myocardial blood vessels. Dr. Gabrielson’s preliminary data demonstrate that chronic 

exposure of mice to SHS significantly reduces cardiac function, associated with a reduction of the HSP90, 

a molecular chaperone for multiple proteins in this pathway. This finding led her to hypothesize that in the 

heart, tobacco smoke exposure reduces the HSP90/ HIF1 alpha-VEGFR 1-2 signaling pathways, resulting 

in impairment of neovascularization in normoxia conditions or after ischemia from myocardial infarction or 

atherosclerosis. Reversing the TSE-induced reduction of HSP90 in the heart should restore HIF1 alpha 

protein-VEGFR receptor signaling, and as a consequence should improve myocardial vascularization and 

heart function after ischemia. 

To test this hypothesis the investigators will determine whether cardiac HSP90 and its client proteins are 

reduced in normal mice exposed to tobacco smoke. Acute and chronic exposure will be examined, as well 

as the TSE effect on VEGFR1/2 activation and myocardial blood vessels density. They will also determine 

whether acute or chronic exposure to tobacco smoke increases cell death and reduces heart function and 

new vessel growth using two models of cardiac ischemia, atherosclerosis, and myocardial infarction. The 

protective role of HSP90 will be examned in the heart during tobacco smoke exposure. 

Dr. Gabrielson and colleagues recently demonstrated that HSP90 binds to erbB2 in the heart and 

inhibits HSP90 function, which predisposes cardiomyocytes to cell death. They will assess whether cardiacspecific 

over-expression of HSP90 in a transgenic mouse model improves cardiac function and increases 

HIF 1 alpha and erbB2 after TSE. They will also determine whether pharmacological induction of HSP90 

by geranlygeranlyacetone (GGA) increases heart function, induces vascularization in the heart and increases 

HIF 1 alpha-VEGF signaling. Inhibition of HSP90 function will be accomplished with siRNA during 

treatment with tobacco smoke condensate, to determine if this predisposes endothelial cells or 

cardiomyocytes to cell death. Dr. Gabrielson’s long-term goals are to understand how SHS exposure 

impacts cardiac signaling pathways and predisposes to cardiovascular disease in order to develop treatment 

strategies that can protect the heart from current or past exposure to tobacco smoke. 

EFFECTS OF SECOND HAND CIGARETTE SMOKE EXPOSURE ON ADINOPECTIN, MTOR, AND VASCULAR DISEASE 

Kathleen A. Martin, PhD; Dartmouth College; CIA 2007 

SHS exposure contribute to the development of a range of cardiovascular diseases, including 

atherosclerosis, coronary artery disease, peripheral vascular disease, intimal hyperplasia and restenosis, 

cardiac hypertrophy, hypertension, and stroke. In particular, cigarette smoke and diabetes are common risk 

factors present in most cases of severe peripheral vascular disease (PVD), which often leads to amputation 

with devastating effects on quality of life. PVD patients frequently have other cardiovascular disease as well. 

While the association between cardiovascular disease and cigarette smoke exposure is clear, the mechanisms 

by which SHS promotes vascular disease are incompletely understood. Understanding the etiology of the 

disease process may suggest new avenues for treatment and prevention in individuals exposed to cigarette 

smoke. Dr. Martin and colleagues propose to study an exciting new link between SHS exposure, 

cardiovascular disease, and dysregulation of adiponectin, a hormone recently implicated in diabetes. Their 

preliminary data indicate that SHS exposure inhibits synthesis of the cardioprotective hormone, 

adiponectin, in mice exposed to SHS. They further show that SHS induces vascular smooth muscle cells 

(VSMC) to dedifferentiate from a quiescent, contractile phenotype, to a dedifferentiated phenotype known 

to contribute to the pathogenesis of vascular disease. The group has previously shown that the mammalian 

target of rapamycin (mTOR) cellular signaling pathway suppresses VSMC differentiation. Their 

preliminary experiments reveal elevated mTOR activity in VSMC in mice exposed to SHS. Notably, 

P A G E 1 3 7

adiponectin signals through activated protein kinase (AMPK), which can suppress mTOR activity. The 

team hypothesizes that cigarette smoke exposure contributes to vascular disease in part by promoting 

VSMC dedifferentiation, and that this dedifferentiation is due to SHS inhibition of adiponectin expression, 

resulting in elevated mTOR activity. To test these hypotheses, four aims are proposed: 1) to determine the 

extent to which SHS exposure modulates VSMC phenotype; 2) to determine whether SHS-induced 

mTOR activity promotes VSMC dedifferentiation and intimal hyperplasia; 3) to determine whether 

adiponectin inhibition underlies the SHS-induced VSMC dedifferentiation; and 4) to identify interventions 

that can reverse the smoke-induced reduction in adiponectin levels, and determine whether this also 

improves VSMC phenotype. The goal is to verify this novel relationship between cigarette smoke exposure, 

mTOR activity and adiponectin in vascular smooth muscle in vivo, and to test methods to reverse the 

smoke-induced reduction of adiponectin, thereby maintaining the cardioprotective function of this 

important hormone. 

LONG-TERM VASCULAR EFFECTS OF SECOND HAND TOBACCO SMOKE 

Matthew L. Springer, PhD; University of California, San Francisco; CIA 2007 

SHS is estimated to cause ~53,000 deaths annually in the US, mostly from cardiovascular disease. It has 

become clear that even mild SHS exposure leads to deleterious effects on health, indicating that simply 

limiting the amount of exposure to SHS does not prevent the negative consequences of that exposure. Dr. 

Springer and his colleagues have developed a way to monitor the changes in the ability of blood vessels to 

react to different circumstances by expanding and contracting to accommodate needed amounts of blood 

flow. They plan to use this to study the effects of different times of exposure and different levels of SHS on 

the decrease in vascular function and on the length of time that the vessels need to recover their full 

function. These results will be compared to changes in specific molecules and cells present in the blood 

vessel wall. In addition to furnishing valuable scientific information about the effects of SHS on the 

cardiovascular system, the work is relevant to public health in that a firmer understanding of the 

deleterious effects of even limited passive smoking will provide additional supportive information for the 

crafting of relevant health benefits to protect the public from environmental hazards of SHS exposure, and 

the prevention of SHS-related diseases. 

EXACERBATION OF VIRAL MYOCARDITIS BY TOBACCO SMOKE THROUGH INCREASED VIRAL LOAD 

AND CARDIAC APOPTOSIS 

James P. Morgan, MD, PhD; Caritis St. Elizabeth’s Medical Center; CIA 2005 

Exposure to tobacco smoke is known to cause deleterious cardiovascular effects. Myocarditis caused by a 

viral infection is a common cause of heart failure with millions of cases estimated worldwide. In this study, 

Dr. Morgan and colleagues tested the hypothesis that exposure to tobacco smoke exacerbates the severity 

of viral myocarditis in mice. Viral myocarditis was generated in 4-week old, male BALB/c mice by 

intraperitonial injection of encephalomyocarditis virus (EMCV). Four groups were studied: 1) control (C, 

no smoke and no virus); 2) smoke only (S, exposure to cigarette smoke for 90 minutes/day); 3) virus only 

(V); and 4) pre-exposure to smoke for 1 week before plus 2 weeks following virus injection (S+V). The 

investigators found that viral inoculation preceded by tobacco smoke exposure increased mortality more 

than 2-fold compared with virus alone. In addition, the mRNA level of atrial natriuretic factor (ANF) was 

significantly higher in S+V than among any of the other 3 groups. Analysis of cardiac function by pressurevolume 

loop measurement showed virus significantly decreased cardiac function compared with that of 

controls with further deterioration observed in the S+V group. Furthermore, the S+V group had a 

significantly decreased level of connexin 43 (Cx43) and increased virus loading. A significantly increased 

rate of apoptosis was found to be associated with the increased activation of apoptosis inducing factor 

(AIF) in hearts exposed to S+V compared to those exposed to V alone. These results suggest that preexposure 

to smoke significantly exacerbates the severity of viral myocarditis, most likely through increased 

viral load and increased cardiomyocyte cell death. 

IMPACT OF PASSIVE SMOKING AND EARLY ATHEROSCLEROSIS IN CHILDREN WITH TYPE I DIABETES MELLITUS 

Petru Liuba, MD, PhD; Lund University; YCSA 2003 

Dr. Liuba`s hypotheses state that: 1) SHS additively interacts with type 1 diabetes mellitus (DM-1) with 

negative consequences on vasculature (arterial endothelial function and structure, microvascular endothelial 

function) and myocardial function depending on the intensity and amount of exposure; 2) that vascular 

changes in diabetic patients exposed to SHS evolve more rapidly toward more advanced lesions than those in 

smoke-free diabetic patients; and 3) that the afore-mentioned putative interplays may be present already in 

1 3 8 P A G E

nondiabetic children with a diabetes-susceptible human leukocyte antigen HLA group (i.e., DQ2/8). The 

study aims include: 1) determination of the impact of SHS on lipid, inflammatory, and immune phenotypes 

in children with DM-1 and in nondiabetic children with diabetes-risk HLA; 2) determination of the eventual 

additive effects of SHS and DM-1 on arterial homeostasis and myocardial function in diabetic children and in 

nondiabetics with diabetes-risk HLA; 3) determination of whether SHS in nondiabetic children with diabetesrisk 

HLA increases the susceptibility for microvasculopathy and DM-1, and whether this risk could be further 

increased by airway infections; and 4) determination of the dynamics of these arterial changes in the SHSexposed 

and non-exposed diabetic and nondiabetic children with the diabetes-HLA risk group. The arterial 

changes are being evaluated by ultrasound assessment of brachial artery endothelial function and carotid 

artery intima-media thickness. Microvascular function is assessed by laser Doppler iontophoresis. Myocardial 

function is assessed by transthoracic ultrasound and by assessment of heart rate variability. Earlier results 

revealed that nearly 20% of DM-1 patients are constantly exposed to SHS in their home environment. 

Patients with both high recurrence of respiratory infections and exposure to tobacco smoke are more prone 

to atherogenic changes in the carotid artery than those with either one or none of these risk factors. Also, 

SHS appears to adversely influence heart rate variability particularly in individuals with genetic HLA-related 

susceptibility to diabetes. The study also demonstrated significant influence of diabetes-risk HLA (DQ 2/8) 

on the development of atherosclerosis and microvasculopathy. Most recently, the research teamdemonstrated 

that, in children with DM-1, plasma levels of vitamin C, which is known to be affected by SHS, indirectly 

correlates with the degree of arterial and microvascular damage. 


Odermarsky M, Andersson S, Pesonen E, Sjöblad S, Ylä-Herttuala S, Liuba P. Respiratory infection recurrence 

and passive smoking in early atherosclerosis in children and adolescents with type 1 diabetes. Eur J 

Clin Invest. 2008 Jun;38(6):381-388. Epub 2008 Apr 24. 

Odermarsky M, Lernmark A, Truedsson L, Liuba P. Pediatr Res. Cutaneous microvascular dysfunction is 

associated with human leukocyte antigen-DQ in youths with type 1 diabetes. 2008 Apr;63(4):420-422. 

Odermarsky M, Nilsson A, Lernmark A, Sjöblad S, Liuba P. Atherogenic vascular and lipid phenotypes in 

young patients with Type 1 diabetes are associated with diabetes high-risk HLA genotype. Am J Physiol 

Heart Circ Physiol 2007 Nov;293(5):H3175-9. Epub 2007 Sep 28. 

SMALL DIAMETER BLOOD VESSEL REGENERATION BY BIOMIMETIC ENGINEERING 

Feng Zhao, PhD; Duke University; YCSA 2007 

Sheet-based tissue engineering avoids the use of synthetic or exogenous materials and can induce in vivo 

integration by host tissue, therefore shows great promise in constructing small diameter vascular grafts with 

inner diameter less than 5 mm and tha have physiologic mechanical properties and long-term patency. Human 

mesenchymal stem cells (hMSCs) are especially attractive for vascular tissue engineering because of their 

extensive self-renewal ability and unique antithrombogenic property. Dr. Zhao and her group have developed 

an aligned hMSC sheet on nanoimprinted poly(dimethylsiloxan) (PDMS) surfaces with the hypothesis that the 

aligned hMSCs will provide a mechanically strong and immunosupressive antithrombogenic cell sheet for the 

construction of tissue-engineered blood vessels (TEBVs) in the regeneration of functional vascular tissues. The 

aligned hMSC sheet was fabricated on the nanopatterned PDMS surfaces (350 nm width, 350 nm depth and 

700 nm periodicity) coated with thermally responsive hydroxybutyl chitosan (HBC) polymer. The HBC 

coating was optimized by adjusting the HBC solution concentration. A well aligned hMSC cell sheet, which 

showed no platelet adhesion properties, was produced when the HBC coating was dissolved at 17 o C. The 

investigators have also expanded hMSCs on nanograted PDMS surfaces under physiologically relevant low 

oxygen tension (2%) to accurately stimulate appropriate extracellular matrix (ECM) protein expression and 

vascular endothelial growth factor (VEGF) secretion. The research team is currently in the process of 

constructing small diameter TEBVs using the aligned hMSC sheet, and will establish an artery bypass animal 

model to evaluate the antithrombogenic property and the long-term patency of the TEBVs. 


Zhao F, Leong KW. Maintaining stemness of human mesenchamyal stem cells on synthetic nanostructures. 

Presented at the BMES Annual Fall Meeting. St. Louis, MO, Oct 1-4, 2008. 

Zhao F, Zhu AP, and Ma T. Photoinductive chitosan modification enhances endothelial cell adhesion, 

proliferation and function on PLA film. Presented at SFB 2008 Translational Research Symposium. 

Atlanta, GA, Sep 11-13, 2008. 

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CARDIOVASCULAR 


SECOND HAND TOBACCO SMOKE PLATELET ACTIVATION AND CARDIOVASCULAR RISK 

Danny Bluestein, PhD; State University of New York at Stony Brook; CIA 2002, 2004 

Dr. Bluestein hypothesizes that SHS significantly increases cardiovascular risk by predisposing platelets to 

activation in areas of elevated arterial flow stress. He and his collaborators developed an assay for platelet 

activation state (PAS) that can be used to establish thrombogenic potential of platelets subjected to SHS. 

His research aims were: 1) to measure platelet activity under flow conditions where platelets are directly 

exposed to pure nicotine, and fractionated sidestream and mainstream cigarette extracts; 2) to measure 

base activity of platelets of non-smoking volunteers exposed and not exposed to SHS; and 3) to measure 

the sensitivity of platelets exposed to SHS to pathological flow conditions simulating arterial stenosis. The 

PI has used this assay to demonstrate that sidestream smoke from high-tar and lowtar cigarettes is equally 

potent, although the mainstream smoke from each of these showed differences, and pure nicotine was 

found to inhibit platelet activation under static and arterial flow. Dr. Bluestein is continuing his work on 

the study of cigarette extract effects on susceptibility of platelets to activation under flow stress conditions. 

He examines the effect of smoke on endothelial cells under flow stress conditions in the presence of 

normal and nicotine-free smoke extracts, measuring standard markers of endothelial cell activation. In the 

last stages of the study, he evaluated the combined effect of smoke and nicotine, and the hypothesis that 

exposure to total cigarette smoke, not pure nicotine, is the initiating factor in platelet adhesion. 


Bluestein D, Rubenstein D, Jesty J. The effects of mainstream and sidestream cigarette smoke and nicotine 

on platelet activation under arterial and coronary flow conditions Presented at the World Congress on 

Medical Physics and Biomedical Engineering. Sidney, Australia, 2003. 

Ramachandran J, Rubenstein D, Jesty J, Bluestein D. Activation of platelets exposed to shear stress in the 

presence of smoke extracts of low-nicotine and zero-nicotine cigarettes: the protective effect of nicotine. 

Nicotine Tob Res 2004;6:835-841. 

Ramachandran J, Rubenstein D, Jesty J, Bluestein D. Cardiovascular risk in low-nicotine cigarettes: platelet 

activation and the effect of nicotine Presented at the BMES 2004 Conference. Philadelphia, PA, 2004. 

Ramachandran J, Rubenstein D, Jesty J, Bluestein D. Effects of low-nicotine cigarette smoke on platelet 

activation under normal coronary flow conditions Presented at the Annual Fall BMES Meeting. 

Nashville, TN, 2003. 

Rubenstein D, Jesty J, Bluestein D. Differences between mainstream and sidestream cigarette smoke 

extracts and nicotine in the activation of platelets under static and flow conditions. Circulation 

2004;109:78-83. 

Rubenstein D, Jesty J, Bluestein D. The effects of mainstream and secondhand cigarette smoke extracts 

and nicotine on platelet activation under normal coronary flow conditions. Annual Fall BMES Meeting. 

Nashville, TN, 2003. 

Schulz-Heik K, Ramachandran J, Bluestein D, Jesty J. Platelet-platelet interactions under shear stress: the 

extent of activation depends on platelet count Presented at the BMES 2004 Conference. Philadelphia, 

PA, 2004. 

SHS AND OUTCOMES IN CONGESTIVE HEART FAILURE 

Kirsten Fleischmann, MD, MPH; University of California, San Francisco; CIA 2003 

Dr. Fleischmann assessed the relationship of exposure to SHS to death, nonfatal myocardial infarction, 

and rehospitalization for heart failure. The PI found that a substantial number of patients with heart failure 

in a large university clinic report SHS smoke exposure and that the clinical event rates in these patients are 

high. Thus, exposure to passive smoking affects several domains of health-related quality of life 

detrimentally. Dr. Fleishchmann is conducting a long-term follow-up to determine whether SHS exposure 

significantly increases the risk of clinical events such as death, myocardial infarction, or heart failure. 

THE EFFECT OF SECOND HAND TOBACCO SMOKE ON EXERCISE CAPACITY 

AND CLINICAL OUTCOMES IN PULMONARY ARTERIAL HYPERTENSION 

Teresa De Marco, MD; University of California, San Francisco; CIA 2003 

Dr. De Marco demonstrated that SHS exposure is prevalent among patients treated for pulmonary 

arterial hypertension (PAH). At baseline, SHS exposure was associated with greater exercise capacity. This 

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observation shows that patients with poor exercise capacity avoid or have limited ability to participate in 

social situations where SHS exposure is common. Despite having lower exercise capacity at baseline, 

patients without SHS exposure demonstrated a greater response to PAH therapy in terms of 6 minute walk 

distance at 6 and 12 months as compared to those with SHS exposure. 

PERIPHERAL VASCULAR HEMODYNAMICS AND VENTRICULAR MECHANICS IN PASSIVE SMOKERS 

Theodore P. Abraham, MD; The Johns Hopkins University; CIA 2004 

Passive smokers are presumed to have higher systolic blood pressure, lower systemic vascular compliance, 

and impaired ventricular relaxation when compared to non smokers. Healthy non-smokers with and without 

SHS exposure were compared as a pilot study to launch a larger and longer term study to evaluate longterm 

biological effects and the positive effects of cessation of SHS exposure on the cardiovascular system. 

NICOTINE REGULATION OF MANGANESE SUPEROXIDE DISMUTASE 

Richard J. Rogers, MD, PhD; University of Florida; YCSA 2004 

Nicotine has been shown to affect the endothelial function of blood vessels in multiple organs. Dr. 

Roger hypothesized that nicotine alters the transcription of basal and inflammatory mediator-inducible 

expression of manganese superoxide dismutase (MnSOD), a mitochondrial enzyme serving as a crucial 

antioxidant within all aerobic organisms. Additional hypotheses were that nicotine alters basal and 

inducible MnSOD gene expression via a nicotinic acetylcholine receptor-mediated pathway, and that 

nicotine affects MnSOD expression by altering important protein-DNA interactions on the regulatory 

region of the MnSOD gene. The initial work has been performed using a rat endothelial cell line. 


Drake TJ, Medley CD, Sen A, Rogers RJ. Stochasticity of manganese superoxide dismutase mRNA 

expression in breast carcinoma cells by molecular beacon imaging. Chembiochem 2005;6:2041-2047. 

Medley CD, Drake TJ, Tomasini JM, Rogers RJ, Tan W. Simultaneous monitoring of the expression of 

multiple genes inside of single breast carcinoma cells. Anal Chem 2005;77:4713-4718. 

ALTERATION IN EXPRESSION OF VASCULAR G-PROTEIN COUPLED RECEPTORS AS A NOVEL MECHANISM 

RESPONSIBLE FOR CARDIOVASCULAR MORBIDITY BY CIGARETTE SMOKING 

Lars Edvinsson, MD PhD; Lund University; CIA 2005 

The molecular mechanisms responsible for cigarette smoke associated cardiovascular morbidity and 

mortality are still not fully understood. Dr. Edvinsson’s team found that lipid soluble cigarette smoke 

particles (DSP) upregulate the expression of G-protein coupled receptor (GPCR) in arterial smooth muscle 

cells (SMC) endothelin type A (ETA) and B (ETB), and thromboxane A2 (TP) receptors. These receptors 

show enhanced contractility and proliferation of the smooth muscle cells, and thus strongly exacerbate the 

arterial wall damage by cigarette smoke in parallel with enhanced cardiovascular morbidity and mortality. 

In order to explore the molecular mechanisms involved, intracellular signalling induced by DSP was 

studied. DSP caused activation of extra cellular-regulated protein kinase 1 and 2 (ERK1/2), p38, protein 

kinase C (PKC) and transcriptional factor Elk1 and NF-kappa B, but not activation of c-Jun N-terminal 

kinase (JNK). These intracellular signalling events are linked to DSP induced upregulation of ETB, ETA 

and TP receptors as revealed by use of specific inhibitors. Specific blockade of ERK1/2, p38 and NF-kappa 

B activation attenuated the DSP-induced upregulation of ETB receptor-mediated contraction and the 

receptor mRNA expression. The DSP-enhanced ETA receptor-mediated contraction was abolished by 

ERK1/2, PKC, Elk1 and NF-kappa B inhibitors. This hypothesis was further supported by the finding 

that the general transcriptional inhibitor, actinomycin D, abolished the DSP-enhanced contraction of ETB 

and ETA receptors. In contrast, the upregulation of TP receptors by DSP occurred through a posttranscriptional 

mechanism, i.e., via enhanced translation. 


Granstrom BW, Xu CB, Nilsson E, Vikman P, Edvinsson L. Smoking particles enhance endothelin A and 

endothelin B receptor-mediated contractions by enhancing translation in rat bronchi. BMC Pulm Med 

2006;6:6. 

Zhang JY, Cao YX, Xu CB, Edvinsson L. Lipid-soluble smoke particles damage endothelial cells and 

reduce endothelium-dependent dilatation in rat and man. BMC Cardiovasc Disord 2006;6:3. 

Zhang W, Zhang Y, Edvinsson L, Xu CB. Up-regulation of thromboxane A2 receptor expression by lipid 

soluble smoking particles through post-transcriptional mechanisms. Atherosclerosis 2008;196:608-16. 

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EFFECTS OF SECOND HAND TOBACCO SMOKE ON SUSCEPTIBILITY OF VENTRICULAR MYOCYTES TO ISCHEMIC 

INJURY 

William H. Barry, MD; University of Utah; CIA 2005 

It is well recognized that cigarette smoking increases the risk of death from ischemic heart disease. It has 

also been demonstrated that exposure of animals to second hand cigarette smoke (CS) increases myocardial 

infarct size produced by ischemia-reperfusion, but it is not clear if a direct effect on myocytes, in addition 

to alterations of the vasculature and blood elements, contributes to these deleterious effects of CS. Extracts 

of CS (CSE) were prepared by bubbling side stream smoke from two cigarettes through physiologic 

HEPES solution. Mouse ventricular myocytes (M) were exposed CSE, or to CN-0 glucose (simulated 

demand ischemia; MI) +/- CSE. M contracture, mitochondrial Ca2+ uptake in digitonin permeabilized 

myocytes, and susceptibility to the mitochondrial permeability transition were measured. Nicotine levels in 

CSE were measured by high performance liquid chromatography/mass selective detector (HPLC/MSD). 

Exposure to CSE increased the percentage of myocytes undergoing contracture and increased susceptibility 

to the mitochondrial permeability transition (MPT). Exposure to CSE increased mitochondrial Ca2+ 

uptake and the uptake was completely inhibited by the free radical scavenger Tiron, which had no significant 

effect on mitochondrial Ca2+ uptake in the absence of CSE. The nicotine concentration in 0.1 % CSE 

was 15.6 ng/ml, a value similar to that observed in arterial blood in humans after smoking. Recent experiments 

in paced adult ventricular myocytes exposed to 2.0 mM CN-0 glucose have shown that 0.1 % CSE 

increases Ca2+ loading. This effect is prevented by the inhibitor of the late Na+ current, Ranolazine, and 

by the radical scavenger Tiron. Increased myocyte Na+ and Ca2+ loading exacerbates angina in patients 

with coronary artery disease, thus these findings provide an experimental basis for the observation that 

exposure to cigarette smoke decreases the angina threshold in coronary artery disease patients. Thus, CSE 

has direct effects on myocyte mitochondrial Ca2+ homeostasis, and increases susceptibility to the MPT. 

The MPT is triggered by mitochondrial Ca2+ overload and increased mitochondrial free radicals, and contributes 

to the development of irreversible myocyte injury during ischemia/reperfusion. Therefore these 

direct myocyte effects account for increased infarct size produced in vivo by exposure to CS. 

TREATING VASCULAR DISEASE BY TARGETING ELASTIN SIGNALING 

Dean Y. Li, MD, PhD; University of Utah; CIA 2005 

Dr. Li’s laboratory has identified novel matrix and matrix-bound proteins that regulate vascular guidance 

and stability. The research group showed that netrins promote vascular and neurovascular regeneration. 

This has direct application to individuals who are exposed to cigarette smoke and who have an increased 

risk of developing peripheral vasculopathy and neuropathy. The team also showed that the slit proteins pay 

a central role in vascular stability and reducing vascular eye disease, the number one cause of blindness in 

patients exposed to cigarette smoke. 


Navankasattusas S, Whitehead KJ, Suli A, Sorensen LK, Lim AH, Zhao J, Park KW, Wythe JD, Thomas 

KR, Chien CB, Li DY. The netrin receptor UNC5B promotes angiogenesis in specific vascular beds. 

Development 2008;135:659-67. 

Wilson BD, Ii M, Park KW, Suli A, Sorensen LK, Larrieu-Lahargue F, Urness LD, Suh W, Asai J, Kock 

GA, Thorne T, Silver M, Thomas KR, Chien CB, Losordo DW, Li DY. Netrins promote developmental 

and therapeutic angiogenesis. Science 2006;313:640-4. 

THE EFFECT OF SECOND HAND TOBACCO SMOKE ON THE RISK OF DEVELOPING ATRIAL FIBRILLATION IN 

PATIENTS WITH PACEMAKERS AND DEFIBRILLATORS 

Byron K. Lee, MD; University of California, San Francisco; YCSA 2004 

There is evidence that smoking plays a role in the pathophysiology of atrial fibrillation (AF). Dr. Lee and 

his collaborators sought to characterize the strength of this association. They analyzed data from the Study 

of Physical Performance and Age-related Changes in Sonomans (SPPARCS) project to determine if there is 

an association between smoking and AF. The SPPARCS project was a community-based longitudinal study 

of physical activity and fitness in people approximately 55 years of age that live in or near the city of 

Sonoma, California. Over 2,000 patients were followed for up to 8 years. Detailed smoking histories and 

medical histories were obtained and electrocardiograms (ECGs) were done every 2 years. Patients were 

deemed to have AF if they had AF on any of these ECGs. In the model adjusted for potential confounders 

including age, hypertension, congestive heart failure, and coronary artery disease, previous smokers had a 

71% greater odds of having AF compared to non-smokers (p = 0.03). History of hypertension and 

congestive heart failure also were associated with the development of AF. Notably, the increase in risk of 

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AF in smokers is persistent even if one has quit smoking for more than 40 years. Specifically, smokers who 

quit more than 20 years ago and less than 40 years ago still had a 97% (p = 0.02) and 136% (p = 0.03) 

greater odds of getting AF respectively. Smoking increases a person’s risk of developing AF. This increase 

in risk is persistent even if a person has quit smoking more than 40 years ago. 

CHRONIC KIDNEY DISEASE 


MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN SMOKERS 

Edgar A. Jaimes, MD; University of Alabama at Birmingham; YCSA 2003 

Dr. Jaimes’ main research goal is to determine the mechanisms through which cigarette smoke causes 

cardiovascular disease. The aims of the study include: 1) identification of the mechanisms by which 

cigarette smoke produces endothelial dysfunction, 2) determination of whether vessels from smokers have 

a phenotypic change that results in increased baseline production of oxygen as a result of smoking, and 3) 

elucidation of the mechanisms involved. Results thus far include the identification of the pathways that 

lead to increased super oxide production in pulmonary artery endothelial and smooth muscle cells 

secondary to cigarette smoke exposure. The main source of the super oxide anion in pulmonary artery 

endothelial cells is the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, whereas 

in smooth muscle cells both NADPH oxidase and xanthine oxidase contribute to cigarette smoke-increased 

production of superoxide anion. In addition the investigators have identified mechanisms by which 

cigarette smoking promotes renal injury. Specifically they have identified nicotine as an important mediator 

of renal injury, which may explain the accelerated progression of renal disease in smokers. The investigators 

have determined that these effects are mediated by increased generation of reactive oxygen species via 

NADPH oxidase activation resulting in increased glomerular cell proliferation and fibronectin production. 

They have determined that the administration of nicotine in vivo worsens renal injury in a model of acute 

glomerulonephritis as well as in a model of diabetic nephropathy (manuscript submitted). Currently they 

are testing the effects of nicotine in a model of 5/6 nephrectomy and determining the role of reactive 

oxygen species and are defining the intracellular signaling processes responsible for these effects. 


Jaimes EA, DeMaster EG, Tian RX, Raij L. Stable compounds of cigarette smoke induce endothelial 

superoxide anion production via NADPH oxidase activation. Arterioscler Thromb Vasc Biol 

2004;24:1031-1036. 

Jaimes EA, Tian RX, Raij L. Nicotine: the link between cigarette smoking and the progression of renal 

injury? Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H76-82. 

Jaimes EA, Tian RX, Joshi MS, Raij L. Nicotine augments glomerular injury in a rat model of acute 

nephritis. Am J Nephrol 2008 Oct 10;29:319-326. 

Mercado C, Jaimes EA. Cigarette smoking as a risk factor for atherosclerosis and renal disease: novel 

pathogenic insights. Curr Hypertens Rep 2007 Mar;9(1):66-72. Review. 

ROLE OF NICOTINE AS MEDIATOR OF THE EFFECTS OF TOBACCO IN THE PROGRESSION OF CHRONIC KIDNEY 

DISEASE 

Edgar A. Jaimes, MD; University of Alabama at Birmingham; CIA 2008 

Cigarette smoking has been identified as the most important cause of preventable morbidity and 

mortality in the U.S. Recent clinical studies suggest that in addition to being an important cardiovascular 

risk, cigarette smoking is an important risk for the progression of chronic kidney disease (CKD). The 

mechanisms by which cigarette smoking promotes the progression of CKD have not been elucidated. 

Recently Dr. Jaimes and colleagues have made the novel observations that human mesangial cells are 

endowed with nicotine acetylcholine receptors (nAChRs) and that nicotine promotes mesangial cell 

proliferation and extracellular matrix production (ECM) via increased generation of reactive oxygen species 

(ROS). Their in vivo preliminary data shows that nicotine worsens glomerular injury in an animal model of 

nephritis. Based on strong preliminary data, they hypothesize that nicotine plays a major role in the 

pathogenesis of CKD by promoting mesangial cell proliferation and extracellular matrix (ECM) deposition 

in the glomerulus and that COX-2-derived prostaglandins and reactive oxygen species (ROS) play a major 

role as mediators of these effects. They will test this hypothesis by indentifying the role of nicotine 

exposure as a risk factor in the progression of glomerulosclerosis and by investigating the effects of 

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nicotine administration in vivo on proteinuria, glomerular injury, and ECM deposition in the 5/6 

nephrectomy model of chronic kidney disease, a well validated animal model of CKD. In addition they will 

determine the effects of nicotine on glomerular production of ROS and cortical COX-2 expression, as well 

as the effects of COX-2 inhibition on renal injury in animals with 5/6 nephrectomy who are receiving 

nicotine. The investigators will establish the mechanisms that mediate the growth promoting effects of 

nicotine in the glomerular mesangium. The working hypothesis is that COX-2-derived prostaglandins and 

cytokines such as TGF-beta and platlet derived growth factor (PDGF) participate as mediators of ECM 

production and proliferation by mesangial cells in response to nicotine. These studies will unveil novel 

mechanisms by which cigarette smoking promotes CKD progression and establish the role of nicotine as 

one of the compounds in cigarette smoke responsible for the deleterious effects of cigarette smoke 

exposure in kidney disease. 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 


TARGETING NRF2 FOR INTERVENING EMPHYSEMA 

Shyam Biswal, PhD; The Johns Hopkins University; YCSA 2002, CIA 2008 

COPD caused by exposure to cigarette smoke (CS) affects more than 16 million Americans and is the 

fourth highest cause of death the in United States. This debilitating disease is characterized by airflow limitation, 

abnormal inflammation, air space enlargement, and the loss of alveolar structure. COPD is expected 

to become the third cause of death worldwide in 2020. Current treatments are inadequate and none have 

been shown to slow the progression of the disease. Anti-inflammatory drugs, which are routinely used successfully 

to manage asthma, are not effective in COPD. Bronchodilators, which constitute the current therapy, 

do not affect the underlying disease process and, therefore, do not slow disease progression towards 

lung function decline and death. There is an urgent need to develop novel therapy to intervene COPD by 

targeting new pathways recently discovered to be involved in its pathogenesis. 

Dr. Biswal’s laboratory recently discovered a novel host factor, nuclear factor-erythroid 2 p45-related 

factor 2 (NRF2), that plays a critical role in determining susceptibility to CS-induced emphysema, allergeninduced 

asthma, and pulmonary pneumonia in mice models by decreasing oxidative stress, apoptosis, and 

inflammation. NRF2 is a transcription factor that regulates the inducible expression of antioxidative genes 

(glutathione pathway-glutamate cysteine ligase catalytic and modifier subunit, and glutathione peroxidase 

and heme oxygenase-1) in response to oxidative and inflammatory stress. Realizing the overarching role of 

NRF2 in determining susceptibility to emphysema and major lung inflammatory diseases in mice models, 

the hypothesis that “Increasing NRF2 activity can enhance the expression of antioxidant and cytoprotective 

pathways thereby, intervening the progression of pulmonary emphysema” will be tested. Specific aim 1 is 

to test the hypothesis that increasing NRF2 activity can intervene CS-induced emphysema using a genetic 

approach. Mice with robust increase of NRF2 activity (and in antioxidant target genes) were generated by 

floxed deletion of NRF2 inhibitor, KEAP1, specifically in lungs as well as globally under inducible control. 

The pulmonary inflammation and emphysema after chronic CS will be studied. Specific aim 2 is to test the 

efficacy of a potent small molecule activator of NRF2 to intervene emphysema. Preliminary studies indicated 

that a triterpenoid compound, 1-[2-Cyano-3-,12-Dioxooleana-1,9(11)-Dien-28-Oyl]imidazole 

(CDDO-Im) is a potent activator of NRF2 in mice leading to increase in antioxidant pathways that inhibit 

inflammation. The hypothesis will be tested by intervening with this drug during progression of CS. The 

proposed studies will help develop a novel therapeutic strategy for intervention of COPD and other lung 

diseases. 


Harvey CJ, Thimmulappa RK, Singh A, Blake DH, Ling G, Wakabayashi N, Fujii J, Myers AC, and Biswal 

S. Nrf2 regulated glutathione recycling independent of biosynthesis is critical for cell survival during 

oxidative stress. Free Radic Biol Med 2009;46:443-453. 

Malhotra D, Thimmulappa RK, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, 

Hogg J, Pare P, Tuder RM, Biswal S. Decline in NRF2 regulated antioxidants in COPD lungs due to 

loss of its positive regulator DJ-1. Am J Respir Crit Care Med 2008;178:592-604. 

Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman 

SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, Biswal S. RNAi-mediated silencing of nuclear factor 

erythroid-2-related factor gene expression in non-small cell lung cancer inhibits tumor growth and 

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increases efficacy of chemotherapy. Cancer Res 2008;68:7975-7984. 


TW, Watson WH, Biswal S. Nrf2 dependent sulfiredoxin-1 expression protects against cigarette smoke 

induced oxidative stress in lungs. Free Radic Biol Med 2009;46:376-386. 

Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, 

Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S. 

Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema 

and cardiac dysfunction in mice. Proc Natl Acad Sci;106:250-255. 

THE EFFECT OF PLTP INDUCTION IN SMOKERS 

Robert F. Foronjy, MD; YCSA 2003, CIA 2008 

Dr. Foronjy hypothesized that plasma phospholipid transfer protein (PLTP) can have significant effects 

on surfactant composition. PLTP can significantly affect the development of smoke-related lung disease by 

modulating the composition and concentration of surfactant proteins and phospholipids within the lung. 

He determined that PLTP activity, measured in sputum from COPD patients, correlates with disease severity 

and progression. His results revealed that there is a marked decrease in PLTP activity in the lung lavage 

of COPD patients. Further studies are ongoing to determine the cause of the decrease in PLTP activity 

and its biological significance. Future studies will explore how the decrease in PLTP activity affects the 

composition and function of lung surfactants. 


Foronjy RF, Nkyimbeng T, Wallace AM, Thankachen J, Okada Y, Lemaitre V, D’Armiento JM. The transgenic 

expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with 

the loss of alveolar elastin. Am J Physiol Lung Cell Mol Physiol 2008;294:L1149-L1157. 

Foronjy, R, Okada Y., Cole, R, D’Armiento, J. Progressive adult-onset emphysema in transgenic mice 

expressing MMP-1. Am J Physiol Lung Cell Mol Physiol 2003;284:L727-L737. 

Foronjy, R, D’Armiento, J. The effect of cigarette smoke derived oxidants on the inflammatory response of 

the lung. Clinical and Applied Immunology Reviews 2006;6:53-72. 

Foronjy R, Mercer B, Maxfield M, Okada Y, Powell C, D’Armiento J. Structural emphysema does not correlate 

with lung compliance: lessons from the mouse smoking model. Experimental Lung Research 

2005;31:547-62. 

Foronjy R, Mirochnitchenko O, Propokenko O, Lemaitre V, Jia Y, Inouye M, Okada Y, D’Armiento J. 

Superoxide dismutase expression attenuates cigarette smoke or elastase generated emphysema in mice. 

Am J Respir Crit Care Med 2006;173:623-631. 

Foronjy R, Sun J, Lemaitre V, D’Armiento J. Transgenic expression of MMP-1 inhibits myocardial fibrosis 

and prevents the transition to heart failure in a pressure overload mouse model. Hypertens Res 

2008;31:725-735. 

Foronjy R, Wallace A, D’Armiento J. The pharmokinetic limitations of antioxidant treatment for COPD. 

Pulm Pharmacol Ther 2008;21:370-379. 

Ghio AJ, Hilborn ED, Stonehuerner JG, Dailey LA, Carter JD, Richards JH, Crissman KM, Foronjy RF, 

Uyeminami DL, Pinkerton KE. Particulate matter in cigarette smoke alters iron homeostasis to produce 

a biological effect. Am J Respir Crit Care Med 2008;178:1130-1138. 

Klotz S, Danzer J, Foronjy R, Oz M, Wang J, Mancini D, D’Armiento J, Burkhoff D. The impact of 

angiotensin-converting enzyme inhibitor therapy of the extracellular collagen matrix during LVAD support. 

Journal of the American College of Cardiology 2006;49: 1166-1174. 

Klotz S, Danzer J, Foronjy R, Oz M, Wang J, Mancini D, D’Armiento J, Burkhoff D. The impact of 

angiotensin-converting enzyme inhibitor therapy of the extracellular collagen matrix during LVAD support. 

J Am Coll Cardiol 2006;49: 1166-1174. 

Lee YC, Block G, Chen H, Folch-Puy E, Foronjy R, Jalili R, Jendresen CB, Kimura M, Kraft E, 

Lindemose S, Lu J, McLain T, Nutt L, Ramon-Garcia S, Smith J, Spivak A, Wang ML, Zanic M, Lin 

SH. One-step isolation of plasma membrane proteins using magnetic beads with immobilized concanavalin 

A. Protein Expr Purif 2008;62:223-229. 

Parvez F, Chen Y, Brandt-Rauf PW, Bernard A, Dumont X, Slavkovich V, Argos M, D’Armiento J, 

Foronjy R, Hasan MR, Eunus HE, Graziano JH, Ahsan H. Nonmalignant respiratory effects of chronic 

arsenic exposure from drinking water among never-smokers in Bangladesh. Environ Health Perspect 

2008;116:190-195. 

Shiomi T, Okada Y, Foronjy R, Schiltz J, Jaenish R, D’Armiento J. Emphysematous changes are caused by 

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degradation of type III collagen in transgenic mice over expressing tissue collagenase. Experimental 

Lung Research. 2003;29:1-15. 

Wise B, Connett J, D’Armiento J, Foronjy R, Friedman P, Goldin J, Louis T, Mao J, Muindi J, O’Connor 

G, Ramsdell J, Ries A, Roth M, Scharf S, Schluger N, Sciurba F, Skeans M, Walter B, Wendt C. Clinical, 

functional, biochemical and imaging outcomes from the feasibility of retinoid treatment for emphysema 

(FORTE) study Chest 2006;130:1334-1345. 

SECOND HAND TOBACCO SMOKE-INDUCED LUNG CELL DEATH VIA NITRIC OXIDE-CYTOCHROME C OXIDASE 

SIGNALING 

Jianliang Zhang, PhD; University of Florida; CIA 2004 

Exposure to SHS contributes to the development of pulmonary emphysema, a deadly disease associated 

with lung alveolar wall destruction. Exhaled tobacco smoke derived from the smoker’s lungs is a key component 

of SHS. Cytotoxic effects of exhaled smoke on lung vascular endothelial cells are unclear. A cell 

model has been used to investigate the molecular mechanisms underlying exhaled smoke-induced lung cell 

death. Exposure of lung vascular endothelial cells to saline buffer-conditioned mainstream smoke results in 

extensive cell death compared to control cells that are exposed to air or unlit cigarettes. Exhaled smoke can 

induce cell death, including apoptosis, as determined by assessments of apoptotic markers such as cell morphology, 

flow cytometry, cytochrome c release, caspase-3 activation, and DNA laddering. Nitric oxide 

(NO) derived from smoke and/or produced by smoke-stimulated cells plays a key role in exhaled smokeinduced 

lung cell death and dysfunction. NO inhibits mitochondrial cytochrome c oxidase, the terminal 

enzyme of the mitochondrial respiratory chain. Inhibition of the enzyme can enhance the leak of reactive 

oxygen species such as superoxide from mitochondria. Excessive superoxide reacts with tobacco smokederived 

or -stimulated NO to form peroxynitrite. Peroxynitrite can modify proteins, including pro-apoptotic 

protein Bax. Elucidating the signal transduction pathways that transmit smoke stimulation to initiation 

of cell death through NO-cytochrome c oxidase signaling will provide additional targets to be tested 

to reduce the incidence of acute and chronic pulmonary diseases associated with SHS exposure. 


Aldonyte R, Brantly M, Block E, Patel J, Zhang J. Matrix metalloproteinase-2 is responsible for nuclear 

matrix degradation in cigarette smoke induced apoptosis in pulmonary artery endothelial cells. Proc of 

the Am Thor Soc 2006; 3:A681. 

Aldonyte R, Hutchinson ET, Jin B, Brantly M, Block ER, Patel J, Zhang J. Endothelial alpha-1-antitrypsin 

attenuates cigarette smoke induced apoptosis. COPD. Journal of Chronic Obstructive Pulmonary Disease 

2008;5:153-162. 

Aldonyte R, Jin B, Brantly M, Block E, Patel J, Zhang J. Alpha-1-antitrypsin uptake and anti-apoptotic 

effect in pulmonary artery endothelial cells is down regulated by blockage of VEGF R2. Proc of the Am 

Thor Soc 2006;3:A305. 

Aldonyte R, Jin B, Brantly M, Block E, Patel J, Zhang, J,. Multi-tasking of major human antiprotease: 

alpha-1-antitrypsin is up taken by lung endothelial cells and ameliorates cigarette smoke-induced apoptosis. 

Presented at The 4th General Meeting of the International Proteolysis Society 2005. 

Zhang J, Block ER, Patel JM. Nitric oxide-enhanced transition of TNF-a-induced apoptosis to necrosis via 

MMP-9 signaling, 2005. Presented at The Sixth Meeting on Programmed Cell Death. Cold Spring 

Harbor Laboratory. Programmed Cell Death. p219. 

Zhang J, Block ER, Patel JM. Bax nitration and oligomerization promotes Bax insertion into mitochondria 

and release of cytochrome c, 2006. Presented at The International Cell Death Society Meeting. June 2- 

5, 2006. 

Zhang J, Block ER, Patel JM. Cigarette smoke-induced upregulation of ET-1 expression is associated with 

extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation/activation of vascular endothelial 

zinc finger 1 (Vezf1), 2006. Presented at Evolution of Pulmonary Hypertension: Emerging Diseases and 

Novel therapeutics Meeting. The National Institute of Health, Bethesda, MD, Dec 7-8, 2006. 

Zhang J, Jin B, Mohammed KA, Block ER, Patel JM, Antony VB. Cigarette smoke-enhanced lung 

endothelial apoptosis and permeability are associated with S-nitrosylation and inhibition of mitochondrial 

cytochrome c oxidase. Proceedings of the American Thoracic Society 2005; 2:A136. 

Zhang J, Narayan VM, Block ER, Patel JM. Peroxynitrite-induced Bax nitration and oligomerization promote 

Bax insertion into mitochondria and release of cytochrome c, 2007. Presented at FAMRI meeting. 

Miami, FL, May 14-16, 2007. 

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EXHALED SMOKE-INDUCED LUNG ENDOTHELIAL APOPTOSIS VIA PEROXYNITRITE-BAX SIGNALING 

Jianliang Zhang, PhD; University of Florida; CIA 2007 

Lung diseases, including emphysema, caused by SHS exposure are some of the gravest global public 

health issues today. A part of the reason for the morbidity is the lung structural changes caused directly or 

indirectly by smoke-induced cell injury and death. Exhaled mainstream smoke is a key component of SHS 

that is inhaled by the smoker upon taking a puff of a cigarette and then breathed out into the air from his 

lungs. Despite well-known cytotoxicity of smoke, the signaling event that triggers endothelial apoptosis is 

unclear. A cell model has been used to investigate the molecular mechanisms underlying exhaled smokeinduced 

cell death and dysfunction. Exposure of lung vascular endothelial cells to saline buffer-conditioned 

mainstream smoke results in extensive cell death, including apoptosis. Peroxynitrite formed from excessive 

superoxide reaction with nitric oxide (NO) can modify proteins, including a pro-apoptosis protein, Bax. 

Modification of Bax contributes to smoke-induced apoptosis. Current investigations focus on the link 

between peroxynitrite-induced modification of Bax and apoptosis of the lung endothelium. Purified Bax 

protein, cultured lung endothelial cells, and intact vessels are used to investigate whether exhaled smokeinduced 

tyrosine modification of Bax at specific sites leads to endothelial cell death. The long-term goal of 

this project is to investigate whether exhaled mainstream smoke damages or destroys lung alveoli, leading 

to the development of emphysema. This would lead to development of better strategies to prevent the loss 

of the quality and quantity of patient lives. 


Zhang J, Narayan V, Block E, Patel J. Hypoxic upregulation of preproendothelin-1 gene expression is 

associated with PI3K signaling in cultured pulmonary vascular endothelial cells, 2008. Presented at The 

International Conference of the American Thoracic Society. Toronto, May 16-21, 2008. (poster discussion) 

American Journal of Respiratory and Critical Care Medicine;177: A591. 

HOST DEFENCE FUNCTIONS OF AIRWAY EPITHELIAL CELLS IN COPD 

Hong Wei Chu, MD; National Jewish Medical and Research Center; CIA 2005, 2008 

Dr. Chu’s hypothesis is that exposure to cigarette smoke reduces human airway epithelial innate defense, 

e.g., toll-like receptor 2 (TLR2) signaling, against the invading bacteria. Restoration of the impaired innate 

pathway in cigarette smoke-exposed airway epithelial cells normalizes epithelial clearance of the invading 

pathogens. The objective of the study is to determine the molecular mechanisms responsible for impaired 

airway epithelial defense against bacteria in COPD patients. The study specific aims include 1) measurement 

of TLR2 signaling molecules and antimicrobial substances in bronchial epithelial cells from COPD 

patients and normal subjects; 2) elucidation of the molecular mechanisms by which cigarette smoke 

inhibits TLR2 signaling and production of antimicrobial substances; and 3) restoration of TLR2 signaling 

activity to normalize bacterial (i.e., Mycoplasma pneumoniae) clearance in cigarette smoke extract-pretreated 

airway epithelial cells. Dr. Chu’s group has completed the collection of primary bronchial epithelial cells 

from COPD patients (n = 10), healthy smokers (n = 10), and healthy non-smokers (n = 10). Dr. Chu’s 

preliminary study has suggested that cigarette smoke exposure modifies airway epithelial cell innate immunity. 

For example, TLR2 expression levels tend to be lower in COPD patients than in healthy smokers. 

Further, cigarette smoke extract in cultured human airway epithelial cells was shown to reduce 

prostaglandin E2 (an anti-inflammatory mediator) production. At present, Dr. Chu’s group is testing the 

effects of cigarette smoke exposure on bacterial clearance from airway epithelium, and determining if 

restoration of TLR2 signaling activity normalizes impaired bacterial clearance from cigarette smokeexposed 

airway epithelium. 


Baqir M, Chen CZ, Martin RJ, Thaikoottathil J, Case S, Minor M, Bowler R, Chu HW. Cigarette smoke 

decreases MARCO expression in macrophages: implication in Mycoplasma pneumoniae infection. Respir 

Med 2008;102:1604-1610. 

Thaikoottathil J, Martin RJ, Zdunek J, Weinberger A, Rino JG, Chu HW. Cigarette smoke extract reduces 

VEGF in primary human airway epithelial cells. Eur Respir J 2009;Jan 7. [Epub ahead of print]. 

A NOVEL ANTI-INFLAMMATORY ROLE FOR ADAM15 IN EMPHYSEMA 

Caroline A. Owen, MD, PhD; Brigham and Women’s Hospital; CIA 2006 

Cigarette smoke strikingly upregulates the expression of a disintegrin and metallopeptidase domain 15 

(ADAM15) on the surface of macrophages and CD8 + T cells in vitro and in the lung in vivo. Exposure of 

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wild-type (WT) mice and mice genetically deficient in ADAM15 (ADAM15 -/- mice) to SHS for 1 to 24 

weeks results in higher lung macrophage and CD8 + T cell counts, higher lung levels of proinflammatory 

mediators, greater weight loss, higher mortality, and greater airspace enlargement in smoke-exposed 

ADAM15 -/- mice compared to WT mice. In response to cigarette smoke exposure, ADAM15 -/- alveolar 

macrophages and CD8 + T cells have reduced rates of apoptosis and necrosis than WT cells. Thus, 

ADAM15 protects the lung from cigarette smoke-induced lung inflammation and airspace enlargement, at 

least in part, by reducing the survival of destructive leukocytes in the lung. Ongoing studies are investigating 

the mechanism by which ADAM15 promotes macrophage cell death during the development of cigarette 

smoke-induced emphysema. In the long term, these studies will facilitate the development of new 

treatment strategies for pulmonary emphysema. 


Campbell EJ, Owen CA. The sulfate groups of chondroitin sulfate- and heparan sulfate proteoglycans in 

neutrophil plasma membranes are novel binding sites for neutrophil elastase and cathepsin G. J Biol 

Chem 2007;282:14645-14654. 

Lonak S, Owen CA. Anti-inflammatory role for ADAM15 in cigarette smoke-induced pulmonary emphysema 

in mice. Journal of Leukocyte Biology 2007;Supplement. 

Lonak SP, Zhuang Y, Mollon J, Knolle M, Cala L, Owen CA. ADAM15 dampens lung inflammation in 

cigarette smoke-exposed mice. Am J Respir Crit Care Med 2008;Abstracts Issue:A241. 

Maeno T, Houghton AM, Quintero PA, Grumelli S, Owen CA, Shapiro SD. CD8+ T cells are required 

for inflammation and destruction in cigarette smoke-induced emphysema in mice. Journal of 

Immunology 2007;178:8090-8096. 

Owen CA. Leukocyte cell surface proteinases: regulation of expression, functions, and mechanisms of surface 

localization. International J Biochemistry and Cell Biology 2008;40:1246-72. 

Owen CA. Pathogenic roles of proteinases in COPD. International Journal of COPD 2008;3:253-268. 

SMOKING IMPAIRS ALPHA 1-ANTITRYPSIN’S PRO-SURVIVAL EFFECT IN THE LUNG 

Irina Petrache, MD; Indiana University; CIA 2006 

The prevailing paradigm of emphysema development in patients with Alpha-1-Antitrypsin (A1AT) deficiency 

emphasizes the role of A1AT as an elastase inhibitor, but A1AT can have broader biological effects. 

Dr. Petrache’s data indicate that A1AT acts as a prosurvival molecule and prevents emphysema by binding 

to and inhibiting active caspase-3, which protects alveolar cells against apoptosis. The hypothesis is that the 

antiapoptotic actions of A1AT are decreased by cigarette smoke through decreasing its interaction with 

caspase-3 and decreasing its uptake in lung endothelial cells. The group determined that cigarette smoke 

inhibits the uptake of human A1AT in primary murine lung endothelial cells by an action both on the protein 

and on the endothelial cells. They have shown that A1AT modified by cigarette smoke has decreased 

caspase-3 inhibitory activity. Furthermore, cigarette smoke impaired the biophysical interaction of A1AT 

with the active caspase-3 protein in vitro. Exposure of mice to cigarette smoke impaired the uptake of 

A1AT in vivo. COPD patient recruitment has been completed and the translational study of the effect of 

cigarette smoke-induced posttranslational changes of circulating A1AT on its antiapoptotic function are 

ongoing. Functional purified A1AT from plasma has been obtained and testing continues on its anticaspase-3 

activity in vitro. The data reveal a novel function of A1AT as a protector against lung destruction 

not only by quenching neutrophil elastase, but also by preventing apoptosis, therefore, expanding the therapeutical 

targets in emphysema. 


Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, Petrache HI, Flotte T, and Tuder RM. 

Alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J of Pathol 

2006;169:1155-1166. 


Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced 

emphysema in mice. J Clin Invest 2004;114:1248-1259. 

Tuder RM, Petrache I. Molecular multitasking in the airspace: alpha1-antitrypsin takes on thrombin and 

plasmin. Am J Respir Cell Mol Biol 2007;37:130-134. 

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NEUROPILIN-1 AND EMPHYSEMA 

Patrice M. Becker, MD; The Johns Hopkins University; CIA 2006 

COPD is the fourth leading cause of death in the United States. Up to 90% of patients with this chronic 

lung disease smoked, yet not all smokers develop the disease. This suggests that other factors, like genetics, 

may predispose patients to lung damage following cigarette smoke exposure. These experiments will evaluate 

whether a particular gene, neuropilin-1, contributes to emphysema development. Neuropilin-1 is a 

receptor on the surface of cells lining the airways and blood vessels in the lung. Two different proteins 

bind neuropilin-1, and both are important determinants of the complex structure of the lung. Data from 

Dr. Becker’s laboratory thus far suggest that genetic deletion of neuropilin-1 in airway epithelial cells in 

vivo leads to mild airspace enlargement. More notably, however, pulmonary epithelial deletion of neuropilin-1 

in vivo promotes emphysema development in response to chronic cigarette smoke exposure. Both 

genetic deletion of epithelial neuropilin-1 in vivo, and neuropilin-1 silencing in vitro, enhance cigarette 

smoke-induced apoptosis of alveolar epithelial cells, showing that airspace remodeling in this model is secondary 

to accelerated epithelial cell death. Ongoing studies are investigating the cellular mechanisms by 

which neuropilin-1 enhances cell survival, as well as cell type specificity of these effects. 

ELASTIN FRAGMENT INHIBITION AS A THERAPY FOR COPD 

Steven D. Shapiro, MD; University of Pittsburgh; CIA 2006 

COPD, of which emphysema is a major component, is a disease that is caused by either direct or SHS 

exposure, and is currently the fourth leading cause of death in the United States. Cigarette smoke exposure 

generates inflammation within the lung. It has long been known that inflammatory cell-mediated 

degradation of elastin alters the structural integrity of the lung. Dr. Shapiro’s laboratory found that elastin 

fragments generated through proteolysis serve as chemokines that attract more destructive inflammatory 

cells to the lung. In the first year of funding, they demonstrated the importance of these fragments in perpetuating 

the disease process (Houghton. JCI 2006). Dr. Shapiro’s laboratory continues to determine the 

inflammatory cell cascades in COPD, and the interactions between elastin, innate immunity, and adaptive 

immunity. They next examined the actions of CD8 + T cells following smoke exposure (Maeno et al. J 

Immunol 2007), and have recently found that mainstream and SHS blunt dendritic cell function resulting 

in impaired T cell activation. This finding helps explain the increased risk of airway infections in adult 

smokers and children exposed to SHS (Robbins et al. J Immunol 2008). They will continue to determine 

the complex innate and adaptive inflammatory network induced by cigarette smoke, and attempt to find 

means to break this vicious cycle to minimize the risk of smoke exposure. 

DOES SECOND HAND CIGARETTE SMOKE MODULATE VITAMIN E UPTAKE IN LUNG TISSUE? 

Giuseppe Valacchi, PhD; University of Siena; CIA 2007 

SHS and oxidative stress caused by inflammation due to SHS is believed to boost COPD pathogeneses. 

Conversely, decreased COPD severity and incidence are associated with consumption of a diet high in 

fruits and vegetables suggesting that higher intake of dietary antioxidant substances are beneficial. 

However, in seeming contradiction, studies of supplementation with vitamin E (a-tocopherol) have not 

been effective in improving COPD-related lung disease end points (such as pulmonary function). It is not 

known why supplements were ineffective. One potential explanation may be that the delivery systems of 

tocopherol are affected by SHS, preventing tocopherol delivery and, therefore, any beneficial effects. While 

the delivery transport systems for the major lipid-soluble antioxidant tocopherol are not well understood, 

studies have shown that the scavenger receptor B1 (SR-B1) plays a prominent role in the uptake of tocopherol 

in a variety of tissues, including lung. They hypothesize that SR-B1 plays an important role in SHS 

ability to alter vitamin E delivery and thereby affects lung function. The PI plans to explore this issue 

regarding SHS and its effects on components of tocopherol-based antioxidant defense by analyzing the levels 

of SR-B1 receptor before and after SHS exposure in lung tissues, and after isolation, in type II cells. In 

the second part of the study, the effects will be analyzed for the modulation by vitamin E dietary manipulation 

of SRB1 levels. The PI hypothesizes that upon lung exposure to SHS and its attendant oxidative 

stress, a positive feedback loop is induced that increases vitamin E consumption while decreasing expression 

of SR-B1, a key means of antioxidant delivery. This combination results in reduced lung vitamin E, 

thereby rendering it more vulnerable to further insult. 

P A G E 1 4 9

REDUCED NEUTROPHIL DEATH IN TOBACCO-INDUCED COPD 

Hongbo R. Luo, PhD; Harvard University; CIA 2007 

Tobacco use, including both active and passive, i.e., exposure to SHS, is by far the most important risk 

factor for COPD. In COPD, there is a chronic inflammation of the small airways and the lung parenchyma 

that leads to a fixed narrowing of small airways and alveolar wall destruction (emphysema). Exaggerated 

neutrophil accumulation in the lungs plays a major role in the pathogenesis of cigarette smoke-induced 

COPD. Neutrophils normally have a very short life span (6-7 hours in blood and 1-4 days in tissue) and 

readily undergo spontaneous programmed cell death (apoptosis). One mechanism leading to the massive 

neutrophil accumulation in cigarette smoke-induced COPD is cigarette smoke-induced delay of neutrophil 

spontaneous death in the lungs. The ultimate goal of the research is to characterize the molecular basis of 

reduced neutrophil spontaneous death in tobacco-induced COPD. The investigators are currently elucidating 

the physiological function and regulation of phosphatidylinositol 3,4,5-trisphosphate/protein kinase B 

(PtdIns(3,4,5)P3/Akt) survival signal in this process. The PI is investigating whether cigarette smokeinduced 

delay of neutrophil spontaneous death can be reversed by inhibiting Akt activity. They will also 

elucidate the molecular mechanisms by which neutrophil death-associated Akt deactivation is suppressed by 

cigarette smoke. The aim is to solidify PtdIns(3,4,5)P3/Akt and related pathways as novel therapeutic targets 

for modulating lung neutrophil half-life in COPD patients. Drugs that downregulate 

PtdIns(3,4,5)P3/Akt should promote neutrophil death, accelerate neutrophil clearance, and, therefore, 

help the resolution of tobacco-induced lung inflammation and damage. 

CIGARETTE SMOKE IMPAIRS REMOVAL OF APOPTOTIC CELLS (EFFEROCYTOSIS) THROUGH RHOA-DEPENDENT 

AND INDEPENDENT MECHANISMS 

R. William Vandivier, MD; University of Colorado; CIA 2007 

Cigarette smoke (CS) is the primary cause of COPD, an effect that is, in part, due to intense oxidant 

stress. Clearance of apoptotic cells (efferocytosis) is a critical regulator of lung homeostasis, which is defective 

in smokers and in patients with COPD, suggesting a role in disease pathogenesis. The PI hypothesized 

that CS would impair efferocytosis through oxidant-dependent activation of RhoA, a known inhibitor of 

this process. Dr. Vandivier’s group investigated the effect of CS on efferocytosis in vivo and ex vivo using 

acute, subacute and long-term mouse exposure models. Acute and subacute CS exposure suppressed efferocytosis 

by alveolar macrophages in a dose-dependent, reversible, and cell-type independent manner, 

while more intense CS-exposure had an irreversible effect. In contrast, CS did not alter ingestion through 

the Fcg receptor. At 24 hours post exposure, the inhibitory effect of CS on apoptotic cell clearance 

depended on oxidants, because the effect was blunted in oxidant-resistant ICR mice, and prevented by 

either genetic or pharmacologic antioxidant strategies in vivo and ex vivo. At this same time point, CS 

inhibited efferocytosis through oxidant-dependent activation of the RhoA/Rho kinase pathway because 1) 

CS activated RhoA, 2) antioxidants prevented RhoA activation by CS, and 3) inhibitors of the RhoA/Rho 

kinase pathway reversed the suppressive effect of CS on apoptotic cell clearance in vivo and ex vivo. In contrast, 

CS inhibited efferocytosis immediately post exposure in a RhoA/Rho kinase independent manner. 

Interestingly, the ability of CS to inhibit efferocytosis was TNFa-dependent at 24 hours post exposure, but 

was TNFa-independent immediately post exposure. These findings advance the hypothesis that impaired 

efferocytosis may contribute to the pathogenesis of COPD, demonstrating the fluidity of the mechanisms 

governing this effect, and suggest the therapeutic potential of drugs targeting the RhoA/Rho kinase pathway. 


Richens TR, Linderman DJ, Xiao YQ, Morimoto K, Day BJ, Henson PM, Vandivier RW. Cigarette smoke 

impairs removal of apoptotic cells (efferocytosis) through oxidant-dependent activation of RhoA. 

Presented at the American Thoracic Society International Conference. Philadelphia, PA, May 17-21, 

2008. 

Vandivier RW, Richens TR, Linderman DJ, Xiao YQ, Boe DM, Morimoto K, Bowler RP, Day BJ, Janssen 

WJ, Henson PM. Cigarette smoke impairs clearance of apoptotic cells through oxidant-dependent activation 

of RhoA. Presented at the Society of Leukocyte Biology International Meeting. Denver, CO, Nov 

6-9, 2008. 

1 5 0 P A G E

GOBLET CELL HYPERPLASIA IN CHRONIC BRONCHITIS 

Yohannes Tesfaigzi, PhD; Lovelace Respiratory Research Institute; CIA 2007 

Exposure to SHS increases the risk of developing chronic bronchitis, a disease associated with an 

increased number of mucus-producing cells in the airways that can suddenly release vast quantities of 

mucus that obstruct the airways. The PI’s studies show that the mechanisms to remove excess numbers of 

mucous cells are dysfunctional in individuals with chronic bronchitis. When screening for regulators of this 

removal process, BIK was identified as an important inducer of cell death in airway epithelial cells. The PI 

found that BIK mRNA levels are reduced in airway epithelial cells obtained by bronchial brushings from 

11 subjects with chronic bronchitis compared to those from 11 controls. The decrease in BIK mRNA levels 

was reproduced in cultured primary airway epithelial cells from five independent donors that were 

exposed to SHS. Exposure of primary human airway epithelial cells to SHS increases the numbers of 

mucous cells but this increase was reversed by ectopic expression of BIK, further supporting the importance 

of BIK. The PI found that BIK increased cell death by blocking the translocation of extracellular signal-regulated 

kinase (ERK1/2) to the nucleus. In addition, when BIK was expressed, the extent of cell 

death was enhanced with increasing activity of ERK1/2, suggesting that cytosolic ERK1/2 strongly 

induces cell death. While Bik -/- mice did not show increased numbers of mucous cells in response to SHS 

exposure, as was hypothesized, the PI found that Bik -/- mice showed increased numbers of epithelial cells 

per mm basal lamina compared to Bik +/+ mice. These studies suggest that factors other than Bik are also 

involved in the development of metaplastic mucous cells in response to SHS. The PI is now focused on 

identifying these factors to provide an animal model system to investigate whether peptides derived from 

Bik can be used to reduce the number of mucous cells and ameliorate the symptoms of chronic bronchitis. 


Mebratu Y, Dickey BF, Evans C, Tesfaigzi Y. The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation 

of activated ERK1/2 to mediate IFNg-induced cell death. J Cell Biol 2008;183:429-439. 

ROLE OF CYCLIC GUANOSINE MONOPHOSPHATE IN TOBACCO SMOKE-INDUCED 

LUNG ENDOTHELIAL DYSFUNCTION AND EMPHYSEMA 

David B. Pearse, MD; The Johns Hopkins University; CIA 2008 

Oxidant-induced pulmonary endothelial cell apoptosis has been implicated in the pathogenesis of cigarette 

smoke (CS)-induced emphysema. In vivo, lung microvascular endothelial cells are subjected to cyclic 

stretch with normal tidal ventilation. Tidal ventilation generates endothelial nitric oxide (NO) and cyclic 

guanosine monophosphate (cGMP, which has been shown to protect other cell types from oxidant injury. 

CS-induced small airway obstruction may attenuate mouse lung microvascular endothelial cells 

(MLMVEC) cyclic stretch, decreasing endothelial cGMP production and potentially sensitizing endothelial 

cells to injury from reactive oxygen species (ROS). Their group wondered whether physiologic levels of 

cyclic stretch would protect against cigarette smoke extract- and ROS-induced MLMVEC apoptosis via a 

cGMP-dependent mechanism. 

To test this hypothesis, MLMVEC were subjected to 5% cyclic stretch (f=60 min -1 ) for 6 hours to 

mimic tidal ventilation. MLMVEC were then exposed to cigarette smoke extract (CSE) (2-4%), 500 mM 

H 2 O 2 , or diluent control and stretched for an additional 18 hours, after which they were stained with 

Hoechst dye and propidium iodide and assessed for apoptotic nuclear morphology and membrane integrity. 

Compared to static cells, 5% cyclic stretch decreased CSE-induced nuclear condensation and fragmentation 

by 50% and decreased H 2 O 2 -induced nuclear condensation/fragmentation by 75%. The protective 

effect of cyclic stretch was blocked by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3- 

a]quinoxalin-1-one (ODQ). To determine if cGMP could be upregulating an antioxidant protein, static 

MLMVEC monolayers were treated with 8p-8-(4-chlorophenylthio)-cGMP (8p-CPT-cGMP) (50 mM) for 

2 hours. The cells were then trypsinized, suspended, and stirred in serum-free media without 8pCPTcGMP. 

Serial aliquots of H 2 O 2 were added at timed intervals to achieve predicted concentrations of 20, 

50, and 100 mM. The change in extracellular H 2 O 2 concentration (D [H 2 O 2 ] ext ) was continuously 

measured with a H 2 O 2 electrode. 

Compared with untreated cells, MLMVEC pretreated with 8p-CPT-cGMP scavenged significantly more 

H 2 O 2 . Specifically, 8pCPT-cGMP decreased the maximal D[ H 2 O 2 ] ext by 33±11, 32± 10, and 25±10% 

in cells exposed to 20, 50, and 100 mM H 2 O 2 , respectively (N=8, P

H 2 O 2 -induced nuclear fragmentation and condensation was also examined. At 18 hours, H 2 O 2 caused a 

two-fold increase in condensed fragmented nuclei that was completely eliminated by 8pCPT-cGMP pretreatment 

(N=5, P

ability to detect early emphysematous changes in the lung. This is especially important for exposure to 

SHS because oftentimes the level of exposure is subtler than what active smokers receive and, therefore, 

much more sensitive detection methods are needed. A highly sensitive, noninvasive image-based detection 

method will not only transform one’s ability to detect and follow treatment of the disease process, but may 

be the only way to detect early emphysematous disease. 


Patz S, Muradian M, Hrovat MI, Hersman, FW, Hatabu H, Butler JP. Xenon MRI of the lung. In: 

Kauczor HU, ed. MRI of the Lung. Springer Verlag, 2009. 

THE ROLE OF BRONCHIO-ALVEOLAR STEM CELLS IN CIGARETTE SMOKE-RELATED EMPHYSEMA 

Shivraj Tyagi, PhD; Brigham and Women’s Hospital; CIA 2008 

COPD is a complex human disease mainly influenced by active tobacco exposure and SHS. A greater 

understanding of pathways contributing to lung maintenance and repair is needed to identify mechanisms 

contributing to COPD. It is believed that following smoke-induced injury to the lung, reparative mechanisms 

are active and may contribute to individual variability in exposure-related disease susceptibility. 

Peroxisome proliferator-activating receptor (PPAR)-gamma is a well-known regulator of cellular differentiation 

and tissue homeostasis/inflammation. Their laboratory has shown that deficiency in PPARgamma 

specifically within airway epithelial cells leads to increased susceptibility to the development of emphysema 

in response to chronic cigarette smoke exposure. Recent studies have discovered a population of airwayderived 

progenitor cells capable of repairing the airway and airspace, bronchioalveolar stem cells (BASCs), 

which are identified by co-expression of Clara cell secretory protein (CCSP) and surfactant protein C 

(SPC). In vitro, these cells show characteristics including self-renewal and multi-potency, such as the ability 

to generate both Clara cells and type II pneumocytes. It is reasoned that BASCs may play a role in repairing 

cigarette smoke-related lung damage in the setting of emphysema. Since airway epithelial cell-targeted 

PPARgamma deficiency leads to increased susceptibility to smoke-related emphysema-like pathology, it is 

suggested that PPARgamma function in BASCs can modify this response by contributing to the regulation 

of BASC differentiation and progenitor cell potential. They have verified PPARgamma expression within 

BASC, and have confirmed targeting of this cell population in airway epithelial cell PPARgamma deficient 

mice. They provide preliminary data describing changes in gene expression in BASCs in wild-type mice following 

smoke exposure and in BASCs deficient in airway epithelial cell PPARgamma. They propose that 

BASCs are necessary for lung repair in response to cigarette smoke exposure and that PPARgamma is capable 

of modulating the progenitor potential of BASCs by controlling cell differentiation. 

They will test these hypotheses by 1) investigating the effect of cigarette smoke exposure upon BASC 

function in vivo and in vitro, and 2) defining the contribution of BASC proliferation and function to 

increased susceptibility to smoke-related lung disease in PPARgamma-deficient mice. These studies will 

extend understanding of the biological functions of BASCs, assess novel mechanisms contributing to cigarette 

smoke-related lung injury and repair, and identify novel targets for therapeutic intervention in 

patients with COPD. 

HAEMOPHILUS INFLUENZAE TOLERANCE: A MECHANISM FOR CHRONIC COLONIZATION IN COPD 

Tricia D. LeVan, PhD; University of Nebraska; CIA 2008 

COPD is the fourth leading cause of mortality worldwide and is characterized by chronic airway inflammation 

and nonreversible airflow limitation. While tobacco smoking is the leading risk factor for COPD, 

even secondary causes of COPD, such as SHS exposure, are a major public health concern. Each year the 

proportion of patients with COPD who are life-long never smokers rises. 

In addition to tobacco smoke being the main etiological factor of COPD pathogenesis, recent studies 

have found that tobacco exposure is a major risk factor for respiratory tract infections. Studies also show 

that cigarette smoke reduces bacterial clearance by impairment of mucociliary clearance, changes in 

pathogen adherence, and disruption of the bronchial epithelium. The bronchial epithelium is in a key position 

to regulate inflammation, but it remains unknown whether the epithelium becomes hypersensitive or 

tolerant to the chronic presence of bacteria. Nontypeable Haemophilus influenzae (NTHi), the most common 

pathogenic bacteria isolated from the airways of patients with COPD, are recognized by bronchial 

epithelial cells by directly interacting with toll-like receptor 2 (TLR2).The overall hypothesis of this study 

is that chronic exposure of bronchial epithelial cells to cigarette smoke and/or NTHi induces innate 

immune dysfunction characterized by bronchial epithelial tolerance that perpetuates chronic colonization 

in individuals with COPD. 

P A G E 1 5 3

The aims of this study are: 1) to determine if prior exposure to tobacco smoke and/or NTHi bacteria 

would induce a state of tolerance to subsequent NTHi exposures in bronchial epithelial cells; 2) to determine 

if tobacco smoke-and/or NTHi-induced tolerance results in altered expression and membrane localization 

of TLR2 in bronchial epithelial cells; 3) to identify intracellular signaling events modulated by 

tobacco smoke- and/or NTHi-induced tolerance in bronchial epithelial cells. 

CIGARETTE SMOKE EXPOSURE AND INFLUENZA VIRUS INFECTION IN HUMAN LUNG 

Wenxin Wu, PhD; University of Oklahoma Health Sciences Center; CIA 2008 

The long-term goal of this work is to understand how cigarette smoking and SHS compromise the 

human innate immune system’s response to influenza virus infection, and to find novel methods to control 

the infection. Active or passive cigarette smoking suppresses the immune system, and smoking is a wellknown 

major risk factor for COPD and respiratory tract infections. Epidemiological studies show that 

influenza infection is seven times more common and is much more severe in smokers than non-smokers. 

Following entry into the respiratory tract, influenza virus infection causes a spectrum of acute clinical syndromes 

ranging from an asymptomatic infection to a primary viral or secondary bacterial pneumonia that 

frequently progresses to a fatal outcome. However, the mechanism by which cigarette smoking suppresses 

the immune system and promotes influenza infection is still unclear. Recent studies have found that 

retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of, and cytokine induction 

by, influenza virus and other RNA viruses. In previous studies, this group established a human lung 

tissue model. They propose to use this model to study cigarette smoking and its effects on the human 

innate immune system. There is no other currently available human model to study this process. These 

studies will enhance understanding of the mechanism of how cigarette smoke extract (CSE) suppresses the 

human immune system and also the process that controls influenza virus infection and inflammation due 

to this pathogen. This will be important in designing strategies for reducing the damage by cigarette 

smoking and for flu prevention and therapy. 

NEUROTROPHINS IN CIGARETTE SMOKE INDUCED AIRWAY HYPERREACTIVITY 

Y. S. Prakash, MD, PhD; Mayo Clinic; CIA 2008 

Enhanced airway smooth muscle (ASM) contractility underlies symptoms in diseases such as bronchitis 

and asthma that occur in humans exposed to SHS. There is currently little information on the cellular 

mechanisms underlying such airway hyperreactivity. Sputum samples of patients with chronic sinusitis, 

bronchitis, and asthma show increased levels of neurotrophins (growth factors most studied in the nervous 

system) such as brain-derived growth factor (BDNF). This group recently showed that BDNF receptors 

(TrkB and p75NTR) are expressed in human ASM, and that BDNF increases ASM intracellular Ca2 + concentration 

([Ca2 + ]i) and force. In this study, they tested the hypothesis that neurotrophins contribute to 

increased contractility with cigarette smoke exposure. 

Fluorescence immunocytochemical studies as well as western analysis of human ASM from third or 

fourth order bronchi demonstrated considerable constitutive expression of BDNF, TrkB, and p75NTR. 

Exposure to 1% cigarette smoke extract (CSE from Kentucky research cigarettes 1RF4) for 24-96 hours 

increased BDNF, TrkB, and especially p75NTR expression. Furthermore, these changes in BDNF and 

receptor expression were compared to exposure to 20 ng/ml of the pro-inflammatory cytokine TNFa only. 

Bronchi obtained from patients with a history of smoking displayed higher TrkB and p75NTR expression. 

In ASM cells exposed for 30 minutes to 10 nM BDNF, [Ca2 + ]i responses to ACh and histamine were significantly 

greater than control, while 10 nM NT3 significantly decreased [Ca2 + ]i responses. CSE exposure 

also increased both [Ca2 + ]i response to histamine and profoundly potentiated the enhancing effect of 

BDNF on histamine responses. Following exposure to TNF alpha, [Ca2 + ]i responses to agonists were significantly 

greater compared to control. Addition of 30-minute exposure to 10 nM BDNF resulted in even 

greater responses to agonist. Suppression of TrkB expression using human TrkB small interfering RNA 

(siRNA) transfection did not significantly alter [Ca2+]i responses to histamine or bradykinin, but substantially 

blunted the enhancing effects of CSE and BDNF on [Ca2 + ]i response to agonist. In contrast, 

p75NTR siRNA had only a small effect on the combined enhancement by CSE and BDNF. 

These data show that cigarette smoke is a potent inducer of the BDNF neurotrophin signaling pathway 

in ASM, and that BDNF may be a key mediator of cigarette-smoke induced airway hyperresponsiveness. 


Prakash, YS, Townsend EA, Thompson MA, Vassallo R, Pabelick CM. Cigarette smoke exposure enhances 

1 5 4 P A G E

neurotrophin signaling in human airway smooth muscle. Presented at the American Thoracic Society 

International Conference (A488),. Toronto, Canada, May 2008. 

ROLE OF NICOTINE IN COPD PROGRESSION 

Diane L. Carlisle, PhD; Magee Women’s Health Corporation; YCSA 2005 

Dr. Carlisle’s research objective is to discover whether nicotine contributes to COPD via effects on airway 

healing, especially with respect to abnormal differentiation of airway fibroblasts. Dr. Carlisle plans to 

identify the signaling pathways initiated by low-dose nicotine exposure, and establish their contribution to 

the changes in differentiation that occurs as the lung tries to heal from tobacco exposure. Preliminary data 

have shown that cultured airway fibroblasts treated with nicotine express signaling pathways associated 

with cell growth and apoptosis. Of interest and concern is that signaling secondary to nicotine occurs in 

doses as low as 1 nM, well within the range of the 1-10 nM concentration of nicotine found in the serum 

of non-smokers exposed to SHS. Based on initial work, the PI expanded her original hypothesis to include 

that nicotine may lead to abnormal healing mechanisms through its influence on stem cells. 

Most recently, Dr. Carlisle has identified that stem cells do express nicotine receptors, and that expression 

persists during differentiation. Analysis of global gene expression changes in cells after directed differentiation 

in the presence or absence of nicotine was performed. Ingenuity pathway analysis indicates that 

specific networks of genes are changes in their expression patterns as a result of nicotine exposure during 

the differentiation process. These data are new, additional evidence that nicotine plays a major role in 

development of COPD by activating signaling pathways that predispose differentiating cells towards abnormal 

phenotypes is required. This research will provide new knowledge about the role of nicotine in 

COPD, particularly the increased predisposition of some individuals to developing lung disease as a result 

of SHS exposure. 


Brekosky J, Ben-Yehudah A, Redinger C, Mich-Basso J, Castro C, Navara C, Schatten G, Carlisle DL. 

Low-dose nicotine and the lung: effects on signaling and healing. Presented at Flight Attendants’ 

Medical Research Institute (FAMRI) Annual Meeting. 2007. 

Carlisle DL, Kinney TN, Brekosky JL, Foley JL, Ben-Yehudah A, Redinger CR, Mich-Basso JD, Castro 

CA, Navara CS, Schatten G. Stem cells express nicotinic receptors before and during directed differentiation. 

Proc Amer Assoc Cancer Res 2008;49:5406. 

Carlisle DL, Brekosky J, Foley J, Ben-Yehudah A, Redinger C, Mich-Basso J, Castro C, Navara C, 

Schatten G. Expression of nicotinic markers during stem cell differentiation. Amer Soc Cell Biol 2007. 

Carlisle DL, Kinney T, Brekosky J, Foley J, Ben-Yehudah A, Redinger C, Mich-Basso J, Castro C, Navara 

C, Schatten G. Directed differentiation of NHP embryonic stem cells into fibroblasts: comparison with 

cultured lung fibroblasts. ISSCR 2008. 

Carlisle DL, Liu X, Hopkins TM, Swick MC, Dhir R, Siegfried JM. Nicotine activates cell-signaling pathways 

through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer 

cells. Pulm Pharm and Ther 2007;20:629-641. 

Carlisle DL, Liu X, Tavlarides MC, Hopkins TM, Siegfried JM. Nicotine promotes survival of NSCLC 

cells in the presence of anti-tumor agents. Proc Amer Assoc Cancer Res 2005;46:A5243. 

Liu X, Carlisle DL, Gaither-Davis A, Tavlarides MC, Siegfried, J.M. Gastrin-releasing peptide induces nonsmall 

cell lung carcinoma cell survival through the Akt pathway. Proc Amer Assoc Cancer Res 

2005;46:A156. 

Liu X, Carlisle DL, Swick MC, Gaither-Davis A, Grandis JR, Siegfried JM. Gastrin-releasing peptide activated 

Akt through the epidermal growth factor receptor pathway and abrogates the effect of gefitnib. 

Exp Cell Res 2007;313:1361-1372. 

GENETIC EPIDEMIOLOGY OF PULMONARY FUNCTION AND COPD 

Jemma B. Wilk, DSc; Boston University; YCSA 2005 

Cigarette smoking is a well-documented causative factor for COPD with up to 20% of COPD cases 

effecting never smoked. Dr. Wilk examines the influence of genetic factors on susceptibility to tobacco 

smoke and the etiology of COPD. Dr. Wilk studies quantitative measurements such as forced expiratory 

volume in 1 second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. By examining single 

nucleotide polymorphisms (SNPs) for an association with measures of quantitative lung function and 

COPD, Dr. Wilk plans to uncover genetic variants influencing pulmonary function. Genomewide associa- 

P A G E 1 5 5

tion (GWA) studies of quantitative pulmonary function measurements in the Framingham Heart Study 

revealed significant association with a region of chromosome 4 that includes the hedgehog-interacting protein 

(HHIP) gene. The SNP association was replicated in an independent sample from the Family Heart 

Study, with association observed for both FEV1/FVC and COPD risk. The identified region of chromosome 

4 is the subject of further investigation to evaluate association between the SNP and the expression 

of nearby genes. 


Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF, Jr., Lipinska I, O’Connor GT, Benjamin EJ. 

Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008;133:19-25. 

Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O’Connor GT. Framingham Heart Study genome-wide 

association: results for pulmonary function measures. BMC Med Genet 2007;8 Suppl 1:S8. 

PERIPHERAL BLOOD MONONUCLEAR CELL PROFILING IN TOBACCO EXPOSURE: 

SUSCEPTIBILITY MARKERS FOR COPD 

Michael G. Edwards, PhD; University of Colorado; YCSA 2005 

Dr. Edwards is interested in the observation that clinically evident COPD only develops in a subset of 

tobacco smoke-exposed individuals. The use of global analysis of peripheral blood gene expression has 

great novel discovery potential. There have been publications of this research concerning peripheral blood 

mononuclear cell (PBMC) gene expression in pulmonary artery hypertension. To this end, the PI has used 

Affymetrix U133 Plus 2.0 arrays to examine differences in global gene expression from PBMCs isolated 

from current and former smokers with and without COPD. Analysis of the microarray data reveals more 

than the expected numbers of transcripts that are significantly different between smokers and non-smokers, 

males and females, and subsets of individuals with and without COPD. The PI has also identified thirteen 

transcripts whose expression shows a significant correlation (Spearman, P

MOLECULAR PHENOTYPE OF EARLY EMPHYSEMA 

Russell Bowler, MD, PhD; National Jewish Medical and Research Center; YCSA 2005 

Oxidants in tobacco smoke play a role in the pathogenesis of emphysema. Preliminary data indicate that 

tobacco smoke effects the induction of antioxidants, and that COPD correlates with oxidative stress and 

antioxidant response, which damage lung proteins. Development of both centrilobular emphysema (CLE) 

and panlobular emphysema (PLE) may have distinct antioxidant properties; genetics and proteomics may 

identify biomarkers in order to identify high-risk patients. Dr. Bowler uses high-resolution CT scans to 

determine affected lung segments in asymptomatic smokers in the early stages of emphysema. This will be 

used to direct bronchoscopy to the affected regions and allow assessment for CLE versus PLE. In those 

found to have preclinical emphysema, bronchoalveolar lavage fluid is used to identify protein targets that 

are susceptible to oxidation and proteolysis. Genotyping is used to identify genetic risk factors for COPD. 

Any biomarkers that are discovered will be compared to markers of oxidative stress or inflammation, which 

are traditional markers of COPD. When protein targets of tobacco-induced oxidation have been identified, 

the bronchoalveolar lavage fluid of each individual will be reanalyzed to determine whether there are statistically 

significant differences among emphysema patient subgroups with respect to oxidation products. The 

PI plans to determine which patients are at higher risk for developing early emphysema, and what role 

oxidative stress may play. 


Bowler RP, Canham ME, Ellison MC. Surface enhanced laser desorption/ionization (SELDI) time-offlight 

mass spectrometry to identify patients with chronic obstructive pulmonary disease. COPD 

2006;3:1-10. 

Bowler RP, Ellison MC, Reisdorph N. Proteomics in pulmonary medicine. Chest 2006; 130:567-574. 

Dahl M, Bowler RP, Juul K, Crapo JD, Levy S, Nordestgaard BG. Superoxide dismutase 3 polymorphism 

associated with reduced lung function in two large populations. Am J Respir Crit Care Med 

2008;78:906-912. 

Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. 

COPD 2007;4:355-384. 

Richens TR, Linderman DJ, Horstmann SA, Lambert C, Xiao YQ, Keith RL, Boe DM, Morimoto K, 

Bowler RP, Day BJ, Janssen WJ, Henson PM, Vandivier RW. Cigarette smoke impairs clearance of apoptotic 

cells through oxidant-dependent activation of RhoA. Am J Respir Crit Care Med 2009; Epub 

ahead of print. 

Sutherland ER, Crapo JD, Bowler RP. N-acetylcysteine and exacerbations of chronic obstructive pulmonary 

disease. COPD 2006;3:195-202. 

BIOLOGY OF IL-13 AND 5-LO IN THE PATHOGENESIS OF COPD 

Yun M. Shim, MD; University of Virginia; YCSA 2005 

Dr. Shim’s research hypotheses are 1) that leukotrienes are critical biological mediators regulating development 

of emphysematous COPD in susceptible cigarette smoke-exposed individuals and 2) that 5-lipoxygense 

and leukotriene A4 hydrolase are important in determining the fate of COPD in susceptible, cigarette-exposed 

individuals with IL-13-depedent and -independent inflammation across a spectrum of chronic 

bronchitis to emphysema. Dr. Shim will characterize expression and localization of IL-13, Th2 inflammatory 

cytokines, and leukotrienes in COPD and normal control patients. A population of 25 to 30 

patients will be recruited for each group and will include individuals with a well-established diagnosis of 

emphysematous smokers, nonemphysematous smokers, and individuals who have never smoked. In addition, 

the same population will be used to determine expression and localization of the enzymes that produce 

leukotrienes in COPD. The direct effects of cigarette smoke on induction of IL-13 and Th2 inflammatory 

cytokines and leukotriene production will be determined using peripheral whole blood. In addition, 

the role of leukotrienes in the pathogenesis of emphysema will be investigated in the IL-13 transgenic 

knock-in murine modeling and IL-13-independent elastase-induced murine emphysema modeling. Results 

from Dr. Shim’s research will lead toward potential new therapies for patients with COPD. 

CIGARETTE SMOKE AND MECHANICAL STRETCH IN COPD 

James C. Lavelle, MD; University of Colorado at Denver and Health Sciences Center; YCSA 2006 

Patients with emphysema have enlarged alveolar spaces, thus, by the Law of Laplace, the alveolar 

epithelium in these patients is subject to greater stresses and strains. Dr. Lavelle is interested in the effects 

of mechanical stretch and cigarette smoke on lung epithelial cells, specifically concerning injury, repair, and 

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propagation of emphysema by alveolar cell apoptosis. Application of injurious strain to cultured A549 and 

Calu-3 alveolar epithelial type-II-like cells results in both plasma membrane disruptions and initiation of 

multiple signaling cascades, and cells exposed to cigarette smoke extract are less able to repair stretchinduced 

membrane breaks. Cyclic strain at 30% amplitude, 0.25 Hz results in rapid activation of the lowmolecular 

weight guanosine triphosphatase, RhoA. Cyclic strain leads to nuclear factor kappa B and activator 

protein 1 dependent elaboration of proinflammatory cytokines such as IL-8. These events are blocked 

by pharmacologic inhibition of Rho with Clostridium botulinum C3 exoenzyme. Ongoing studies will further 

elucidate the transcriptional program elicited by stretch, and will examine the effects of stretch and 

cigarette smoke extract on the structure and function of the actin cytoskeleton, with special attention to 

the role of RhoA activation in the repair of stretch-induced plasma membrane disruptions and the effects 

therein of cigarette smoke extract. It is hypothesized that the inflammatory milieu induced by stretch and 

the deleterious effect of cigarette smoke on plasma membrane repair synergize to contribute to alveolar cell 

apoptosis and the propagation of emphysema. 

SERINE PROTEASE INHIBITOR E2 AND COPD 

Sorachai Srisuma, MD, PhD; Mahidol University, Bangkok; YCSA 2006 

COPD is a complex disease influenced by environmental and genetic factors. Prominent pathological 

features observed in patients with COPD include emphysema, small airway fibrosis, mucus overproduction, 

and the formation of bronchus-associated lymphatic tissue. Overwhelming evidence suggests the presence 

of genetic factors, in addition to alpha-1-antitrypsin (or serine proteinase inhibitor clade A, member1) deficiency 

contributes to the development of COPD in the general population. Using a combination of genetic 

linkage, microarray gene expression, and genetic association studies, serine proteinase inhibitor clade E, 

member 2 (SERPINE2) has been identified as a novel candidate susceptibility gene for COPD. SERPINE2 

is a cell and matrix-associated inhibitor of thrombin and plasmin, with described functions in the brain and 

genitourinary system. Dysregulation of SERPINE2 gene expression was observed in the lung tissue of 

patients with reduced pulmonary function measurements. SERPINE2 gene expression was highly regulated 

across mouse lung development, with maximal expression coincident with alveolar maturation. Prominent 

immunolocalization in adult mouse and human lungs was observed in the conducting airway epithelium as 

well as in the tunica adventitia of pulmonary vasculature, whereas no staining was detected in distal airspaces. 

In an effort to gain insight into the physiological role of SERPINE2 in the lung, Dr. Srisuma laboratory 

studied the lung morphology of SERPINE2-knockout (SERPINE2 -/- ) mice. Interestingly, the lung morphology 

of adult SERPINE2 -/- animals showed spontaneous peribronchial mononuclear cell infiltration. 

At 32 weeks of age, SERPINE2 -/- mouse lungs displayed moderate to large area of mononuclear cell 

aggregates in 11 out of 13 (11/13= 85%) in airways, but only 10 out of 36 (10/36= 22%) age-matched 

control lungs. To further characterize these infiltrates, Dr. Srisuma’s laboratory performed immunostaining 

for CD3 (T-lymphocytes) and B220/CD45R (B-lymphocytes). These results indicated that the inflammatory 

infiltrates are mainly composed of T- and B-lymphocytes. Their data suggested that SERPINE2 contributes 

to the control of pulmonary homeostasis by preventing and/or limiting inflammatory cell recruitment 

and that variation in its function may confer susceptibility to cigarette smoke-related lung disease in 

humans. 



Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced 

emphysema in mice. J Clin Invest 2004;114:1248-1259. 

CELL-BASED THERAPY FOR CIGARETTE SMOKE-RELATED LUNG DISEASE 

Andrew A. Wilson, MD; Boston University; YCSA 2007 

Current therapies for COPD are largely aimed at the alleviation of symptoms rather than cure of the 

underlying disease process. Recent advances in the understanding of the biology of COPD suggest potential 

molecular and genetic targets for therapy; however, an inability to target the tissue and cell-types 

involved in COPD pathogenesis has severely limited the development of novel treatments for this disease. 

The research project is aimed at the development of a novel method designed to overexpress therapeutic 

molecules and knock down the expression of deleterious genes specifically in alveolar macrophages, the 

cell-type most responsible for tobacco-induced lung injury. To accomplish this goal, the PI developed a 

lentiviral system capable of selectively targeting alveolar macrophages and allowing the inducible overex- 

1 5 8 P A G E

pression of genes or interfering RNAs (RNAi) capable of modulating lung inflammation or elastolysis. The 

PI has performed introductory experiments in mice demonstrating that this system is capable of transducing 

alveolar macrophages in vivo resulting in long-term expression of human alpha-1-antitrypsin (A1AT) in 

the epithelial lining fluid at levels that would theoretically be protective in patients deficient in this protein. 

The PI has demonstrated that overexpression of A1AT by this method partially protects these animals from 

developing emphysema after treatment with intratracheal elastase. Dr. Wilson is now testing this technique 

to see if it confers similar protection from cigarette smoke-mediated injury. Future experiments will be 

aimed at modifying this lentiviral system to decrease the expression of gene products in the alveolar 

macrophage that are involved in the development of COPD and at testing this system in human cells ex 

vivo. 

INFLUENCE OF ARHGEF1 ON PULMONARY IMMUNITY 

John M. Hartney, PhD; University of Colorado; YCSA 2007 

Leukocyte migration and adhesion are integral parts of a normal inflammatory response. Genetic variation 

in genes important for these processes may predispose certain individuals to chronic inflammatory diseases 

such as COPD or emphysema. The investigators have generated a mouse line deficient for a single 

protein (Arhgef1) whose leukocytes display altered migration and adhesion properties. These mice also 

spontaneously develop symptoms similar to COPD. Dr. Hartney’s group has determined by transfer of 

bronchoalveolar lavage leukocytes that the airspace leukocytes are sufficient to cause pathology in a normal 

lung. The investigators have also discovered that when peritoneal macrophages are plated on fibronectin 

they exhibit exaggerated matrix metalloproteinase (MMP) production via the a5b1 integrin pair. A manuscript 

describing these findings has recently been submitted for publication. 

Additionally, using quantitative flow cytometry and a monoclonal antibody for Arhgef1, they have found 

that humans with COPD express much lower levels of this protein (Arhgef1) than healthy individuals. 

Neither smoke exposure nor lipopolysaccharide (LPS) stimulation altered the level of Arhgef1 expression in 

murine leukocytes, suggesting that differences in expression may be due to genetic factors. If these findings 

are replicated in future studies they could explain in part why only some individuals are susceptible to 

develop COPD when exposed to tobacco smoke. Based on the findings in patients with COPD, they have 

obtained additional pilot funding through their institution to examine the response of bronchoalveolar 

lavage macrophages to integrin ligands from healthy individuals and patients with COPD. In conjunction 

with these human studies, they are currently conducting experiments with a murine model to determine 

how Arhgef1 regulates integrin-mediated MMP production. Together these studies may help science gain 

a better understanding of who may be susceptible to develop COPD. In addition, the identification of the 

receptor and/or ligand responsible for the Arhgef1-dependent signaling pathway could represent a novel 

target for altering MMP production in the lungs of patients with COPD. 

THE ROLE OF THROMBOSPONDIN-1 IN EMPHYSEMA 

Michael E. Ezzie, MD; Ohio State University; YCSA 2007 

COPD is a worldwide epidemic and the fourth leading cause of death in the United States, affecting 

over 16 million people. More than 85% of COPD in the United States is due to smoking tobacco, and the 

incidence is rising, particularly in women. In addition, the Environmental Protection Agency (EPA) 

released a report in late 1992 that concluded, among other things, that second hand tobacco smoke was 

harmful to the lung function of non-smokers. New models of emphysema have identified new cellular 

pathways involved in the pathogenesis of COPD, implicating transforming growth factor-beta (TGF-beta) 

in the development of emphysema. Thrombospondin-1 (TSP-1) is a protein with many functions, including 

regulation of TGF-beta and other activators of emphysema. Dr. Ezzie’s group is investigating the role 

of TSP-1 in emphysema through a translational approach, using a mouse model of emphysema along with 

samples from human lungs. They hypothesized that loss of TSP-1 activity is a contributor to the development 

of emphysema and further investigation of the effect of smoking on mice that lack TSP-1 will determine 

if they get more emphysema than wild-type mice exposed to smoke. To accomplish these goals, the 

team is generating the emphysema mouse model through a process that requires the mice to undergo 9 

months of smoke exposure. In addition, they have recruited lung samples from smokers with varying 

degrees of COPD and begun work to analyze these samples for TSP-1. 

CXCL5 IS CENTRAL TO CIGARETTE SMOKE-INDUCED NEUTROPHIL INFLUX 

Sambithamby Jeyaseelan, DVM, PhD, Louisiana State University; YCSA 2007 

The role of a protein molecule in the lung, chemokine (C-X-C motif) ligand 5 (CXCL5), that is pro- 

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duced mainly by alveolar type-II epithelial cells in response to a bacterial product, endotoxin (lipopolysaccharide, 

LPS) has recently been discovered. LPS is only one of the numerous active ingredients in cigarette 

smoke. The overall objective of this investigation is to determine the role of CXCL5 in neutrophil influx in 

the lungs and to demonstrate the effects associated with CXCL5-induced neutrophil accumulation in 

response to cigarette smoke. Viable and fertile Cxcl5 gene-deficient mice (Cxcl5 -/- ) have successfully been 

generated. These mice were used to demonstrate that they express similar levels of mRNA and protein of 

the chemokine KC and macrophage-inflammatory protein- 2 (MIP-2), despite the absence of Cxcl5, when 

compared to their littermate controls (Cxcl5 +/+ ). However, impaired neutrophil influx was observed in 

Cxcl5 -/- mice at 8 hours (80% reduction) and 24 hours (20% reduction) when compared with their littermate 

controls (Cxcl5 +/+ ) after an in vivo Escherichia coli LPS challenge. Experiments are being conducted 

to determine the role of Cxcl5 in lung inflammation in mice in response to SHS exposure. Moreover, a 

correlation has been established between human epithelial cell-derived neutrophil-activating protein-78 

(ENA-78) levels in bronchoalveolar lavage fluid and neutrophil accumulation in COPD patients. These 

research findings will help to develop new therapeutic strategies for preventing or reducing the ultimate 

development of COPD. 


Cai S, Zemans RL, Young SK, Worthen GS, Jeyaseelan S. MD-2 dependent and -independent neutrophil 

accumulation during E. coli pneumonia. Am J Respir Cell Mol Biol 2008 [Epub ahead of print]. 

Craig A, Mai J, Cai S, Jeyaseelan S. Neutrophil recruitment to the lungs during bacterial pneumonia. 

Infect Immun 2009;77:568-575. 

Smoak K, Madenspacher J, Jeyaseelan S, Williams B, Dixon D, Poch KR, Nick JA, Worthen GS, Fessler 

MB. Effects of liver x receptor agonist treatment on pulmonary inflammation and host defense. J 

Immunol 2008;180:3305-3312. 

Walker JE, Odden AR, Jeyaseelan S, Zhang, P, Bagby GJ, Nelson S, Happel KI. Ethanol exposure impairs 

LPS-induced pulmonary LIX expression: alveolar epithelial cell dysfunction as a consequence of acute 

intoxication. Alcohol Clin Exp Res 2009;33:357-365. 

REGULATORS OF CIGARETTE-INDUCED ENDOTHELIAL CELL APOPTOSIS 

Rachel Damico, MD, PhD; The Johns Hopkins University; YCSA 2008 

Cigarette smoke (CS) exposure is unquestionably the most frequent cause of COPD. As the fifth leading 

cause of death world wide, COPD is responsible for an estimated 2.5 million deaths annually. Accelerated 

endothelial cell apoptosis is now recognized as an important early determinant of lung destruction and 

resultant emphysema in COPD. Multiple investigators have demonstrated that endothelial cell apoptosis is 

increased in the lung tissue of smokers and patients with COPD compared to non-smokers. Endothelial 

cell apoptosis is sufficient to induce emphysema in multiple animal models of COPD. Blockade of apoptosis 

prevents development of disease in select models, suggesting that apoptosis is necessary for development 

of emphysematous changes in the lung. Oxidative stress, inflammation, and protease/antiprotease imbalance 

all have the potential to promote endothelial apoptosis, emphasizing endothelial apoptosis as a potential 

nodal point in the pathogenesis of COPD. As such, apoptosis becomes an attractive target for therapeutic 

intervention. However, the molecular basis of smoking-induced endothelial cell injury remains 

unclear. This information could provide rational therapeutic targets to prevent endothelial cell apoptosis 

and disease progression. Macrophage migration inhibitory factor (MIF) is an antiapoptotic cytokine 

expressed by human endothelial cells. CS is known to contain numerous potential apoptogens, including 

reactive oxygen species (ROS) and the bacterial toxin, lipopolysaccharide (LPS). 

The PI has previously demonstrated that MIF antagonizes LPS-induced apoptosis of human pulmonary 

endothelial cells (HPEC) and plays a critical role in the expression of the apoptosis inhibitor, FLICE-like 

inhibitory protein (FLIPshort). MIF also possesses oxidoreductase activity, and, thus, may modify the 

redox status of the cell. The capacity of MIF to antagonize LPS-induced HPEC apoptosis, regulate apoptosis 

inhibitors, and potentially antagonize ROS leads the group to investigate its role in HPEC responses 

to CS. Their hypothesis is that MIF acts as an endogenous endothelial antiapoptotic factor governing the 

sensitivity of endothelial cells (EC) to CS-induced apoptosis. The overall goal of this project is to characterize 

the molecular determinants of endothelial survival and apoptosis, and translate these discoveries into 

new treatments in CS-associated COPD. 

Alveolar cell apoptosis has been recently implicated in the pathogenesis of COPD and emphysema via 

increased alveolar wall destruction. Additionally, the p38 mitogen activated protein (MAP) kinase, a potential 

mediator of alveolar cell apoptosis, has been shown to be activated in alveolar walls in patients with 

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COPD. However, the downstream effectors of p38 MAP kinase involved in mediating the development 

and severity of COPD remain unknown. 

Human pulmonary arterial endothelial cells were exposed to cigarette smoke extract (CSE) for increasing 

time periods. Cell lysates were assessed for protein expression by Western blotting. In parallel experiments, 

apoptotic cells were identified using fluorescent microscopy and Hoechst staining. 

There was significant activation/phosphorylation of p38 MAP kinase and its downstream effectors, i.e. 

MK2 and heat shock protein 27 (HSP27), accompanied by dephosphorylation of the prosurvival enzyme 

protein kinase B (AKT). Furthermore, exposure to CSE induced apoptosis, which was prevented by inhibition 

of p38 MAP kinase and MK2 with SB203580 (20µM), KKKALNRQLGVAA (10µM) respectively. 

Lastly, phosphorylation of HSP27 correlated with induction of apoptosis. 

Taken together, these results show that phosphorylation of HSP27 may be necessary for CSE-mediated 

apoptosis. Possible mechanisms include loss of molecular chaperoning function upon phosphorylation of 

HSP27 thereby potentiating the proapoptotic enzyme, caspase 3, as well as inhibiting the prosurvival 

kinase AKT. 

ROLE OF THE WNT-BETA-CATENIN PATHWAY IN EPITHELIAL INJURY BY PMN IN EMPHYSEMA 

Rachel L. Zemans, MD; National Jewish Medical and Research Center; YCSA 2008 

Neutrophil (PMN) transepithelial migration is critical to the pathogenesis of epithelial injury in emphysema. 

It is known that PMN migration induces epithelial injury in part via nondegradative mechanisms 

resulting in disassembly of junctional complexes and apoptosis. However, the specific intracellular pathways 

by which these effects occur are largely undefined. Methods. CALU-3 human lung epithelial cells were 

cultured on the underside of inverted transwells, and PMN were induced to transmigrate across the epithelium. 

Epithelial cells were purified from migrating PMN by magnetic separation, and their complementary 

DNA (cDNA) was subjected to gene array analysis using Agilent 44K human microarray chips. In separate 

experiments, PMNs were induced to migrate across epithelial monolayers plated on either small (0.4 mm) 

or large (3 mm) pore transwell filters, followed by lysis of epithelial cells and immunoblotting. 

PMN transmigration resulted in epithelial injury as determined by a decrease in transepithelial resistance 

and histologic appearance of epithelial defects. Gene array pathway analysis suggested modulation of the 

WNT-beta-catenin pathway with alterations in expression of Frizzled 1, 2, 4, and 10, Wnt 1, 2b, 3a, 5a, 8a 

and b, 11, and Dickkopf protein (DKK). Modulation of this pathway was confirmed by immunoblotting, 

which revealed dephosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3 (GSK-3) in 

response to PMN transmigration. Moreover, these events were prevented by the use of small pore filters, 

suggesting that these pathways are activated by contact-dependent mechanisms rather than by soluble 

mediators. 

Data indicate that the WNT-beta-catenin pathway is modulated in epithelial cells in response to PMN 

transmigration in a contact-dependent manner. It is hypothesized that modulation of this signaling pathway 

will play a critical role in emphysema. In the future, they will examine the modulation of this pathway 

by exposure of the epithelium to cigarette smoke before PMN transmigration. 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 


NONINVASIVE ASSESSMENT OF THE LOWER RESPIRATORY TRACT IN RESPONSE TO SECOND HAND TOBACCO 

SMOKE 

Richard A. Robbins, MD, PhD; Carl T. Hayden VA Medical Center; CIA 2003 

Few studies have compared sputum, bronchoalveolar lavage (BAL), and exhaled breath condensate 

(EBC) obtained from the same individuals on the same day. Dr. Robbins group has collected EBC, BAL, 

and sputum from 35 subjects: 15 smokers, 10 non-smokers, 4 former smokers, and 6 non-smokers heavily 

exposed to SHS. Total protein was elevated in sputum (482 + 99.2 mg/ml) compared to BAL or EBC (78 

+ 11, 34 + 8 mg/ml, p0.7, each 

comparison). Sputum contained a higher percentage of neutrophils compared to BAL (17.8 + 5.9 vs. 4.0 + 

1.5%, p

concentrations of inflammatory indices such as percentage neutrophils, protein, and leukotriene B4 than 

other sources of lower respiratory fluids, although the inflammatory indices tend to correlate between the 

different sampling techniques. 


Garcia A, McHugh M, Ballering JG, Hoyt JC, Hayden JM, Robbins RA. Neutrophils, protein and LTB4 

are increased in sputum compared to bronchoalveolar lavage and exhaled breath condensate. Am J Resp 

Crit Care Med 2005;171:A844. 

Garey KW, Neuhauser MM, Robbins RA, Danziger LH, Rubinstein I. Markers of inflammation in exhaled 

breath condensate of young healthy smokers. Chest 2004;125:22-26. 

Numanami H, Koyama S, Nelson DK, Hoyt JC, Freels JL, Habib MP, Amano J, Haniuda M, Etsuro Sato 

E, Robbins RA. Serine protease inhibitors modulate smoke-induced chemokine release from human lung 

fibroblasts. Am J Resp Cell Mol Biol 2003;29:613-619. 

MATRIX-INDUCED EPITHELIAL ACTIVATION IN BRONCHITIS 

Maureen Horton, MD; The Johns Hopkins University; YCSA 2003 

Dr. Horton’s group has defined the ability of fragments of the extracellular matrix component hyaluronan 

(HA) to promote epithelial cell-induced inflammation. The PI determined that HA fragments employ 

innate immune Toll-like receptor-2 (TLR-2) to mediate its effects. Additionally, blocking TLR-2 inhibits 

HA fragment-induced inflammation and disease. Furthermore, the TLR-2-deficient animals are protected 

from noninfectious lung injury. Specifically, HA fragments induce IL-8 and inducible protein 10 gene 

expression in airway epithelial cells by different signaling pathways, mitogen-activated protein kinase 

(MAPK), and nuclear factor-kappa B, respectively. These observations indicate that broken down extracellular 

matrix, in the form of HA fragments, employ the same activating receptors as infectious agents and, 

thus, provide a mechanism by which HA can promote the chronic inflammation of bronchitis in the 

absence of infection. Such studies have offered insight into the role of epithelial cells in inflammation and 

to the identification of potential clinical inhibitors. The PI predicts these studies with potential therapeutic 

agents will serve as preclinical data in support of clinical trials of these agents to help treat and possibly 

reverse the debilitating symptoms and tissue destruction that characterize chronic bronchitis. 

BIOMARKERS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 

Robert E. Walter, MD; Boston University; YCSA 2003 

Dr. Walter’s research utilizes the multigenerational, multi-cohort Framingham Heart Study (FHS) to better 

understand the mechanisms underlying the development of chronic airflow obstruction resulting from chronic 

tobacco smoke exposure (COPD). FHS has a wide range of longitudinal measures, including lung function 

and tobacco smoke exposure. The genetic information and the variety of biomarkers of inflammation, oxidant 

stress, and endothelial function measured at various times points offer a unique opportunity to explore the 

mechanisms, including gene-by-environmental interactions, linking cigarette smoke to pulmonary disease. 


Walter RE, Guo CY, Chen T, Lee TA, Weiss KB, O’Connor GT. Chronic obstructive pulmonary disease in 

the Framingham Heart Study, 2006. Presented at the American Thoracic Society. 

Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF, Jr., Lipinska I, O’Connor GT, Benjamin EJ. 

Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008;133:19-25. 

Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O’Connor GT. Framingham Heart Study genome-wide 

association: results for pulmonary function measures. BMC Med Genet 2007;8 Suppl 1:S8. 

DIAGNOSTIC TECHNIQUES 


DETECTION OF PASSIVE SMOKE EXPOSURE IN CHILDREN AND ADULTS USING ORAL BASED RAPID TEST 

TECHNOLOGY 

R. Sam Niedbala, PhD; Lehigh University; CIA 2006 

Passive exposure to tobacco smoke causes a variety of illnesses ranging from mild allergic reactions to 

some forms of cancer. Knowing that exposure brings risk, a rapid test to quickly assess exposure to SHS 

would create a valuable tool for researchers and clinicians, particularly in evaluating vulnerable populations 

1 6 2 P A G E

such as children, allowing intervention and/or prevention of future disease. A new test that detects low 

levels of the breakdown products of nicotine has been developed. This test employs small amounts of saliva, 

making it noninvasive and easy to use, thus, having the potential to assist front-line physicians and 

researchers to identify those at risk of illness caused by SHS. The challenge has been to first develop and 

then assemble various reagents that will rapidly identify the lowest possible level of nicotine metabolites 

from a viscous oral fluid sample. During the development of all reagents for construction of a rapid on-site 

assay, a variety of derivatives were developed for use as haptens. These haptens were coupled to carrier 

proteins under a variety of conditions chosen to improve the analytical sensitivity of the assay. Additionally, 

these conjugates were used as immunogens to generate antibodies. Evaluation of candidate hapten 

conjugates with antibodies was initially performed using a gold standard micro plate ELISA to determine 

antibody specificity, sensitivity, and precision. A candidate showing sensitivity, using the micro plate format, 

of near 1.0 ng/mL was chosen. Once qualified in the micro titer plate assay, reagents were then tested for 

feasibility in a lateral flow format. The lateral flow format is designed to be an on-site test capable of 

detecting 2 to 20 ng/mL of cotinine from a saliva sample using an inexpensive reader that uses a 

complimentary metal-oxide semiconductor (CMOS) image sensor to quantify a reporter signal in the visible 

range. Earlier work with various human gland fluids, following a small dose of nicotine ingestion, suggest 

that oral fluids to be tested may be collected from either the parotid or submandibular oral glands. The 

outcome of the project has been a 20-minute on-site test that may become a useful tool in the near future. 

SCREENING AND DIAGNOSIS OF LARYNGEAL CANCER WITH OCT 

Brian J. F. Wong, MD, PhD; University of California, Irvine Medical Center; CIA 2007 

Tobacco smoke produces a spectrum of changes in the delicate vocal cord epithelial layers, which may 

vary from benign processes such as chronic laryngitis to malignant and premalignant conditions such as 

dysplasia, carcinoma in situ, and frank invasive laryngeal cancer. Since it is extremely difficult to distinguish 

among these disorders, current diagnostic practices require a true vocal cord (TVC) biopsy. Biopsy requires 

microsurgery, which places the patient at significant risk for iatrogenic dysphonia. Dr. Wong proposes to 

construct an optical coherence tomography (OCT)-based device for use in the office to image and 

differentiate early laryngeal cancers from benign laryngeal diseases. OCT is a noncontact, emerging 

imaging modality that uses light to construct high-resolution (7 micron), cross-sectional images of tissue 

to depths of up to 1-2 mm. In previous FAMRI-supported work, the larynx and upper aerodigestive tract 

were imaged in more than 200 patients during surgery, and they accumulated the world’s largest series of 

OCT images in this anatomic region. OCT’s sensitivity has been defined to detect cancer in the larynx 

during operative endoscopy. The focus of the current work is technology development that will allow OCT 

to move out of the operating room and into the offices and clinics where it can be used to screen and 

diagnose patients at risk for cancer and other tobacco-related laryngeal diseases. 

The objectives of this study are to 1) design and construct an advanced OCT image system integrated 

for use with an office-based laryngeal endoscopy imaging system; 2) perform large-scale screening of 

patients at risk of laryngeal cancer; and 3) correlate OCT vocal cord images with biopsies in the subset of 

patients undergoing microlaryngeal surgery for cancer diagnosis. The PI projects that OCT laryngeal 

imaging will be performed in an office setting without anesthesia or sedation. At least 500 adult patients 

will be enrolled and their vocal cords will be imaged using OCT. Over the course of the study, the PI 

estimates that at least 100 subjects will undergo surgical endoscopy with biopsy, which will allow 

correlation of OCT images with conventional histology. He expects the instrument to allow assessment of 

1) vocal cord basement membrane integrity; 2) basement membrane violation by epithelial tumors (which 

is the hallmark of invasive carcinoma); and 3) the true lateral and deep extension of vocal cord tumors. 

The development of this technology and instrumentation will enable otolaryngologists to 1) better screen 

and identify patients at high risk for early laryngeal cancer; 2) monitor and observe patients with tobaccorelated 

vocal cord problems; and 3) aid in planning laryngeal microsurgery. Further, OCT imaging will 

provide a means of documenting changes in three-dimenstional vocal cord microstructure over time. The 

PI hypothesizes that OCT has the potential to become as vital as CT and MRI for managing early head 

and neck malignancies because it provides such exquisite detail on tissue microstructure on the epithelium, 

where the disease originates. Introducing this technology into the clinic will revolutionize care of laryngeal 

cancer, vocal cord disease, and speech disorders. 


Karamzadeh AM, Jackson R, Guo S, Ridgway JM, Wong H, Ahuja GS, Chao MC, Liaw L-H, Chen Z, 

Wong B. Characterization of submucosal lesions using optical coherence tomography in the rabbit 

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subglottis. Arch Otolaryngol Head Neck Surg 2005;131:499-504. 

Torkian B, Guo S, Jahng AW, Liaw L-H, Chen Z, Wong BJF. Noninvasive measurement of ablation crater 

size and thermal injury after CO2 laser in the vocal cord with optical coherence tomography. 

Otolaryngol Head Neck Surg 2006;134:86-91. 

Wang Y, Bachman M, Li G-P, Guo S, Wong BJF, Chen Z. Low-voltage polymer-based scanning cantilever 

for in vivo optical coherence tomography. Opt Lett 2005;30:53-55. 

Wong BJF, Jackson RP, Guo S, Ridgway JM, Mahmood U, Su J, Shibuya TY, Crumley RL, Gu M, 

Armstrong WB, Chen Z. In vivo optical coherence tomography of the human larynx: normative and 

benign pathology in 82 patients. Laryngoscope 2005;115:1904-1911. 

PRODUCTION OF ANTI-COTININE MONOCLONAL ANTIBODY AND DETECTION OF 

SECOND HAND TOBACCO SMOKE EXPOSURE 

Zhiyong Cui, PhD; Dartmouth College; YCSA 2006 

When a child is seen by a doctor for ear, nose, throat, or respiratory problems, it would be very useful 

to detect whether the child is suffering from SHS exposure. Providing a doctor with the ability to 

document a child’s exposure to SHS should initiate changes to prevent further SHS exposure. The present 

work will develop a simple test for SHS exposure. Nicotine is one of the principal agents in tobacco. It is 

metabolized very quickly, with a half-life of only 20 minutes in serum, and thus is not a reasonable target 

for a screening test. The concentrations of cotinine, the major metabolite of nicotine, are not influenced by 

confounding factors. Its average half-life in blood is 19 hours. Cotinine has been widely used as a 

biomarker of tobacco exposure. Currently, there is a test available using a relatively insensitive polyclonal 

cotinine antibody that can check saliva, urine or blood samples for smoke exposure, but it is only useful for 

high levels of exposure from direct smoking. 

With two haptens, keyhole limpet hemocyanin (KLH)-cotinine and bovine serum albumin (BSA)- 

cotinine, Dr. Cui’s group produced a monoclonal anticotinine immunoglobulin M (IgM) cell line by using 

hybridoma technique. Clone 119.2 produced 39 mg/mL of monoclonal anticotinine IgM antibody in cell 

culture. They have synthesized two new antigens, KLH-extended chain-cotinine and BSA-extended chaincotinine. 

Unfortunately, these two new antigens failed to produce IgG anticotinine monoclonal antibody. 

Now, they are synthesizing cotinine-KLH and cotinine-BSA multiple conjugates (one KLH/BSA molecule 

conjugated with two or more cotinine molecules) as new haptens. In the meantime, the present 

monoclonal anticotinine IgM antibody is being purified and will be developed as a lateral flow test, 

specifically, for detection of SHS exposure in urine or saliva. 

DIAGNOSTIC TECHNIQUES 


NOVEL MICROVESSEL STRUCTURE IMAGING STRATEGIES FOR EARLY DETECTION OF LUNG CANCER RELATED 

TO SHS EXPOSURE 

Justin D. Pearlman, MD, PhD; Dartmouth College; CIA 2003 

Dr. Pearlman assessed the feasibility of characterizing tumor angiogenesis noninvasively for early, 

accurate cancer diagnosis using sophisticated MRI-based analysis that can visualize and characterize 

microvascular development in vivo. A three-dimensional robotic microscope was developed as a method for 

characterizing the effects of early cancers on microvascular changes. Additionally, a dynamic MRI was 

developed to evaluate pulmonary vasculature in and around early cancer nodules to distinguish them from 

inflammatory nodules and benign lesions, such as scar tissue. 


Huang H, Ford J, Gao L, Pearlman JD. Early lung cancer detection from secondhand smoke based on 

registered perfusion MRI. Oncol Rep 2006;15:1081-1084. 

Huang H, Shen L, Makedon F, Zhang S, Greenberg M, Gao L, Pearlman JD. A clustering-based approach 

for prediction of cardiac resynchronization therapy ACM, 2005. Presented at the Symposium on Applied 

Computing. Santa Fe, NM. 

Shen L, Gao L, Zhuang Z, DeMuinck E, Huang H, Makedon, Pearlman J. An interactive 3D visualization 

and manipulation tool for effective assessment of angiogenesis and arteriogenesis using computed 

tomographic angiography, 2005. Presented at the SPIE Medical Imaging meeting. San Diego, CA, Feb 

12-17, 2005.. 

1 6 4 P A G E

Pearlman JD, Drinane M, Laidlow M. MRA microvascular mapping of lungs for early diagnosis of cancer 

in primary and second-hand smokers, 2005. Presented at the Procedures of the 15th International 

Society for Magnetic Resonance in Medicine Scientific Meeting and Exhibition. Miami, FL. 

Qin J, Chittenden TW, Gao L, Pearlman JD. Automated migration analysis based on cell texture: method 

and reliability. BMC Cell Biol 2005;3:6-9. 

Shen L, Gao L, Zhuang Z, deMuinck E, Makedon F, Pearlman JD. An interactive 3D visualization and 

manipulation tool for effective assessment of angiogenesis and arteriogenesis using computed 

tomographic angiography [abstract]. In: Galloway RL, Cleary KR, eds. Proceedings of SPIE. Medical 

Imaging 2005: Visualization, Image-Guided Procedures, and Display, Apr, 2005. 

Shen L, Zheng W, Gao L, Huang H, Makedon F, Pearlman JD. Modeling time-intensity profiles for 

pulmonary nodules in MR images. Presented at The 27th Annual International Conference of the IEEE 

Engineering in Medicine and Biology Society. Shanghai, China, Sept 1-4, 2005. 

Shen L, Zheng W, Gao L, Huang H, Makedon F, Pearlman JD. Spatio-temporal modeling of lung images 

for cancer detection. Oncol Rep 2006;15:1085-1089. 

Wang Y, Makedon F, Ford JC, Pearlman JD. HykGene: a hybrid approach for selecting marker genes for 

phenotype classification using microarray gene expression data. Bioinformatics 2005;21:1530-1537. 

Wang Y, Makedon F, Pearlman JD. Tumor classification based on DNA copy number aberrations 

determined using SNP arrays. Oncol Rep 2006;15:1057-1059. 

Wang Y, Makedon F, Pearlman JD. Tumor classification based on DNA copy number aberrations 

determined using SNP Arrays. Oncol Rep 2005;15:1057-1059. 

RISK FACTORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE 

Francine L. Jacobson, MD; Harvard University; CIA 2004 

Dr. Jacobson’s hypothesis states that exposure to SHS as a cause of COPD is equal in importance to 

that of cigarette smoking, and can lead to changes detectable on high-resolution chest CT scans. This 

hypothesis has been tested by CT scanning of normal never-smokers with significant exposure to SHS, 

compared with never-smokers without SHS exposure and patients with severe COPD. Subtle CT scan 

findings in never-smokers exposed to second hand tobacco smoke, who have normal lung function, include 

small airway thickening and subtle loss of lung parenchyma. Although too subtle to consider the 

individuals abnormal, the changes in lung structure are similar to the dramatic changes seen in patients 

with severe early onset COPD. The well-studied normal middle-aged cohort of 16 individuals developed 

from this study provides new insight into the range of the normal CT appearance of lung along with the 

relationship to SHS exposure and increases radiologist reporting of subtle changes that may precede 

clinical development of COPD. 

ECG-GATED MULTIDETECTOR CT OF AORTIC DISTENSIBILITY 

Joel Fletcher, MD; Mayo Clinic; CIA 2004 

Abdominal aortic distensibility is related to hypertension, cardiovascular mortality, and abdominal aortic 

aneurysm (AAA) rupture. Dr. Fletcher’s research involves the use of electrocardiogram (ECG)-gated 

multidetector CT technology. This advanced method produces CT images that can show pulsatile motion 

of the abdominal aorta. Dr. Fletcher’s objective is to optimize these techniques and develop software 

algorithms that can automatically and reproducibly calculate regional changes in aortic pulsatility, focusing 

on patients with AAA. The PI will test the hypothesis that aortic aneurism distensibility is an independent 

risk factor for AAA rupture or a candidate for intervention. One hundred patients with AAA who are likely 

to be followed by CT scanning and unlikely to undergo immediate surgery will be recruited. These 

individuals will undergo time-resolved ECG-gated multidetector CT angiography at baseline and 1-year 

follow up. Novel aortic distensibility software will be used to create aortic pulsatility maps and quantitate 

maximum aortic distensibility associated with each AAA. This information will be compared to clinical 

outcome to determine if aneurism distensibility can predict rupture. Once developed, the technique will be 

optimized to minimize radiation dose, while achieving reproducible aortic distensibility measurements. 


Fletcher J. ECG-gated multidetector CT of aortic pulsatility: validation and ongoing clinical study, 2005. 

Presented at the FAMRI Symposium. Miami, FL. 

Fletcher J. ECG-gated multidetector CT of aortic pulsatility: validation and ongoing clinical study, 2005. 

Presented at the SOMATOM User’s Conference. Rome, Italy, May, 2005. 

Zhang J, Bruesewitz M, Primak A, Fletcher JG, McCollough CH. Partial reconstructions in multi- 

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detector row CT (MDCT), 2005. Presented at the Radiological Society of North America Scientific 

Assembly and Annual Meeting Program. Chicago IL, Nov, 2005. 

Zhang J, Fletcher JG, Bruesewitz M, Primak A, McCollough CH. Inaccuracies in the measurement of 

object size and attenuation resulting from partial scan reconstruction artifacts, 2005. Presented at the 

Radiological Society of North America Scientific Assembly and Annual Meeting Program. Chicago, IL, 

Nov, 2005. 

Zhang J, Fletcher JG, Primak A, McCollough CH. Variation in the measurement of object size and 

attenuation using partial scan reconstruction algorithms in cardiac CT, 2005. Presented at the Sixth 

International Conference on Cardiac Computed Tomography Sponsored by Massachusetts General 

Hospital and Harvard Medical School. Boston, MA, Jul, 2005. 

Zhang J, Fletcher JG, Raghavan, Araoz P, Vrtiska TJ, McCollough CH. Validation of vessel distensibility 

measurement using ECG-gated MDCT, 2005. Presented at the Radiological Society of North America 

Scientific Assembly and Annual Meeting Program. Chicago, IL, Nov, 2005. 

DIFFUSION HELIUM MRI-DIAGNOSIS PRE-CLINICAL EMPHYSEMA 

Talissa Altes, MD; University of Virginia; CIA 2004 

Dr. Altes studied the use of diffusion helium MRI as a new method to detect early changes of 

emphysema in persons exposed to SHS. Using hyperpolarized helium-3 (3He) as the contrast agent, 

diffusion MRI images the size and morphology of the distal airspaces of the lung. This technique appears 

to be very sensitive in determining early changes in emphysema. As recently presented at the Radiological 

Society of North America in Chicago in November 2007, Dr. Altes and colleagues found that 67% of 

active smokers, 27% of healthy people with a high exposure to SHS, and only 4% of healthy people with a 

low exposure to SHS had changes in their lungs, detectable using hyperpolarized 3He MRI. This 

demonstrates that SHS is damaging to the lung and shows a dose-response relationship between cigarette 

smoke exposure and changes in the lung. 

DIAGNOSIS OF PREMALIGNANT ORAL LESIONS VIA A MULTIPARAMETRIC CELL SCANNING SYSTEM 

Abraham Hirshberg, MD, DMD; Tel Aviv University; CIA 2005 

Cigarette smoking, exposure to SHS, ethanol use, and premalignant lesions remain the main risk factors 

for oral cancer development. Most of these cancers can only be diagnosed at an advanced stage. The aim of 

Dr. Hirshberg’s research is to develop a noninvasive diagnostic tool for detecting genetically-altered cells in 

premalignant oral lesions and in normal-looking oral mucosa in high-risk patients, using a technique that 

combines morphological observations and fluorescent in situ hybridization (FISH). Genetic alterations, 

especially chromosomal numerical aberrations (aneuploidy), appear to be promising prognostic indicators 

for the study of oral cancer. Dr. Hirshberg proposed to use oral brush samples to collect cells from 

suspicious lesions and from normal-appearing mucosa of high-risk patients, to analyze ploidy. The PI hopes 

to detect aneuploid cells by chromosomal analysis at the single-cell level; these cells are generally missed by 

traditional histopathology. In leukoplakic and cancerous lesions, the multiparametric results will be 

compared to histopathological examination. If a good correlation is determined, the use of this method 

may result in a life-saving screening test that detects hidden malignant potential in second hand tobacco 

smokers, smokers, and others at high risk for oral cancer. Dr. Hirshberg has already shown a direct 

correlation between the presence of aneuploid cells in brush samples from oral leukoplakia and the severity 

of the histopathologic diagnosis, and the outcome of the patients. 

All samples obtained from cancerous lesions contained a significant proportion of aneuploid cells. 

Aneuploid cells have been detected in early stages of oral carcinogenesis, even in lesions diagnosed as 

epithelial hyperplasia or mild dysplasia with normal-looking epithelial cells. Aneuploid cells were found also 

in other high-risk patients, i.e., patients with oral lichen planus (OLP), smokers, and patients with lung 

cancer; over 2% of aneuploid cells were detected in 24% of patients with OLP and in 12% of the heavy 

smokers. Three patients with premalignant lesions, 2 with oral leukoplakia, and one with OLP developed 

squamous cell carcinoma in 3-years follow up; in these patients, a significant proportion of the cells were 

aneuploid. Most of aneuploid cells examined in the brush samples had normal morphology. This method is 

easy to perform, reproducible, and highly sensitive. Aneuploid cells can be detected in early stages of oral 

carcinogenesis. The supplement of a brush sample and the combined morphological and FISH analysis 

increase the specificity in predicting the nature of a suspicious oral lesion in order to guide treatment and 

improve the outcome of these patients. 

1 6 6 P A G E

THE MACRONOME AS A TOOL FOR EARLY CANCER DIAGNOSIS 

Samuel R. Denmeade, MD; The Johns Hopkins University; CIA 2005 

Dr. Denmeade’s research involves proteomics-based strategies to analyze body fluids for changes in 

protein profiles and the presence of individual proteins that may be useful as tumor biomarkers. The 

challenging aspect of this approach is that only a small portion of the population of circulating proteins 

may be involved in the disease of interest. Proteases meet the requirements for reliably secreted biomarkers 

and potential therapy targets. Alpha-2-macroglobulin (A2M) is a broad-spectrum protease inhibitor that 

covalently binds proteases. Investigation of the population of A2M-bound proteases, known as the 

macronome, may generate proteomic profiles relevant to disease, and distinct from profiles present in 

normal blood. Bladder cancer, which is often not detected until it is at an advanced stage and for which 

there is no screening test, was thought to be a good model for macronomic analysis. This strategy will be 

used by Dr. Denmeade to map circulating protease changes specific to bladder cancer. The technique will 

be validated by A2M capture of proteases, in vitro, from media conditioned with a bladder cancer cell line. 

The macronome technique will then be tested in a mouse model, and, finally, in human bladder cancer 

patients. Through this technique, Dr. Denmeade hopes to find the proverbial needle in the haystack to use 

as a cancer biomarker. This could lead to earlier diagnosis of bladder and similar cancers, when they are 

more amenable to curative treatment. 


Kumar SK, Williams SA, Isaacs JT, Denmeade SR, Khan SR. Modulating paclitaxel bioavailability for 

targeting prostate cancer. Bioorg Med Chem 2007;15:4973-84. 

DISEASE PREVENTION 


SECOND HAND TOBACCO SMOKE GLOBAL RESEARCH NETWORK 

Andrew Hyland, PhD; Roswell Park Cancer Institute; YCSA 2002; CIA 2007, 2008 

This award expands the evidence base for SHS education in low-income and developing countries. Dr. 

Hyland and colleagues set out to expand the network of SHS researchers from those representing 20 

countries to over 30 countries, and to foster research comparing levels of SHS, support for SHS education, 

and potential economic impacts of SHS standards in different countries. In the first year of this award, an 

air quality study assessing the levels of particulate matter (of which SHS is a major contributor) in the 

restaurants, pubs, and transportation outlets in 32 countries has been published in Tobacco Control. Several 

additional countries are being added to this study with particularly strong representation from Latin 

America. New collaborations with the China Centers for Disease Control and Prevention have led to 

additional air quality studies as well as some of the first studies assessing customer and restaurant owner 

perceptions about SHS and their perceived impact on health and economics. Additional collaborators in 

Mexico and Argentina are working on projects assessing whether newly implemented smoke-free initiatives 

in these countries adversely impact economic indicators. Future work will continue to expand the SHS 

research base outside of the United States so that it provides greater relevance to other parts of the world 

now considering SHS initiatives. 


Abrams S, Mahoney M, Hyland A, Cummings KM. Clean indoor air laws protect hospitality workers: 

evidence from New York State, 2005. Presented at the National Conference on Tobacco or Health. 

Chicago, IL, May 4-6, 2005. 

Abrams SM, Mahoney MC, Hyland A, Cummings KM, Davis W, Song L. Early evidence on the 

effectiveness of clean indoor air legislation in New York state. Am J Public Health 2006;96:296-298. 

Abrams SM, Mahoney MC, Hyland A, Cummings KM. A cross-sectional study of secondhand smoke 

exposure in western New York, 2003. Presented at the 10th Annual Society for Research on Nicotine 

and Tobacco Meeting. Scottsdale, AZ, Feb 18-21, 2004. 

Bauer JE, Hyland A, Li Q, Steger C, Cummings KM. A longitudinal assessment of the impact of 

smokefree worksite policies on tobacco use. Am J Public Health 2005;95:1024-1029. 

Bauer U, Hyland A, Juster H. Evaluating the impact of a statewide smoke-free work place law, NYS, 2003. 

Presented at the National Conference on Tobacco or Health. Boston, MA, Dec 10-12, 2003. 

Borland R, Yong HH, Cummings KM, Hyland A, Anderson S, Fong GT. Determinants and consequences 

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of smoke-free homes: findings from the International Tobacco Control (ITC) Four Country Survey. Tob 

Control 2006;15 Suppl 3:iii42-iii50. 

Borland R, Yong HH, Siahpush M, Hyland A, Campbell S, Hastings G, Cummings KM, Fong GT. 

Support for and reported compliance with smoke-free restaurants and bars by smokers in four countries: 

findings from the International Tobacco Control (ITC) Four Country Survey. Tob Control 2006;15 

Suppl 3:iii34-iii41. 

Carpenter CM, Connolly GN, Travers M, Hyland A, Cummings KM. Health meetings do not belong in 

smoky cities. Tob Control 2006;15:69-70. 

Carter CL, Carpenter MJ, Higbee C, Travers M, Hyland A, Bode A, Thacker S, Alberg A. Fine particulate 

air pollution in restaurants and bars according to smoking policy in Charleston, South Carolina. J S C 

Med Assoc 2008;104:82-85. 

Connolly GN, Carpenter C, Travers MJ, Hyland A. Closing session: results of Chicago Air Monitoring 

study, 2005. Presented at the National Conference on Tobacco or Health. Chicago, IL, May 4-6, 2005. 

Farrelly MC, Nonnemaker JM, Chou R, Hyland A, Peterson KK, Bauer UE. Changes in hospitality 

workers’ exposure to secondhand smoke following the implementation of New York’s smoke-free law. 

Tob Control 2005;14:236-241. 

Fong G, Hyland A, Hammond D, Borland R, Hastings G, Cummings KM, McNeil A, Anderson S. 

Changes in knowledge, attitudes, and behavior following the Irish Smoke-Free Law: findings from the 

ITC-Ireland/U.K. survey, 2005. Presented at the Society for Research on Nicotine and Tobacco. 

Prague, Czech Republic, Mar 20-23, 2005. 

Fong GT, Hyland A, Borland R, Hammond D, Hastings G, McNeill A, Anderson S, Cummings KM, 

Allwright S, Mulcahy M, Howell F, Clancy L, Thompson ME, Connolly G, Driezen P. Reductions in 

tobacco smoke pollution and increases in support for smoke-free public spaces following the 

implementation of comprehensive smoke-free workplace legislation in the Republic of Ireland: findings 

from the ITC Ireland/UK survey. Tob Control 2005;000:1-8. 

Higbee C, Bauer JE, Cummings KM, Wieczorek W, Alford T, Hyland A. Avoidance of smoky 

establishments: findings from Erie and Niagara Counties in New York. J Public Health Manag Pract 

2004;10:508- 510. 

Higbee C, Travers M, Hyland A, Cummings KM, Dresler C. Global air monitoring study: a multi-country 

comparison of levels of indoor air pollution in different workplaces results from Tunisia. Tunis Med 

2007;85:793-797. 

Higbee C, Travers M, Hyland A, Cummings KM, Dresler C. Global air monitoring study: a multi-country 

comparison of levels of indoor air pollution in different workplaces results from Tunisia. Tunis Med 

2007 Sep;85:793-797. French. 

Hyland A, Hassan LM, Higbee C, Boudreau C, Fong GT, Borland R, Cummings KM, Yan M, Thompson 

ME, Hastings G. The impact of smokefree legislation in Scotland: results from the Scottish ITC 

Scotland/UK longitudinal surveys. Eur J Public Health 2009. 

Hyland A, Higbee C, Bauer J, Giovino G, Wieczorek W, Alford T, Cummings KM. Non-smokers avoid 

smoky establishments: findings from Erie/Niagara Counties, NY, 2003. Presented at the National 

Conference on Tobacco or Health. Boston, MA, Dec 10-12, 2003. 

Hyland A, Higbee C, Hassan L, Fong GT, Borland R, Cummings KM, Hastings G. Does smoke-free 

Ireland have more smoking inside the home and less in pubs than the United Kingdom? findings from 

the international tobacco control policy evaluation project. Eur J Public Health 2008;18:63-65. 

Hyland A, Puli V, Cummings M, Sciandra R. New York’s smoke free regulations: effects on employment 

and sales in the hospitality industry. Cornell Hotel and Restaurant Administration Quarterly 2003;44:9- 

16. 

Hyland A, Travers MJ, Dresler C, Higbee C, Cummings KM. A 32-country comparison of tobacco smoke 

derived particle levels in indoor publicplaces. Tob Control 2008;17:159-165. 

Hyland A, Travers MJ, Higbee C, Cummings KM, Dresler C, Carpenter C, Connolly G. A 24-country 

comparison of levels of indoor air pollution in different workplaces, 2006. Report presented at the 2006 

World Conference on Tobacco or Health. 

Hyland A. Clean air policies: science informing public health policy, 2005. Presented at the Biological and 

Environmental Measurement in Tobacco Research: A Transdisciplinary Workshop. Toronto, Ontario, 

Canada, May 19-20, 2005. 

Hyland A. Economic and other aspects of clean indoor air policies [Invited Plenary], 2004. Presented at 

the Norwegian National Tobacco Control Conference. Oslo, Norway, Apr 2004. 

Hyland A. Multi-city air monitoring study: public policy and exposure to secondhand smoke, 2005. 

1 6 8 P A G E

Presented at the Society on Nicotine and Tobacco. Prague, Czech Republic, Mar 20-23, 2005. 

Jones SC, Travers MJ, Hahn EJ, Robertson H, Lee K, Higbee C, Hyland A. Secondhand smoke and 

indoor public spaces in Paducah, Kentucky. J KyMed Assoc 2006;104:281-8. 

Juster HR, Loomis BR, Hinman TM, Farrelly MC, Hyland A, Bauer UE, Birkhead GS. Declines in 

hospital admissions for acute myocardial infarction in New York state after implementation of a 

comprehensive smoking ban. Am J Public Health 2007;97:2035-9. 

Kang JM, Jiang Y, Lin XG, Yang Y, Nan Y, Li Z, Liu RL, Feng GZ, Wei XS, Travers MJ, Li Q, Hyland A. 

[Study on the level of tobacco-generated smoke in several restautants and bars in Beijing, China]. 

Zhonghua Liu Xing Bing Xue Za Zhi 2007;28:738-41. 


[Study on the level of tobacco-generated smoke in several restautants and bars in Beijing, 

China]Zhonghua Liu Xing Bing Xue Za Zhi 2007 Aug;28(8):738-41. Chinese. 

Levy DT, Hyland A, Higbee C, Remer L, Compton C. The role of public policies in reducing smoking 

prevalence in California: results from the California tobacco policy simulation model. Health Policy 

2007;82:167-85. 

Liu RL, Yang Y, Liu XR, Chang AL, Gong J, Zhao BF, Liu T, Jiang Y, Hyland A, Li Q. Knowledge and 

attitudes towards second hand smoking among hospitality patronage in five cities in China. Zhonghua 

Liu Xing Bing Xue Za Zhi. 2008 May;29(5):421-5. Chinese. 

Mihaltan F, Munteanu I, Higbee C, Travers M, Hyland A, Cummings KM, Dresler C. Global air 

monitoring study: a multi-country comparison of levels of indoor air pollution in different workplaces. 

Results from Romania, May 2006. Pneumologia 2006;55:156-60. 

On March 16, 2006 the results of research: How Smoke-free Laws Improve Air Quality: A Global Study 

of Irish Pubs, was released as a live webcast. This work involved collaboration between Dr. Connolly and 

FAMRI Cahan Distinguished Professor K Michael Cummings, PhD, MPH, FAMRI YCSA recipient 

Andrew Hyland, PHD as well as Carrie Carpenter, MS and Mark Travers, MS. 

Schneider S, Seibold B, Schunk S, Jentzsch E, Patschke-Langer M, Dresler C, Travers MJ, Hyland A. 

Exposure to secondhand smoke in Germany: air contamination due to smoking in German restaurants, 

bars, and other venues. Nicotine Tob Res. 2008 Mar;10(3):547-55. Erratum in: Nicotine Tob Res. 

2008 Apr;10(4):745. 

Sendizik T, Fong G, Travers M, Hyland A. Measuring ETS exposure in automobiles. Presented at the 

Second Annual Symposium for Research to Inform Tobacco Control. Toronto, Ontario Canada, Nov 9- 

11, 2005. 

Travers M, Cummings KM, Bauer U, Hyland A. Effect of New York State Clean Indoor Air Law on 

employment, alcohol excise tax collections, and number of alcohol serving establishments. Presented at 

Society for Research on Nicotine and Tobacco. Scottsdale, Arizona, Feb, 2004. 

Travers M, Cummings KM, Hyland A. Indoor air quality before and after the New York Clean Indoor Air 

Law in Western New York hospitality venues, July to September 2003. Presented at Society for Research 

on Nicotine and Tobacco. Scottsdale, Arizona, Feb 2004. 

Travers MJ, Cummings KM, Hyland A, Repace J, Babb S, Pechacek T, R C. Indoor air quality in 

hospitality venues before and after the implementation of a clean indoor air law - Western New York, 

2003. Morb Mortal Wkly Rep 2004; 53:1038-1041. 

Travers MJ, Cummings KM, Repace JL, Hyland A. Indoor air pollution in bars and restaurants in 9 U.S. 

cities Presented at the International Society of Exposure Analysis. Philadelphia, PA, Oct 17-21, 2004. 

Travers MJ, Homer M, Hyland A. Wyoming Air Monitoring Study. Report prepared for Wyoming 

Department of Health, Substance Abuse Division, 2005. 

Travers MJ, Hyland A, Higbee C. Kentucky Air Monitoring Study: Paducah. Report prepared for 

McCracken County Medical Society, 2006. 

Travers MJ, Hyland A, Higbee C. Kentucky Air Monitoring Study: Richmond and Berea: Report prepared 

for Madison County Health Department, 2005. 

Travers MJ, Hyland A. Chicago Air Monitoring study. Report prepared for Metropolitan Chicago 

American Lung Association, 2005. 

Travers MJ, Hyland A. Indiana Air Monitoring Study, December 2004-January 2005. Report prepared for 

Indiana Tobacco Prevention and Cessation, 2005. 

Travers MJ, Hyland A. Michigan Air Monitoring Study: Ann Arbor: Report prepared for Tobacco-Free 

Michigan, 2005. 

Travers MJ, Hyland A. New Jersey Air Monitoring Study, August 18th to September 27th 2005. Report 

prepared for New Jersey G.A.S.P. and the American Cancer Society, 2005. 

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Travers MJ, Hyland A. Wisconsin Air Monitoring Study, October 13th to November 6th 2005. Report 

prepared for Friends of Clean Air Works, 2005. 

CHANGING PEDIATRIC PRACTICE TO ADDRESS SECOND HAND TOBACCO SMOKE EXPOSURE 

Jonathan P. Winickoff, MD, MPH; Massachusetts General Hospital; 2003 YCSA 

Dr. Winickoff’s goal is to develop and test a pediatric office system to enhance the delivery of evidencebased 

tobacco control services with a resulting decrease in childhood exposure to SHS and the diseases 

caused from exposure to SHS. The three phases of the research study include 1) an exploratory study 

consisting of the preliminary adaptation of an evidence-based tobacco control strategy to the pediatric 

outpatient setting, 2) a qualitative study using focus groups from eight pediatric practices to elicit 

pediatrician and key staff responses, barriers, and solutions to implementing the proposed strategy, and 3) 

an intervention study examining the feasibility and efficacy of implementing within the pediatric office 

setting the tobacco control system developed in Phase 1 and refined in Phase 2. The study was designed to 

justify a larger trial with randomization at the practice level. 


Hazlehurst B, Sittig DF, Stevens VJ, Smith KS, Hollis JF, Vogt TM, Winickoff JP, Glasgow R, Palen TE, 

Rigotti NA. Natural language processing in the electronic medical record: assessing clinician adherence 

to tobacco treatment guidelines. AM J Prev Med 2005;29:434-439. 

Kavanaugh M, McMillen RC, Pascoe JM, Southward LH, Winickoff JP, Weitzman M. The co-occurrence 

of maternal depressive symptoms and smoking in a national survey of mothers: implications for family 

health and healthcare. Ambul Pediatr 2005;5:341-348. 

Park ER, Wolfe TJ, Gokhale M, Winickoff JP, Rigotti NA. Preparedness to provide preventive counseling: 

reports of graduating primary care residents at academic health centers. J Gen Intern Med 2005;20:386- 

391. 

Thomson CC, Siegel M, Winickoff JP, Biener L, Rigotti NA. Household smoking bans and adolescents’ 

perceived prevalence of smoking and social acceptability of smoking. Prev Med 2005;41:349-356. 

Tyc VL, Hovell MF, Winickoff J. Reducing secondhand smoke exposure among children and adolescents: 

emerging issues for intervening with medically at-risk youth. J Pediatr Psychol 2008;33:145-55. 

Weitzman M, Cook S, Auinger P, Florin TA, Daniels S, Nguyen M, Winickoff JP. Tobacco smoke 

exposure is associated with the metabolic syndrome in adolescents. Circulation 2005;112:862-869. 

Winickoff JP, Berkowitz AB, Brooks K, Tanski SE, Geller A, Thompson C, Lando HA, Curry S, 

Muramoto M, Prokhorov AV, Best D, Weitzman M, Pbert L. State of the art interventions for officebased 

parental tobacco control. Pediatrics 2005;115:750-760. 

Winickoff JP, Buckley VJ, Palfrey JS, Perrin JM, Rigotti NA. Intervention with parental smokers in an 

outpatient pediatric clinic using counseling and nicotine replacement. Pediatrics 2003;112:1127-1133. 

Winickoff JP, Hillis VJ, Palfrey JS, Perrin JM, Rigotti NA. A smoking cessation intervention for parents of 

children hospitalized with respiratory illness: the Stop Tobacco Outreach Program. Pediatrics 

2003;111:140-145. 

Winickoff JP, McMillen RC, Bronwen CC, Klein JD, Rigotti NA, Tanski SE, Weitzman M. Addressing 

parental smoking in pediatrics and family practice: a national survey of parents. Pediatrics 

2003;112:1146-1151. 

Winickoff JP, Tanski SE, McMillen RC, Klein JD, Rigotti NA, Weitzman M. Child healthcare clinicians’ 

use of medications to help parents quit smoking: a national parent survey. Pediatrics 2005;115:1013- 

1017. 

Winickoff JP, Park ER, Hipple BJ, Berkowitz A, Vieira C, Friebely J, Healey EA, Rigotti NA. Clinical 

Effort Against Secondhand Smoke Exposure (CEASE): Development of Framework and Intervention. 

Pediatrics 2008;122:e363-e375. 

Winickoff JP, Friebely J, Tanski SE, Sherrod C, Matt GE, Hovell MF, McMillen RC. Beliefs about the 

health effects of “Thirdhand” smoke and home smoking bans. Pediatrics 2009;123:e74-e79. 

REVERSING TOBACCO MARKET RESEARCH ON YOUNG ADULTS AND BAR INTERVENTIONS TO DECREASE 

YOUNG ADULT SMOKING 

Pamela Ling, MD, MPH; University of California, San Francisco; YCSA 2004 

Dr. Ling and colleagues are exploring the possible prevention of tobacco-smoke-related diseases by 

developing an improved understanding of how the tobacco industry markets cigarettes to young adults 

ages 18- 24. The PI’s work utilizes market research strategies found by studying previously secret tobacco 

1 7 0 P A G E

industry documents. Young adults are considered in two ways: defining different types of young adults by 

general attitudes, activities, goals, aspirations, personality, and brand usage. The second strategy defines 

young adult segments based on opinions regarding smoking issues such as second hand tobacco smoke, 

the social acceptability of smoking, and smoking strategies. Public health campaigns for segments of the 

young adult population have been designed; their effectiveness in decreasing smoking behavior by 

promoting early cessation and by preventing experimenting young smokers from becoming established 

adult smokers will be evaluated. 


Anderson SJ, Dewhirst T, Ling PM. Every document and picture tells a story: using internal corporate 

document reviews, semiotics, and content analysis to assess tobacco advertising. Tob Control 

2006;15:254- 261. 

Anderson SJ, Ling PM, Glantz SA. Implications of the federal court order banning the terms “light” and 

“mild”: what difference could it make? Tob Control 2007;16:275-279. 

Anderson SJ, Ling PM. And they told two friends, and so on, and so on: RJ Reynolds’ viral marketing of 

Eclipse. Tob Control 2008;17(4):222-229. 

Anderson SJ, Pollay RW, Ling PM. Taking ad-Vantage of lax advertising regulation in the USA and 

Canada: reassuring and distracting health-concerned smokers. Soc Sci Med 2006;63:1973-1985. 

Hafez N, Ling PM. Finding the Kool Mixx: how Brown & Williamson used music marketing to sell 

cigarettes. Tob Control 2006;15:359-66. 

Ling PM, Glantz SA. Tobacco industry consumer research on socially acceptable cigarettes. Tob Control 

2005;14:e3 

Ling PM, Neilands TB, Glantz SA. The effect of support for action against the tobacco industry on 

smoking among young adults. Am J Public Health 2007;97:1449-56. 

Ling PM, Neilands TB, Nguyen T, Kaplan CP. Psychographic segments based on attitudes about smoking 

and lifestyle among Vietnamese adolescents. J Adolesc Health 2007 Jul;41(1):51-60. 

Mars S, Ling PM. Meanings and Motives: Experts Debating Tobacco Addiction. American Journal of 

Public Health 2008 Oct;98(10):1793-802. Epub 2008 Aug 13. 

Song AV, Ling PM, Neilands TB, Glantz SA. Smoking in movies and increased smoking among young 

adults. Am J Prev Med 2007;33:396-403. Erratum in: Am J Prev Med. 2008 Jan;34(1):86. 

SECOND HAND TOBACCO SMOKE IN MEXICAN AMERICAN HOUSEHOLDS 

Alexander V. Prokhorov, MD, PhD; University of Texas M.D. Anderson Cancer Center; CIA 2006 

A randomized controlled trial of reducing second hand tobacco smoke and adopting tobacco-free air 

standards through Project Clean Air San Antonio (CASA) is currently in progress with 90 Mexican 

American households located in the Houston metropolitan area. These households represent part of an 

ongoing large-scale study of cancer prevention in Mexican Americans spearheaded by MD Anderson 

investigators. Household prescreenings began in October 2007 and home visits began in November 2007. 

During the home visits, field research assistants traveled out to the homes of the participants to gather 

baseline survey information as well as set up two nicotine monitors in two separate rooms within the 

home. Each nicotine monitor has a unique barcode that will help indicate which room it was placed in. 

The nicotine monitors were left within the households for 7 days, after which they were picked up by the 

field research assistants. The nicotine monitors will be placed again in the same households at 6 months 

and 12 months to evaluate the effect of the intervention. The nicotine monitors have been analyzed at 

University of California Berkeley’s School of Public Health. The first phase of the CASA study is right on 

target according to the timeline and near completion of the targeted goal of 90 participants. To date 85 

participants are in various stages of completion. Seventy-one participants have successfully completed the 

monitor setup and the removal/interview. An additional 11 have received the monitor setup and have 

been scheduled for the removal/interview. Four other participants have completed a partial interview. The 

first stage was completed. Follow-up will commence in May/June 2008 as scheduled according to the 

timeline. The recruitment team conducted recruitment in various areas of Houston with large 

representation of the Hispanic residency. The team conducted targeted recruitment in washaterias, 

businesses, health fairs, and other public gatherings. The recruitment efforts were complex due to the fact 

that most of the participants stated that they smoked but did not want to readily admit they smoked in the 

home at any time. Careful questioning whether they smoked occasionally, in separate rooms, anytime 

during day, in the garage attached to their home etc., was successful in recruiting many of the participants. 

The CASA surveys are being conducted on Tablet personal computers (PCs). All of the participants 

P A G E 1 7 1

understood there would be several visits and expressed their desire to complete all the required visits. The 

participants did not experience any problems in having the study conducted on the PCs. They were able to 

view the questions before they were answered. Some of the participants conveyed their concerns about the 

air quality from the industrial plants surrounding their homes rather than the smoke in their homes. In 

two of the homes, where pregnant teenagers also lived, and they did not seem to be concerned about 

others smoking in the home. Other participants did not seem to think there was any harm from smoke if 

the smoker was in another room and if they never smoked in front of the children. 





PREVALENCE OF SMOKE-FREE CAMPUSES IN U.S. HOSPITALS AND BEST PRACTICES FOR IMPLEMENTATION 

Sharon Milberger, ScD; Henry Ford Health System; CIA 2007 

In 1992 the Joint Commission introduced standards to make hospital buildings smoke-free, resulting in 

the nation’s first industry-wide ban on smoking in the workplace. Now a new trend has emerged: the 

smoke-free hospital campus, with smoking prohibited outdoors, at entranceways, on the grounds, and in 

parking areas. Although many studies have examined the development, adoption, and effects of indoor 

smoke-free initiatives in healthcare settings, to the investigators’ knowledge, no organization has 

systematically evaluated the challenges to implementing or the impact of the transition to a smoke-free 

hospital campus. The study, conducted in two phases, will help fill this gap. The investigators have 

completed Phase I of the study and have developed and administered a web-based survey to 4,494 US 

hospitals in order to establish baseline rates of existing smoke-free campuses and correlate the adoption of 

such initiatives with the rates of inpatient cessation counseling provided to patients. 1,916 hospitals 

(42.6%) responded to the survey. A matched, random sample of 105 non-responder hospitals were 

contacted by telephone to assess non-respondent bias. Of the participating hospitals, 45.2% (865) reported 

having a smoke-free campus environment (i.e., smoking is prohibited on all hospital property, indoors and 

outside, and have no designated smoking areas). A similar prevalence of smoke-free campus policies 

(45.7%) was seen in the non-responder hospitals. No differences were observed in hospital size (# of beds) 

or setting (urban or rural) between those hospitals with and without smoke-free campuses. In contrast, 

significantly more private, non-private hospitals (57%) adopted such standards than for-profit hospitals 

(31.1%). Moreover, psychiatric hospitals (31.5%) were significantly less likely than general hospitals (48.5%) 

to have implemented a smoke-freee campus initiative. Similarly, teaching hospitals (38.4%) were less likely 

than non-teaching hospitals (50.9%) to have adoped a similar initiative. The findings from Phase I were 

presented at the 14th World Conference on Tobacco or Health in Mumbai, India. During Phase II, the 

team is working closely with hospitals that have adopted standards successfully to document their efforts as 

case studies, identify best practices across various types of organizations, and create and distribute a tool-kit 

of resources for hospitals considering or in the process of adopting smoke-free campus standards. 


Milberger S, Davis RM, Holm AL. Pet owners’ attitudes and behaviors related to smoking and secondhand 

smoke: A pilot study. Tob Control Feb:2009;[Epub ahead of print]. 

ADVANCES IN MONITORING EXPOSURE TO SECOND HAND TOBACCO SMOKE IN THE AIR AND IN THE BODY 

Mark J. Travers, PhD; Roswell Park Cancer Center; YCSA 2006 

This study will validate the latest methods in air monitoring and integrating them with measurements of 

biological markers of exposure to tobacco smoke pollution as well as validate and advance models of 

second hand tobacco smoke exposure and risk assessment, which will hopefully serve as the new 

foundation on which societal changes for decisions relating to the health effects of second hand tobacco 

smoke can be based. The investigators are currently conducting a global air monitoring effort in over 40 

countries around the world, measuring exposures to tobacco smoke pollution and informing the debate 

over smokefree air initiatives. 


Alpert HR, Carpenter CM, Travers MJ, Connolly GN. Environmental and economic evaluation of the 

Massachusetts Smoke-Free Workplace Law. J Community Health 2007;32:269-281. 

1 7 2 P A G E



Carter CL, Carpenter MJ, Higbee C, Travers MJ, Hyland A, Bode A, Thacker S, Alberg A. Fine 

particulate air pollution in restaurants and bars according to smoking policy in Charleston, South 

Carolina. J S C Med Assoc, 2008. 104(4): p. 82-5. 

Connolly GN, Carpenter C, Alpert HR, Skeer M, Travers MJ. Evaluation of the Massachusetts Smoke-free 

Workplace Law. Report prepared for Harvard School of Public Health, Division of Public Health 

Practices, Tobacco Research Program, 2005. 


study. Presented at the National Conference on Tobacco or Health. Chicago, IL, May 4-6, 2005. 

Higbee C, Travers M, Hyland A, Cummings KM, Dresler C. [Global air monitoring study: a multicountry 

comparison of levels of indoor air pollution in different workplaces results from Tunisia]. Tunis 

Med 2007;85:793-7. 

Hyland A, Cummings M, Travers M, Steger C, contributors. Fifteen Months After the New York State 

Clean Indoor Air Act: What’s Changed in Erie and Niagara Counties and What Hasn’t. Report prepared 

for Erie/Niagara Tobacco-Free Coalition, 2004. 

Hyland A, Travers M, Cummings KM. One Year After the New York State Clean Indoor Air Act: What’s 

Changed and What Hasn’t. Report prepared for Erie/Niagara Tobacco-Free Coalition, 2004. 

Hyland A, Travers MJ, Dresler C, Higbee C, Cummings KM. A 32-country comparison of tobacco smoke 

derived particle levels in indoor public places. Tob Control 2008. 


comparison of levels of indoor air pollution in different workplaces. Report presented at the 2006 World 

Conference on Tobacco or Health, 2006. 

Hyland A, Travers MJ. Multi-City Air Monitoring Study (7-CAMS), March-July 2004. Report prepared 

for Self Magazine, 2004. 


indoor public spaces in Paducah, Kentucky. J Ky Med Assoc 2006;104:281-8. 


[Study on the level of tobacco-generated smoke in several restautants and bars in Beijing, China]. 

Zhonghua Liu Xing Bing Xue Za Zhi 2007;28:738-41. 

Maziak W, Ali RA, Fouad MF, Rastam S, Wipfli H, Travers MJ, Ward KD, Eissenberg T. Exposure to 

secondhand smoke at home and in public places in Syria: a developing country’s perspective. Inhal 

Toxicol 2008;20:17-24. 

Mihaltan F, Munteanu I, Higbee C, Travers M, Hyland A, Cummings KM, Dresler C. Global air 

monitoring study: a multi-country comparison of levels of indoor air pollution in different workplaces. 

Results from Romania, May 2006. Pneumologia 2006;55:156-60. 





Schneider S, Siebold B, Schunk S, Jentzsch E, Dresler C, Travers MJ, Hyland A. Exposure to second-hand 

smoke in Germany: Air contamination due to smoking in German restaurants, bars, and other venues. 

Nicotine Tob Res 2008;10(3):547-555. 

Sendizik T, Fong G, Travers M, Hyland A. Measuring ETS exposure in automobiles. Presented at the 

Second Annual Symposium for Research to Inform Tobacco Control. Toronto, Ontario Canada, Nov 9- 

11, 2005. 







Travers MJ, Carpenter C. Conducting indoor air quality studies. Presented at the National Conference on 

Tobacco or Health. Chicago, IL, May 4-6, 2005. 




P A G E 1 7 3

Travers MJ, Cummings KM, Repace JL, Hyland A. Indoor air pollution in bars and restaurants in 9 U.S. 

cities Presented at the International Society of Exposure Analysis. Philadelphia, PA, Oct 17-21, 2004. 

Travers MJ, Homer M, Hyland A. Wyoming Air Monitoring Study. Report prepared for Wyoming 

Department of Health, Substance Abuse Division, 2005. 

Travers MJ, Hyland A, Higbee C. Kentucky Air Monitoring Study: Paducah. Report prepared for 


Travers MJ, Hyland A, Higbee C. Kentucky Air Monitoring Study: Richmond and Berea: Report prepared 

for Madison County Health Department, 2005. 

Travers MJ, Hyland A. Chicago Air Monitoring study. Report prepared for Metropolitan Chicago 


Travers MJ, Hyland A. Indiana Air Monitoring Study, December 2004-January 2005. Report prepared for 

Indiana Tobacco Prevention and Cessation, 2005. 

Travers MJ, Hyland A. Michigan Air Monitoring Study: Ann Arbor: Report prepared for Tobacco-Free 


Travers MJ, Hyland A. Michigan Air Monitoring Study: Lansing. Report prepared for Tobacco-Free 


Travers MJ, Hyland A. Michigan Air Monitoring Study: Novi. Report prepared for Tobacco-Free 


Travers MJ, Hyland A. New Jersey Air Monitoring Study, August 18th to September 27th 2005. Report 

prepared for New Jersey G.A.S.P. and the American Cancer Society, 2005. 

Travers MJ, Hyland A. Wisconsin Air Monitoring Study, October 13th to November 6th 2005. Report 

prepared for Friends of Clean Air Works, 2005. 

Travers MJ, Lee K. Particulate air pollution in Irish pubs is grossly underestimated. Am J Respir Crit Care 

Med 2008;177:236-7; author reply 237-8. 

Travers MJ, Mowery P. Using air-quality monitoring as a strategy for smokefree regulations. Presented at 

the Centers for Disease Control and Prevention National Tobacco Control Program Meeting. Atlanta, 

GA, Oct 24-27, 2005. 

Travers MJ. Issues involved in particulate monitoring studies: focus on the TSI SidePak. Presented at the 

Biological and Environmental Measurement in Tobacco Research: A Transdisciplinary Workshop. 

Toronto, Ontario Canada, May 19-20, 2005. 

Vardavas CI, Kondilis B, Travers MJ, Petsetaki E, Tountas Y, Kafatos AG. Environmental tobacco smoke in 

hospitality venues in Greece. BMC Public Health 2007;7:302. 

HEALTH IMPACT STUDY OF SMOKEFREE INITIATIVES IN LATIN AMERICA 

Ernesto Sebrié, MD MPH; Roswell Park Cancer Institute; YCSA 2008 

The health risks of SHS exposure are well documented. However, what is less well understood is the 

health benefits achieved by enacting public standards to limit people’s exposure to SHS. Several studies 

have shown reductions in exposure to SHS following enactment of a comprehensive smokefree initiatives, 

but only a handful of studies have actually documented changes in health outcomes. Twelve recent studies, 

six from the US, one from Canada, and five from Western Europe, have reported reductions in acute 

myocardial infarction (AMI) following implementation smokefree standards. However, these studies vary 

widely in their estimates of the impact of the smokefree rule on population-level cardiovascular events. In 

most Latin American countries, smoking indoors is the norm, and smokefree standards have only recently 

become a subject of public health debate. Uruguay was the first Latin American country to adopt 

comprehensive smokefree standards in 2006 and thus represents a unique venue to investigate how 

cardiovascular health outcomes have been impacted. This research project has two specific aims. The first 

aim is to test the hypothesis that the comprehensive smokefree standard in Uruguay will be associated with 

reductions in AMI hospital admissions. The second aim is to examine prospectively how smokers in 

Uruguay have responded to the smokefree regulations. This is the first comprehensive study conducted in 

a developing country in Latin America to evaluate the impact of a comprehensive smokefree standards on 

health outcomes as well as public beliefs, attitudes, and behaviors related to the initiative. 

1 7 4 P A G E

EVALUATING THE CHARACTERISTICS THAT INFLUENCE PERSUASIVENESS OF SECOND HAND TOBACCO SMOKE 

ADVERTISEMENTS 

Maansi Bansal-Travers, PhD; Roswell Park Cancer Center; YCSA 2008 

The Task Force on Community Preventive Services at the CDC recently called for more research to 

establish the features of advertising that increase support for adoption of smoke-free standards, especially in 

homes and cars. There are not any studies that have explicitly attempted to evaluate the effectiveness of 

different SHS advertisements targeting parents to motivate adoption of such standards for their home and 

car. Dr. Bansal-Travers’ study will fill this knowledge gap. This experimental study will examine how 

different characteristics of anti-SHS television advertisements such as the execution features of the 

advertisement (i.e., use of testimonials versus. negative visceral images), its focus (i.e., health effects versus 

social norms), and intended target audience (i.e., parents versus general audience) interact to affect 

comprehension, appraisal, recall, engagement with the advertising, and intention to adopt smoke-free 

standards in households and cars where one or both parents smoke. It is hypothesized that advertisements, 

which utilize personal testimonials and dramatize the health consequences of SHS exposure, and which 

specifically target parents will be better recalled, appraised more highly, and rated higher in terms of 

increasing support for smoke-free home and car standards compared to advertisements that do not share 

these characteristics. Another question addressed by this project is the extent to which the findings can be 

generalized across different cities and countries. This study will employ a sample of 40 advertisements 

designed to communicate risks of SHS exposure, collected by the Office on Smoking and Health at the 

CDC. Advertisements will be shown to parents in Buffalo, NY, and Columbia, SC, to see if parents in 

different cities respond in the same way to anti-SHS messages and appeals. Ten Spanish-language 

advertisements will also be tested in a pilot test in Mexico City to examine how these methods translate in 

different countries and languages. Analyses will include ranking persuasiveness of different ads, what themes 

and characteristics predict higher rates of parent comprehension and overall appraisal, and at follow-up, what 

ads persuade higher rates of recall, discussion, and intention to adopt smoke-free home and car standards. 

DISEASE PREVENTION 


DEVELOPMENT AND IMPLEMENTATION OF SMOKING RESTRICTIONS 

Lisa A. Bero, PhD; University of California, San Francisco; CIA 2003 

Dr. Bero developed a history for initiatives banning smoking on airlines by conducting a systematic review 

to identify all governmental standards that restricted or banned smoking on airlines in the United States and 

abroad. The PI determined the following timelines: 1) all U.S. federal regulatory proceedings pertaining to 

smoking restrictions on passenger aircraft and their outcomes from 1969 to 1985; 2) all federal attempts to 

restrict airline smoking from 1969 through 2000; 3) the adoption of smoking restrictions on aircraft placed 

in the context of other important events; 4) international initiatives restricting airline smoking. The PI 

performed an assessment of the relative roles of research evidence and other factors restricting smoking on 

airlines. Using the 1987 legislation banning smoking on flights of 2 hours or less and the extension of that 

ban to include most domestic flights was adopted in 1989. All available legislative debates, hearings, 

committees, and conference reports on each of the two initiatives were compiled. All of the key factors that 

contributed to the enactment of the airline smoking bans in 1987 and 1989 were outlined. The extensive 

timelines that were developed and thorough identification of tobacco industry activities over the 30 year 

period provided an understanding of the scientific, social, and political context in which these two initiatives 

were enacted. Taken together, this information makes it possible to discern the relative importance of the 

various factors that went into the enactment of the smoking bans. 


Baba A, Cook D, McGarity T, Bero LA. Legislating “sound science” regulation: Role of the tobacco 

industry. Am J Public Health 2005;95:s20-s27. 

Dalton S, Dunsby J, Bero LA. Narrative skills in the shaping of workplace smoking restrictions legislation 

Presented at the Annual Meeting of the American Sociological Association, 2004. 

Jewell C, Rose D, Bero LA. Public participation in the regulatory process: The case of California’s 

ergonomics rule Presented at the Annual Meeting of the Law and Society Association, 2005. 

Lopipero P, Bero LA. Tobacco interests or the public interest: 20 years of industry strategies to undermine 

airline smoking restrictions. Tob Control 2006;15:323-332. 

P A G E 1 7 5

REDUCING SHS: CARDIAC AND ASTHMA OUTCOMES 

Ellen J. Hahn, DNS, RN; University of Kentucky; CIA 2004 

Dr. Hahn evaluated the effects of a community initiative in Lexington Kentucky to reduce exposure to 

SHS on cardiac and asthma outcomes including the rate of hospital and emergency department (ED) 

discharges, length of stay, and total hospital costs. Differences in event rates between before and after 

changes in smoke-free environments were determined. The models based on the negative binomial 

distribution assumption fit the data well. Relative risks (RR), 95% confidence intervals (CIs) for RR’s, and 

corresponding tests of significance for the period variable were determined. The results of this study 

indicate that the risk of asthma ED visits declined by 18% after the clean air initiative and that there was a 

22% decline in the risk of acute myocardial infarction (AMI) events during the same period for females 

when all 72 months are included in the model; the relative risk for AMI for males between the two time 

periods was stable. This is the first study that has considered differential effects of smoke-free initiatives for 

males and females. 



indoor public spaces in Paducah, Kentucky. J Ky Med Assoc 2006;104:281-288. 

PREVENTION OF TOBACCO-RELATED DISEASE 

Stephen P. Teret, JD, MPH; The Johns Hopkins University; CIA 2004 

Dr. Teret’s research examined: 1) new arguments about the use of the Americans with Disabilities Act to 

regulate smoking and second hand tobacco smoke exposure in public places and the workplace; 2) the 

appropriateness of class action lawsuits against the tobacco industry; 3) possible lessons for tobacco 

litigation that can be learned from lawsuits against other product manufacturers; and 4) legal issues that 

may be raised by the possibility that one or more tobacco companies could enter bankruptcy as a result of 

litigation. 


Vernick JS, Rutkow L, Teret SP. Public health benefits of recent litigation against the tobacco industry. 

JAMA 2007;298:86-89. 

EDUCATION 


INCREASING SECOND HAND TOBACCO SMOKE AWARENESS, COMPETENCY, 

AND SCREENING AMONG MEDICAL PROFESSIONALS: EXPANDING THE MEDICAL CURRICULUM 

Mark S. Gold, MD; University of Florida; CIA 2007 

The goal of this project is to expand medical education related to SHS from the classroom to the clinic. 

Drs. Gold, Merlo, and colleagues are developing and testing an SHS-related educational intervention (i.e. 

interactive online lecture and clinical practice with standardized patients). The main outcome measure is 

the revised 2007 SHS Competency Exam. Students from the University of Florida College of Medicine 

(UFCOM) class of 2009 were administered the exam, and will serve as a no treatment, no pre-test control 

group. Students from the Class of 2010 were pre-tested at the beginning of their second year and posttested 

at the beginning of their third year, serving as a no-treatment control group. This year, students 

from the Class of 2011 were pre-tested at the beginning of their second year, are undergoing the full 

educational intervention, and will be post-tested at the beginning of their third year. The investigators have 

developed a library of standardized patient cases to highlight various SHS-related disorders. They have also 

developed a 1-hour online lecture related to SHS-related standards, medical complications, and suggested 

interventions. These educational interventions will be distributed to each College of Medicine in the 

United States free of charge. In addition, Dr. Merlo was appointed to chair a task force to evaluate the 

medical curriculum within the UFCOM for inclusion of tobacco- and SHS-related educational 

components. The investigators continue to collaborate with colleagues in other departments at the 

University of Florida and with the local Area Health Education Center (AHEC) and Tobacco Prevention 

and Control Partnership to improve campus-wide education and make the community aware of these 

efforts. 

1 7 6 P A G E

SECOND HAND TOBACCO SMOKE COUNSELING FOR PARENTS OF HOSPITALIZED PEDIATRIC PATIENTS 

Alan C. Geller, MPH, RN; Harvard University; CIA 2007 

The primary study aims are twofold: 1) to evaluate current SHS assessment and counseling practices of 

hospital-based pediatric nurses; and 2) to develop a systems-change demonstration project to enhance 

assessment and counseling of the smoking parents/caregivers of hospitalized children. The first part of 

Phase 1 of the study, consisting of focus groups, key informant interviews, and survey refinement with 

pediatric nurses from Boston, Philadelphia, New Jersey, and Atlanta has been completed. The 

developmental work is in advance of conducting surveys with members of the Society of Pediatric Nurses 

at their April 2008 national meeting as well as mailing of the survey to members. Survey respondents 

include bedside nurses as well as those in educational and administrative capacities. Information from the 

national surveys will identify the barriers, propose improvements to data recording systems, and seek to 

develop innovative systems’ approaches and intervention strategies intended to improve nurseparent/caregiver 

communication for SHS reduction. More specifically, the completed survey will be the 

first national survey of the practice of tobacco cessation counseling to the parents of children hospitalized 

with smoking-related pediatric diseases. The investigators will be able to assess the frequency with which 

pediatric nurses perform the 5As (ask, advise, assess, assist, and arrange) with their patients’ parents and 

caregivers. Nurses’ confidence level for performing these tasks will also be assessed, determination of the 

potential barriers for helping parents develop a smoking cessation plan will be made, and nurses will be 

asked to provide resources and information that they need to effectively counsel parents and develop new 

hospital-wide systems. 





EXPANDING GRANTEES RESEARCH CAPABILITIES THROUGH PRESERVATION OF 

TOBACCO DISEASE DOCUMENTS 


AIRLINE AND AIRPORT SMOKING RESTRICTIONS AS REFLECTED IN THE TOBACCO INSTITUTE’S DOCUMENTS 

Anthony Brown, BS; Roswell Park Cancer Institute; BDA 2003 

This grant allows the PI and his team to scan and place online 9 million pages of the approximately 19 

million pages ultimately to be scanned in cooperation with the New York State Attorney General’s Office. 

Additionally, Mr. Brown has constructed an indexed collection of documents relevant to the history of 

smoking and the airline industry and developed a user-friendly, Web-based timeline interface to aid in the 

use of the documents online. In addition, a large video collection has been digitized for the Legacy Library 

at University of California, San Francisco. Roswell Park Institute has placed some of the videotapes online 

through http://www.tobaccovideos.com. These collections can be viewed at http://roswelldocs.com and 

through http://tobaccodocuments.org. 


Cummings KM, Brown A, O’Connor R. The cigarette controversy. Cancer Epidemiol Biomarkers Prev 

2007;16:1070-1076. 

EXPANDING GRANTEES RESEARCH CAPABILITIES THROUGH PRESERVATION OF 

TOBACCO DISEASE DOCUMENTS 


FAMRI-GUILFORD DIGITAL LIBRARY OF DOCUMENTS 

Karen Butter, MLS; University of California, San Francisco; 2003 BDA 

FAMRI funding supported scanning, optical character recognition, indexing, and creation of an online 

repository for 6.7 million pages of British American Tobacco (BAT) Company documents to allow free 

public access via the Internet. These documents are of tremendous importance since they contain 

invaluable scientific research, including data on second hand tobacco smoke, and evidence as to how the 

P A G E 1 7 7

tobacco companies fought tobacco control efforts, including efforts to protect people from second hand 

tobacco smoke worldwide. The BAT Document Archive was launched in October 2004, and averages 

1300 users and 21,000 page views per month. 

EXPOSURE TO SECOND HAND TOBACCO SMOKE 


CHRONIC CIGARETTE SMOKE EXTRACT TREATMENT SELECTS FOR APOPTOTIC DYSFUNCTION AND MITOCHON- 

DRIAL MUTATIONS IN MINIMALLY TRANSFORMED ORAL KERATINOCYTES 


Cigarette smoke demonstrates a carcinogenic effect through chronic exposure, not acute exposures. 

However, current cell line models study only the acute effects of cigarette smoke. Using a cell line model, 

Dr. Califano and his group compared the effects of acute versus chronic cigarette-smoke-extract (CSE) on 

mitochondria in minimally-transformed oral keratinocytes (OKF6). 

OKF6 cells were treated with varying concentrations of CSE for 6-months and analyzed monthly by 

flow cytometry for mitochondrial-membrane-potential (MMP), cytochrome-c release, caspase-3 activation, 

and viability after CSE-exposure. At each time point the same assays were performed after 24hrs of 

valinomycin, which is a MMP depolarizing agent treatment. The mitochondrial-DNA of chronically CSEtreated 

cells was sequenced. 

After 6 months of CSE treatment, the cells were increasingly resistant to CSE-mediated and valinomycin 

induced cell death. In addition, chronic CSE-treatment caused chronic depolarization of MMP, 

cytochrome c release, and caspase activation. Cells grown in the presence of the only CSE vapor also 

exhibited the same resistance and chronic baseline apoptotic activation. Mitochondrial DNA sequencing 

found that chronic CSE treated cells had more amino acid changing mitochondrial mutations than acutely 

treated cells. 

CSE treatment of normal cells selects for apoptotic dysfunction as well as mitochondrial mutations. 

These findings suggest that chronic tobacco exposure induces carcinogenesis via selection of apoptosis 

resistance and mitochondrial mutation in addition to previously known genotoxic effects that were found 

by acute treatments. Chronic models of tobacco exposure on upper aerodigestive epithelia may be more 

insightful than models of acute exposure in studying head and neck carcinogenesis. 

SECOND HAND TOBACCO SMOKE EXPOSURE AMONG BAR AND NIGHTCLUB EMPLOYEES 

Ana Navas-Acien, MD, PhD; The Johns Hopkins University; CIA 2006 

Bars and nightclubs have the highest concentrations of SHS of all public places, posing a serious risk for 

bar/nightclub employees. Unfortunately, these working places have generally been excluded from smokefree 

initiatives. The objective of this study is to assess exposure of bar and nightclub employees to SHS in 

more than 20 countries around the world using a common protocol. The study is being conducted in 20 

major cities worldwide, including Baltimore City. In each city, 10 bars and nightclubs and up to five 

employees per bar/nightclub will be selected. Air and hair nicotine concentrations will be analyzed by gas 

chromatography at the Johns Hopkins Bloomberg School of Public Health. As of February 2009, 

fieldwork has been completed in the following locations: Baltimore City (USA), Argentina, Armenia, 

Bangladesh, Chile, China, Georgia, Ghana, Guatemala, Guyana, India, Indonesia, Kyrgyzstan, Mexico, 

Nigeria, Pakistan, Peru, Philippines, Poland, Russia, Thailand, Ukraine, Uruguay, and Vietnam. In 

addition fieldwork is being conducted in Turkey and Kazakhstan. By objectively documenting airborne and 

personal exposure to second hand tobacco smoke in bars and nightclubs worldwide, the present study is 

helping to achieve smoke-free public places that protect workers. 


Barnoya J, Mendoza-Montano C, Navas-Acien A. Secondhand smoke exposure in public places in 

Guatemala: comparison with other Latin American countries. Cancer Epidemiol Biomarkers Prev 

2007;16:2730-27305. 

Jones M, Navas-Acien A, Yuan J, Wipfli H, Samet JM, Breysse P. Secondhand tobacco smoke exposure in 

motor vehicles. International Society for Environmental Epidemiology 20th Conference, Pasadena, CA, 

Oct 2008. 

Navas-Acien A, Wipfli H, Avila-Tang E, Kim S, Yuan J, Shahrir SF, Jones M, Samet JM, Breysse PN. 

Secondhand tobacco smoke exposure among bar and nightclub employees. Society for Research on 

1 7 8 P A G E

Nicotine and Tobacco. 1st Asian Regional Conference, Bangkok, Thailand, October 2008. 

Suwanampai P, Navas-Acien A, Strickland PT, Agnew J. Involuntary tobacco smoke exposure and urinary 

levels of polycyclic aromatic hydrocarbons in the United States 1999-2002. Cancer Epidemiol Prev 

Biomarkers 2009;18:884-893. 

SECOND HAND TOBACCO SMOKE AND SIDS: A LARYNGEAL CONNECTION? 

Donald Bartlett, Jr., MD; Dartmouth College; CIA 2007 

The incidence of the sudden infant death syndrome (SIDS) is increased by unknown mechanisms in 

overheated environments and by personal and second-hand maternal cigarette smoke exposure during 

pregnancy. The laryngeal chemoreflex (LCR), i.e., apnea, in response to intralaryngeal water, milk, gastric 

contents or other fluids, is much more prominent in newborn animals and human infants than in adults 

and therefore has caused some cases of SIDS. Dr. Bartlett and colleagues have found that the LCR is 

exaggerated in neonatal piglets and rats that are warmed 1-3 0 C above their normal body temperature. 

Warming the medulla in or near the nucleus of the solitary tract, while keeping body temperature constant, 

reversibly exaggerates the LCR, strongly implying a medullary site of action for the previously 

demonstrated effect of whole body warming. The research team exposed pregnant rats to artificially 

generated cigarette smoke or to nicotine, and studied the rat pups to see whether the effect of high body 

temperature on the duration of the LCR is enhanced. They completed a study that defined the influence 

of hyperthermia on the LCR duration as a function of age in rat pups not exposed to cigarette smoke. The 

hyperthermic exaggeration of the LCR is most striking in the youngest rats, aged 5 days or less, and 

disappears by 20 days of age. Subsequent findings with maternal smoke exposure during pregnancy 

showed a further exaggeration of reflex apnea in the youngest animals. Gestational treatment with nicotine 

results in a similar prolongation of the LCR. These results indicate that maternal exposure to cigarette 

smoke prolongs laryngeal reflex apnea in the offspring, due at least in part to gestational nicotine exposure. 


Xia L, Leiter JC, Bartlett D, Jr. Laryngeal apnea in rat pups: effects of age and body temperature. J Appl 

Physiol 2008;104:269-274. 

Xia L, Crane-Godreau, M, Leiter JC, Bartlett D, Jr. Gestational cigarette smoke exposure and 

hyperthermic enhancement of laryngeal chemoreflex in rat pups. Respir Physiol & Neurobiol 

2009;165:161-166. 

Xia L, Crane-Godreau M, Deng B, Leiter JC, Bartlett D, Jr. Prolongation of laryngeal chemoreflex by 

hyperthermia is exaggerated in pre-natally smoke-exposed rat pups. Presented at the Flight Attendants 

Medical Research Institute Annual Symposium, Boston Massachusetts, May 12-14, 2008. 

SECOND HAND TOBACCO SMOKE EMISSIONS OF REDUCED EXPOSURE PRODUCTS 

Gregory N. Connolly, DMD, MPH; Harvard School of Public Health; CIA 2007 

Dr. Connolly has been a very productive researcher in the area of SHS exposure. He has undertaken a 

number of interesting studies concerning potential reduced exposure products (PREPs), which are a newer 

style of tobacco product with sophisticated designs that have been marketed as “safer” despite inadequate 

evidence in support of such claims. The tobacco industry has styled PREPs to enhance consumer appeal 

and to perpetuate smoking among those who might otherwise quit. Although the Institute of Medicine 

has issued recommendations for PREP assessment, including analysis of toxins in mainstream emissions, 

investigation of their sidestream and SHS emissions have been neglected. Mainstream emissions of PREPs 

may, in some circumstances, be lower than conventional products, and this message has been emphasized 

in industry marketing strategies. Such messages may lead consumers erroneously to believe that sidestream 

and emissions of PREPs also are reduced and are potentially safer. The tobacco industry has manipulated 

cigarette product design to reduce aversive sensory qualities of cigarette SHS to increase consumer and 

public acceptance of cigarette products and reduce public demand for clean indoor air standards. Research 

is required to compare PREP sidestream emissions with conventional products, and to determine whether 

industry design and marketing of PREPs has improved sensory perceptions of SHS and increased 

consumer acceptance, compared with conventional products. Dr. Connolly investigated this with four 

complementary strategies: 1) investigation of tobacco industry research and development through internal 

documents and patents; 2) measurement of standard and intensive machine yield PREP sidestream 

emissions compared with conventional tobacco products; 3) evaluation of human subjects’ perceptions of 

the sensory qualities (odor, visibility and irritation) of PREP SHS compared with a conventional product; 

and 4) assessment of the effect of industry advertisement and website messaging of “low SHS” on PREP 

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consumer acceptance through Web-based surveys. The findings of this research will provide data to inform 

strategies to communicate public health risks of PREPs, and develop important guidelines for sidestream 

smoke emissions. 

SMOKE-FREE AIR LAWS, EXPOSURE AND HEALTH IN ADOLESCENTS 

Gregory N. Connolly, DMD, MPH; Harvard School of Public Health; CIA 2008 

Every day, more than 15 million children are exposed to SHS at home, with millions also exposed in day 

care centers, schools, restaurants, and other places. Scientific evidence shows causal relationships between 

exposure to SHS and a range of developmental and respiratory effects in neonates, infants, children, and 

adolescents. Children exposed to SHS are at an increased risk for sudden infant death syndrome, acute 

respiratory infections, ear problems, and more severe asthma. SHS exposure among children has decreased 

substantially since 1992-1993 when the national prevalence of households with smoke-free home rules was 

43% and less than one percent of the US population was protected by 100% smoke-free workplace 

standards. Eliminating smoking in indoor spaces fully protects non-smokers from SHS, yet no evidence has 

been reported to demonstrate reductions in pediatric diseases resulting from these declines in SHS 

exposure of children. Dr. Connolly hypothesizes that reductions in SHS exposure of children are associated 

with fewer SHS-caused pediatric illnesses and reduced utilization of health services. To investigate this 

hypothesis he will examine the association between SHS exposure of children in the home and SHS-related 

pediatric diagnoses and symptoms in all US health care settings and the association between SHS exposure 

of children in the home and health services utilization for treatment of SHS-related pediatric diagnoses and 

symptoms in all US health care settings. He will use a cross-sectional observational design involving 

secondary data analysis of existing national and state-level data sets. The outcome measures will be SHSrelated 

pediatric diagnoses and symptoms and health services utilization for treatment of SHS-related 

pediatric diagnoses and symptoms. The exposure measures will be percentage of households with an adult 

smoker and any children, percentage of households with smoking restrictions, percentage of households 

with an adult smoker, with smoking allowed and any children, percentage of children exposed to SHS in 

the home, percentage of population coverage with comprehensive smoke-free workplace rules, and 

percentage of coverage with smoke-free day care centers standards. The outcome measurements will be 

obtained from the National Ambulatory Medical Care Survey, the National Hospital Ambulatory Medical 

Care Survey, and the Healthcare Cost and Utilization Project Kids’ Inpatient Database. The exposure 

measurements will be determined from the Behavioral Risk Factor Surveillance System and Current 

Population Survey-Tobacco Use Supplements, and wll be analyzed by analysis of variance and multivariable 

regression modeling. 

Dr. Connolly used data from the 1999-2006 National Health and Nutrition Examination Survey, a 

cross-sectional survey designed to monitor the health and nutritional status of the US population, to 

investigate the association between smoke-free standards coverage and SHS exposure among non-smoking 

youths (3-19 years) in the US. Serum cotinine levels were available for 11,486 non-smoking youths from 

117 survey locations. Each location was categorized into one of three groups indicating extensive, partial, 

and no coverage by a smoke-free law. SHS exposure was defined as having serum cotinine levels greater 

than or = 0.05 ng/ml. In addition, cotinine was analyzed as a continuous outcome for years 2003-2006. 

Among non-smoking youths living in counties with extensive smoke-free law coverage, 32.7% were 

exposed to SHS, compared with 49.5% with partial coverage, and 64.7% with no standards. Adjusting for 

covariates, youths residing in counties with extensive coverage had 0.31 times the odds of SHS exposure 

and youths with partial coverage had 0.58 times the odds of SHS exposure compared to those residing in 

counties without smoke-free standards. These results suggest that smoke-free standards are an effective 

strategy for reducing SHS exposure not only in adults, but in youth as well. 

TOBACCO SMOKE ENDOTOXIN 

Lennart P. Larsson, PhD; Lund University; CIA 2007 

Recent research has shown that tobacco smoke contains large amounts of bacterial lipopolysaccharides 

(LPS, endotoxin), a family of inflammatory toxins from Gram-negative bacteria known to cause severe 

respiratory disease upon inhalation. By using gas chromatography-mass spectrometry technology Dr. 

Larsson measured LPS-specific 3-hydroxy fatty acids, peptidoglycan-specific muramic acid, and fungalspecific 

ergosterol in cigarettes of 37 brands purchased in six different countries in Europe and Asia and in 

10 brands of American cigarettes purchased in the US. The PI found that: 1) “light” and “full flavor” 

cigarettes do not differ with respect to the microbial components mentioned; 2) the levels of some of these 

components, mainly ergosterol, were comparatively low in certain local Asian brands of cigarettes; 3) the 

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American cigarettes purchased in the US were very similar in microbial marker composition; and 4) there 

is a direct correlation between the amounts of microbial components in the cigarette tobacco and in 

mainstream smoke. In short, side stream smoke is rich in bacterial and fungal components which causes 

those exposed to tobacco smoke to develop similar symptoms - chronic bronchitis, chronic sinusitis, and 

asthma. 


Larsson L Pehrson C, and Szponar B. Bacterial and fungal components in tobacco smoke. Presented at 

14th World Conference on Tobacco or Health, Mumbai, March 2009. 

Larsson L, Szponar B, Pehrson C. Endotoxin and other microbial compounds in cigarette tobacco and 

smoke. Presented 1) at FAMRI´S seventh scientific symposium, Boston, May 2008, and 2) at ATS 

annual international conference, Toronto, May 2008. 

Larsson L, Szponar B, Pehrson C. Tobacco smoke endotoxin. Presented at FAMRI´S sixth scientific 

symposium, Miami, May 2007. 

Larsson L, Szponar B, Ridha B, Pehrson C, Dutkiewicz J, Krysinska-Traczyk E, Sitkowska J. Identification 

of bacterial and fungal components in tobacco and tobacco smoke. Tobacco Induced Diseases 2008; 

4:1-9. 

Pehrson C, Ridha B, Szponar B, Larsson L. Microbial marker patterns in smoke and tobacco of cigarettes 

purchased in six different countries. Presented at AAAI annual meeting, Philadelphia, March 2008. 

Sebastian A, Pehrson C, Larsson L. Elevated concentrations of endotoxin in indoor air due to cigarette 

smoking. Journal of Environmental Monitoring 2006; 8: 519 - 522. 

REDUCING SECOND HAND TOBACCO SMOKE EXPOSURE AMONG YOUNG CHILDREN 

Abu S. Abdullah, MD, PhD, MPH, MFPH; Boston University; CIA 2008 

SHS is a health hazard to infants and children, in whom it is associated with lower respiratory tract 

infections, wheezing, cough, middle ear infections, and sudden infant death syndrome. The high 

prevalence of smoking in adults in many developing countries (e.g. in China, 61% among men, 7% among 

women) results in many children being exposed to SHS, but data on the effectiveness of a smoking 

hygiene intervention to reduce SHS among young children (e.g., under age 5) is lacking in China or other 

developing countries. In this research project, Dr. Abdullah aims to examine the effectiveness of smoking 

hygiene intervention (SHI) delivered by a community health worker (CHW) in 3 different contacts to 

reduce SHS exposure and improve respiratory health among young children in urban settings in China. 

The specific aims are: 1) to obtain baseline data on SHS exposure among young children, health status of 

young children and smoking status of parents and other household members; 2) to generate preliminary 

effectiveness data for CHW-delivered SHI; and 3) to develop culturally appropriate biochemical measures 

to assess children’s exposure to household SHS. Dr. Abdullah and colleagues propose to conduct this 

study, which will be divided into two parts, in Shanghai, China. The first part is a pre-intervention baseline 

assessment study; the second, a randomized controlled trial among households in urban Shanghai. Families 

with a young child below 5 years of age and at least one smoker in the household will be invited to 

participate in the study. All smokers in the intervention group will receive CHW-delivered SHI (behavioral 

counseling to address health hazards of SHS for children and brief advice to quit or to adopt a no smoking 

standard around children) and educational pamphlets on hazards of SHS. The control group will receive 

no SHS reduction or quit smoking-related intervention but will recceive a placebo education pamphlet on 

child development issues. The control group subjects will receive the same SHI as the intervention group 

upon completion of the follow up assessment. Follow-up will be carried out at 1 and 6 months after the 

first contact. Urine cotinine level of all children and air nicotine level of a sub-sample of households will be 

measured at the first contact and at 1 and 6 months. The main outcome measures are: improvement of 

smoking hygiene practices within the household as reported by the subjects (i.e. reduction in the number 

of cigarettes smoked indoors at home while a child was present during the previous week) and reduction in 

children’s cotinine concentrations in urine at 6-month follow up. 

A MULTIPLE STAKEHOLDER STUDY REGARDING THE IMPACT OF SECONDHAND SMOKE IN MULTIUNIT HOUSING 

Andrew Hyland, PhD; Roswell Park Cancer Institute; CIA 2008 

Exposure to SHS has been shown to be associated with significant morbidity and mortality. With the 

increasing normative trend of clean indoor air standards prohibiting smoking in public places such as 

worksites, bars, and restaurants, the home is increasingly becoming the primary source of SHS exposure 

for many people. Given that one-quarter of Americans (about 80 million people) currently live in multiunit 

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housing, there is a need for scientific research to better understand the health risks caused by SHS to these 

individuals. Dr. Hyland is investigating one of the few studies to develop a science base on whether SHS 

exposure in multiunit buildings occurs and what stakeholders’ views are on the issue. He aims to answer 

three research questions: 1) whether SHS from inside apartments where smoking occurs transfers to nonsmoking 

apartments in the same building; 2) whether tenants and the general population support 

standards to restrict smoking in multiunit buildings; and 3) whether building owners/managers believe 

that smokefree multiunit building standards could result in economic losses. To answer the first study 

question, Dr. Hyland and collaborators will use TSI SidePak air monitors to gather real-time data on levels 

of PM2.5, a marker for SHS, in a convenience sample of up to 168 private residences in 20 multiunit 

housing buildings of various sizes in Western New York State and New York City. PM2.5 levels in adjacent 

smoking and non-smoking units will be compared to determine the extent of SHS transfer between units. 

The team hypothesizes that elevated levels of PM2.5 will be detectable in non-smoking units adjacent to 

units where smoking is occurring and that the size of the increase will be proportionate to the number of 

cigarettes smoked in adjacent apartments. To answer the latter study questions, they will perform 

nationally representative surveys of the general population (n=1,200, including an oversample of 800 

tenants) and owners/managers that make key decisions for multiunit housing buildings (n=400) to assess 

perceptions, attitudes and practices regarding SHS exposure as well as support and barriers for 

comprehensive smokefree multiunit housing initiatives. The team hypothesizes that few multiunit buildings 

will have written smokefree standards due to economic concerns, but that a sizeable fraction of tenants and 

the general population would support such standards. This research will document the extent to which 

SHS is a potential health risk to individuals living in multiunit housing, identify barriers to implementation 

of standards, and realize opportunities for educational efforts for relevant stakeholders. 

FETAL AND INFANT EXPOSURE TO SHS AND ITS ROLE IN CHRONIC DISEASE 

Manolis Kogevinas, MD, PhD; University of Crete; CIA 2008 

FETAL is a birth cohort that will prospectively examine a population sample of approximately 4000 subjects, 

2000 pregnant women and their 2000 children, from the prefecture of Heraklion, Crete, Greece. All 

pregnant women residents of the prefecture of Heraklion that become pregnant during one year are contacted 

during the first weeks of gestation and subsequently followed up, interviewed and clinically examined 

during 6 different clinical investigation days during pregnancy and infancy, until the child’s 24th 

month of age. 

Greece’s high levels of measured SHS exposure and the population’s adherence to the Mediterranean 

diet provide the ideal population for investigating the hypothesis that maternal exposure to SHS during 

pregnancy is associated with a wide spectrum of impacts to the fetus and the child including, genotoxicity 

measured at birth (e.g., DNA adducts, micronuclei) adverse reproductive outcomes (e.g., preterm delivery, 

spontaneous abortion, small for gestational age, low birth weight, intrauterine growth restriction and 

growth in infancy), and to what extent these are reduced through adherence to the Mediterranean diet. 

Infant neurodevelopment, predisposition to the metabolic syndrome and childhood allergies, wheezing and 

asthma will also be investigated. 

SHS exposure is quantified using questionnaire data for the whole cohort and by using biomarker analysis, 

namely cotinine and 4-Methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL; a metabolite of nicotine 

and a tobacco specific lung carcinogen respectively) in a significant sub-sample analyzed at the Department 

of Laboratory Medicine of Boston Children’s Hospital. 

FETAL’s ties to other projects of the birth cohort, the HiWate and NewGeneris, will result in a broader 

field of research that will cover an extensive list of prenatal, postnatal and infant variables of a large cohort 

study. The FETAL study will allow for SHS biomarker exposure analysis and subsequent correlation with a 

plethora of indices from both the above ongoing supporting studies, thus providing significant added value 

to the FAMRI funding for SHS research. 

The research team’s relevant experience in birth cohorts, environmental exposure and nutrition, the 

existing ongoing collaboration between the University of Crete and the Harvard School of Public Health 

on tobacco related studies, the Boston Children’s Hospital laboratory expertise and guidance from invited 

US experts in the field will ensure the project’s success. 

The dissemination of the FETAL study’s findings to the public, public health experts, end-users and 

stakeholders will play an important role in stimulating public health initiatives, media attention and promoting 

the adoption of smoke-free environments thus dramatically increasing the awareness of pregnant 

women and their families to the impacts of SHS exposure on in-utero predisposition and development of 

acute and chronic disease. 

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EVALUATING ONLINE CLINICAL OFFICE-SYSTEMS TRAINING TO ADDRESS SECOND HAND TOBACCO SMOKE 

EXPOSURE OF CHILDREN 

Jonathan P. Winickoff, MD, MPH; Massachusetts General Hospital; CIA 2008 

The objective of this study is to develop and test an online system to train pediatric offices in ways to 

address the problem of children’s exposure to SHS. This is a serious and prevalent health issue, with over 

twenty-four percent of children living in a home with a smoking parent. Children exposed to SHS are at 

increased risk for low birth weight, asthma, bronchiolitis, sinusitis, bacterial respiratory infections, 

decreased lung growth, decreased exercise tolerance, cognitive deficits, and sudden infant death syndrome 

(SIDS). Unfortunately, many pediatricians do not systematically advise parents to establish strictly enforced 

home and car no-smoking rules. The research plan will be divided into two phases. The specific aims of the 

first phase are to develop an online training for pediatricians to address the SHS exposure of children and 

parental smoking, based on the strategies learned during in-person CEASE (Clinical Effort Against 

Secondhand Smoke Exposure) trainings. The specific aims of the second phase of the study are to test the 

feasibility and efficacy of the online training for implementing an office system to address the SHS 

exposure of children in the home and car, and to elicit practicing pediatrician and key staff responses to the 

specific components of the training in order to explore the intervention implementation process for the 

pediatric office setting. Two pediatric practices will be recruited and randomized to control and 

intervention status. The pediatricians at the intervention practice will take the PediaLink training and use 

the enhanced Web site to support their office system change. The control practice will receive standard of 

care tobacco control pamphlets. Prior to implementation, office staff at both practices will complete a 

validated survey that explores practice behavior and change. This survey will also be given at the 12 week 

post-intervention point. The pre- and post-intervention clinician surveys will be compared in analysis to 

understand the impact of the online training and website on self-reported practice change. Detailed 

feasibility and process evaluation will inform tobacco control strategy in pediatric offices nationwide and 

will provide pilot data for a randomized controlled dissemination trial through the American Academy of 

Pediatrics practice research network. 

TRENDS IN SECOND HAND TOBACCO SMOKE EXPOSURE AND PEDIATRIC ILLNESS IN THE U.S. 

Hillel R. Alpert, BSc, SM; Harvard School of Public Health; CIA 2008 

Dr. Alpert and others, including Dr. Connolly, are performing research that examines the hypothesis 

that reductions in SHS exposure of children are associated with fewer smoke-related pediatric illnesses and 

reduced health services utilization by examining relationships between SHS exposure in children and SHSrelated 

pediatric diagnoses and symptoms and associated health services utilization in all health care 

settings (ambulatory, emergency department, and in-hospital). They are analyzing a cross-sectional 

observational study with measures of pediatric illnesses and health care utilization determined from the 

national and state-specific databases to determine exposure variables (percentage of children exposed to 

SHS in the home, percentage of population coverage by comprehensive smoke free workplace laws, 

percentage of smoke free day care center standards, etc.). They have determined that the national 

prevalence of households with smoke-free home rules increased from 43.2% in 1992-1993, when less than 

one percent of the U.S. population was protected by 100% smoke free indoor air standards, to 72.2% in 

2003. National health care and utilization data will help quantify the potential public health benefits and 

health care cost savings of reducing SHS exposure among children. 


Alpert H. Factors associated with youth support of public smoking bans in developing countries 

worldwide: Results from the Global Youth Tobacco Survey. Presented at 14th World Conference on 

Tobacco or Health. Mumbai, India, March 8-11, 2009. 

Alpert H. Manipulation of free nicotine and its dosing to target high risk groups. presented at the cigarette 

industry’s entry into the smokeless tobacco market: research and policy questions and concerns. Meeting 

at Harvard School of Public Health. Boston, MA, July 10, 2008. 

Alpert H. Role of the secondary school environment on secondhand smoke exposure among Cypriot 

youth. Presented at 14th World Conference on Tobacco or Health, Mumbai, India, March 8-11, 2009. 

Alpert H. Youth attitudes and public smoking ban policies in developing countries worldwide: Results 

from the global youth tobacco survey. Presented at 14th World Conference on Tobacco or Health. 

Mumbai, India, March 8-11, 2009. 

Alpert HR, Connolly G, Rosen LJ. Freedom from tobacco. Israel Med Assoc J 2008;10:92. 

Alpert HR, Connolly GN, Koh H. After the master settlement agreement: Targeting and exposure of 

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youth to magazine tobacco advertising. Health Affairs 2008;27(6)503-512. 

Alpert HR., Spalletta R, Connolly GN, O’Connor RJ. Recent advances in cigarette ignition propensity 

research and development. Fire Technology, December 2008. 

Alpert, H. Trends in second hand tobacco smoke exposure and pediatric illness in the U.S. Presented at 

Joint Conference of Society for Research on Nicotine and Tobacco (SRNT) and SRNT-Europe. Dublin, 

Ireland, April 27-30, 2009. 

Christophi CA, Kolokotroni-Zacharopoulou O, Alpert HR, Warren CW, Jones NR, Demokritou P, 

Connolly GN. Prevalence and social environment of cigarette smoking in Cyprus youth. BMC Public 

Health 2008;8:190. 

Connolly GN, Alpert HR. Trends in the use of cigarettes and other tobacco products. 2000-2007. JAMA 

2008;299:2629-2630. 

Kreslake JM, Ferris Wayne G, Alpert HR, Koh HK, Connolly GN, Tobacco industry control of menthol in 

cigarettes and targeting of adolescents and young adults, Am Jl Pub Health 2008;98:1-9. 

Leistikow BN, Kabir Z, Connolly GN, Clancy L, Alpert HR. Male tobacco smoke load and non-lung 

cancer mortality associations in Massachusetts BMC. Cancer 2008, 8:341. 

SECOND HAND TOBACCO SMOKE AND HEAD AND NECK CANCER 

Edward Peters, DMD, SM, ScD; Louisiana State University; YCSA 2003 

SHS exposure is responsible for the development of serious adverse health effects, including lung cancer, 

heart disease, and asthma. Creating smoke-free workplaces and public places is the cornerstone of many 

public health efforts to reduce SHS exposure throughout the United Sates, as well as internationally. While 

hospitality venues such as restaurants will become non-smoking, many other establishments that are 

classified as bars, taverns, or nightclubs will be exempt. Dr. Peters is conducting a statewide study of air 

quality across the state of Louisiana, before and after enacting of the change in smoke-free and smokefilled 

environments. The study focuses predominately on assessing the quality of air in smoking and nonsmoking 

restaurants, bars, and gaming establishments. The purpose is to examine indoor air quality and 

assess the presence of on-premise smoking. Air quality was measured from October 1, 2006 to March 31, 

2007 in bars and restaurants in Louisiana. The goal of this study is to provide the LA tobacco prevention 

partners high quality data from which to evaluate the impact of ACT 815, and to develop future tobacco 

related changes. The purpose of the LA Air Monitoring Study (LAAMS) is to examine indoor air quality in 

a sample of bars and restaurants and other venues that may be impacted or exempt from ACT 815. The 

relation between indoor air pollution and the presence of on-premises smoking will be evaluated. The PI 

hypothesized that indoor air will be less polluted in those venues where smoking is prohibited, and where 

smoking does not occur compared to those places where smoking is present. The LAMS was conducted as 

a joint venture between the Louisiana State University Health Science Center School of Public Health and 

the Coalition for Tobacco Free Louisiana (TFL). This study was performed throughout the state of 

Louisiana. Two 3-month sampling frames were employed, the last 3 months of 2006 and the second 

quarter of 2007. Air monitoring was conducted with TSI SidePak AM510 Personal Aerosol Monitor to 

sample and record the levels of respirable suspended particles (RSP). The differences in the average RSP 

were measured in places that are smoke free and places that are not. A time-weighted average fine 

particulate matter with a diameter smaller than 2.5 microns (PM 2.5) level for each venue and mean PM 

2.5 level for each of the venue types will be calculated. The mean RSP levels of all venues will be compared 

to those that may be classified as smoke free and those that are not. A comparison between smoke free and 

not smoke free for each venue type will be compared and contrasted using the Mann-Whitney Test. 

Descriptive statistics, such as venue volume, number of patrons, and the average smoker density (number 

of lighted cigarettes/ 100 m3), will be estimated. In addition, time plots to show the level of PM 2.5 

throughout the duration of sampling for each region and the state will be developed. 


Peters ES, McClean MD, Liu M, Eisen EA, Mueller N, Kelsey KT. The ADHIC polymorphism modifies 

the risk of squamous cell carcinoma of the head and neck associated with alcohol and tobacco use. 

Cancer Epidemiol Biomarkers Prev 2005;14:476-482. 

CHILDHOOD SECOND HAND TOBACCO SMOKE EXPOSURE: DELAYED NEUROPSYCHIATRIC EFFECTS 

Adriaan W. Bruijnzeel, PhD; University of Florida; YCSA 2006 

Dr. Bruijnzeel hypothesizes that exposure to SHS during childhood causes adaptations in brain reward 

and stress systems that potentiate the positive (e.g., mild euphoria) and negative (e.g., depression) 

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einforcing effects of nicotine, and thereby increases the likelihood of progressing from experimenting with 

cigarettes to habitual smoking during early adulthood. The effects of tobacco smoke exposure on the selfadministration 

of nicotine in adult rats were investigated. The results of this study showed that passive 

exposure to tobacco smoke greatly reduces the self-administration of nicotine. A decrease in nicotine selfadministration 

is usually interpreted as a decrease in the rewarding effects of nicotine. Exposure to tobacco 

smoke may potentially decrease the rewarding effects of nicotine by downregulating brain nicotinic 

receptors. Dr. Bruijnzeel and his collaborator at the University of Kentucky demonstrated for the first time 

using rats prepared with electrodes that exposure to tobacco smoke affects nicotinic receptor levels in the 

brain. Thus, children who have been exposed to high levels of tobacco smoke are nicotine dependent 

despite the fact that they have never smoked themselves. Dr. Bruijnzeel and colleagues investigated if preadolescent 

tobacco smoke exposure would affect nicotine withdrawal during adulthood. The outcome of 

this study shows that pre-adolescent tobacco smoke exposure does not exacerbate nicotine withdrawal 

during adulthood. A follow up study is being conducted to investigate if pre-adolescent tobacco smoke 

exposure affects the rewarding effects of nicotine during adulthood. Taken together, these studies indicate 

that passive exposure to tobacco smoke leads to nicotine dependence and decreases the rewarding affects 

of nicotine, due to tobacco smoke-induced changes in nicotine receptor levels in the brain. 

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward 

system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full 

spectrum of tobacco smoke constituents. Dr. Bruijnzeel wanted to determine if chronic passive exposure to 

tobacco smoke leads to nicotine dependence in rats. The intracranial self-stimulation procedure was used 

to assess the negative affective aspects of nicotine withdrawal in rats. Somatic signs were recorded from a 

checklist of nicotine abstinence signs. Nicotine self-administration was used to investigate if exposure to 

smoke affects the positive reinforcing properties of nicotine. Nicotinic receptor autoradiography was used 

to investigate if exposure to smoke affects central alpha 7 nAChRs and non- alpha 7 nAChRs levels 

(primarily alpha 4-beta 2 nAChRs). The nAChR antagonist mecamylamine elevated the brain reward 

thresholds of the rats chronically exposed to smoke and did not affect the brain reward thresholds of the 

control rats. Elevations in brain reward thresholds are indicative of a negative mood state. Furthermore, 

mecamylamine induced more somatic withdrawal signs in smoke exposed rats than in control rats. Nicotine 

self-administration was decreased 1 day after the last smoke exposure sessions and was returned to control 

levels 5 days later. Smoke exposure increased alpha 7 nAChR levels in the CA2/3 region, hilus of dentate 

gyrus, and stratum oriens and increased non-alpha 7 nAChR levels in the dentate gyrus. It appears 

therefore that passive exposure to tobacco smoke leads to nicotine dependence as indicated by precipitated 

somatic and affective withdrawal signs and an upregulation of nAChRs in the hippocampus. These studies 

indicate that passive exposure to tobacco smoke has similar effects on the brain as active smoking. 

SIMULATION OF SECOND HAND TOBACCO SMOKE DEPOSITION IN THE AIRWAYS 

Jeffrey J. Heys, PhD; Arizona State University; YCSA 2006 

SHS is composed of airborne particles that are deposited in the airways. However, the relationship 

between airborne particles and smoking does not end there, because some experimental treatments for the 

damage caused by airborne pollutants are therapeutic drugs that are themselves inhalable. The objective of 

Dr. Heys’ studies is to better understand the movement and deposition of inhaled particles, both 

destructive and therapeutic. The impacts of this work include better risk assessment, improved prediction 

of likely tumor locations, and improved targeting of inhalable therapeutic drugs. A higher-order 

mathematical model of airflow and particle transport in the human airways is being developed that will 

provide a more accurate prediction of particle deposition location at lower computational costs. Accurate 

computational geometries of patient specific airways have been developed. The mathematical models are 

being validated by measuring the deposition of radio labeled tobacco smoke in rats. Initial experimental 

efforts are focused on validating and improving methods for radio labeling SHS. Experiments have 

provided strong agreement with the simulation predictions. 


Heys JJ, Knott B, Gedeon T, Kim Y. Modeling arthropod filiform hair motion using the penalty immersed 

boundary method. J Biomech Eng 2008;41(5):977-984 

Heys JJ, Lee E, Manteuffel TA and McCormick SF. An alternative least-squares formulation of the navierstokes 

equations with improved mass conservation. J Comp Physics 2007;226:994-1006. 

Merchant B, Heys JJ. Effects of variable permeability on aqueous humor outflow. Appl Comp 

Math 2008;196:371-380 

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Stukel JM, Heys JJ, Caplan MR. Optimizing delivery of multivalent constructs for detection of secondary 

tumors. Ann Biomed Eng 2008;36(7):1291-1304. 

Wong SS, Vargas J, Thomas A, Fastje C, McLaughlin M, Camponovo R, Lantz RC, Heys JJ, Witten ML. 

In vivo comparison of epithelial responses for S-8 versus JP-8 jet fuels below permissible exposure 

limit. Toxicology 2008;254(1-2): 106-111. 

HOOKAH USE AND SECOND HAND TOBACCO SMOKE 

Nada Kassem, PhD; San Diego State University; YCSA 2006 

The purpose of this proposal is to investigate the patterns and determinants of hookah tobacco use and 

second hand hookah tobacco smoke exposure among college students. Dr. Kassem’s study consists of two 

arms: a behavioral arm and a clinical arm. To date, a Web-based survey on hookah tobacco use was 

implemented with a random sample of undergraduate students and a population sample of graduate 

students at San Diego State University. The theoretical foundation of the behavioral arm of this study is 

the Behavioral Ecological Model (BEM). The framework of the BEM is being used as a guide to inform 

potential interventions by identifying social, cultural, and environmental determinants of hookah tobacco 

use specific to college students. Findings from the Web-based survey will be reported in a series of 

manuscripts in which the first two manuscripts are in preparation. Data collected for the clinical arm of the 

study has been completed. Twelve participants provided urine and air samples to measure hookah lounge 

SHS exposure. Each participant collected a total of nine urine samples. Three samples were collected prior 

to visiting a hookah lounge and six samples were collected after visiting the hookah lounge. Participants 

visited one hookah lounge for 1 to 3 hours once a month for 3 consecutive months. In February 2009, 

urine samples were shipped to the lab to be analyzed for 4-methylnitrosamino-1-(3-pyridyl)-1-butanol and 

its glucuronides, 1-hydroxypyrene, cotinine, as well as cotinine half-life due to hookah tobacco smoke 

exposure. Dr. Kassem expects to receive the results of the urine samples in May of 2009. The air samples 

collected containing a total of 6 hours of hookah lounge SHS were analyzed for nicotine. Results from the 

air samples will be reported with the results from the urine samples in publishable manuscripts. 

PSE RATES AND CORRELATES: KOREANS/KOREAN AMERICANS 

Suzanne C. Hughes, PhD, MPH; San Diego State University; YCSA 2006 

Dr. Hughes’ research examines the extent and determinants of SHS exposure among Korean Americans 

and Koreans, known for their high male smoking rates. The aims are to: 1) estimate and compare the 

prevalence and correlates of SHS exposure among Korean Americans, and among Koreans for cultural 

comparison, 2) assess physiological, emotional, and socio-cultural aspects of SHS exposure, 3) explore the 

role of home smoking bans on SHS exposure using cross-sectional data, 4) examine whether home 

smoking bans reduce SHS exposure using a longitudinal design; and 5) design a culturally tailored 

intervention to reduce SHS exposure. The results from telephone survey data on the prevalence and 

determinants of SHS exposure among Korean Americans and Koreans have been published in three articles 

documenting high levels of SHS exposure among children and non-smokers. Eight focus groups of Korean 

American men and women have been conducted. Manuscripts on non-smokers’ reactions to SHS and on 

socio-cultural aspects of SHS exposure are in preparation. Complete home smoking bans (but not partial 

bans) were associated with lower SHS exposure compared to no bans. Longitudinal analyses of baseline 

follow-up data for the California sample are underway, and an intervention is being designed based on 

results from the telephone surveys, focus groups, and 15 key informant interviews. Altogether, this 

research will enhance the understanding of SHS exposure among immigrant groups such as Korean 

Americans, and lead to culturally appropriate interventions. 


Hofstetter CR, Ayers JW, Irvin VL, Kang Sim DE, Hughes SC, Reighard F, Hovell MF. Does church 

participation facilitate tobacco control? A Report on Korean Immigrants. J Immigr Minor Health 2009 

Feb 10. [Epub ahead of print]. 

Hughes SC, Corcos IA, Hofstetter CR, Hovell MF, Irvin VL, Park HR, Paik HY. Children’s exposure to 

environmental tobacco smoke at home in Seoul, Korea. Asian Pac J Cancer Prev 2008;9:491-496. 

Hughes SC, Corcos IA, Hofstetter CR, Hovell MF, Irvin VL, Park HR, Paik HY, Ding DM. Home 

smoking restrictions among Koreans in Seoul. Asia Pac J Public Health 2009;21(1):63-70. 

Hughes SC, Corcos IA, Hofstetter CR, Hovell MF, Irvin VL. Environmental tobacco smoke exposure 

among Korean American non-smokers in California. Nicotine Tob Res 2008;10(4):663-670. 

1 8 6 P A G E

Hughes SC, Corcos IA, Hofstetter CR, Hovell MF, Seo DC, Irvin VL, Park HR, Paik HY. Secondhand 

smoke exposure among non-smoking adults in Seoul, Korea. Asian Pac J Cancer Prevention 

2008;9:247-252. 

Hughes SC, Hovell MF, Hofstetter CR, Irvin VL, Park HR, Paik HY. Home smoking policy and ETS 

exposure among Koreans in Seoul. Tob Control 2008;17(1):71-72. 

SECOND HAND TOBACCO SMOKE, PEDIATRIC HEALTHCARE USE, AND SPENDING 

Douglas Levy, PhD; Harvard Medical School; YCSA 2008 

SHS exposure causes a variety of childhood ailments. Children have high levels and rates of exposure to 

SHS because most of their exposure takes place in the home. Though SHS-related morbidity in children 

has been extensively studied, few studies have examined the burden this morbidity places on the healthcare 

system. Because of the higher prevalence of smoking among low socioeconomic adults, children in lower 

income families are most likely to be exposed to household SHS. The effect of children’s exposure to 

household SHS on Medicaid spending is a vital public health question that has not yet been addressed. Dr. 

Levy seeks to exploit up-to-date data assets to refine measures of the relationship between children’s 

exposure to household SHS and pediatric healthcare use and health expenditures. With this information, it 

will be possible to predict specifically how reducing household SHS exposure will affect physician visits, 

emergency department visits, and healthcare spending. Public health professionals will be able to use the 

information to develop, value, and promote strategies to reduce household SHS exposure. Dr. Levy is 

using the nationally representative Medical Expenditures Panel Survey to evaluate the short-term effect of 

household SHS exposure on pediatric healthcare utilization, health expenditures, number of days of school 

children miss, and the number of work days adults miss to care for others. Sub-analyses will specifically 

investigate the impact of children’s exposure to SHS on Medicaid spending versus spending by other 

payers. Ultimately, the intent is to use mathematical modeling to project the effects of changes to tobacco 

standards and treatment practice on household smoking rates and pediatric healthcare use and spending. 

These aims are a first step towards understanding the consequences of household SHS exposure. In future 

years this research will expand to encompass more wide-ranging and long-term effects of household SHS 

exposure. 


Levy DE. Healthcare expenditures of children who live with smokers. Presented at the American Academy 

of Pediatrics (AAP) Julius B. Richmond Center of Excellence Tobacco Consortium Meeting. Atlanta, 

GA, January 22-23, 2009. 

WELL-BABY CLINIC-BASED INTERVENTION 

Laura Rosen, PhD; Tel Aviv University; YCSA 2008 

Dr. Rosen’s primary goal is to develop and test a theory-based intervention, situated in the well-baby 

clinic that will reduce infant exposure to SHS. A secondary goal is to increase knowledge of measurement 

of SHS exposure in infants, and explore the relationship between early SHS exposure and health care utilization. 

A study of SHS exposure will be performed in 100 infants to learn about the relationship between 

measures of SHS in the local population and its relationship to health care utilization. Eighteen clinics will 

be randomized equally to intervention and control, and parents of 30 infants will be recruited per clinic. 

The primary response variable will be exposure of infants to SHS. The control group will be offered the 

intervention at the end of the study. Intervention and its development social marketing techniques will be 

used to develop a feasible, brief intervention. 

SHS exposure will be measured using cutting-edge technology, and knowledge about measurement of 

SHS in infants will be enhanced. The cluster-randomized design will provide high quality information on 

effectiveness. An effective program could be implemented nationally and sustainably in Israel’s well-baby 

care system and serve as a prototype for interventions in other countries struggling with the problem of 

infant SHS exposure. 


Rosen L, Zucker D, Rosenberg E, Connolly G. Secondhand smoke in Israeli bars, pubs, and cafes. Israel 

Medical Association Journal 2008;10:1-4. 

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EXPOSURE TO SECOND HAND TOBACCO SMOKE 


QUANTIFYING HUMAN EXPOSURE TO SHS 

Paul Switzer, PhD; Stanford University; CIA 2003 

The investigators performed SHS particle measurements in the outdoors and demonstrated that the 

respirable particle concentration in public places when smoking is going on exhibits a variation in 

concentrations depending on the distance from the smoker and the position of the individual with respect 

to the wind. Peak and average outdoor SHS levels near smokers rivaled indoor tobacco smoke 

concentrations when active smoking was occurring. Thus outdoor SHS is hazardous under certain 

conditions of wind and smoker proximity. Measurements of average pollutant levels of carbon dioxide 

(CO 2 ) in any direction just above or below the source and 1 meter away increased by 20-24 mg/m3 on 

average for every added mg/mm of emissions; and that a person standing 0.25 meters away from a source 

for 1 hour under changing air flow conditions would inhale an estimated 300-600 nanograms for every 

milligram of pollutant mass emitted during the same period. This is comparable to exposures reported for 

indoor exposure to SHS. In indoor measurements it was shown that closing a door between rooms 

effectively prevented transport of air pollutants, reducing the average concentration in the room without 

the source by nearly 100% relative to the source room. When doors were left open, the reduction in 

average concentrations was only 20-50%. Opening a window in a room containing a source could reduce 

average concentrations by 10-60% depending on wind conditions and the width of the window opening. 

An indoor air model accurately predicted the observed percent reduction in average concentrations. 

Pollution in cars was measured under a variety of conditions. The time series of concentrations measured 

inside the vehicles were consistent with the solutions of mathematical models designed to predict interior 

pollutant concentrations in motor vehicles. These results are important for assessing the risks of smoking in 

automobiles. Modeling exposure in multicompartment homes indicated that the multicompartment nature 

of these dwellings, manifested as inter-room differences in pollutant levels and the movement of people 

among zones, can cause substantial variation in nonsmoker SHS exposure. The two most effective 

strategies in reducing SHS exposure in homes were shown to be isolation of the smoker in a closed room 

with an open window and a ban on smoking whenever the nonsmoker was at home. The use of open 

windows to supply local or cross ventilation, or the operation of portable filtration devices in smoking 

rooms provided moderate exposure reductions. Closed doors, by themselves, were not effective. 


Klepeis NE, Ott WR, Switzer P. Real-time monitoring of outdoor environmental tobacco smoke 

concentrations: A pilot study. Technical Report for Department of Statistics, Stanford University, 2004. 

AIRWAY RESISTANCE AND CYTOGENETIC ABNORMALITIES ASSOCIATED WITH TOBACCO SMOKE EXPOSURE 

Martin Mahoney, MD, PhD; Roswell Park Cancer Institute; CIA 2003 

On July 24, 2003, New York State enacted a statewide Clean Indoor Air Law (CIAL), which eliminated 

smoking in nearly all indoor public places, creating a unique opportunity to compare exposures among 

hospitality and non-hospitality workers before and after enactment of this standard. Dr. Mahoney 

interviewed a group of non-smokers recruited from the western New York State (NYS) region to assess 

exposures to SHS. These self-administered surveys were critical to assessing the impact of the CIAL in 

NYS. The number of hours of SHS exposure reported during the 4 days prior to the baseline interview 

decreased from 7.0 hours pre-law to 3.0 hours post-law and there was a significant reduction of SHS 

exposure among non-casino hospitality workers. There was no significant change in reported exposures 

among casino workers or among non-hospitality workers. Since tribally-owned casinos are exempt from the 

CIAL and still allow smoking, no real change in SHS exposure among casino workers was anticipated. 

These results provide clear evidence of a substantial reduction in work site SHS exposure among hospitality 

workers that is attributable to the NYS clean indoor air standards. 


Abrams S, Mahoney M, Hyland A, Cummings KM. Clean indoor air laws protect hospitality workers: 

evidence from New York State. Presented at the National Conference on Tobacco or Health. Chicago, 

IL, May 4-6, 2005. 

Abrams SM, Mahoney MC, Hyland A, Cummings KM, Davis W, Song L. Early evidence on the 

effectiveness of clean indoor air legislation in New York State. Am J Public Health 2006;96:296-298. 

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Abrams SM, Mahoney MC, Hyland A, Cummings KM. A cross-sectional study of secondhand smoke 

exposure in western New York, 2003. Presented at the 10th Annual Society for Research on Nicotine 

and Tobacco Meeting. Scottsdale, AZ, Feb 18-21, 2004. 

Paszkiewicz GM, Timm EA, Jr., Mahoney MC, Wallace PK, Sullivan Nasca MA, Tammela TL, Hutson A, 

Pauly JL. Increased human buccal cell autofluorescence is a candidate biomarker of tobacco smoking. 


SECOND HAND TOBACCO SMOKE EXPOSURE AND HEALTH IN A BLUE-COLLAR POPULATION 

Francine Laden, ScD; Harvard University; YCSA 2002 

Dr. Laden hypothesized that: 1) exposure to SHS is an independent predictor of respiratory symptoms 

and illness in the US trucking industry, when controlled for active smoking and exposure to diesel exhaust; 

2) factors such as job site and duties, terminal characteristics, region of the country, local smoking rates, 

and company of employment influence the extent of SHS exposure; and 3) plasma levels of C-reactive 

protein (CRP), a marker of chronic inflammatory process of the cardiovascular system and soluble 

intercellular adhesion molecule-1 (sICAM-1), a marker of vascular endothelial activation and inflammation, 

are positively associated with SHS exposure. The research aims were: 1) to define the relationship between 

SHS exposure and chronic respiratory symptoms and respiratory illness based on a cross-sectional analysis 

among 4,500 trucking company workers; 2) to determine the factors influencing exposure to SHS in the 

trucking industry and validate the self report of SHS exposure provided by a questionnaire; and 3) to 

collect blood samples from responders to the cross-sectional survey through the mail and assess levels of 

CRP and sICAM-1. In a validation study performed in the field, self-reported time spent in a designated 

smoking area and the numbers of people smoking in the area were predictive of exposure to vapor-phase 

nicotine as measured by a passive monitor worn in the breathing zone. Variation in enforcement of 

smoking standards in the workplace also influenced exposure. Detailed questionnaires covering SHS 

history and respiratory symptoms were mailed to 4,500 trucking company workers who had answered an 

initial smoking history questionnaire. Two thousand three hundred workers responded and preliminary 

analyses suggest that the prevalence of adverse health outcomes, including respiratory symptoms and 

allergies, is greater in non-smokers exposed to recent second hand tobacco smoke compared to nonsmokers 

who are not exposed. One hundred thirty blood samples have been returned to the laboratory 

along with nicotine badges worn during the 2 days immediately before blood draw. All data from the 

questionnaire have been entered and cleaned; the vapor phase nicotine analyses and analyses of blood 

markers have been completed. Statistical analyses on the association of SHS with markers of inflammation 

was conducted. 

ADULT HEALTH CONSEQUENCES OF PRENATAL AND POSTNATAL SECOND HAND TOBACCO EXPOSURE 

Stephen L. Buka, ScD; Harvard School of Public Health; CIA 2006 

Dr. Buka’s study was to determine whether there are identifiable health sequelae of early SHS exposure 

(both in utero and during early childhood), and to identify pathways through which early exposure 

influences the risk of adult health problems. Using data from a well-defined cohort of approximately 2000 

individuals followed from the prenatal stage through age 40, the primary aim was to prospectively examine 

the relationship between chemically validated in utero tobacco exposure and adult health outcomes. The 

design of the study controlled for the potential confounding effects of factors such as parental 

socioeconomic status, a major limitation of much prior research. The aims of the study were achieved 

through secondary data analysis of a unique long term prospective study of a representative community 

sample, the New England cohorts of the National Collaborative Perinatal Project. The results of these 

analyses will considerably bolster the limited world literature on the long term health effects of prenatal 

and postnatal second hand tobacco exposure. 

HORMONAL CHANGES FROM TOBACCO EXPOSURE 


STEROID HORMONES CONCENTRATIONS ASSOCIATED WITH ACTIVE AND PASSIVE CIGARETTE SMOKING 

Offie P. Soldin, PhD, MBA, MSc; Georgetown University; CIA 2006 

There is a gap in knowledge regarding the effects of cigarette tobacco smoke on steroid hormone levels 

in women of reproductive age. Dr. Soldin and her collaborators conducted a three-arm study of active 

smokers, passive smokers and non-smokers to determine the associations with serum androstenedione, 

P A G E 1 8 9

aldosterone, cortisol, corticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate 

(DHEAS), estrone, 16-hydroxyestrone, 17-b-estradiol, estriol, progesterone, 17-b-hydroxyprogesterone, 

testosterone, 11-deoxycortisol and 25-OH Vitamin D3. The study was conducted in the Metropolitan 

Washington D.C. area (2006-2008) on healthy women of reproductive age (18-44y) at the follicular stage 

of their menstrual cycle. Study arms were determined both by self-report and serum cotinine 

measurements. Serum hormone concentrations were measured using isotope dilution tandem mass 

spectrometry (LC/MS/MS) (API-5000). The investigators found statistically significant differences among 

the three study arms in serum concentrations of 16-hydroxyestrone, aldosterone and 25-hydroxyvitamin 

D3, as well as in the ratios of many of these steroid hormones. These differences may be instrumental in 

causing some of the adverse effects attributed to active and passive smoking including problems leading to 

infertility and diseases related to cigarette tobacco smoke exposure. 


Soldin OP, Soldin SJ, Ressom H, Landy HJ. Hormone Changes in Women of Reproductive Age 

Associated with Tobacco Smoke Exposure using Metabolomics. Presented at the Soc Gynecological 

Investigations Meeting, March 2008. 

Soldin OP, Soldin SJ, Ressom H, Landy LJ. Tobacco Smoke Exposure Associations with Thyroid 

Hormone Changes in Women of Reproductive Age. Presented at the Annual Meeting of the American 

Thyroid Association, October 2007. 

Soldin OP, Marian C, Loffredo CA, Gilbert S, Ressom H, Shields PG. Hormonal Changes in Women of 

Reproductive Age due to Tobacco Smoke Exposure and Genetic Predisposition. Presented at the Future 

research on Endocrine Disruption: Translation of Basic and Animal Research to Understand Human 

Disease Meeting, NIEHS and USEPA sponsored, August 2007. 

RANDOMIZED CONTROLLED TRIALS (RCT) OF FAMILY INTERVENTIONS TO REDUCE 

SECONDHAND TOBACCO SMOKE (SHS) EXPOSURE IN INFANTS AND MOTHERS 

Sophia Siuchee Chan, PhD; University of Hong Kong; CIA 2007 

In an effort to understand the household smoking behavior of fathers, and to explore mothers’ 

perceptions and experiences in improving household smoking hygiene, and helping fathers to quit, Dr. 

Chan has undertaken a number randomized controlled trial (RCT) interventions. 

Some interventions have used nurses to provide an intense program of counseling; other studies have 

used telephone interviews and distribution of educational packets. Both pilot and large scale studies have 

been conducted. 

Based on pilot data, smoking cessation interventions for the smoking fathers through empowering the 

non-smoking mothers in families with infants and babies were developed. The preliminary data show that 

the majority of the fathers continued to smoke at home, and few mothers actively stopped fathers smoking 

at home or convinced them to quit. However, some interventions were successful in getting fathers to 

reduce their smoking in the home, and to distance themselves from infants and babies when they smoked. 

Theory-based interventions are being designed to empower mothers to implement the household nosmoking 

strategy, educate them regarding the hazards of SHS, and motivate them to include family 

members as a unit for the discussion of smoking cessation. 

The ultimate goal of these studies is to reduce SHS exposure so as to control the risk of SHS healthrelated 

illnesses in the household. The results from Dr. Chan’s studies will provide unprecedented evidence 

of the effectiveness of smoking cessation interventions that reduce household SHS exposure in non- 

Western populations. These studies can serve as an exemplary model for future efforts in fighting SHS 

exposure in other environments and in other Asian countries. 


Yau JPL, Chan SSC, Lam TH, Fong DYT. A randomized controlled trial (RCT) of a family intervention 

to reduce secondhand smoke (SHS) exposure in infants and mothers. Presented at the 13th Research 

Postgraduate Symposium. Hong Kong. December 10-11, 2008. 

Yau JPL, Chan SSC, Lam TH, Fong DYT. A randomized controlled trial of a family intervention to 

reduce secondhand smoke (SHS) exposure in babies. Presented at the U21 Doctoral Nursing Research 

Forum at Health Sciences Meeting. Virginia, USA, September 15-19, 2008. 

Chan SSC, Yau J, Leung DYP, Leung AYM, Leung GM, Leung S, Emmons K, Lam TH. Exploring mothers’ 

experiences in improving smoking hygiene at home: A qualitative study. Presented at the Society for 

Research on Nicotine and Tobacco First Asian Regional Conference. Bangkok, Thailand, Oct 28-31, 2008. 

1 9 0 P A G E

IMMUNE FUNCTION IMPACTED BY TOBACCO SMOKE 


A2A RECEPTOR ANTAGONISM AS A NOVEL MEANS TO ENHANCE VACCINE THERAPY FOR THE TREATMENT 

AND PREVENTION OF BREAST CANCER 

Jonathan D. Powell, MD, PhD; Columbia University; CIA 2006 

The ability of the immune system to specifically recognize antigen makes it a potentially powerful tool in 

terms of developing modalities to treat breast cancer. However, in spite of many recent advances in 

identifying tumor antigens, immunotherapy has yet to live up to its full potential. In part this is due to the 

ability of tumors to evade immune destruction by turning off tumor-antigen specific immune cells. 

Recently, data have emerged demonstrating that the A2a adenosine receptor plays an important role in 

downmodulating immune responses. Dr. Powell’s lab has been able to demonstrate that A2a engagement 

of T cells not only inhibits T cell function but also promotes the generation of T cell tolerance and T- 

regulatory cells. Since the tumor microenvironment contains high concentrations of adenosine, the 

investigators propose that tumor-derived adenosine acts to inhibit immune function and promote tumorspecific 

T cell tolerance. Indeed, recent data using A2a receptor (A2aR) null mice indicate that such mice 

mount more robust antitumor responses leading to their enhanced ability to reject tumor challenge. In 

addition, these mice respond better to tumor-specific vaccines as treatment for pre-existing tumors. 

Mechanistically, these data suggest that A2aR mice are resistant to anergy induction in vivo and develop 

less antigen-specific Lag-3+ regulatory T cells. Currently, the research team is examining the affect of 

specific A2aR antagonists to enhance tumor vaccines in tumor-bearing wild-type mice. The PI predicts that 

such studies will identify an A2aR antagonist compound that can be integrated into clinical trials. 


Sikder HA, Huso DL, Zhang H, Wang B, Ryu B, Hwang ST, Powell JD, Alani RM. Disruption of Id1 

reveals major differences in angiogenesis between transplanted and autochthonous tumors. Cancer Cell 

2003;4:291-299. 

Zarek PE, HuangCT, Lutz ER, Kowalski J, Horton MR,Linden J, Drake CG, Powell JD. Blood 

2008;111:251-259. 

SECOND HAND TOBACCO SMOKE, IMMUNITY AND ALLOGRAFT REJECTION 

Zhenhua Dai, MD, PhD; University of Texas Health Center at Tyler; CIA 2008 

Transplantation is emerging as a more common and critical approach to save lives of patients at the endstage 

of various organ diseases including the heart and kidney. However, studies on the role of cigarette 

smoking in allograft rejection and alloimmunity in a cause-effect manner are lacking. 

Current protocols to induce long-term allograft survival include conventional immunosuppression, 

costimulatory blockade and the generation of regulatory T cells (Treg), etc. In particular, approaches to 

suppress memory T cell generation but induce Treg cells are essential for long-term allograft survival. Dr. 

Dai’s preliminary data have shown that SHS increases memory T cell number and hinders allograft survival 

induced by CD40/CD154 costimulatory blockade. In this proposal he hypothesizes that SHS shortens 

allograft survival by suppressing Treg cell development but promoting memory T cell recall. In Aim 1, the 

PI investigates the impact of SHS on the function of memory CD4+ and CD8+ T cells. In Aim 2, he will 

study whether SHS suppresses the generation and function of CD4+CD25+FoxP3+ Treg cells. Finally, in 

Aim 3, he will examine whether targeting memory T cells and administering Treg cells suppress allograft 

rejection related to SHS. In this study, a murine cardiac transplant model will be implemented and 

recipient mice will be exposed to a precision-guided smoke chamber mimicking SHS. This study for the 

first time will provide insight into the immunologic mechanisms by which SHS promotes allograft 

rejection. This proposal also has clinical implications for the prevention and treatment of graft rejection 

caused by the exposure to SHS. 

ALTERATIONS IN DENDRITIC CELL-MEDIATED IMMUNITY CAUSED BY SMOKING 

Robert Vassallo, MD; Mayo Clinic; YCSA 2005 

Dr. Vassallo proposes that cigarette smoking and nicotine suppress the function of dendritic cells in a 

very specific fashion. The PI hypothesizes that smoking diminishes host immune responses necessary for 

elimination of tumors and infections, and enhances the development of immune responses that lead to 

allergy and asthma. Using a murine smoking model the goals are to: 1) determine the effect of smoking on 

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the expression of numerous genes that regulate key dendritic cell functions using a genomic approach; 2) 

determine how cigarette smoking affects dendritic cell function; and 3) determine how smoking may skew 

immunity so as to favor the establishment of asthma. 


Carmona EM, Vassallo R, Vuk-Pavlovic Z, Standing J, Kottom T, Limper AH. Pneumocystis cell wall b- 

glucans induce dendritic cell co-stimulatory molecule expression and inflammatory activation through a 

Fas-Fas Ligand mechanism. J Immunol. 2006;177(1):459-467. 

Kobayashi T, Iijima K, Radhakrishnan S, Vassallo R, Lawrence C, Pease LR, Kita H. Asthma-related 

environmental fungus, Alternaria, activates dendritic cells and produces potent Th2 adjuvant activity. J 

Immunol 2009;182(4):2502-10. 

Kroening PR, Barnes TW, Pease L, Limper A, Kita H, Vassallo R. Cigarette smoke-induced oxidative stress 

suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways. J Immunol 

2008;181(2):1536-47. 

Vassallo R, Kroening PR, Parambil J, Kita H. Nicotine and oxidative cigarette smoke constituents induce 

immune-modulatory and pro-inflammatory dendritic cell responses. Mol Immunol 2008;45(12):3321- 

3329. 

Vassallo R, Tamada K, Lau JS, Kroening PR, Chen L. Cigarette smoke extract suppresses human dendritic 

cell function leading to preferential induction of Th-2 priming. J Immunol 2005;175:2684-91. 

INNATE IMMUNITY AND TOBACCO SMOKE 

Maria Antonieta Guerrero-Plata, PhD; University of Texas Medical Branch at Galveston; YCSA 2007 

Exposure to tobacco smoke is associated with increase in the frequency and severity of respiratory 

infections. The innate immune system is the first line of host defense against pathogens and recognizes 

microorganisms via a limited number of effector molecules, including type I interferon (IFN-a/b). IFNa/b 

is one of the key anti-viral molecule which is produced by specialized cells called plasmacytoid 

dendritic cells (pDC). In this work, Dr. Guerro-Plata will pursue the hypothesis that exposure to SHS 

affects the ability of the immune system to fight respiratory viral infections by interfering with the 

production of innate immune molecules such as IFN type I and/or with the activation and recruitment of 

pDC to the sites of infection. These studies will investigate the clinical relevance of the innate immune 

response in the context of co-exposure to viral respiratory pathogens and SHS and dissect the molecular 

and cellular basis of this interaction. The results of these studies will help in the design of new strategies to 

boost immunity against respiratory viruses under unfavorable environmental conditions characterized by 

exposure to SHS. 


Castro S, Garofalo RP, Guerrero-Plata A. Inhibition of dendritic cell activation by cigarette smoke extract. 

Presented at the 48th Annual Meeting, Society of Toxicology. Baltimore, MD, March 15-19, 2009. 

Castro S, Garofalo RP, Guerrero-Plata A. Mechanisms of inhibition of viral-induced interferon production 

in human dendritic cells by cigarette smoke extract. Presented at the 2009 Annual McLaughlin 

Colloquium on Infection and Immunity. Galveston, TX, Feb 26, 2009. 

Guerrero-Plata A, Kolli D, Hong C, Casola A, Garofalo RP. Subversion of pulmonary dendritic cell 

function by paramyxovirus infections. J Immunol. 2009;182:3072-3083. 

Guerrero-Plata A, Kolli D, Hong C, Casola A, Garofalo RP. Impairment of lung dendritic cell antigen 

presenting capacity by paramyxovirus infections. Presented at the AAI Annual Meeting. San Diego CA, 

April 5-9, 2008. 

Guerrero-Plata A, Kolli D, Hong C, Casola A, Garofalo RP. Respiratory syncytial virus and human 

metapneumovirus impair the antigen presentation capacity of pulmonary dendritic cells. Presented at the 

Annual Meeting of the American Society for Virology. Ithaca, NY, July 12-15, 2008. 

Guerrero-Plata A, Kolli D, Hong C, Casola A, Garofalo RP. Trafficking of dendritic cell subsets to the 

lung controls viral replication and pathology in human metapneumovirus infection. Presented at the XIV 

International Congress of Virology. Istanbul, Turkey. August 10-15, 2008. 

MOLECULAR MECHANISM OF PHOSPHATIDYLINOSITOL 3-KINASE (PI-3K) ACTIVATION IN FLAGELLIN/TOLL-LIKE 

RECEPTOR 5-DEPENDENT SIGNALING 

Sang Hoon Rhee, PhD; University of California, Los Angeles; YCSA 2007 

PI3K activation is essential for intestinal epithelial cell proliferation in vitro and in vivo. Bacterial 

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flagellin, released from commensal and enteroinvasive microbes in the human gut, stimulates Toll-like 

receptor 5 (TLR5) leading to proinflammatory responses and activation of PI3K in colonic epithelial cells. 

However, the molecular mechanisms by which TLR5 activates PI3K have not been well investigated. In 

this study, Dr. Rhee determined the signaling pathways involved in flagellin/TLR5-induced PI3K 

activation in human colonocytes. In order to determine PI3K activation in vitro, expression of TLR5 or its 

adaptor molecule, MyD88, was silenced by stable transfection of TLR5 or MyD88 siRNA constructs, 

respectively, in non-transformed NCM460 human colonocytes. Several TLR5 mutants harboring pointmutated 

tyrosine residues, including SH-2-domain binding motif ‘YXXM’ in the cytoplasmic TIR domain 

of TLR5, were generated by site-directed mutagenesis. Co-immunoprecipitation assays were performed to 

determine the association between TLR5 and MyD88 or PI3K. 

The investigators showed that flagellin exposure to NCM460 cells transiently activated PI3K within 10- 

30 min, while blocking PI3K reduced IL-8 production in colonocytes. TLR5 silencing blocked PI3K 

activation by flagellin, indicating that TLR5 specifically mediates PI3K activation in colonocytes. 

Immunoprecipitation studies showed that TLR5 recruits the p85 regulatory subunit of PI3K to its 

cytoplasmic TIR domain following flagellin stimulation, and MyD88 interacted with TLR5 in a timedependent 

manner. Additional immunoprecipitation studies with TLR5 mutant constructs demonstrated 

that the SH-2 binding ‘YXXM’ motif in the TIR domain of TLR5 is not involved in p85 recruitment, 

implying that p85 is indirectly recruited to TLR5. Moreover, silencing MyD88 expression in colonocytes 

disrupted PI3K activation and blocked the association between TLR5 and the p85 regulatory subunit. 

Thus, PI3K activation in TLR5-associated signaling in human colonocytes is MyD88-dependent. 

ROLE OF SERPINB1 IN CIGARETTE SMOKE-INDUCED DEFECTIVE ANTIMICROBIAL DEFENSE 

Charaf Benarafa, DVM, PhD; Immune Disease Institute; YCSA 2008 

Oxidative damage induced by SHS leads to cellular injury and inflammation in the lung and these events 

are associated with increased risk for pulmonary infection. The direct effects of repeated smoke exposure 

and the additional burden produced by recruited leukocytes that release proteases, oxidants and 

inflammatory mediators on the lungs, can cause dysregulation of the immune response to pathogens. 

SERPINB1 (also known as monocyte neutrophil elastase inhibitor, MNEI) is an ancestral member of the 

serpin (SERine Protease INhibitor) family and one of the most potent inhibitors of the neutrophil serine 

proteases: elastase, cathepsin G and proteinase-3. Dr. Benarafa and collaborators have recently developed a 

model of protease-antiprotease imbalance by deleting the mouse gene. Serpinb1-deficient (serpinb1-/-) 

mice have a late-onset defective immune response to acute Pseudomonas aeruginosa infection and fail to 

clear the infection due to increased neutrophil death and proteolysis of surfactant protein-D (SP-D). Dr. 

Benarafa hypothesizes that SERPINB1 participates in the protection of cellular and molecular antimicrobial 

mechanisms dysregulated by the oxidative and inflammatory damage induced by cigarette smoke. To test 

this hypothesis, the scientists are investigating: 1) whether oxidative damage induced by exposure to 

cigarette smoke affects SERPINB1 expression in lung cells in vitro and in vivo; 2) whether the 

combination of oxidative injury of cigarette smoke and the antiprotease defect of serpinb1-/- mice 

increases the susceptibility to subacute bacterial lung infection; and 3) whether recombinant SERPINB1 

preserves the innate immune response to P. aeruginosa infection in wild-type mice exposed to cigarette 

smoke. These studies are to define a role for SERPINB1 in regulating damage caused by cigarette smoke 

components, and protecting molecular and cellular components of the healthy lung innate immune 

response. Importantly, inhaled recombinant SERPINB1 may be considered as a possible adjunct treatment 

in cases of pulmonary exacerbation caused by bacterial infection in COPD patients. 

THE INFLUENCE OF SECOND HAND CIGARETTE SMOKE ON THE INNATE IMMUNE FUNCTION 

OF NASAL EPITHELIAL CELLS. 

James A. Jukosky, PhD; Dartmouth College; YCSA 2008 

Adults and children exposed to SHS have an elevated risk of developing chronic sinus and bronchial 

infections, asthma, and allergies. This suggests that cigarette smoke (CS) has adverse effects on immune 

defenses. The goal of Dr. Jukosky’s study is to understand which innate immune responses are altered by 

CS exposure. Epithelial cells are the key to innate immunity and the first line of defense against infection. 

Airway epithelial cells form a physical barrier, but also respond to the presence of microbes by secreting 

antimicrobials, cytokines and chemokines. These molecules can neutralize infectious microorganisms 

and/or provide signals critical to the initiation of adaptive immune responses. Preliminary results show 

that aspects of innate immune protection provided by nasal epithelial cells are altered by CS exposure. Dr. 

Jukosky’s data demonstrate that nasal epithelial cell secretion of CCL20, (a protein that has antimicrobial 

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and signaling functions), is suppressed by CS. In the Beas-2b transformed airway epithelial cell line, CS 

exposure decreased the antimicrobial activity of these cells and decreased transcription and secretion of the 

protein CCL20. The investigators also measured CCL20 in nasal washes of human subjects and found that 

those exposed to CS or SHS had decreased concentrations of CCL20 compared to non-smokers. Even 

subjects with prior, but not recent, CS exposure had low CCL20 levels implying that the immune response 

of epithelial progenitor cells is impaired in a permanent manner by CS exposure. Dr. Jukosky seeks to verify 

his preliminary data and test the production of other related antimicrobial and signaling molecules in 

humans with no CS exposure, prior CS exposure (6 months to 5 years ago), current SHS exposure, and 

subjects with current primary CS exposure (smokers). In Aim 1 the investigators are testing the hypothesis 

that CS alters both constitutive production and induction by lipotechoic acid (LTA) challenge of important 

innate immune molecules from primary human nasal epithelial (PHNE) cells. In Aim 2, the study 

focuses on the nasal secretions of the same volunteers and test the hypothesis that cigarette smoke exposure 

alters the steady-state levels of the same innate immune molecules in the nasal passage. Taken together, 

these studies will provide in vivo evidence of the effects of CS exposure on the immune function of 

PHNE and show whether prior CS exposure induces permanent changes in the progenitor cells in the 

nasal mucosa. The results of these studies should improve understanding of how CS exposure influences 

the development of infection in the upper airways, thus aiding in future prevention, diagnosis and treatment, 

as well as educational efforts for public awareness about the dangers of CS exposure. 

IMMUNE FUNCTION IMPACTED BY TOBACCO SMOKE 


ONTOGENY OF CYTOKINE IMMUNE RESPONSES: ROLE OF SECOND HAND TOBACCO SMOKE 

Deborah A. Gentile, MD; Allegheny-Singer Research Institute; CIA 2004 

SHS is a risk factor for the development of childhood asthma. Dr. Gentile compared subjects with and 

without exposure to SHS (determined by serum cotinine levels). The number of dendritic cells and 

CD4+CD25+ cells in those individuals without exposure was significantly higher than in those who had 

been exposed to SHS. No significant differences were seen in CD8+CD38+ lymphocytes or cyokine 

production in these two groups, but there were age-related decreases in the absolute numbers of 

CD4+CD25+ cells, CD8+CD38+ lymphocytes, and dendritic cells. CD8+ cells that produce interleukin 

(IL) 4 and IL13 also decreased in number with respect to age. However, interferon (IFN) gamma from 

CD8+ cells and cytokines from CD4+ cells and dendritic cells did not decrease as a function of age. These 

results indicate that there is a differential immune response in children related to age and related to 

exposure to SHS. 

INFECTIOUS DISEASES 


SHS AND INFLUENZA-INDUCED RESPONSES IN NASAL EPTHELIUM 

Ilona Jaspers, PhD; University of North Carolina at Chapel Hill; CIA 2006 

Exposure to SHS has been associated with increased susceptibility to infection with respiratory viruses. 

Influenza virus infections continue to cause significant mortality and morbidity in the United States and 

worldwide every year. However, there are few data on the effects of SHS exposures on influenza infections 

in humans. The objectives of this project are to determine whether exposure to SHS enhances the 

susceptibility to influenza virus infections in humans in vivo and whether this effect is mediated by SHSinduced 

oxidative stress. The proposed study is subdivided into two interdependent studies: One which 

will determine the effects of SHS exposure on influenza infections in healthy human volunteers in vivo, 

and one which uses an in vitro model of differentiated human nasal epithelial cells to confirm and expand 

the in vivo findings, and to examine potential cellular mechanisms mediating the effects of SHS on 

influenza virus infections. For the human in vivo study, Dr. Jasper is measuring the effects of naturally 

occurring SHS exposure on influenza infections in human volunteers in vivo using the live attenuated 

influenza virus (LAIV) vaccine. This vaccine is a cold-adapted influenza virus that infects and replicates in 

the nasal epithelium, without spreading to the lower airways and inducing serious adverse health effects. A 

small group of smokers were also recruited for comparison. Preliminary analyses indicate that markers of 

viral replication are increased in individuals exposed to SHS compaired to non-exposed controls. Study 

1 9 4 P A G E

groups had similar baseline nasal lavage fluid (NLF) inflammatory markers, and all groups had transiently 

increased NLF inflammation (% neutrophils, cytokines) during days 1-4 following LAIV. However, 

subjects naturally exposed to SHS showed blunted responses compared to controls for changes in 

cytokines IL-6 and IP-10. Similarly, nasal epithelial cells obtained from subjects exposed to cigarette smoke 

showed increased viral replication and decreased influenza-induced type I interferon production in vitro. 

The investigators are currently examining whether these changes are associated with epigenetic 

modifications of key antiviral defense genes in nasal epithelial cells. These data show that cigarette smoke 

exposure increases viral replication but blunts early inflammatory and antiviral responses to virus both in 

vitro and in vivo. Dr. Jaspers speculates that chronic exposure to tobacco smoke alters host defense 

responses at the mucosal surface by epigenetically modifying gene transcription, and, thus, increasing 

susceptibility to viral infection. 


Noah TL, Murphy P, Zhang W, Herbst M, Jaspers I. Effects of environmental tobacco smoke on nasal 

responses to live attenuated influenza virus. Presented at the Annual Meeting of the American Thoracic 

Society. Toronto, May 16-21, 2008. 

MENOPAUSE 


SMOKE AND EARLY MENOPAUSE: MECHANISMS AND MODEL SYSTEMS 

Diego H. Castrillon, MD, PhD; University of Texas Southwestern; CIA 2006 

Despite definitive evidence that tobacco smoke inhalation accelerates menopause and results in early 

infertility, there has been almost no research, and consequently few insights, into the mechanisms by which 

tobacco smoke exposure, including SHS, disrupts normal ovarian function. Because menopause is due to 

the gradual loss and eventual depletion of primordial follicles (eggs), Dr. Castrillon hypothesizes that the 

result of tobacco smoke is an acceleration of ovarian aging via direct damage to the primordial follicle. To 

address this question, he and his collaborators developed a model system to clarify the major mechanisms 

by which SHS results in ovarian damage. To model the consequences of SHS on ovarian function in the 

most biologically relevant experimental system possible, female mice were subjected to SHS using a 

custom-fitted automated cigarette-smoking machine. Adult female mice were exposed to SHS for 16 or 22 

weeks to mimic the impact of chronic SHS exposure. Detailed histologic analyses of ovaries from SHStreated 

and control female mice were performed. Decreased numbers of primordial follicles were evident at 

16 and 22 weeks, demonstrating a direct toxic effect on primordial follicles. Other studies have been 

performed to determine if an increased rate of oocyte death contributes to, or is the primary mechanism 

driving, SHS-associated primordial follicle depletion. The investigators use counts of inflammatory cells to 

determine if such cells are recruited to SHS-damaged ovaries and might therefore contribute to the 

observed SHS damage or response. 


Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, 

Perera SA, Liang MC, Cai D, Naumov GN, Bao L, Contreras CM, Li D, Chen L, Krishnamurthy J, 

Koivunen J, Chirieac LR, Padera RF, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, 

Janne PA, Johnson BE, Meyerson M, Kwiatkowski DJ, Castrillon DH, Bardeesy N, Sharpless NE, Wong 

KK. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007;448:807-810. 

NEUROBEHAVIORAL CONSEQUENCES OF TOBACCO EXPOSURE 


TOBACCO SMOKE AND EARLY HUMAN NEUROBEHAVIOR 

Kimberly Yolton, PhD; Cincinnati Children’s Hospital; CIA 2007 

The goal of this study is to investigate the impact of prenatal and postnatal tobacco smoke exposure on 

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development and behavior, from the newborn period to age 2 years, using an NIH-funded 398-person 

birth cohort. Pregnant women were enrolled between 13 and 19 weeks gestation, and biomarkers of 

tobacco exposure were collected throughout pregnancy. Cotinine was measured in maternal blood, hair, 

and urine, during pregnancy, at delivery, and in newborn meconium, to quantify prenatal exposure. 

Cotinine has been measured in child serum at 12 and 24 months to quantify early childhood exposure. 

Newborn assessments were conducted during the first 36 hours after birth and at 5 weeks to assess the 

impact of prenatal tobacco smoke exposure and changes in neurobehavior that may occur over the first 

month as the infant adapts to the extrauterine environment. Assessments of development and behavior 

problems have been completed at 12 and 24 months to evaluate longer-term neurobehavioral outcomes. 

Analyses will include linear regression and structural equation modeling to describe the relationships 

among tobacco smoke exposure and infant/child neurobehavioral outcomes. 

In this sample of infants (whose exposure to tobacco smoke during pregnancy resembled nationallyreported 

rates) Dr. Yolton has found significant differences in neurobehavioral outcomes associated with 

higher tobacco smoke exposure. These outcomes varied by race. With higher levels of tobacco smoke 

exposure, nonBlack infants were more agitated, aroused, and less able to calm themselves and participate in 

activities, whereas Black infants were less responsive during the assessment. These racial differences in 

neurobehavior could be related to metabolic differences in nicotine metabolism manifested as disparities in 

the consequences of nicotine exposure. The findings of this study show that even low levels of exposure to 

tobacco smoke may impact infant neurobehavior. 

Further analysis of newborn data using causal modeling techniques will begin Summer 2009 when 

meconium data become available. In Fall 2009, the focus of the analyses will shift to longer-term outcomes 

that may be influenced by prenatal and postnatal tobacco smoke exposure by examining 24 month 

developmental and behavioral outcomes. 


Yolton K, Khoury J, Hornung R, Dietrich K, Succop P, Lanphear B. Environmental tobacco smoke 

exposure and child behaviors. J Dev Behav Pediatr 2008:29(6):450-457. 

MECHANISMS OF ENVIRONMENTAL TOBACCO SMOKE-INDUCED NERVOUS SYSTEM MALFORMATIONS AND 

CANCERS 

Annie W. Chan, MD; Massachusetts General Hospital; CIA 2008 

Prenatal exposure to SHS is one of the most ubiquitous and hazardous of environmental exposures. 

Pregnant women are particularly vulnerable to SHS exposure. One of the most prevalent and significant 

impact on the embryos and fetus from exposure to SHS is congenital malformation of the nervous system. 

Maternal exposure to SHS has also been strongly associated with increased risk of brain tumors in children 

and young adults. Of all the SHS-induced tumors, meningioma is the most common. Given the significant 

impact of SHS on the fetus, non-smokers, and society, it is critical to understand the underlying biological 

mechanism of SHS-induced defects in the developing nervous system. A rapidly evolving body of literature 

suggests that neurodevelopmental pathologies such as brain tumors arise from developmental stem cells or 

progenitor cells. Dr. Chan’s hypothesis is that neural stem cells are particularly vulnerable to toxic effects 

of SHS. The PI and her colleagues have found that SHS-exposed neural stem cells undergo abnormal activation 

of signaling pathways and abnormal development. The objective of this research is to define the 

molecular mechanisms of SHS on neural stem cell abnormal differentiation and tumorigenesis and thereby 

identify targets that could be treated. The fulfillment of the aims will not only lead to understanding of the 

biological mechanisms of SHS-induced neural maldevelopment in specific, but will also provide a new 

framework for prevention and treatment that of cancers in general result in significant benefit to society. 

NEUROBEHAVIORAL CONSEQUENCES OF TOBACCO EXPOSURE 


SECOND HAND TOBACCO SMOKE AND THYROID DISEASE 

Rachel Ying Vun Chong, MD; The Johns Hopkins University; CIA 2002 

Dr. Chong’s research pursued abnormal cortisol responses to stress. Abnormal hypothalamicpituitaryadrenal 

(HPA) function is a fundamental endocrine abnormality identified in individuals exposed to 

tobacco smoke. This abnormality may play an important role in insulin resistance, cardiovascular events, 

and decreased bone mineral density in persons subjected to SHS exposure. The endogenous opioid system 

1 9 6 P A G E

is one of several neurotransmitter systems modulating the HPA axis response to stress. The cold pressor 

test (CPT), a pain stressor that activates both endogenous opioid and HPA axis activity, was used to elicit 

cortisol responses among young adults to determine whether individual differences in the mu-opioid 

receptor gene are associated with differences in cortisol response to the CPT. It was found that Whites 

have a more robust HPA axis response to the Trier Social Stress Test (TSST) compared with Blacks, even 

after controlling for several socioeconomic and psychological factors. There were no differences in 

subjective response to the TSST to explain the difference in HPA axis response. 

FUNCTIONAL MRI INVESTIGATION OF IMPAIRED LEPTIN REGULATION DUE TO SECOND HAND TOBACCO SMOKE 

Yijun Liu, PhD; University of Florida; CIA 2004 

Leptin, a hormone released by fat cells, is a peripheral anorectic signal that acts on the brain. It has been 

found that serum leptin levels in tobacco smokers are significantly higher than levels in non-smokers, and 

there is evidence implicating elevated leptin levels in cerebrovascular and cardiovascular disease. Dr. Liu’s 

hypothesis is that the functional regulation of leptin in the brain may be impaired due to SHS, leading to 

elevated blood leptin levels, which may contribute to SHS-related conditions in cerebrovascular and 

cardiovascular diseases. The specific aims of this study are to test the working hypotheses that: 1) leptin is 

associated with central anorectic regulatory pathways localized in the hypothalamus, and that this 

functional regulatory mechanism is impaired in subjects chronically exposed to SHS; and 2) leptin may 

modulate brain responses to smoking-related cues during hunger and sated conditions; and this 

modulation of the affective (anxiety-inducing and hedonic) processes may be altered by smoking or SHS 

exposure. To achieve the aims, Dr. Liu correlated functional MRI with biochemical measurements such as 

leptin, insulin, and counter-regulatory hormones such as epinephrine and norepinephrine in groups of 

SHS-exposed individuals, chronic smokers, and non-smokers. 

PREGNANCY AND PERINATAL EFFECTS FROM TOBACCO EXPOSURE 


PERINATAL NICOTINE, CARBON MONOXIDE AND NEURODEVELOPMENT 

J. Timothy O’Neill, PhD; Uniformed Services University of the Health Sciences; CIA 2008 

Maternal smoking has been associated with several neurological disorders including attention deficit disorder 

and autism. However, the origins of these neurological disorders are not well understood. In utero 

exposure to nicotine or carbon monoxide (CO), the major toxic constituents of cigarette smoke, have been 

associated with the same neurological disorders. Cellular and molecular explanations of these alterations are 

incomplete. Appropriate migration and communication of neurons during development is critical. Dr. 

O’Neill‘s long-term goal is to understand the effects of perinatal primary and secondary tobacco smoke on 

brain development. Nicotine and CO have the independent potential for causing brain developmental 

abnormalities. Dr. O’Neill and colleagues are examining this by studying migration in the neocortex during 

the perinatal exposure of mice to nicotine and CO. Their specific goal is to understand consequences 

of perinatal nicotine and CO on the development of the neocortex. They hypothesize that each will disrupt 

the normal migration of neurons to the neocortex and that in combination will have a synergistic 

effect and that this will be due in part to alterations in the balance of neurotransmitters. These hypotheses 

are being tested in the several specific aims. 

The goal of their Specific Aim 1 is to determine the effect of perinatal exposure to CO and nicotine on 

migration and laminar fate of neurons. Their strategy is to inject pregnant mice being exposed to CO, 

nicotine, or both on different days during development with bromodeoxyuridine to map the disposition of 

neurons born on those days. To understand how CO and nicotine influence the extracellular signaling 

mechanisms that influence corticogenesis. Dr. O’Neill and colleagues are examining the distribution, number, 

and morphology of cells stained for a variety of neurotransmitters and their receptors. They are also 

studying specific proteins in migrating neurons to identify subpopulations to determine if specific subtypes 

of interneurons are sensitive to CO and nicotine. The goal of their Specific Aim 2 is to determine if migration 

of cells from the ganglionic eminences (GE) or the neocortical ventricular zone (VZ) is changed as a 

consequence of perinatal nicotine or CO exposure and if alteration involves modification of neurotransmitters. 

Their strategy is to examine organotypic brain slice cultures and track cell migration from the GE or 

VZ to the cortex by injecting lipophylic crystals of 1,19-dioctadecyl-3,3,39,39-tetramethylindocarbocyanine 

perchlorate (DiI) into the GE or VZ. The knowledge gained may determine therapeutic targets and 

interventions to reduce behavioral problems associated with children of smoking mothers. Mice born of 

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dams exposed to 75 ppm (1 pack/day) or 150 ppm (2+ pack/day) CO have an altered distribution of cells 

in the cerebral cortex. The CO-induced redistribution of cells occurs as early as 4 days of life and persists 

into adulthood. These maldistributions are regionally specific with the caudal portions of the brain 

responding differently to CO than the rostral brain. In addition, the ectopically distributed cells are predominantly 

gamma aminobutyric acid (GABA)ergic interneurons, which migrate into the neocortex from 

the ganglionic eminence rather than the neocortical VZ. Since the GABAergic neurons migrate in a 

lengthy tangential path, CO may disrupt this route of travel more substantially than the radial path from 

the neocortical ventricular zone. 


Trentini JF, Juliano SL, O’Neill JT. The effects of prenatal exposure to low levels of carbon monoxide on 

neocortical development, 2008. Presented at the Society for Neuroscience Annual Meeting. Nov, 2008. 

ROLE OF ERK IN AHR IN PRENATAL TOBACCO SMOKE EXPOSURE 

Shashibushan P. Singh, PhD; Lovelace Respiratory Research Institute; CIA 2005 

The effects of in utero exposure to cigarette smoke on children’s health might primarily stem from the 

adverse effects on the immune system. Dr. Singh examined the effects of pre- and postnatal sidestream cigarette 

smoke on spleen cell responses. Results show that postnatal exposure of newborn mouse pups to 

sidestream cigarette smoke through the first 6 weeks of life strongly suppresses the antibody response of 

spleen cells (Singh et al., 2006). The reduction in the antibody response seen within 6 weeks of postnatal 

smoke exposure is much quicker than in adult mice. While the postnatal exposure to cigarette smoke did 

not affect the mitogenic response of T- and B-cells, the exposure inhibited the T cell receptor-mediated 

rise in the [Ca2+]i. These results suggest that the early postnatal period is highly sensitive to the immunosuppressive 

effects of SHS, and the effects are causal with impaired antigen-mediated signaling in T cells. 

Prenatal exposure to cigarette smoke causes airway hyperreactivity, and the effect may be related to 

increased activity of a lung-associated cyclic adenosine monophosphate (cAMP)-phosphodieasterase, 

PDE4. Sensitization and subsequent challenge with an allergen significantly increased pulmonary resistance 

in neonates exposed to maternal cigarette smoke. Results indicate suppression of pulmonary resistance by 

PDE4-selective inhibitor rolipram indicating involvement of PDE4 enzyme. Rolipram treatment also attenuated 

induced muscarinic receptors, M1 and M3, expression significantly in the lungs. Interactive relationship 

between these cellular molecules could potentially delineate pathway by which in utero exposure to 

cigarette smoke affects lung function. 


Singh SP, Razani-Boroujerdi S, Pena-Philippides JC, Langley RJ, Mishra NC, Sopori ML. Early postnatal 

exposure to cigarette smoke impairs the antigen-specific T cell responses in the spleen. Toxicol Lett 

2006;167:231-237. 

EFFECTS OF SECOND-HAND TOBACCO ON THE IMMATURE LUNG 

Kathleen J. Haley, MD; Harvard University; CIA 2007 

Dr. Haley’s data indicates that exposure to SHS during gestation causes abnormal pulmonary gene 

expression early in lung development and continues throughout gestation. Dr. Haley’s murine model of 

developmental SHS exposure demonstrates that such exposure causes abnormal postnatal lung structure, 

including fewer alveoli, decreased elastin, and pulmonary vascular abnormalities. Dr. Haley and colleagues 

hypothesized that abnormal retinoic acid (RA) signaling could contribute to all of the postnatal lung 

abnormalities seen in their model. They tested this hypothesis by examining lung tissue from mice with 

and without gestational SHS exposure (n = at least 5 per group) at the following time points: embryonic 

day 18, day of birth, and postnatal days 3, 5, 7, 10, and 14. These time points sampled the canalicular, saccular, 

and alveolar stages of lung development. Quantitative PCR analysis demonstrated that gestational 

SHS exposure caused decreased expression of several components of the RA pathway, including RA receptors 

(RAR) alpha and beta, retinoid X receptor alpha, and the synthesizing enzyme retinaldehyde dehydrogenase 

1. The effects of gestational tobacco smoke varied with the stage of lung development, and were 

most pronounced in the early alveolar stage. They then tested the hypothesis that developmental SHS 

exposure disrupts RA signaling pathway functioning by treating A549 cells with cigarette smoke condensate 

(CSC). Their findings indicate that cigarette smoke extract (CSC) significantly decreases RAR-dependent 

RA response element (RARE) activation in A549 cells. This is associated with decreased expression of 

RAR alpha and RXR alpha and increased expression of chicken ovalbumin upstream promoter transcription 

1 9 8 P A G E

factor-1 (COUP-TF1/Nr2f1), all of which could decrease RA signaling. Their recent studies have demonstrated 

that the decreased RARE activation is associated with decreased nuclear extract binding to the most 

abundant RARE, DR5. 

Given the effects on RA component expression and their in vitro studies showing decreased function of 

the RA pathway following cigarette smoke exposure, Dr. Haley and colleagues hypothesized that gestational 

tobacco smoke would cause decreased expression of RA-dependent genes in the postnatal lung. They 

subjected RNA extracted from lung tissue in mice, with and without gestational tobacco smoke exposure, 

to quantitative PCR analysis to test this hypothesis. Their analysis showed that gestational SHS exposure 

caused decreased expression of surfactant protein B and vascular endothelial growth factor, which are both 

important for alveolar development and maturation. Their recent studies demonstrated that extra-pulmonary 

RA-regulated processes, such as T regulatory cell development, are also adversely affected by 

intrauterine cigarette smoke exposure. Additionally, they have shown that intrauterine smoke exposure 

causes abnormalities in a second nuclear receptor pathway, the vitamin D signaling pathway. Thus, their 

studies have demonstrated that in utero exposure to SHS disrupts the expression and function of the RA 

and vitamin D signaling pathways in the developing lung and results in abnormalities in RA-dependent 

processes in the postnatal animal. 

MATERNAL SMOKING: FETUSES IN WITHDRAWAL? 

Laura Stroud, PhD; The Miriam Hospital, Brown University; CIA 2007 

Little is known regarding effects of maternal smoking during pregnancy on offspring behavior during 

the fetal and newborn periods. One key unanswered question is whether exposure to maternal cycles of 

daytime smoking and overnight abstinence results in symptoms of withdrawal/abstinence in the fetus. This 

study is the first to examine the possibility of a fetal withdrawal syndrome from exposure to maternal 

smoking. The aims are to characterize 1) differences in fetal behavior and withdrawal symptoms following 

maternal smoking versus overnight abstinence; 2) links between fetal and newborn behavior; and 3) effects 

of SHS exposure on fetal and infant behavior. Dr. Stroud and colleagues have pioneered use of ultrasound 

technology to evaluate fetal behavior including withdrawal symptoms. In this ongoing study, these techniques 

are applied to examine the possibility of a smoking-related fetal withdrawal process. Smoking and 

non-smoking mothers matched on socioeconomic status, alcohol use, race, and age are being recruited 

through an ongoing longitudinal study of prenatal smoking and infant withdrawal. Mothers complete two 

fetal behavioral examinations including measures of withdrawal. Smoking mothers complete one exam following 

overnight abstinence and another following ad libitum smoking. Infant neurobehavior and withdrawal 

are assessed over the first 30 days of life. 

Preliminary results from the fetal ultrasound data showed, as expected, that carbon monoxide (CO) levels 

were significantly higher for smokers versus non-smokers for the fetal session following ad libitum 

smoking (F = 10.5, p< .01). They also found a significant smoking group by time interaction for CO 

levels (F = 22.9, p< .001), such that a significant decrease in CO levels emerged for smokers between ad 

libitum and abstinence sessions but no differences in CO levels emerged for non-smokers. Dr. Stroud and 

colleagues also conducted some preliminary analyses in support of the three study aims. For Aim 1, consistent 

with their hypothesis of differences in fetal behavior in smoking-exposed versus unexposed fetuses, 

they found greater reactivity to the vibro-acoustic stimulus (VAS; 100% reactive versus 50% reactive across 

both fetal sessions), shorter latency to react (M’s = 45 vs. 155 seconds for the fetal session following 

overnight abstinence), and faster recovery (M’s = 45 vs. 153 seconds across both fetal sessions) in exposed 

relative to unexposed fetuses. For Aim 2, they found high-magnitude inverse correlations between seconds 

to respond to the VAS and scores on the withdrawal scale of the infant neurobehavioral examination in the 

first days of life (r’s = .26-.76) such that shorter latency to respond to the VAS was associated with greater 

signs of neonatal withdrawal. For the exploratory aim, they found high magnitude associations between 

maternal SHS exposure during pregnancy and latency to react to the VAS (r’s = .36-.46) such that greater 

exposure was associated with longer latency to respond to the VAS. Results are preliminary but suggest 

strong associations between maternal smoking and exposure to SHS and fetal and infant behavior. Results 

from this study will lead to critical advances in determining mechanisms underlying effects of prenatal 

smoking exposure. Results also have important clinical and public health implications, including early identification 

and targeted intervention efforts to protect offspring at risk for later adverse outcomes and novel 

intervention efforts to help pregnant smokers quit. 


Crespo F, Lense M, Salisbury A, Stroud LR. Maternal smoking and fetal neurobehavior: a pilot study. 

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Poster Presentation at the 11th International Conference on Toxicology. 2007. 

Lense M, Stroud LR, Niaura R, Shenassa E, Lipsitt L, Paster R, LeWinn K, Buka S. Markers of fetal nicotine 

exposure and neonatal neurobehavior: The National Collaborative Perinatal Project. Presented at 

the 14th Annual Society for Research on Nicotine and Tobacco Meeting. Portland, OR, Feb 27-Mar 1, 

2008. 

Marcello D, Lense M, Salisbury A, Stroud LR. Links between fetal and infant response in smokingexposed 

and unexposed offspring: a pilot. Poster Presentation at the 38th Annual International Society 

for Research on Psychoneuroendocrinology Conference, 2007. 

Stroud LR, Paster RL, Papandonatos G, Niaura R, Salisbury AL, Battle C, Lagasse L, Lester B. Maternal 

smoking during pregnancy and newborn neurobehavior: effects at 10-27 days. J Pediatr 2009;154:10- 

16. 

Svenson AE, Stroud LR, Lester B, Lagasse L, Salisbury A, Niaura R. Does breast-feeding moderate the 

influence of smoking during pregnancy on newborn behavior? Poster Presentation at the Annual Mental 

Health Sciences Research Day. Brown Medical School, 2008. 

SECOND-HAND TOBACCO SMOKE AND NEONATES AND PREDISPOSITION TO COPD AND DURABLE EFFECTS OF 

NEWBORN CIGARETTE SMOKE EXPOSURE ON THE ADULT LUNG 

Sharon A. McGrath-Morrow, MD; The Johns Hopkins University; CIA 2007 

Exposure to cigarette smoke is the most frequently recognized risk factor for the development of 

COPD. Impaired alveolar growth during infancy may increase the risk of developing COPD in adulthood. 

The degree of altered lung structure in conjunction with oxidative stress, cell apoptosis, protease imbalance, 

inflammation, and altered immunity may determine the severity and onset of COPD. Early postnatal 

insults such as prematurity or lower respiratory tract infections may disrupt alveolar growth, thus increasing 

the likelihood of developing COPD when exposed to cigarette smoke later in life. The overall objective of 

the study is to understand the mechanisms that increase susceptibility of developing lung to cigarette 

smoke, leading to impaired lung function and increased likelihood of COPD in adulthood. Preliminary 

studies revealed that chronic cigarette smoke exposure led to increased oxidative stress, apoptosis, and 

increased transforming growth factor-beta signaling in newborn lungs of mice. At 8 weeks of age, mice 

exposed to neonatal cigarette smoke had a mild but significant increase in airspace size suggesting that cigarette 

smoke in the neonatal period can subsequently alter adult lung structure. Neonatal SHS can also 

polarize immature lung towards a more pronounced TH2 response. Significant down-regulation of many 

type 1 and type 2 interferon-response genes were found, suggesting a link between cigarette smoke exposure 

in infancy and inhibition of TH1 response gene expression. Taken together, these findings will help 

explain the association between cigarette smoke exposure in infancy and increased risk of COPD later in 

life. 

Exposure to SHS during early postnatal life may cause durable changes in the adult lung as well. To 

evaluate this, Dr. McGrath-Morrow and her collaborators exposed newborn C57/B6 mice to two weeks of 

CS in the newborn period and then assessed lung structure and function at six months of age. Gene 

expression profiling was also performed to determine if exposure to CS in early life could alter gene 

expression in the adult lung. 

The investigators showed that at six months, mice exposed to two weeks of CS in the newborn period 

had a modest but significant increase in total lung capacity (TLC) compared to controls (1.5ml +/- 0.1 

versus 1.3 ml +/-0.1.) Active and passive cigarette smoking are risk factors among women of reproductive 

age, leading to reproductive health morbidity, including fetal and infant mortality, and developmental 

problems with the newborn. However, the underlying physiological mechanisms for these ill-effects are not 

fully understood. Some of the suspected mechanisms responsible for these adverse effects may involve 

hormonal disturbances and may be associated with both antithyroid and stimulating effects on the thyroid. 

The objective of Dr. McGrath-Morrow’s study was to quantitate and compare serum thyroid hormone 

and thyrotropin concentrations in active smokers, passive smokers and non-smokers, and determine 

associations with cigarette tobacco smoke exposure. Serum was obtained from women (18-44y). 

Thyroxine (T4), triiodothyronine (T3) and cotinine concentrations were quantified using isotope dilution 

high performance liquid chromatography tandem mass spectrometry (LC/MS/MS), and thyroidstimulating 

hormone (TSH) concentrations by chemiluminescence. 

The investigators found that median TSH concentrations were lower in active smokers compared to 

passive smokers and non-smokers (non-exposed.) Median serum T3 concentrations were consistently lower 

in active smokers than non-smokers. Pair-wise comparisons of the three study groups indicate statistically 

significant differences in mean T4 (Pvalue=0.0065) and T3 (Pvalue=0.0013). 

2 0 0 P A G E

This study is unique in examining the association of serum cotinine and thyroid hormone concentrations 

using LC/MS/MS in women smokers, passive smokers and non-smokers. Active and passive exposure to 

cigarette tobacco smoke causes a mild stimulating effect on the thyroid as reflected in low normal serum 

TSH levels in this cohort of women. 


McGrath-Morrow S, Rangasamy T, Cho C, Susson T, Neptune E, Wise R, Tuder RM, Biswal S. Impaired 

lung homeostasis in neonatal mice exposed to cigarette smoke. Am J Respir Cell Mol Biol 2008;38:393- 

400. 

EFFECT OF SECOND HAND TOBACCO SMOKE ON FETAL BODY SIZE AND BRAIN SIZE 

Hamisu M. Salihu, MD; University of Medicine and Dentistry of New Jersey; YCSA 2003 

The main purpose of this project is to estimate the association between prenatal tobacco smoke exposure 

and fetal and brain growth trajectories using ultrasound measurements. The results of the study will add 

substantially to current knowledge regarding the relationship between SHS exposure and fetal morbidity in 

utero. 


Alexander GR, Wingate MS, Salihu H, Kirby RS. Fetal and neonatal mortality risks of multiple births. 

Obstet Gynecol Clin North Am 2005;32:1-16. 

Alexander MR, Salihu HM, Dwight RJ. Survival of triplets born to United States teenagers. Am J Obstet 

Gynecol 2004;191:2097-2102. 

Alio AP, Salihu HM. Maternal determinants of pediatric preventive care utilization among blacks and 

whites. J Natl Med Assoc 2005;97:792-797. 

Aliyu MH, Jolly PE, Ehiri J, Salihu HM. High parity and adverse birth outcomes. Exploring the maze. 

Birth 2005;32:45-59. 

Aliyu MH, Salihu HM, Keith LG, Ehiri JE, Islam MA, Jolly PE. Extreme parity and risk of stillbirth. 

Obstet Gynecol 2005;106:446-453. 

Aliyu MH, Salihu HM, Keith LG, Ehiri JE, Islam MA, Jolly PE. High parity and fetal morbidity outcomes. 


Aliyu MH, Salihu HM, Keith LG, Ehiri JE, Islam MA, Jolly PE. Trends in birth across high parity groups 

by race/ethnicity and maternal age in the United States. J Natl Med Assoc 2005;97:799-804. 

Ananth CV, Smulian JC, Srinivas N, Getahun D, Salihu HM. Risk of infant mortality among twins in relation 

to placental abruption: contributions of preterm birth and restricted fetal growth. Twin Res Hum 

Genet 2005;8:524-531. 

Boulet S, Alexander GR, Salihu HM. Secular trends in c-section rates among macrosomic deliveries in the 

United States, 1989-2000. J Perinatol 2005;25:569-576. 

Chalo RN, Salihu HM, Nabukera S, Zirabamuzale C. Referral of high-risk pregnant mothers by trained 

TBAs in Buikwe county, Uganda. J Obstet Gynaecol 2005;25:554-557. 

Emusu D, Salihu HM, Aliyu ZY, Pierre-Louis BJ, Druschel CM, Kirby RS. Gastroschisis, low maternal 

age, and fetal morbidity outcomes. Birth Defects Res A Clin Mol Teratol 2005;73:649-654. 

Jaquet D, Shailender S, Alexander GR, Czernichow P, Collin D, Salihu HM, Kirby RS, Lavy-Marchal C. 

Significant paternal contribution to the risk of small-for-gestational age. Br J Obstet Gynaecol 

2005;112:153-159. 

Kirby RS, Salihu HM. The contribution of birth weight and birth weight characteristics to developmental 

outcome. Am J Perinatol 2005;22:227-229. 

Kristensen S, Salihu HM, Keith LG, Kirby RS, Fowler KB, Pass MB. SGA subtypes and mortality risk 

among singleton births. Early Hum Dev 2007;83:99-105. 

Naik E, Karpur A, Taylor R, Ramaswami B, Ramachandra S, Balasubramaniam S, Galwankar S, Sinnott J, 

Nabukera S, Salihu HM. Rural Indian tribal communities: an emerging high-risk group for HIV/AIDS. 

BMC Int Health Hum Rights 2005;5:1. 

Salihu HM, Aliyu HM, Akintobi TH, Bosny JPL, Kirby RS, Alexander GR. The impact of advanced 

maternal age (> or = 40 years) on birth outcomes among triplets: a population study. Arch Gynecol 

Obstet 2005;271:132-137. 

Salihu HM, Aliyu MH, Kirby RS. Fetal growth of twins in nicotine-exposed uterine environment. Am J 

Perinatol 2005;22:421-427. 

Salihu HM, Aliyu MH, Sedjro JE, Oluwatade OJ, Alexander GR. Teen twin pregnancies and fetal growth 

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inhibition among Blacks and Whites. Am J Perinatol 2005;22:335-339. 

Salihu HM, Bagchi S, Aliyu ZY, Kirby RS, Alexander GR. Advanced maternal age and fetal growth inhibition 

of triplets. J Reprod Med 2005;50:319-326. 

Salihu HM, Bagchi S, Sharma PP. A novel method of quantifying birth weight discordance in quadruplets. 

Am J of Perinatol 2006;23:223-228. 

Salihu HM, Bekan B, Aliyu MH, Rouse DJ, Kirby RS, Alexander GR. Perinatal mortality associated with 

abruptio placenta in singletons and multiples. Am J Obstet Gynecol 2005;193:198-203. 

Salihu HM, Ekundayo OJ, Kristensen S, Sharma PP, Badewa AP, Kirby RS, Alexander GR. Childhood 

pregnancy (10-14 years old) and risk of stillbirth in singletons and twins. J Pediatr 2006;148:522-526. 

Salihu HM, Emusu D, Aliyu Z, Kirby RS, Alexander GR. Survival of “pre-viable” infants in the United 

States. Middle European Journal of Medicine 2005;117:324-332. 

Salihu HM, Emusu D, Aliyu ZY, Pierre-Louis BJ, Druschel CM, Kirby RS. Omphalocele, advanced maternal 

age and fetal morbidity outcomes. Am J Med Genet 2005;135A:161-165. 

Salihu HM, Emusu D, Sharma PP, Aliyu ZY, Oyelese Y, Druschel CM, Kirby RS. Parity effect on preterm 

birth and growth outcomes among omphalocele-affected infants. Eur J Obstet and Gynecol Reprod Biol 

2006;128:91-96. 

Salihu HM, Fitzpatrick L, Aliyu MH. Racial disparity in fetal growth inhibition among singletons and multiples. 

Am J Obstet Gynecol 2005;193:198-203. 

Salihu HM, Garces I, Sharma PP, Kristensen S, Ananth CV, Kirby RS. Stillbirth and infant mortality 

among Hispanic singletons, twins and triplets in the United States. Obstet Gynecol 2005;106:789-796. 

Salihu HM, Kinniburgh, Aliyu MH, Kirby RS, Alexander GR. Racial disparity in stillbirth among singleton, 

twin and triplet gestations in the United States. Obst Gynecol 2004;104:734-740. 

Salihu HM, Mardenbrough-Gumbs WS, Sedjro JE, Aliyu MH, Pierre-Louis BJ, Kirby RS, Alexander GR. 

Influence of nativity on neonatal survival of Black twins in the United States. Ethn Dis 2005;15:276- 

282. 

Salihu HM, McCainey TN, Williams AT, Aliyu MH, Dimmitt RA, Alexander GR. Intrauterine tobacco 

smoke exposure and hyaline membrane disease among triplets. J Obstet Gynaecol 2005;25:23-27. 

Salihu HM, Sharma PP, Aliyu MH, Kristensen S, Grimes-Dennis J, Kirby RS, Smulina J. Is SGA a marker 

of future fetal survival in utero? Obstet Gynecol 2006;107:851-856. 

Salihu HM, Sharma PP, Kristensen S, Blot C, Alio AP, Ananth CV, Kirby RS. Risk of stillbirth following a 

cesarean section: black-white disparity. Obstet Gynecol 2006;107:383-390. 

Salihu HM, Sharma PP, Peters S. Twinning and risk for stillbirth subtypes in pediatric mothers. Twin Res 

Hum Genet 2006;9:673-676. 

Salihu HM, Shumpert MN, Aliyu MH, Kirby RS, Alexander GR. Smoking-associated fetal morbidity 

among older gravidas: a population study. Acta Obstet Gynecol Scand 2005;84:329-334. 

Salihu HM, Williams M, Emusu D. Perinatal mortality in the normal siblings of anomalous triplets. Obstet 

Gynecol 2005;105:1419-1429. 

Sharma PP, Salihu HM, Oyelese Y, Ananth CV, Kirby RS. Is race a determinant of stillbirth recurrence? 


Sharma PP, Salihu HM. Very low maternal age (10-14) and stillbirth phenotypes. Arch Gynecol Obstet 

2006;274:19-20. 

Tita ATN, Salihu HM, Ramsey PS. Impact of anomalous triplets on morbidity outcomes of normal in 

utero siblings. Obstet Gynecol 2006;107:1352-1356. 

MATERNAL EXPOSURE TO SECOND HAND TOBACCO SMOKE AND PREGNANCY OUTCOMES 

John D. Meeker, MS, ScD; University of Michigan; YCSA 2005 

Of the thousands of chemicals in cigarette smoke, some are known to be reproductive toxins. Smoking 

has been shown to cause a decrease in female fertility and fetal development, but no study thus far has 

investigated the effects of SHS on early pregnancy. In this epidemiological study, Dr. Meeker uses archival 

data acquired from over 2,500 couples who had taken part in a study of factors influencing in vitro fertilization 

(IVF) results. These data include medical and lifestyle questionnaires, SHS self-assessment, the 

results of IVF treatment, and urine cotinine measurements. The present study would use the extensive 

database to investigate the association between SHS exposure and IVF results, adjusting for confounders. 

The dependent variables include number of oocytes retrieved, percent of fertilized oocytes that develop 

into normal appearing zygotes, and embryo implantation rates. Additionally, Dr. Meeker plans to use the 

percent of treatment cycles that result in clinical pregnancy and live birth, birth length and weight, preterm 

birth, and clinical pregnancy loss. Archived follicular fluid will be used to measure cotinine levels as a meas- 

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ure of direct oocyte exposure. Dr. Meeker hypothesizes that this study would provide the first human data 

demonstrating the causal link between SHS exposure and impaired embryo development and/or early 

pregnancy loss. Preliminary results reported in two recent peer-reviewed papers from this work shows a 

nexus between women who reported having parents who smoked while they (the women) were children 

growing up and an increased risk of miscarriage. 


Meeker JD, Missmer SA, Vitonis AF, Cramer DW, Hauser R. Risk of spontaneous abortion in women 

with childhood exposure to parental cigarette smoke. Am J Epidemiol 2007;166(5):571-575. 

Meeker JD, Missmer SA, Cramer DW, Hauser R. Maternal exposure to second-hand tobacco smoke and 

pregnancy outcome among couples undergoing assisted reproduction. Hum Reprod 2007;22:337-345. 

Meeker JD, Rossano MG, Protas B, Diamond MP, Puscheck E, Daly D, Paneth N, Wirth JJ. Cadmium, 

lead and other metals in relation to semen quality: human evidence for molybdenum as a male reproductive 

toxicant. Manuscript in peer review. Environ Health Perspect 2008;116(11):1473-1479. 

ALTERED GENE EXPRESSION IN VASCULAR ENDOTHELIAL CELLS IN RESPONSE TO OXIDATIVE STRESS FROM 

SECOND HAND SMOKE 

Mark L. Martinez, MD; University of Utah; YCSA 2006 

The biologic effects of SHS on the unborn fetus are largely unknown. Despite recent advances, there 

appears to be a debate between special interests in the tobacco industry and public health officials regarding 

the direct effects of SHS and unfavorable health outcomes. However, the individual at the most risk 

appears to be the developing fetus, which relies on a common blood supply with the mother for delivery of 

oxygen and nutrients, as well as for protection from environmental toxins. There is a nexus between maternal 

cigarette smoke exposure and delayed fetal growth, abnormal development of the circulatory system, 

and fetal death. These adverse outcomes are the result of poor blood flow through the umbilical vessels to 

the fetus. The reasons for this are not understood, although evidence indicates that in response to cigarette 

smoke the umbilical vessels constrict, thereby limiting blood flow to the fetus. In addition, SHS generates 

biochemical substances called oxidants that damage blood vessels and cause harm to the fetus. Dr. 

Martinez’s goal is to understand the molecular mechanisms in the maternofetal circulation that cause this 

abnormal vascular response due to SHS-induced oxidants. This is important in understanding mechanisms 

by which cigarette smoking has adverse health effects. In addition, new knowledge could provide therapeutic 

options to mothers who are unable or unwilling to avoid SHS. These ongoing studies focus on the 

effects of SHS on the endothelial cells that line the human vasculature in all parts of the body, including 

the umbilical vessels. There is evidence that dysfunction of endothelial cells is an important part of the 

increased vascular tone that leads to fetal disease. One mechanism is the expression of genes such as 

endothelin-1, the most potent vascular constrictor in humans. Transcription of some messenger RNAs and 

their ability to direct the production of these protein products can also be influenced by post-transcriptional 

regulation. The process of post-transcriptional regulation and the genes that are controlled in this fashion 

are largely unknown in endothelial cells, and dysregulation of these events through oxidant injury from 

maternal exposure to tobacco smoke during pregnancy has important implications for the health of the 

unborn fetus. The functional role of post-transcriptional regulation of endothelin-1 in endothelial cells will 

be determined following activation with hydrogen peroxide, an important oxidant that is generated by cigarette 

smoke. Dr. Martinez has evidence to indicate that the production of endothelin-1 is regulated by the 

RNA binding protein T cell intracellular antigen 1-related protein (TIAR), and that abnormal regulation 

of TIAR through the formation of stress granules due to oxidant stress in endothelial cells is responsible 

for vascular injury and dysregulated vascular tone. In addition, the PI is determining if endothelial cells 

obtained from the placentas of mothers exposed to SHS secrete an excessive amount of endothelin-1, and 

whether this is due to abnormal post-transcriptional regulation by TIAR. The correlation between these 

basic molecular mechanisms, fetal outcome, and exposure to SHS as a causative agent are being investigated. 

These studies will generate important new knowledge in critical areas that have not been sufficiently 

studied 

LOW LEVEL PRENATAL TOBACCO EXPOSURE AND INFANT WHEEZE 

Adam Spanier, MD, PhD, MPH; Cincinnati Children’s Hospital; YCSA 2007 

Respiratory disease poses a large burden to children’s health, and tobacco exposure plays a major role in 

childhood respiratory health. The primary aim of this project is to elucidate the relationship of prenatal 

tobacco exposure with infant respiratory health. The specific aims are to 1) test which measure of prenatal 

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tobacco exposure (biologic measures and parent report) is most strongly associated with wheeze episodes 

and respiratory infections in the first 2 years of life; and 2) investigate the association of maternal SHS 

exposure during pregnancy with the risk of wheeze episodes and respiratory infections in infant offspring. 

By using direct and objective biomarkers of exposure the investigators can test and quantify risks more 

accurately and at lower levels of exposure than earlier research. Additionally, by focusing on tobacco exposure 

in non-smoking mothers, they can test for effects of tobacco exposure at levels previously thought to 

be inconsequential. The results will lead to interventions to reduce the burden of respiratory disease in this 

vulnerable population that has been involuntarily subjected to tobacco exposure. Currently, biomarker 

assays are being completed. Outcome data for participants up to the age of 24 months has now been collected. 

Dr. Spanier and colleagues have started tabulating baseline exposure, baseline characteristics, and 

outcome data. The next step will be to clean the dataset and begin modeling. 

EFFECTS OF SECOND HAND TOBACCO SMOKE ON PLACENTAL STEM CELL DIFFERENTIATION 

Teresa M. Erb, MD; Magee Women’s Health Corporation; YCSA 2007 

Tobacco smoke exposure, both first and second hand, is a known risk factor for intrauterine growth 

restriction (IUGR). IUGR from cigarette exposure parallels maternal spiral artery restriction. However, the 

direct placental target remains unknown. Smoke exposure could inhibit remodeling of these arteries by 

altering development of the placental stem cells (PSCs) that regulate spiral arterial invasion. The recognition 

that covalent DNA and histone modifications play a role in diverse biological functions, such as 

embryonic development and regulation of inflammatory gene expression, indicates the global importance 

of epigenetics and chromatin structure on gene function. Cigarette smoke-mediated oxidative stress 

increases targeted chromatin modifications, such as histone acetylation of pro-inflammatory gene transcripts. 

These histone modifications parallel the up-regulating nuclear factor kappa-B (NF-kappa B) activity, 

a known pro-inflammatory transcription factor. Oxidative stress has also been shown to suppress histone 

deacetylase (HDAC) 2 activity and expression, which is recruited by the glucocorticoid receptor to switch 

off NF-kappa B gene expression. Since HDACs are also known to regulate gene expression for critical cellular 

processes such as cell cycle progression and differentiation, they may be mechanistically involved in 

altered PSCs development seen in SHS exposure, ultimately leading to abnormal remodeling of maternal 

spiral arteries. The objective is to uncover the mechanisms for smoke-induced altered placental development, 

which will shed light into the etiologies and potential therapies to a host of other reproductive outcomes 

including recurrent pregnancy loss, unexplained infertility, and improvement of in vitro fertilization 

implantation success rates. 

PREGNANCY AND PERINATAL EFFECTS FROM TOBACCO EXPOSURE 


EFFECT OF SECONDHAND CIGARETTE SMOKE, RSV BRONCHIOLITIS AND PARENTAL ASTHMA ON URINARY 

CYSTEINYL LTE4 

Jesse P. Joad, MD, MS; University of California, Davis; CIA 2002 

Cysteinyl leukotrienes promote airway inflammation, bronchoconstriction, and mucus hypersecretion. 

Cigarette smoking and respiratory syncytial virus (RSV) bronchiolitis are known to increase urinary cysteinyl 

leukotriene E4 (uLTE4), the end product of the cysteinyl leukotriene biosynthetic pathway. Dr. Joad 

and colleagues tested three hypotheses. These were that 1) SHS exposure increases uLTE4 in well infants 

and in those hospitalized for RSV bronchiolitis; 2) SHS increases length of hospital stay for those with 

RSV bronchiolitis; and 3) infants with parent(s) with asthma will have higher uLTE4. Parental asthma for 

infants hospitalized with RSV bronchiolitis (n = 79) and Well babies (n = 31) was determined by questionnaire. 

Urine was analyzed for LTE4, cotinine, and creatinine. SHS exposure was determined by cotinine to 

creatinine ratio. Chi square or t tests were used to determine significant differences between two groups. A 

three-way analysis of variance compared the effects of SHS exposure and parental asthma on uLTE4 in 

Well versus RSV babies. Independent variables predicting length of hospital stay were determined by stepwise 

multiple regression. High SHS exposure and RSV significantly increased uLTE4. The SHS induced 

increase in uLTE4 was seen in infants with no parental asthma but not in those with parental asthma. 

Length of hospital stay positively correlated with uLTE4. Dr. Joad and colleagues concluded that SHS 

exposure may increase the severity of bronchiolitis RSV-infected infants by enhancing production of cysteinyl 

leukotrienes in infants with no parental asthma 

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Kott KS, Salt BH, McDonald RJ, Jhawar S, Bric JM, Joad JP. Effect of secondhand cigarette smoke, RSV 

bronchiolitis and parental asthma on urinary cysteinyl LTE4. Pediatr Pulmonol 2008;43:760-766. 

CAUSES OF PERINATAL AND INFANT MORTALITY DUE TO FETAL NICOTINE EXPOSURE 

Hugo Lagercrantz, MD, PhD; Karolinska Institutet; CIA 2005 

Unborn fetuses exposed to tobacco products are at an increased risk of abortion, fetal death, and sudden 

infant death syndrome (SIDS)-related fatalities. Evidence suggests that these individuals may suffer instability 

of blood pressure and heart rate control. Dr. Langercrantz’s study objective is to describe the developmental 

changes in reflex blood pressure regulation and heart rate in normal, healthy infants, as well as in 

those infants at risk secondary to maternal use of tobacco products during pregnancy. The research methods 

included evaluation of the infant baroreflex by tilt table examination as well as induction of mild 

hypercapnia. Abnormal results may indicate delay or alteration in the cardiovascular stabilizing reflexes of 

the infant. The findings have included anomalies in SHS-exposed infants indicative of delayed, immature 

or disrupted baroreflect development. By age 3 months (the period of greatest risk for SIDS) reflex function 

was especially weak in SHS-exposed infants; the first evidence of early-onset cardiovascular pathophysiology 

and tobacco-exposure before birth. 


Cohen G, Lagercrantz H., Katz-Salamon M. Abnormal circulatory stress responses of preterm graduates. 

Ped Res 2007;61(1-3). 

EFFECTS OF PASSIVE SMOKING AND NICOTINE ON THE DEVELOPMENT OF CNS BODY IMAGE AND MOTOR SKILL 

Jens Schouenborg, MD; Lund University; CIA 2005 

The starting point for this study was the finding that information regarding body constitution is adaptively 

laid down in the spinal cord of the fetus and that sensory feedback on fetal movements are used in 

this learning mechanism. Given that cholinergic mechanisms are important in many forms of plasticity and 

learning, the aim of the project was to evaluate whether SHS and nicotine disturb mechanisms that tune 

the central nervous system sensorimotor systems, resulting in lifelong defects in motor ability and sensory 

capacity. It is already known that nicotine binds to a subgroup of cholinergic receptors, which play an 

important role in learning and memory. The results so far show that nicotine exposure during development, 

in a dose dependent manner, does indeed distort the body image in the spinal cord and significantly 

alter the sensitivity in the nociceptive withdrawal reflexes indicating interventions at multiple sites. Most 

importantly, the distortion of the spinal body image is still present in the adult mice after only 1 week of 

exposure to nicotine. Since the sensorimotor circuits in the spinal cord serve as building bricks in higher 

order systems it is likely that the impaired body representation will be reflected in impaired motor skill as 

well. The conclusion reached is that nicotine exposure during early development can cause permanent 

damage in the sensorimotor systems. This finding will serve to convince mothers to stop smoking in order 

to protect their unborn children. 

SINUSITIS 


PATHOGENESIS OF CHRONIC SINUSITIS IN RELATIONSHIP TO TOBACCO SMOKE EXPOSURE 

Daniel L. Hamilos, MD; Massachusetts General Hospital; CIA 2003 

Dr. Hamilos is investigating chronic rhinosinusitis (CRS), a persistent inflammatory condition prone to 

periodic flares and in which classic signs of bacterial infection are often absent. The epithelium represents 

the natural interface between the sinuses and the environment of microbes and exogenous agents such as 

SHS. It plays a significant role in innate immune responses. A 1-hour pulse exposure to cigarette smoke 

extract (CSE) was shown to have a significant effect on nasal epithelial cell viability and induced multiple 

genes of importance to epithelial innate immunity and inflammatory responses. Healthy control (HC) and 

CRS primary epithelial cells (PNTEC) were shown to be equally sensitive to the effects of CSE on cellular 

viability. HC and PNTEC cells showed a similar pattern of basal gene expression with the exception of 

expression of the chemokine MCP-3, which was shown to be expressed at > 2-fold greater levels in CRS 

subjects. Preliminary studies of mRNA induction in response to inflammatory stimuli suggested that CRS 

patients may be less responsive to normal inflammatory stimuli from microbial organisms. This was partic- 

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ularly true for the chemokine GRO-a that showed a significantly reduced level of expression in response to 

the panel of stimuli, which included TNF alpha (TNF alpha) and lipopolysaccharide (LPS). For most 

mRNA species, combined stimulation with CSE and TNFa or LPS provided additive gene induction, 

which suggests that CSE may exaggerate epithelial responses to viral and bacterial infection as well as allergic 

inflammation, resulting in the symptoms of chronic rhinosinusitis. 

PATHOGENESIS OF CHRONIC RHINOSINUSITIS IN RELATION TO SECOND HAND CIGARETTE SMOKE AND 

ABNORMAL EPITHELIAL INNATE IMMUNITY 

Daniel L. Hamilos, MD; Massachusetts General Hospital; CIA 2008 

Cigarette smoking has been identified as the most important cause of preventable morbidity and mortality 

in the U.S. Recent clinical studies suggest that in addition to being an important cardiovascular risk, 

cigarette smoking is an important risk for the progression of chronic kidney disease. The mechanisms by 

which cigarette smoking promotes the progression of chronic kidney disease have not been elucidated. 

Recently Dr. Hamilos and colleagues have made the novel observations that human mesangial cells are 

endowed with nicotine acetylcholine receptors (nAChRs) and that nicotine promotes mesangial cell proliferation 

and extracellular matrix production (ECM) via increased generation of reactive oxygen species 

(ROS). Their in vivo preliminary data suggest that nicotine worsens glomerular injury in an animal model 

of nephritis. Based on their strong preliminary data, they hypothesize that nicotine plays a major role in 

the pathogenesis of chronic kidney disease by promoting mesangial cell proliferation and ECM deposition 

in the glomerulus and that cyclooxygenase 2 (COX-2) derived prostaglandins and ROS play a major role 

as mediators of these effects. The hypothesis is tested by pursuing the two specific aims. For Aim 1 they 

are identifying the role of nicotine exposure as a risk factor in the progression of glomerulosclerosis. They 

are investigating the effects of nicotine administration in vivo on proteinuria (Bradford), glomerular injury 

score (histology), and ECM deposition (western blot, immunohistochemistry) in the 5/6 nephrectomy 

model of chronic kidney disease, a well validated animal model of chronic kidney disease. In addition, they 

are determining the effects of nicotine on glomerular production of ROS [lucigenin and dichlorodihydrofluorescein 

diacetate (DCF-DA)], the effects of nicotine on cortical COX-2 expression (immunohistochemistry 

and western blot) in this model and the effects of COX-2 inhibition on renal injury in animals 

with 5/6 nephrectomy and receiving nicotine. For Aim 2 they are establishing the mechanisms that mediate 

the growth promoting effects of nicotine in the glomerular mesangium. The working hypothesis for 

this aim is that COX-2 derived prostaglandins and cytokines, such as transforming growth factor beta 

(western blot and ELISA) and platelet-derived growth factor (PDGF) (western blot and ELISA), participate 

as mediators of (western blot) production and proliferation (3H-thymidine) by mesangial cells in 

response to nicotine. These studies will unveil novel mechanisms by which cigarette smoking promotes 

chronic kidney disease progression and establish the role of nicotine as one of the compounds in cigarette 

smoke responsible for the deleterious effects of tobacco in kidney disease. 

TOBACCO SMOKE EXPOSURE, INNATE IMMUNITY, AND CHRONIC SINUSITIS 

Andrew P. Lane, MD; The Johns Hopkins University; CIA 2004, 2007 

The research explores the effect of tobacco smoke on the immune function of the nasal and sinus 

mucosa. Tobacco smoke is known to promote or exacerbate sinusitis in susceptible individuals, and tobacco 

exposure is an independent risk factor for the early failure of medical and surgical sinusitis therapy. 

Previous work demonstrated that the function of the local immune system within the nose is diminished in 

patients with chronic sinusitis. In the current FAMRI study, the scientists are investigating whether tobacco 

smoke exposure impacts the innate immune function of the nasal lining, thereby predisposing individuals 

to develop sinusitis. They are examining immune gene expression in nasal tissue obtained from patients 

with varying degrees of SHS exposure, while also using a cell culture model to determine the effect of 

tobacco smoke on sinus epithelial cells derived from sinusitis patients and control subjects. The initial 

results indicate that the tobacco smoke component, acrolein, suppresses expression of critical anti-microbial 

products produced by epithelial cells in vitro. Recently, Dr. Lane developed a modified cell culture medium 

that allows testing the effect of whole tobacco smoke in a similar fashion. The investigators are focusing 

on the expression of multiple epithelial cell gene targets involved in both the innate and the adaptive 

immune system of the nose and sinuses. Currently, they are focusing on determining whether a subject’s 

history of smoke exposure is associated with an impaired ability of their sinus epithelial cells to respond to 

bacterial stimuli. Failure of nasal mucosal immunity to eliminate bacteria and other potential pathogens is 

an important underlying factor in the development of chronic sinusitis among smoke-exposed individuals. 

2 0 6 P A G E


Kim J, Myers AC, Chen L, Pardoll D, Truong-Tran Q, McDyer J, Lane A, Fortuno L, Schleimer RP. 

Constitutive and inducible expression of B7 family of ligands by human airway epithelial cells. Amer J 

Resp Cell Molec Biology 2005;33:280-289. 

Schleimer RP, Sha Q, Vandermeer J, Lane AP, Kim J. Epithelial responses in airway inflammation and 

immunity. Clin Exp Allergy Rev 2004;4:176-182. 

CONTRIBUTION OF SECOND HAND TOBACCO SMOKE TO SINUSITIS 

Noam A. Cohen, MD, PhD; University of Pennsylvania; YCSA 2004 

Dr. Cohen investigates the role of SHS as a cause of chronic rhinosinusitis (CRS) by correlating exposure 

to the severity of sinus disease and sinonasal ciliary beat frequency. Additionally, he plans to study second-messenger 

cascades altered by SHS and their contribution to CRS. Further implications of this work 

in determining the effect of SHS on cilia elsewhere in the body may lead to a better understanding of asthma 

as well as diseases of the female reproductive tract. The aims of the study include 1) the identification 

of the prevalence of SHS exposure and active smoking in a cohort of CRS patients; and 2) the demonstration 

that exposure to SHS reduces sinonasal ciliary function. The initial task, creating a reproducible 

method of measuring sinonasal beat frequency, was accomplished by use of differential interference contrast 

micrography and high-speed digital video. Dr. Cohen’s laboratory also verified the similarity of biopsies 

taken from several nasal anatomical regions in CRS patients. 

LABORATORY STUDIES OF HUMAN NASAL EPITHELIUM 

Johnny L. Carson, PhD; University of North Carolina at Chapel Hill; CIA 2004, 2007 

This FAMRI-supported project has recently completed a study that involves assessment of ciliary beat 

frequency (CBF) in the nasal epithelium of human subjects based on lifestyle exposures to tobacco smoke. 

An analysis of nasal epithelial CBF was performed among 61 subjects in three groups comprised of 1) 

active smokers; 2) non-smokers exposed by occupation or domestic living conditions to SHS; and 3) nonsmokers 

with no exposure to SHS. These studies demonstrated that active smokers and non-smokers 

exposed to SHS exhibit persistently upregulated CBF. In fact, these studies indicated that CBF characteristics 

among non-smokers exposed to SHS exhibit greater similarity to those of active smokers than to nonsmokers 

even though their exposure level, based on urine cotinine assays, may be orders of magnitude 

lower than that of smokers. The general view of the regulation of CBF is that irritant exposure transiently 

upregulates CBF until the abatement of the irritant challenge when it is restored to baseline levels. 

However, since the sampling of subjects was not targeted to times proximal to specific tobacco smoke 

exposure events, the data indicate that lifestyle exposures to tobacco smoke result in a persistent upregulation 

of CBF, whether through active smoking or simply via SHS exposure. While upregulation of CBF in 

the short-term is considered a beneficial protective defense mechanism, the physiologic basis for upregulation 

resides in the generation of nitric oxide, a proinflammatory mediator, which may, in the longer term, 

interact with cellular elements in ways capable of promoting adverse health effects. These studies implicate 

tobacco smoke exposure in the persistent upregulation of nasal epithelial CBF, a response that may represent 

the first quantifiable health effect of tobacco smoke exposure. In consideration of the cellular basis of 

ciliary beat upregulation, this response suggests the existence of a cell metabolic background associated 

with tobacco smoke exposure that may portend the emergence of more adverse health effects in the future. 

New studies funded by this grant are analyzing the persistence of accelerated CBF in cultured nasal mucosa 

of smoke-exposed subjects relative to non-smokers. 


Carson, JL. Human ciliopathies: an overview of the first one hundred years (Invited). Microsc Microanal 

2008;14(suppl 2):146-147. 

Carson JL, Brighton, LE, Jaspers I, Hazucha M, Song R, Zhou H. Persistent upregulation of nasal epithelial 

ciliary beat frequency among smokers and individuals exposed to environmental tobacco smoke. 

Presented at the American Thoracic Society International Conference. Toronto, Canada, May 16-21, 

2008. 

Carson, JL. Human ciliopathies: an overview of the first one hundred years. Presented at the Joint 

Meeting of the Microscopy Society of America, Microbeam Analysis Society, and International 

Metallographic Society. Albuquerque, NM, Aug 3-7, 2008. 

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EPITHELIUM AND IMMUNOMODULATION IN CHRONIC RHINOSINUSITIS (CRS) 

Jean Kim, MD, PhD; The Johns Hopkins University; CIA 2004 

Studies from Dr. Kim’s laboratory show that nasal epithelial cells are able to communicate with the 

inflammatory coordinating T cells through cell surface-containing costimulatory molecules, specifically the 

B7 costimulatory family. The hypothesis is that exacerbations of chronic rhinosinusitis (CRS) result in 

increased expression of these costimulatory molecules. Dr. Kim plans to use specific and reproducible 

assays to quantitate costimulator expression, in vitro and in vivo in humans. Initial studies will measure 

costimulatory molecule expression by polymerase chain reaction and flow cytometry, before and after CRS 

exacerbation. Further research, using cultured nasal epithelial cells, would probe the mechanism of the 

effect of CRS stimuli, such as cytokines and rhinovirus on costimulator expression. Dr. Kim anticipates that 

these studies will give insight into the CRS-related interactions between epithelial cells and T cells. 


Heinecke L, Proud D, Sanders S, Schleimer RP, Kim J. Induction of B7-H1 and B7-DC expression on airway 

epithelial cells by the Toll-like receptor 3 agonist double-stranded RNA and human rhinovirus infection: 

in vivo and in vitro studies. J Allergy Clin Immunol 2008;121:1155-1160. 

Kim J, Myers AC, Chen L, Pardoll D, Truong-Tran Q, McDyer J, Lane A, Fortuno L, Schleimer RP. 

Constitutive and inducible expression of B7 family of ligands by human airway epithelial cells. Amer J 

Resp Cell Molec Biology 2005;33:280-289. 

Schleimer RP, Sha Q, Vandermeer J, Lane AP, Kim J. Epithelial responses in airway inflammation and 

immunity. Clin Exp Allergy Rev 2004;4:176-182. 

SECOND HAND TOBACCO SMOKE EXPOSURE INCREASES BIOFILMS FORMATION AND SUBSEQUENT CILIARY 

DYSFUNCTION 

James N. Palmer, MD; University of Pennsylvania; CIA 2006 

Chronic sinusitis is one of the most common diseases treated by physicians in the United States, and is 

responsible for a yearly estimated cost of six billion dollars to society. However, little is known about what 

causes this condition. There is evidence that shows there is a relationship between tobacco smoke exposure 

and bacterial infections in the sinuses. Excess smoke exposure and infections can cause chronic sinusitis by 

damaging the cilia that sweep particles out of the nose and sinuses. It has been established that individual 

bacteria can grow together into a three-dimensional colony called a biofilm, similar to a coral reef. Patients 

that have chronic sinusitis associated with these coral reef type structures in their sinuses are almost impossible 

to cure, because antibiotics do not work against them. Dr. Palmer will determine whether SHS exposure 

will allow bacterial biofilms to grow faster in the sinuses, and if they grow faster, whether more 

biofilms in the sinuses means the cilia will stop working. Dr. Palmer plans to perform this experiment by 

first growing the sinus lining from patients after sinus surgery in a Petri dish and then pretreat some of 

those specimens with cigarette smoke condensate. Bacteria that form biofilms will be added to the tissue in 

the dish to determine if more biofilms have formed (and whether the cilia stop working) in those exposed 

to cigarette smoke. The expectation is that the ciliary damage caused by cigarette smoke will decrease the 

defenses of the sinonasal mucosa, and biofilms will be seen in larger numbers by electron microscopy, and 

the cilia will be damaged. Knowledge about cigarette smoke causing cilia dysfunction through increased 

biofilm formation will help to identify new treatment pathways for chronic sinusitis. 

EFFECTS OF SECOND HAND TOBACCO SMOKE ON SINONASAL IMMUNITY 

Rodney J. Schlosser, MD; Deanne Lathers, PhD; Charleston Research Institute; CIA 2006 

Chronic rhinosinusitis (CRS) affects nearly 16% of the US population each year, resulting in billions of 

dollars in healthcare expenditures. Increasing evidence demonstrates that many patients with CRS have 

abnormal immune responses that can be triggered by a variety of inhaled substances, including SHS. The 

innate defense system is the first step in the immune response to these inhaled pathogens and directs subsequent 

adaptive immune responses. Innate immunity includes production of complement, surfactant proteins 

(SPs) and free radicals and variations in these innate defenses by SHS likely increases susceptibility to 

bacterial, viral, and fungal infections. Dr. Schlosser and colleagues have found increased SP-A, B, and D 

gene expression and protein production in certain types of sinusitis associated with Th1 adaptive immune 

responses. Their in vitro tissue explant model has demonstrated an increased Th1 adaptive response as 

measured by IL-8 both within the tissue and as a secreted mediator with increasing exposure to both cigarette 

smoke condensate and cigarette smoke extract. This IL-8 response is abolished by superoxide dismutase, 

indicating that tobacco smoke causes Th1 inflammation via production of free radicals. Additionally, 

2 0 8 P A G E

aberrations in the complement pathway occur in some subsets of CRS, possibly due to smoke exposure. 

These results will provide information on the therapeutic potential of correcting innate abnormalities as a 

novel treatment approach for SHS-induced CRS and the abnormal immune response it causes. 

Determination of SP, complement, and oxidative inflammation in CRS will enable better understanding of 

the role of the innate defense system of the upper airway and expedite the development of novel therapeutic 

modalities for SHS-induced CRS. 


Ahn CA, Lathers D, Wise SK, Mulligan R, Schlosser RJ. Quantification of dendritic cells in chronic rhinosinusitis. 

Presented at the Annual American Academy of Otolaryngology - Head and Neck Surgery 

Meeting. Washington DC, Sept 16-19, 2007. 

Skinner ML, Schlosser RJ, Neal JG, Woodworth BA, Hall J, Newton D, Baatz JE. Innate and adaptive 

mediators in cystic fibrosis and allergic fungal rhinosinusitis. Am J Rhinol 2007;21(5):538-541. 

Skinner ML, Schlosser RJ, Neal JG, Woodworth BA, Hall J, Newton D, Baatz JE. Innate and adaptive 

mediators in cystic fibrosis and allergic fungal rhinosinusitis. Presented at the American Rhinologic 

Society Meeting. Chicago, IL, May 19-20, 2006. 

Woodworth BA, Wood R, Baatz JE, Schlosser RJ. SPA-1, SPA-2, and SP-D gene expression in chronic rhinosinusitis. 

Presented at the American Rhinologic Society Meeting. Toronto, Canada Sept 16, 2006. 

Woodworth BA, Wood R, Baatz JE, Schlosser RJ. Sinonasal surfactant protein A1, A2, and D is elevated in 

cystic fibrosis: A preliminary report. Otolaryngol Head Neck Surg 2007;137(1):34-38. 

Woodworth BA, Wood R, Bhargave G, Cohen NA, Baatz JE, Schlosser RJ. Surfactant protein B detection 

and gene expression in chronic rhinosinusitis. Laryngoscope 2007;117(7):1296-1301. 

Woodworth BA, Wood R, Bhargave G, Cohen NA, Baatz JE, Schlosser RJ. Surfactant protein B detection 

and gene expression in chronic rhinosinusitis. Presented at the Triologic Society Combined Sections 

Meeting Program. Marco Island, FL, Feb 14-15, 2007. 

EVALUATING CD137 AS A NOVEL TREATMENT IN A NEW TOBACCO-EXACERBATED MODEL 

OF CHRONIC SINUSITIS 

Rodney J. Taylor, MD, MPH; University of Maryland; CIA 2007 

It is possible that chronic rhinosinusitis (CRS) can be eradicated and prevented by stimulation through 

the CD137 receptor. The aims are to develop an immune-mediated murine model of sinusitis, evaluate the 

additional impact of tobacco exposure on CRS, and both cure and prevent CRS by activating the co-stimulatory 

receptor CD137. CRS is caused by inflammation within the mucosa of the nose and paranasal 

sinuses; it is one of the most common health care problems in the US and affects more than 32 million 

Americans annually, making it more common than arthritis and hypertension. Sinusitis has an adverse 

impact on quality of life, and is increasing in both prevalence and incidence. Factors such as allergy and 

infectious causes contribute to the development of CRS and the observed cascade of inflammation that 

ensues. There is evidence that the co-stimulatory molecule cd137 (4-1bb) inhibits allergy-mediated asthma. 

The goal of this study is to develop both a murine model of allergy mediated CRS and a model of 

tobacco-exacerbated CRS. By using mice with well-described sinus anatomy, the investigators will endeavor 

to create these models using a known allergen and immunogen, ovalbumin, resulting in a localized allergic 

reaction that will occur in the sinuses and nasal cavity leading to mucosal thickening and infiltration of 

eosinophils and other chronic inflammatory cells. By identifying tobacco exposure as an exacerbating factor 

in sinusitis, they will bring light to this public health risk and strengthen the scientific support for changes 

in public health. 

SECOND-HAND SMOKE AND SINUSITIS: EFFECT OF SIDESTREAM SMOKE ON SINUS OSTIAL PATENCY 

John Balmes, MD; Dennis Shusterman MD, MPH; University of California, San Francisco; CIA 2008 

SHS exposure can produce a variety of upper airway / mucosal symptoms, including eye, nose and 

throat irritation, nasal congestion, rhinorrhea, Eustachian tube dysfunction, sinus headaches, and 

potentially sinusitis. The laboratory of Drs. Balmes and Shusterman has previously shown that nasal 

exposure to various irritants produces transient airflow obstruction, particularly among individuals with 

pre-existing allergic rhinitis. Among the test irritants they have used in this experimental model is acetic 

acid vapor, which is also present in SHS. They speculate that irritant-induced nasal mucosal swelling could 

predispose toward the development of sinusitis, since sinus ostial patency can also be compromised by 

mucosal swelling. Sinus ostial obstruction is recognized as a cause of sinusitis. In the past, sinus ostial 

P A G E 2 0 9

patency was best assessed using high-resolution sinus CT scanning; however, sinus CT is cumbersome, 

costly, and measures sinus ostial anatomy, but not function. Nasal nitric oxide (NO) is present in high 

concentrations in the sinuses and humming in individuals with patent sinus ostia mixes the air between the 

sinuses and nasal cavity, thereby increasing measured nasal NO. The response of nasal NO to humming 

holds promise as a noninvasive, functional measure of ostial patency, which is better suited than CT 

scanning to studying the effects of environmental airborne irritants. The investigators propose to combine 

their established model of measuring nasal obstruction (nasal airway resistance by active posterior 

rhinomanometry) with an estimation of the patency of sinus ostia using the response of nasal NO to 

humming. They will study 16 subjects each of allergic rhinitics and normal controls. In year one of their 

study, they compared the magnitude of the humming-induced spike in nasal NO with objective 

osteomeatal patency, as documented by CT scanning. In the second year, subjects will have their nasal 

airway resistance and nasal NO response to humming measured before and after exposure (on separate 

days) to either clean air or sidestream tobacco smoke (STS). They hypothesize that the allergic rhinitic 

group, compared to controls, will not only demonstrate acute increases in nasal airway resistance after 

inhaling sidestream smoke, but will also show a decrease in the normal NO spike seen with humming. 

Successful conduct of this study would establish a link between irritant-related nasal airflow obstruction 

and impairment of sinus function which, in turn, will provide insight into a potential SHS-sinusitis link. 

SECOND HAND TOBACCO SMOKE EXACERBATION OF ALLERGIC RHINITIS 

M. Boyd Gillespie, MD; Charleston Research Institute; CIA 2008 

SHS often causes symptoms of nasal congestion, rhinorrhea, and conjunctival irritation, but mechanisms 

by which this occurs are unknown. Dr. Gillespie’s central hypothesis is that SHS triggers local release of 

neurogenic mediators that augments the classic Th2 adaptive response of allergic rhinosinusitis (AR), exacerbates 

symptoms, and impairs quality of life. Dr. Gillespie’s first aim is to clinically determine if SHS exposure 

worsens AR symptoms. The second aim is to investigate in vivo mechanisms of action of SHS-induced 

rhinitis by determining the relationship between changes in local neurogenic and adaptive mediators. The 

third aim is to establish cause-effect relationships for observed differences in neurogenic mediators, Th2 

adaptive cyto/chemokines, and downstream effector molecules using an in vitro AR model. To date, Dr. 

Gillespie and colleagues have found that nerve growth factor is increased and brain derived neurotrohpic 

factor is decreased in allergic rhinosinusitis tissue. Correlations to SHS exposure using hair nicotine is 

pending. Their overall hypothesis is that SHS-induced exacerbations of allergic rhinosinusitis will be caused 

by release of local neurogenic mediators. These mediators will exacerbate the classic Th2, immunoglobulin 

E mediated immunologic response, and worsen symptoms in AR patients. Their long-term objective is to 

establish that SHS leads to more severe symptoms in AR patients, confirm this cause-effect relationship, 

and provide a direct translation from the underlying pathophysiologic mechanisms of this disease to real 

world clinical observations that may lead to improved patient care. 

MOLECULAR MECHANISMS OF SPATIOTEMPORAL REGULATION OF LEUKOCYTE CHEMOTAXIS 

AND ITS DYSREGULATION INVOLVED IN CHRONIC SINUSITIS 

Jin Zhang, PhD; The Johns Hopkins University; YCSA 2004 

Increased eosinophil chemotaxis and decreased neutrophil migration have been linked to chronic sinusitis, 

yet the pathophysiology of the disorder and mechanisms of leukocyte chemotaxis are not well understood 

at the molecular level. The goal of Dr. Zhang’s work is to determine the molecular mechanisms controlling 

cell polarization and directional movement in leukocyte chemotaxis, and thus identify the molecular-component 

changes involved in chronic sinusitis. Data have shown that the phosphoinositide pathway is 

needed to mediate leukocyte chemotaxis, which involves two kinases, phosphoinositide-3 kinase (PI3K) 

and protein kinase B (Akt), and a phosphatase and tensin homologue deletion on chromosome 10 

(PTEN). The approach uses a combination of live-cell imaging, protein engineering, and chemical and 

molecular biology. Understanding the spatiotemporal regulation of leukocyte chemotaxis by the 

P13K/Akt/PTEN pathway should lead to elucidation of the key molecular components of the abnormal 

chemotaxis found in chronic sinusitis. 


Ananthanarayanan B, Qiang N, Zhang J. Signal propagation from membrane messengers to nuclear effectors 

revealed by reporters of phosphoinositide dynamics and Akt activity. Proc Natl Acad Sci U S A 

2005;102:15081-15086. 

2 1 0 P A G E

REVERSAL OF TOBACCO-RELATED CHRONIC SINUSITIS 

Bradford A. Woodworth, MD; University of Alabama at Birmingham; YCSA 2008 

Chronic rhinosinusitis (CRS) affects 16% of the US population with an estimated aggregated cost of six 

billion dollars annually in healthcare expenditures. Although the pathophysiology leading to rhinosinusitis 

is complex, evidence indicates that sinonasal mucosal inflammation and decreased mucociliary clearance 

(MCC) are major contributing factors. Sinonasal respiratory epithelium is a highly regulated inert barrier 

that is primarily responsible for MCC. Normal respiratory epithelial MCC is an important host defense 

mechanism that is dependent on proper ciliary beating and the biological properties of the airway surface 

liquid (ASL). The epithelium separates the airway from the external environment and is constantly exposed 

to a variety of exogenous agents (e.g., bacteria, allergens, and inhaled pollutants) capable of initiating an 

inflammatory reaction. Furthermore, mounting evidence indicates that SHS may contribute to respiratory 

epithelium dysfunction by inciting inflammation, decreasing ciliary function, and altering the composition 

of the ASL by inhibiting epithelial chloride (Cl-) secretion. Methods to decrease mucosal inflammation and 

increase MCC in patients with SHS-related CRS are needed. One potential pharmacologic intervention is 

the trace element zinc. Zinc has many beneficial effects in humans, including anti-oxidant, anti-apoptotic, 

and anti-inflammatory properties. Furthermore, topical zinc rescues Cl- secretion in cystic fibrosis respiratory 

epithelium and increases ciliary beat frequency (CBF). The central hypothesis of this study is that 

exposure to SHS induces CRS by inhibiting mucociliary function and promoting inflammation. Dr. 

Woodworth’s long-term objective is to determine the therapeutic potential of zinc to reverse SHS effects 

on sinonasal respiratory epithelium by improving CBF, decreasing inflammation, and improving epithelial 

Cl- secretion. For Specific Aim 1 Dr. Woodworth and colleagues will examine the relationship between 

SHS, zinc deficiency, and CRS in human subjects by correlating zinc levels and SHS exposure to CRS 

signs and symptoms. Specific Aim 2 will use in vitro murine sinonasal epithelium to 1) characterize inflammatory 

profiles after exposure to SHS in combination with lipopolysaccharide (LPS) using multiplex 

cytokine analysis; 2) explore SHS effects on CBF with high speed digital video imaging; and 3) determine 

the SHS effects on epithelial Cl- secretion by studying vectorial ion movement in a modified Ussing chamber. 

They will also examine whether zinc decreases the SHS and LPS associated inflammation, reverses the 

inhibitory effect of SHS on CBF, and rescues SHS-inhibited Cl- secretion. This work has direct implications 

for understanding SHS-related effects on respiratory epithelium and explores one of many novel 

translational therapies, from bench to bedside, in the management of SHS-associated respiratory disease. 

SINUSITIS 


TOBACCO SMOKE AND GENE EXPRESSION IN SINUS MUCOSA 

Vladimir Vincek, MD, PhD; University of Miami; CIA 2004 

Dr. Vincek’s goal was to determine the effect of SHS and first hand smoking on development and worsening 

of chronic rhinosinusitis (CRS). The long-term goal was to elucidate and understand the complexity 

of the various factors leading to the development of CRS. Dr. Vincek hypothesized that tobacco smoke 

causes changes in the gene expression pattern of histologically normal upper respiratory mucosa and stroma 

that lead to CRS development. The specific aim was to determine through microarray analysis the gene 

expression profiles of nasal mucosal epithelium, with and without tobacco smoke exposure. The study closes 

the knowledge gap concerning the effects of tobacco smoke on gene expression in the upper respiratory 

mucosa. The outcome of this study is expected to shed light on why there is a worse long-term outcome 

for therapy of CRS in those exposed to second hand tobacco smoke and in smokers. 

CORRELATION OF CHRONIC SINUSITIS AND TOBACCO SMOKE 

Jeffrey S. Wolf, MD; University of Maryland; CIA 2004 

Dr. Wolf’s research revolved around developing an objective strategy to test the hypothesis that tobacco 

smoke exposure increases severity of chronic rhinosinusitis (CRS). His laboratory conducted a prospective 

study enrolling 90 consecutive patients with severe CRS who were scheduled for sinus surgery after failing 

maximal medical therapy. During surgery, maxillary sinus mucosa was biopsied and evaluated for ciliary 

ultrastructure, mitochondrial DNA, and presence of cotinine. Further measures included a blinded grading 

of sinus computed tomography scans, a validated questionnaire about tobacco smoke exposure and severity 

of sinus-related disease, and serum cotinine. His laboratory has enrolled 90 patients and a paper submitted 

for publication. They found a correlation between quality of life and tobacco smoke exposure. There were 

P A G E 2 1 1

significant increases in sinusitis symptom severity in active smokers, asthmatics, patients with environmental 

allergies, and those with cotinine in their serum. There were multiple individual correlations between independent 

variables and sino-nasal outcome test 20 (SNOT-20) scores. Serum cotinine level, the number of 

cigarettes smoked per day, and the number of second hand cigarettes exposed to per day all significantly 

correlated with worse quality of life. The research team found a five-variable predictive model of total 

SNOT score (R2 = 0.366, p = 0.0019). The parameters included in this model were previous cigarettes 

smoked per day, active smokers, serum cotinine, allergy, and female gender. 

SKIN AND SECOND HAND SMOKE 


PASSIVE CIGARETTE SMOKE IN THE PATHOGENESIS OF SKIN CANCER 

Barry Starcher, PhD; University of Texas Health Center at Tyler; CIA 2004 

Although cigarette smoking causes SCC of the skin, the pathogenic mechanisms are still not well understood. 

Chronic exposure to sunlight, i.e., ultraviolet (UV) B irradiation, is the most common cause of 

nonmelanoma skin tumors. In the present study, the effects of passive cigarette smoke were studied, superimposed 

on UVB irradiation on tumor development, skin pathology, and matrix changes in skin tumor in 

hairless SKH-1 mice. Groups of 10 mice were exposed to 0.1 Joules per square centimeter (J/cm 2 ) of 

UVB five times a week for 20 weeks and/or exposure to passive cigarette smoke from 40 cigarettes a day 

over the same time period. UVB exposure resulted in an average of four large squamous cell tumors and 

15 papillomas per mouse, whereas exposing the mice to both UVB + passive cigarette smoke completely 

prevented the skin tumor formation. Oxidative DNA damage was investigated and there were no significant 

changes in the levels of DNA adducts between control, smoke, UV, and UV + smoke groups with the 

exception of 8-oxy guanine, which was significantly reduced in the presence of passive cigarette smoke. 

Immunohistochemistry results revealed that tumor necrosis factor receptor 2, glycogen synthase kinase 3 

beta, nuclear factor kappa B (NF-kappa B)/p65, the monoclonal antibody KI-67, and cyclooxygenase 2 

were markedly up-regulated by UVB exposure, whereas passive smoke exposure combined with the UVB 

irradiation completely blocked the expression of these proteins. The results suggest that passive smoke 

exposure prevents UVB induced tumors in mice by altering the NF-kappa B signaling pathway of tumorigenesis. 

SKIN AND SECOND HAND SMOKE 


NICOTINIC RECEPTORS ALTER GENE EXPRESSION IN KERATINOCYTES 

Sergei A. Grando, MD, PhD, DSc; University of California, Irvine; CIA 2002, 2005 

Dr. Grando continued his novel research into the contribution of nicotine and tobacco smoke-induced 

alterations on the growth regulation of epidermal keratinocytes. His premise for this research was that 

chronic nicotine exposure disturbs the equilibrium between growth-promoting and growth-inhibiting 

effects of the cytotransmitter acetylcholine (ACh), leading to an abnormal cell cycle and early squamatization. 

The aims were to 1) identify the long-term effects of nicotine and SHS on attainment of a specific 

cell state in cultured keratinocytes and 2) determine the ACh metabolism and signaling in these cells. To 

elucidate the physiological mechanisms determining keratinocyte lateral migration, Dr. Grando is studying 

the signaling pathway that mediates cholinergic regulation of chemotaxis and galvanotropism, a natural 

model of cell reorientation to direction of future migration via use of direct current. Results suggest that 

keratinocyte galvanotaxis is essentially chemotaxis toward the concentration gradient of ACh created by the 

highly positively charged field. Modifiers of the Ras/Raf-1/mitogen activated protein kinase kinase- 

1/extracellular signal-regulated kinase (MEK1/ERK) signaling pathway was shown to alter choline-directed 

chemotaxis and galvanotropism, suggesting the same signaling steps were engaged. Additionally, a7 

nicotinic and M1 muscurinic receptors work together to orient a keratinocyte to the direction of its migration. 

Both seem to engage the Ras/Raf-1/MEK1/ERK pathway leading to upregulate sedentary integrin 

expression necessary for stabilization of the out pouching at the keratinocyte’s leading edge. Therefore, 

this study demonstrated that the Ras/Raf-1/MEK1/ERK pathway is involved in the reorientation of keratinocytes 

that is needed for chemotaxis and galvanotaxis. 

2 1 2 P A G E


Arredondo J, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA. Receptor-mediated tobacco toxicity: 

acceleration of sequential expression of {alpha}5 and {alpha}7 nicotinic receptor subunits in oral 

keratinocytes exposed to cigarette smoke. FASEB J 2007 [Epub ahead of print]. 

Arredondo J, Chernyavsky AI, Webber RJ, Grando SA. Biological effects of SLURP-1 on human keratinocytes. 

J Invest Dermatol 2005;125:1236-1241. 

Arredondo J, Hall LH, Ndoye A, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Beaudet 

AL, Grando SA. Central role of fibroblast alpha3 nicotinic acetylcholine receptor in mediating cutaneous 

effects of nicotine. Lab Invest 2003;83:207-225. 

Arredondo J, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Vetter DE, Grando SA. 

Functional role of alpha7 nicotinic receptor in physiological control of cutaneous homeostasis. Life Sci 

2003;72:2063-2067. 

Arredondo J, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Kummer W, Lips K, Vetter DE, 

Grando SA. Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium. 

J Cell Biol 2002;159:325-336. 

Arrendondo J, Chernyavsky A, Marubio L, Beaudet A, Jolkovsky D, Pinkerton K and Grando S. Receptormediated 

tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral 

epithelial cells. Amer J Pathol 2005;166(2):597-613. 

Chernyavsky AI, Arredondo J, Karlsson E, Wessler I, Grando SA. The Ras/Raf-1/MEK1/ERK signaling 

pathway coupled to integrin expression mediates cholinergic regulation of keratinocyte directional 

migration. J Biol Chem 2005;280:39220-39228. 

Chernyavsky AI, Arredondo J, Marubio LM, Grando SA. Differential regulation of keratinocyte chemokinesis 

and chemotaxis through distinct nicotinic receptor subtypes. J Cell Sci 2004;117:5665-5679. 

Chernyavsky AI, Arredondo J, Wess J, Karlsson E, Grando SA. Novel signaling pathways mediating reciprocal 

control of keratinocyte migration and wound epithelialization by M3 and M4 muscarinic receptors. 

J Cell Biol 2004;166:261-272 

Grando SA. Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of 

non-canonical ligands of epithelial nicotinic acetylcholine receptors. J Pharmacol Sci 2008;106:174-179. 

Nguyen VT, Chernyavsky AI, Arredondo J, Bercovich D, Orr-Urtreger A, Vetter DE, Wess J, Beaudet AL, 

Kitajima Y, Grando SA. Synergistic control of keratinocyte adhesion through muscarinic and nicotinic 

acetylcholine receptor subtypes. Exp Cell Res 2004;294:534-549. 

SPERMATOGENESIS 


SECOND HAND TOBACCO SMOKE AS A POTENTIAL CAUSE OF SPERMATOGENIC FAILURES 

AND MALE INFERTILITY 

Margarita Vigodner, PhD; Stern College, Yeshiva University; YCSA 2008 

Cigarette smoking is one of the major lifestyle factors adversely influencing the health of human beings. 

Smokers have a higher prevalence of common diseases, such as atherosclerosis and COPD with significant 

impact on various systems. For example, there is much information on the hazardous effects of cigarette 

smoking on the female reproductive system, with decreased fecundity and fertility well documented. Less is 

known about the effects of cigarette smoking on the male reproductive system. However, some research 

has noted a negative health effect of cigarette smoking on sperm morphology and mobility. The health 

effect of SHS on male fertility is essentially undefined. This grant will focus on the impact of SHS on male 

spermatogenesis, using laboratory mice as the human surrogates and advanced type of cell analysis, instead 

of old classical techniques for study spermatogenesis. Following animal exposure to environmental cigarette 

smoke different spermatogenic parameters will be assessed and changes occurring in testicular genes 

following the exposure of animals to SHS will be performed. Together, these studies will lead to a more 

comprehensive understanding of spermatogenesis and its regulation and of the clarification of possible reasons 

for SHS-related abnormalities during male cell development. This knowledge, in turn, will lead to 

better treatment of previously unexplained cases of male infertility and the improvement of human healthcare. 

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VISION 

ONGOING RESEARCH 

GENE PROFILING SECOND HAND TOBACCO SMOKE AND MACULAR DEGENERATION 

George Inana, MD, PhD; University of Miami; CIA 2007 

Tobacco smoke has been related to many health-related problems, including lung diseases, cardiovascular 

problems, and cancer. Diseases related to the eye are no exception, and age-related macular degeneration 

(AMD), the number one cause of blindness for people over 60, has been caused by smoke. Genes and 

environmental factors are important for AMD, which is a complex disease in which changes in expression 

of multiple genes are thought to play a role, making it difficult to identify them. Since tobacco smoke has 

been shown to increase the incidence of AMD, it must affect these genes and may be an important clue for 

identifying them. This is the approach Dr. Inana proposes to take to identify genes that are important for 

causing AMD. A custom gene expression profiling strategy called CHANGE has been developed and many 

genes have been identified that may be important for AMD. The strategy is to expose experimental animals 

(mice) to SHS and determine what genes are affected in the retinal pigment epithelium (RPE)/choroid 

and retina of the eye, the site of AMD. These genes will then be compared to the AMD candidate genes 

that have been identified, and genes that fulfill both criteria will be identified. These will be excellent candidates 

for AMD and will be further analyzed individually. To date, a Teague smoking machine has been 

set up, and cohorts of mice have been exposed to SHS for 3 and 6 weeks. RNA has been isolated from the 

eyes and used for global gene expression profiling, yielding 1089 and 2248 genes showing differential 

expression in the 6 week- and 3 week-smoked retina compared to control, respectively, and 3529 and 

4391 genes showing differential expression in the 6 week- and 3 week-smoked RPE/choroid compared to 

control, respectively. Some of the pathways shown to be affected by the Gene Map Annotator and Pathway 

Profiler (GenMAPP) and glutamate 1-semialdehyde aminotransferase (GSAT) pathway analyses include the 

electron transport chain, structural constituent of the eye lens, and tissue, endocrine, and central nervous 

system specific genes. The differentially expressed genes from the SHS smoking experiments are being 

compared to the AMD candidate genes from the CHANGE analyses to identify overlapping genes for further 

study. The RNAs from the smoking experiments are also being used for direct hybridization analysis 

of the CHANGE AMD genes to identify genes related to both. Genes identified by this strategy will be 

further investigated for their causal and mechanistic relationship to AMD. 

ROLE OF SMOKING IN AGE-RELATED MACULAR DEGENERATION 

Maria Marin-Castano, MD, PhD; University of Miami; CIA 2008 

Age-related macular degeneration (AMD) is the principal cause of irreversible, registered legal blindness 

in the elderly, affecting 14 million patients in the US alone. It is characterized by progressive degeneration 

of the retina, retinal pigment epithelium (RPE), and underlying choroids, which results in severe vision 

loss. The earliest clinically visible abnormality in AMD is the accumulation of drusen between the RPE and 

choroids. Drusen deposition is a significant risk factor for progression to choroidal neovascularization 

(CNV), the hallmark of late AMD. Most cases of blindness are caused by neovascular AMD characterized 

by CNV, the invasion of abnormal new vessels into the retina from the subjacent vascular bed (choroid). 

To date, the mechanism(s) of how, or whether, drusen provoke CNV remains undefined. Drusen deposition 

and neovascular AMD share many pathogenic features with cardiovascular diseases, especially the contribution 

of pro-inflammatory cytokines and growth factors, and a strong association with cigarette smoke. 

This study will test three hypotheses. The first is that smoke-related quinones directly suppress monocyte 

chemotactic protein-1 (MCP-1) in the RPE, what impairs macrophage recruitment and thus favors debris 

accumulation and drusen deposition. However, debris deposition will contribute to the CNV process by 

increasing recruitment of macrophages probably as a negative feedback mechanism. The second is that 

quinones and nicotine disrupt the balance between pigment epithelium-derived factor (PEDF) and vascular 

endothelial growth factor (VEGF) secretion by RPE cells, leading to CNV. The third hypothesis is the 

combination of nicotine with quinones increases VEGF production, extracellular matrix, proliferation, and 

migration of choroidal vascular endothelial cells, contributing to enhance CNV. The hypotheses will be 

tested in rodents and humans. The capacity of cigarette smoke to induce drusen deposition, geographic 

atrophy, and increase the severity of CNV will be evaluated on control and MCP-1 knockout mice. In 

human AMD, a case-control study of non-smoker and passive-smoker AMD patients will be performed to 

evaluate the association between blood levels of MCP-1 and quinones, and drusen deposition. Similarly, 

the association between, cotinine and quinones blood and urine levels and neovascular AMD will be 

assessed. The proposed application is innovative and exciting, especially the idea that SHS can induce sup- 

2 1 4 P A G E

pression/reduction of MCP-1 and long-lasting changes in the balance between PEDF and VEGF. If confirmed, 

analysis of blood MCP-1, PEDF, VEGF, quinones, nicotine, and cotinine, as well as analysis of 

urine quinones and cotinine, will serve as biomarkers for risk of progression of AMD. Importantly, results 

from this study will be directly applicable to other cardiovascular diseases associated with SHS. 

A ROLE FOR CATHEPSIN B IN SECOND HAND TOBACCO SMOKE-RELATED VASCULAR DISEASES 

Eunok Im, PhD; University of California, Los Angeles; YCSA 2006 

SHS increases the risk of ocular diseases. For instance, the vascularized form of age-related macular 

degeneration (AMD), one of the malicious vascular diseases that lead to blindness in the elderly, is tightly 

associated with SHS. Therefore, identifying regulators of vessel formation will aid in finding early diagnostic 

tools and ways to prevent disease progression. Dr. Im discovered that cathepsin B (a lysosomal cysteine 

protease) inhibits angiogenesis by suppressing pro-angiogenic factors (vascular endothelial cell growth factor) 

and generating anti-angiogenic factors (endostatin). These findings reveal cathepsin B as modulator of 

angiogenesis. The goal of Dr. Im’s project is to fully elucidate the mechanism by which cathepsin B modulates 

pro- and anti-angiogenic factors, and apply this information to the development of effective approaches 

to control SHS-induced angiogenesis. First, it will determine if cathepsin B inhibits angiogenesis. By 

comparison of ocular angiogenesis in cathepsin B null mice and control mice expansion of the understandings 

of how cathepsin B affects AMD will occur. Second, assessment of the combination of SHS and loss 

of cathepsin B will be conducted. Tests will be performed to show if SHS promotes angiogenesis within 

the eye and if the combination of SHS and loss of cathepsin B intensifies angiogenesis. Finally, Dr. Im and 

colleagues will investigate how cathepsin B regulates the stability of hypoxia-inducible factor 1 subunit a 

(HIF-1a), and the outcome of these studies will substantially advance the understanding of how HIF-1a is 

controlled. The molecular dissection of angiogenesis will enable better treatment and control of diseases 

arising from SHS. 


Rhee SH, Im E, Pothoulakis C. Toll-like receptor 5 engagement modulates tumor development and 

growth in a mouse xenograft model of human colon cancer. Gastroenterology 2008;135(2):518-528. 

VISION 


INFLAMMATION, SMOKING, AND BLINDNESS FROM OCULAR NEOVASCULARIZATION 

Scott W. Cousins, MD; Duke University; CIA 2004 

Neovascular acute macular degeneration (AMD), typified by choroidal neovascularization and invasion 

of abnormal new blood vessels into the retina, has pathogenic features similar to other cardiovascular diseases, 

particularly macrophage infiltration. AMD is caused by exposure to cigarette smoke. Dr. Cousins’ 

research tested the hypothesis that tobacco smoke-related nicotine acts upon circulating monocytes to 

induce partially activated monocytes in the blood. The monocytes are recruited to the eye in areas of 

choroidal neovascularization and lead to increasingly severe neovascularization via tumor necrosis factor 

alpha (TNF-alpha) production (a potent cytotoxic and angiogenic factor). The relationships between neovascular 

AMD, blood cotinine levels, and partial activation of blood monocytes were evaluated in a human 

case-control study of passive and active smokers versus non-smokers. If a relationship were confirmed, it 

would allow blood monocyte activation status to serve as a biomarker for risk of AMD progression. The 

results of this study are also applicable to other cardiovascular diseases caused by exposure to cigarette 

smoke. A similar study in mice evaluated the capacity of passive and active cigarette smoke (or nicotine) to 

affect bone marrow progenitor cells, causing them to differentiate into activated monocytes after smoking 

cessation. Results demonstrated that mice exposed to cigarette smoke suffered more severe pathology in 

the bone marrow stem cells than those who were not exposed. Dr. Cousins’ results carry an implication of 

particular interest to FAMRI, i.e., that flight attendants and others exposed to SHS may have long-term 

changes in bone marrow stem cells predisposing them to vascular diseases, including atherosclerosis and 

macular degeneration, long after cessation of the cigarette smoke exposure. 

P A G E 2 1 5

FAMRI DISTINGUISHED PROFESSORS 

FAMRI confers Distinguished Professor Awards to certain outstanding individuals who have contributed 

significantly to the study of the health effects of SHS exposure. There are two types of these 3-year awards: 

1) the Bland Lane International Distinguished Professor Award for researchers abroad; and 2) the Dr. 

William Cahan Distinguished Professor Award for researchers within the United States. 

THE BLAND LANE INTERNATIONAL DISTINGUISHED PROFESSOR AWARD: BATTLING 

TO PREVENT AND CURE DISEASES FROM TOBACCO SMOKE ON AN INTERNATIONAL 

LEVEL 

LARS EDVINSSON, MD PhD; 2005 

Dr. Edvinsson is a professor of medicine at Lund University in Sweden. He is the first recipient of the 

Bland Lane International Distinguished Professor award. Cigarette smoke and SHS are strong risk factors 

for cardiovascular disease and known to induce damage to the arterial wall yet the molecular mechanisms 

responsible are still not fully understood. Dr. Edvinsson and colleagues are investigating these mechanisms 

and found that lipid soluble cigarette smoke particles (DSP) up-regulate the expression of G-protein 

coupled receptor (GPCR) in arterial smooth muscle cells (SMC); e.g., endothelin type A (ETA) and B 

(ETB), and thromboxane A2 (TP) receptors. These receptors show enhanced contractility and 

proliferation of the smooth muscle cells, may strongly exacerbate the arterial wall damage by cigarette 

smoke and are associated with enhanced cardiovascular morbidity. In order to explore the molecular 

mechanisms, intracellular signalling induced by DSP was studied; DSP caused activation of extra cellularregulated 

protein kinase 1 and 2 (ERK1/2), p38, AKT, protein kinase C (PKC) and transcriptional factor 

Elk1, but no activation of c-Jun N-terminal kinase (JNK). These intracellular signalling events are linked to 

DSP-induced up-regulation of ETB, ETA and TP receptors as revealed by use of specific inhibitors. 

Blockade of ERK1/2, p38 and NF-kappa B activation attenuated the DSPinduced up-regulation of ETB 

receptor-mediated contraction and the receptor mRNA expression. The DSP-enhanced ETA receptormediated 

contraction was abolished by ERK1/2, PKC, Elk1 and NF-kappa B inhibitors. In addition, a 

general transcriptional inhibitor, actinomycin D, abolished the DSP-enhanced contraction of ETB and 

ETA receptors. In contrast, the upregulation of TP receptor occurred through a post-transcriptional 

mechanism; enhanced translation. Understanding the molecular mechanisms responsible for smoke 

induced GPCR receptor upregulation may provide new strategies for treatment of associated cardiovascular 

disease. 

THE DR. WILLIAM CAHAN DISTINGUISHED PROFESSORS: BATTLING TO PREVENT 

AND CURE DISEASES FROM TOBACCO SMOKE 

ALAN BLUM, MD; 2002 

Alan Blum is a Professor of Family Medicine and Director of the Center for the Study of Tobacco and 

Society at the University of Alabama, where he holds the Wallace Endowed Chair in Family Medicine. Dr. 

Blum has been documenting the fight for clean indoor air, with a specific focus on the leadership provided 

by flight attendants in the origins of non-smokers’ rights issues, and the propaganda and corporate 

conduct of the tobacco industry designed to thwart efforts by the health community to end the smoking 

pandemic. He has concentrated on several themes, including: 1) the significant historical role of flight 

attendants in the tobacco control movement; 2) the use of propaganda by the tobacco industry to thwart 

public health efforts; 3) the alliances cultivated by the tobacco industry, most notably with organized 

medicine; 4) health activism on tobacco since 1950; and 5) the challenges that remain in counteracting a 

resilient and dynamic tobacco industry. Dr. Blum has used his extensive historical records to create 

innovative and interesting smoking-related exhibitions for a number of museums. 


Blum A, Jacobi L. Philip Morris. In: Goodman J, ed. Tobacco: Scribner’s Turning Points in History Series. 

Farmington Hills, MI: Macmillan/Scribner, 2004. 

Blum A, Siegel M. Foundation award is an anti-smoking hypocrisy [commentary] The Tuscaloosa News. 

Blum A, Solberg E, Wolinsky H. Precious little progress in war on smoking (Commentary with focus on 

Illinois) Chicago Sun Times. 

Blum A, Solberg E, Wolinsky H. The Surgeon General’s report on smoking and health 40 years later: Still 

wandering in the desert. Lancet 2004;363:97-98. 

Blum A, Solberg E, Wolinsky H. Up in smoke: 40 years after Alabamian’s report, tobacco still ravaging 

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lives (Commentary with focus on Alabama) The Birmingham News. 

Blum A, Solberg E, Wolinsky H. Where there’s smoke, there’s money from big tobacco (Commentary 

with focus on California) Los Angeles Times. 

Blum A, Solberg E. The anti-smoking movement post 1950. In: Goodman J, ed. Tobacco: Scribner’s 

Turning Points in History Series. Farmington Hills, MI: Macmillan/Scribner, 2004. 

Blum A, Solberg E. The Tobacco Pandemic. In: Mengel MB, Holleman WL, Fields SA, eds. Fundamentals 

of Clinical Practice, 2nd Edition. New York: Kluwer Academic/Plenum Publishers, 2002:671-687. 

Blum A. Smoking aloft: An illustrated history. Tob Control 2004;13:i4-7. 

Blum A. Smoking and air travel. In: Goodman J, ed. Tobacco: Scribner’s Turning Points in History Series. 

Farmington Hills, MI: Macmillan/Scribner, 2004. 

Blum A. Up in Smoke: Tobacco and Flight Attendant Health [exhibition catalogue]. San Francisco Airport 

Museums, 2004. 

Blum A. Wholly smoke. American association of editorial cartoonists notebook 2004;46:10-12. 

DAVID M. BURNS, MD; 2002 

David M. Burns is Professor Emeritus at the University of California, San Diego Medical School. Dr. 

Burns’ expertise is in pulmonary and critical care medicine. He has written extensively on the study of SHS 

in the work place. He has contributed to a number of US Surgeon General’s Report; in particular, Dr. 

Burns was senior editor for the landmark 1979 Surgeon General’s Report written by Julius B. Richmond, 

MD, who was the first Chair of FAMRI’s Medical Advisory Board. This was the first report to describe the 

health dangers of SHS exposure. Dr. Burns has studied how this exposure varies by location and correlated 

it with individual state initiatives and job category. Dr. Burns is committed to providing a strong scientific 

foundation for smoke-free air. He has used a vast amount of available data to establish disease risk models 

for estimating lung cancer and all cause mortality from smoking behaviors. The models should be able to 

predict future occurrence of lung cancer and define the cost/benefit relationships of smoking cessation 

efforts and lung cancer screening programs. 

RONALD M. DAVIS, MD, 2002 (1956-2008) 

Ronald M. Davis was the Director, Center for Health Promotion and Disease Prevention at the Henry 

Ford Health System, Michigan and President of the American Medical Association. FAMRI sadly reports 

that Dr. Davis passed away on November 10, 2008. Before his untimely death, Dr. Davis and his coinvestigators 

had completed a national survey of airport smoking restrictions, which was published in 

Morbidity and Mortality Weekly Report, a publication of the US Centers for Disease Control and 

Prevention. He conducted a case-control study to confirm the causal nexus between SHS exposure and 

chronic sinusitis, chronic non-allergic rhinitis, and chronic allergic rhinitis. Dr. Davis and his colleagues 

worked with groups that support local and statewide initiatives to reduce exposure to SHS. They also 

worked with leaders at Henry Ford Health System to establish smoke-free campuses for the system’s 

hospitals and ambulatory medical centers. In addition, he studied the effects of second hand tobacco 

smoke exosure on pets. The 2009 Luther L. Terry Award for Outstanding Individual Leadership was 

bestowed posthumously. He is sorely missed. 

STANTON A. GLANTZ, PhD; 2002 

Stanton A. Glantz is a Professor of Medicine at University of California San Francisco. Dr. Glantz’s 

articles relating to the scientific impact of SHS exposure have appeared in the American Journal of Public 

Health, Journal of the American Medical Association, Tobacco Control, and others. He has coauthored two 

major reviews that establish SHS exposure as a cause of heart disease. Dr. Glantz uses his award to fund 

several projects related to SHS, including: 1) biological effects on the heart, blood, and vascular system; 

and 2) activities the tobacco industry used to counter the effects of smoking on growing public awareness 

of dangers caused by SHS. Dr. Glantz’s research revealed that being married to a smoker or working in a 

smoke-filled environment is associated with about a 30% increased risk of a heart attack compared to those 

who are non-exposed. For comparison the effect of active smoking is a 100% to 200% increase in risk. A 

comparison of the biological effects of smoke on factors that affect cardiovascular function have 

consistently revealed that the effects of SHS exposure are approximately 80% that of active smoking, with 

effects appearing at low doses. Dr. Glantz also used tobacco industry documents released as a result of 

litigation to understand the tobacco industry’s secret efforts to undermine the science that establishes the 

link between SHS exposure with disease. This body of information underscores the value of public 

education regarding the dangers of SHS, not only to help people avoid SHS exposure, but also because it 

P A G E 2 1 7

is a strong motivator for smoking cessation. Dr. Glantz received the 2009 Luther L. Terry Award for 

Distinguished Career. 


Barnoya J, Glantz S. The tobacco industry’s worldwide ETS consultants project: European and Asian 

components. Eur J Public Health 2005. 

Barnoya J, Glantz SA. Cardiovascular effects of second hand smoke nearly as large as smoking. Circulation 

2005;111:2684-2698. 

Glantz SA. Morbidity and Mortality Weekly Report, December 24, 2004, a publication of the US Centers 

for Disease Control and Prevention. 

Ling PM, Glantz SA. Tobacco industry consumer research on socially acceptable cigarettes. Tob Control 

2005;14:e3. 

Mandel LL, Glantz SA. Hedging their bets: tobacco and gambling industries work against smoke-free 

policies. Tob Control 2004;13:268-276. 

Neilsen K, Glantz SA. A tobacco industry study of airline cabin air quality: dropping inconvenient findings 

[review]. Tob Control 2004;13:i20-i29. 

Zhu B, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, Cooke JP. Second hand smoke 

stimulates tumor angiogenesis and growth. Cancer Cell 2003;4:191-196. 

STEVEN S. HECHT, PhD; 2002 

Stephen S. Hecht is Professor and Wallin Chair in Cancer Prevention at the School of Pharmacy at the 

University of Minnesota. He has focused on improved methods for quantifying 4-(methylnitrosamino)-1- 

(3-pyridyl)-1-butanol (NNAL) and its glucuronides in human urine; markers that are used to investigate 

human uptake of carcinogens from SHS. NNAL and its glucuronides (collectively termed NNAL) are 

metabolites of the tobacco-specific lung carcinogen 4-(Methylnitrosamino)-1-(3- pyridyl)-1-butanone 

(NNK), which is a potent lung carcinogen. Total NNAL is a highly effective biomarker for SHS exposure. 

Dr. Hecht developed a method for the analysis of total NNAL in urine. This assay is highly sensitive and 

rapid and can be used in large clinical and epidemiologic studies. The method was used in a study on nonsmoking 

hospitality workers who were exposed to SHS in the workplace. The study indicated that working 

day exposure was greater than non-working days and has important health effects on non-smoking 

employees. Dr. Hecht has also examined the impact of clean indoor air initiatives in Washington and 

Oregon and demonstrated that non-smoking workers exposed to workplace SHS have elevated levels of 

NNK, nicotine, and cotinine in their bodies, associated with hours of workplace exposure. This is further 

evidence that all workers should be protected from workplace exposure to SHS, and underscores the 

necessity for smoke-free bars and restaurants. 


Carmella SG, Han S, Fristad A, Yang Y, Hecht SS. Analysis of total 4-(methylnitrosamino)-1-(3-pyridyl)-1- 

butanol (NNAL) in human urine. Cancer Epidemiol Biomarkers Prev 2003;12:1257-1261. 

Carmella SG, Le K, Hecht SS. Improved method for determination of 1-hydroxypyrene in human urine. 


Hecht SS. Carcinogen derived biomarkers: applications in studies of human exposure to secondhand 

tobacco smoke. Tob Control 2003;13:i48-i56. 

Hecht SS. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 

2003;3:733-744. 

Tulanay O, Hecht SS, Carmella SG, Zhang Y, Lemmonds C, Murphy S, Hatsukami D. Urinary 

metabolites of a tobacco-specific lung carcinogen in non-smoking hospitality workers. Cancer Epidemiol 


JAMES REPACE, MSc; 2002 

James Repace, a biophysicist, is a visiting Assistant Clinical Professor at Tufts University School of 

Medicine and a consultant on SHS issues in the hospitality industry. Mr. Repace explored a remarkably 

diverse set of projects on SHS and exposure to SHS, ranging from exposure and doses of flight attendants 

in the smoky skies, of workers and patrons in smoky restaurants, bars, and hotels, to levels of smoke in 

outdoor cafes, on cruise ships at sea, and on college campuses. In addition, he investigated the precision 

and accuracy of multiple types of monitors for SHS measurements. He has shown that it would take 

tornado-like levels of ventilation or air cleaning to control tobacco smoke pollution in hospitality venues to 

2 1 8 P A G E

within acceptable levels of lung cancer and heart disease mortality risk, as defined by federal guidelines for 

minimum risk from hazardous air pollution. He has demonstrated a set of physical and pharmacokinetic 

equations for SHS that make it possible to inter-correlate atmospheric markers such as respirable particles, 

nicotine, and carbon monoxide, with each other and with biomarkers such as hair nicotine, and cotinine 

from serum, saliva, or urine. In collaboration with others he has used this methodology to estimate levels 

of fine particle air pollution in bars from the urine cotinine of patrons and compared them to the federal 

air quality index for outdoor air pollution alerts. This exposure analysis methodology is available to 

students of public, occupational, and environmental health via a key chapter in the CRC Press textbook on 

exposure analysis. 


Hedley AJ, McGhee SM, Repace JL, et al. Analysis of dose, exposure, and risk for Hong Kong catering 

workers exposed to secondhand smoke at work only presented at the joint 12th Conference of the 

International Society of Exposure Analysis and the 14th Conference of the International Society for 

Environmental Epidemiology. Vancouver, Canada, Aug 11-15, 2002. 

Hedley AJ, McGhee SM, Repace JL, Wong L-C, Yu YSM, Wong T-W, Lam T-H. Risks for heart disease 

and lung cancer from passive smoking by workers in the catering industry. Toxicol Sci 2006;90:539-548. 

Mulcahy M, Evans DS, Hammond SK, Repace JL, Byrne M. Secondhand smoke exposure and risk 

following the Irish smoking ban: an assessment of salivary cotinine concentrations in hotel workers and 

air nicotine levels in bars. Tob Control 2005;14:384-388. 

Mulcahy M, Repace JL. Passive Smoking Exposure and Risk for Irish Bar Staff. Proceedings of the 9 th 

International Conference on Indoor Air Quality and Climate 2002;Vol II:144-149. 

Ott WR, Repace JL. Modeling and measuring indoor air pollution from multiple cigarettes smoked in 

residential settings [Poster] International Society for Exposure Analysis. Stresa, Italy, 2003. 

Repace JL, Al-Delaimy WK, Bernert JT. Correlating Atmospheric and Biological Markers in Studies of 

Secondhand Tobacco Smoke Exposure and Dose in Children and Adults. J Occup Environ Med 2006; 

48:181-194. 

Repace JL, Ott WR, Klepeis NE, Wallace LA. Predicting environmental tobacco smoke concentrations in 

California homes Presented at the 10th Annual Conference of the International Society of Exposure 

Analysis (Session: Environmental tobacco smoke: determining concentrations & assessing exposures). 

Asilomar, Monterey, CA, Oct 24-27, 2000:5E-04p. 

Repace JL. Controlling Tobacco Smoke Pollution. Technical Feature, ASHRAE IAQ Applications 

2005;6:11-15. 

Repace JL. Flying the Smoky Skies: Secondhand Smoke Exposure of Flight Attendants. Tob Control 

2004;13:i8-i19. 




NANCY RIGOTTI, MD; 2002 

Nancy A. Rigotti is a Professor of Medicine, Harvard Medical School, and Director, Tobacco Research 

and Treatment Center at Massachusetts General Hospital. Dr. Rigotti conducted a study to advance 

knowledge about the extent and impact of strategies to reduce SHS exposure and discourage tobacco use 

among young adults in US colleges. Dr. Rigotti used retrospective data and showed that college student 

tobacco use has declined since its peak in 1997-1999. These analyses showed strong student support for 

the full spectrum of tobacco control programs on college campuses, including the institution of smoke-free 

housing policies that have been recommended by the American College Health Association. Dr. Rigotti 

created a tobacco control research training program at Massachusetts General Hospital’s Tobacco Research 

and Treatment Center. Dr. Rigotti also developed interventions for pediatricians to use while addressing 

parents about their children’s exposure to SHS and conducted longitudinal analyses that measure the 

impact of household smoking education on adolescents’ exposure to SHS and rate of smoking initiation. 


Albers A, Siegel MB, Cheng DM, Rigotti NA, Biener L. Effect of local restaurant and bar smoking 

regulations on secondhand smoke exposure among Massachusetts adults. Am J Public Health 

2004;94:1959-1964. 

Albers AB, Siegel M, Cheng DM, Biener L, Rigotti NA. Relation between local restaurant smoking 

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egulations and attitudes towards the prevalence and social acceptability of smoking: a study of youths 

and adults who eat out predominantly at restaurants in their town. Tob Contr 2004;13:347-355. 

Halperin A, Rigotti NA. U.S. public universities’ compliance with recommended tobacco control policies. 

J Am Coll Health 2003;51:181-188. 

Hazlehurst B, Sittig DF, Stevens VJ, Smith KS, Hollis JF, Vogt TM, Winickoff JP, Glasgow R, Palen TE, 

Rigotti NA. Natural language processing in the electronic medical record: assessing clinician adherence 

to tobacco treatment guidelines. AM J Prev Med 2005;29:434-439. 

Moran S, Thorndike AN, Armstrong K, Rigotti NA. Physicians’ missed opportunities to address tobacco 

use during prenatal care. Nicotine Tob Res 2003;5:363-368. 

Moran SE, Wechsler H, Rigotti NA. Social smoking among U.S. college students. Pediatrics 

2004;114:1028-1034. 

Park ER, Wolfe TJ, Gokhale M, Winickoff JP, Rigotti NA. Preparedness to provide preventive counseling: 

reports of graduating primary care residents at academic health centers. J Gen Intern Med 2005;20:386- 

391. 

Rigotti NA, Moran SE, Wechsler H. U.S. college students’ exposure to tobacco promotions at bars, clubs, 

and campus social events: prevalence and relationship to tobacco use. Am J Public Health 2005;95:138- 

144. 

Rigotti NA, Regan S, Moran SE, Wechsler H. Student support for tobacco control policies recommended 

for U.S. colleges: a national survey. Tob Control 2003;12:251-256. 

Siegel M, Albers AB, Cheng DM, Biener L, Rigotti NA. Effect of local restaurant regulations on 

progression to established smoking among youths. Tob Control 2005;12:300-306. 

Siegel M, Albers AB, Cheng DM, Biener L, Rigotti NA. Effect of local restaurant smoking regulations on 

environmental tobacco smoke exposure among youths. Am J Public Health 2004;94:321-325. 



Siegel M, Albers AB, Cheng DM, Rigotti NA, Biener L. Effects of restaurant and bar smoking regulations 

on exposure to environmental tobacco smoke among Massachusetts adults. Am J Public Health 

2004;94:1959-1964. 

Siegel MB, Albers A, Cheng DM, Rigotti NA. The effect of local restaurant smoking regulations on 

secondhand smoke exposure among youth. Am J Public Health 2004;94:321-325. 

Skeer M, Cheng DM, Rigotti NA, Siegel M. Secondhand smoke exposure in the workplace. Am J Prev 

Med 2005;28:331-337. 

Thomson CC, Gokhale M, Siegel M, Biener L, Rigotti NA. State-wide evaluation of youth access 

ordinances in practice: effects of the implementation of community-level regulations in Massachusetts. J 

Public Health Manag Pract 2004;10:481-489. 

Thomson CC, Siegel M, Winickoff J, Biener L, Rigotti NA. Household smoking bans and adolescents’ 


Winickoff JP, Buckley VJ, Palfrey JS, Perrin JM, Rigotti NA. Intervention with parental smokers in an 

outpatient pediatric clinic using counseling and nicotine replacement. Pediatrics 2003;112:1127-1133. 

Winickoff JP, Hillis VJ, Palfrey JS, Perrin JM, Rigotti NA. A smoking cessation intervention for parents of 

children hospitalized with respiratory illness: the Stop Tobacco Outreach Program. Pediatrics 

2003;111:140-145. 

Winickoff JP, McMillen RC, Bronwen CC, Klein JD, Rigotti NA, Tanski SE, Weitzman M. Addressing 

parental smoking in pediatrics and family practice: a national survey of parents. Pediatrics 

2003;112:1146-1151. 

Winickoff JP, Tanski SE, McMillen RC, Klein JD, Rigotti NA, Weitzman M. Child healthcare clinicians’ 

use of medications to help parents quit smoking: a national parent survey. Pediatrics 2005;115:1013- 

1017. 

MICHAEL B. SIEGEL, MD, MPH; 2002 

Michael B. Siegel is Professor and Associate Chairman, Social and Behavioral Sciences, at Boston 

University School of Public Health. His research has addressed the health effects of SHS exposure on 

individuals to assess the impact of local clean indoor air initiatives in Massachusetts. He focused on three 

major outcomes: 1) exposure to SHS among adults and youths in bars and restaurants; 2) smoking-related 

attitudes and social norms among youths and adults; and 3) changes in smoking behaviors among adults 

and youths. He used a baseline telephone survey of nearly 4,000 youths and more than 6,000 adults in 

Massachusetts, with a two-year follow-up survey. In addition, the local restaurant and bar smoking 

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egulations in each of the 351 towns in Massachusetts have been analyzed and classified. These two 

databases have been merged. Findings demonstrate that smoke-free restaurant regulations can be effective 

in reducing exposure of the public to SHS, although weak regulations are not adequate to protect the 

public. Dr. Siegel’s research demonstrates that workplace smoking initiatives, and local smoke-free bar and 

restaurant standards have a substantial impact on reducing SHS exposure. In addition, these strategies 

appear to change social norms regarding smoking, particularly the perceived prevalence of smoking in the 

community and the perceived level of social acceptability of smoking. As a result, workers are protected 

from SHS exposure, and the effect on preventing initiation of youth smoking is significant. 


Albers A, Siegel MB, Cheng DM, Rigotti NA, Biener L. Effect of local restaurant and bar smoking 

regulations on secondhand smoke exposure among Massachusetts adults. Am J Public Health 

2004;94:1959- 1964. 

Albers AB, Siegel M, Cheng DM, Biener L, Rigotti NA. Relation between local restaurant smoking 

regulations and attitudes towards the prevalence and social acceptability of smoking: a study of youths 

and adults who eat out predominantly at restaurants in their town. Tob Control 2004;13:347-355. 

Blum A, Siegel M. Foundation award is an anti-smoking hypocrisy [commentary] The Tuscaloosa News. 



Siegel M, Albers AB, Cheng DM, Biener L, Rigotti NA. Effect of local restaurant smoking regulations on 

environmental tobacco smoke exposure among youths. Am J Public Health 2004;94:321-325. 



Siegel M, Albers AB, Cheng DM, Rigotti NA, Biener L. Effects of restaurant and bar smoking regulations 

on exposure to environmental tobacco smoke among Massachusetts adults. Am J Public Health 

2004;94:1959-1964. 

Siegel M, Barbeau EM, Osinubi OY. The impact of tobacco use and secondhand smoke on hospitality 

workers. Clin Occup Environ Med 2006;5:31-42. 

Siegel M, Skeer M. Exposure to secondhand smoke and excess lung cancer mortality risk among workers 

in the “5 B’s”: bars, bowling alleys, billiard halls, betting establishments, and bingo parlours. Tob 

Control 2003;12:333-338. 

Siegel MB, Albers A, Cheng DM, Rigotti NA. The effect of local restaurant smoking regulations on 

secondhand smoke exposure among youth. Am J Public Health 2004;94:321-325. 

Skeer M, Cheng DM, Rigotti NA, Siegel M. Secondhand smoke exposure in the workplace. Am J Prev 

Med 2005;28:331-337. 

Skeer M, George S, Cheng DM, Hamilton WL, Siegel M. Town-level characteristics and smoking policy 

adoption in Massachusetts: are local restaurant smoking regulations fostering disparities in health 

protection? Am J Public Health 2004;94:286-292. 

Skeer M, George S, Land M, Cheng DM, Siegel M. Smoking in Boston bars before and after a 100% 

smoke-free regulation: an assessment of early compliance. J Public Health Manag Pract 2004;10:501- 

507. 

Skeer M, Siegel M. The descriptive epidemiology of local restaurant smoking regulations in Massachusetts: 

an analysis of the protection of restaurant customers and workers. Tob Control 2003;12:221-226. 

Thomson CC, Gokhale M, Siegel M, Biener L, Rigotti NA. State-wide evaluation of youth access 

ordinances in practice: effects of the implementation of community-level regulations in Massachusetts. J 

Public Health Manag Pract 2004;10:481-489. 

Thomson CC, Siegel M, Winickoff J, Biener L, Rigotti NA. Household smoking bans and adolescents’ 


ALLAN M. BRANDT, PhD; 2003 

Allan M. Brandt is Dean of Harvard Graduate School of Arts and Sciences. He has served as an advisor 

and expert for the reduction of harms associated with smoking, and his research and writings on tobacco 

are part of a larger work on the history of epidemic disease and public health. Dr. Brandt’s FAMRI 

research resulted in his history of the 20th Century pandemic of public health entitled The Cigarette 

Century. The book brings to fruition a decade of research on the social and cultural history of cigarette 

smoking and diseases in the twentieth century. His study traces the dramatic rise of cigarette consumption, 

new scientific approaches that expose the serious harm caused by smoking, and the half-century of denials 

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y the tobacco industry of the harmfulness of their product. Included are the approaches to regulating 

tobacco use and the history of litigation against the tobacco companies. The study traces the 

transformation in the success of the litigation that accounts for the shifts in legal and public perception of 

the harms of smoking and the corporate responsibility for the diseases generated by cigarette smoke. 


Brandt A. Difference and Diffusion: Cross-Cultural Perspectives on the Rise of Anti-Tobacco Policies. In: 

Feldman E, Bayer R, eds. Unfiltered: Conflicts over Tobacco Policy and Health. Cambridge: Harvard 

University Press, 2004. 

Brandt A. From Analysis to Advocacy: Crossing Boundaries as a Historian of Health Policy. In: Huisman 

F, Warner JH, eds. Locating Medical History: the Stories and Their Meanings. Baltimore: Johns Hopkins 

University Press, 2004. 

Brandt A. From Nicotine to Nicotrol: Addiction, Cigarettes and American Culture. In: Tracy SW, Acker 

CJ, eds. Altering American Consciousness: Essays on the History of Alcohol and Drug Use in the 

United States. Amherst: University of Massachusetts Press, 2004. 

Brandt A. The Culture of Consumer Confidence: Engineering Smoking in the Twentieth Century Smoke: 

A Global History of Smoking. London: Reaktion Books, 2005. 

Gardner MN, Brandt A. The doctors’ choice Is America’s choice: the physician in US cigarette 

advertisements,1930-1953. Am J Public Health 2006;96:222-232. 

RICHARD D. HURT, MD; 2003 

Richard D. Hurt is a Professor of Medicine and Director, Nicotine Dependence Center at the Mayo 

Clinic in Rochester, Minnesota. He has been active in initiatives throughout Minnesota for smoke-free 

environments. Dr. Hurt’s work involved health assessment of flight attendants (FAs) previously exposed to 

SHS, and he has assessed candidate genes to determine factors for predisposition towards development of 

tobacco-caused diseases. FAs who were exposed to SHS and confined to the cabin space of airlines suffer a 

range of tobacco-related adverse health effects. Exposed FAs that stopped working due to health problems 

reported a higher incidence of sinusitis, pneumonia, middle ear infections, hay fever, and allergies when 

compared to FAs who did not stop work due to health problems. Exposure to SHS in airline cabins clearly 

contributed to these health problems. 

THOMAS L. PETTY, MD; 2003 

Thomas L. Petty is founding chairman of the National Lung Health Education Program (NLHEP) and 

former head of the Department of Pulmonary Medicine at the University of Colorado School of Medicine. 

Dr. Petty is often referred to as the “father of pulmonary medicine”. He is interested in promoting 

knowledge about new technologies and approaches to the early diagnosis and treatment of patients with 

lung cancer and chronic obstructive pulmonary disease (COPD). He believes that patients with 

unsuspected lung cancer could be detected in a primary care outpatient practice by use of spirometry, 

which is an effective means of identification and assessment of progress. Dr. Petty is editor and Chief of 

Lung Cancer Frontiers, a newsletter dedicated to advancing knowledge about lung cancer. Its emphasis is 

on early identification and treatment. 

JONATHAN SAMET, MD; 2003 

Jonathan Samet was Chairman of the Department of Epidemiology at the Johns Hopkins School of 

Public Health, and served as Senior Scientific Editor of The Health Consequences of Involuntary Exposure to 

Tobacco Smoke: A Report of the Surgeon General 2006, the first Surgeon General’s report to conclude that 

exposure of non-smokers to tobacco smoke causes disease. He has recently moved to the Keck School of 

Medicine at the University of Southern California. Dr. Samet’s FAMRI supported research created a 

common protocol that was used in order to generate a global profile of SHS exposure among women and 

children worldwide to estimate the associated their risks. The data is useful locally and will support more 

progressive smoke-free strategies and programs aimed at reducing SHS exposure. The study characterized 

exposure to SHS using questionnaires, passive nicotine monitors, and analysis of hair samples for the 

presence and level of nicotine. Dr. Samet completed a study in 2007 that was carried out in 30 countries in 

Latin America, Europe, Asia, and the Western Pacific. In each country, 40 homes were selected, 75% 

having at least one male smoker and a child under the age of ten, and 25% with no smokers in the home. 

The specific sample strategy was based on convenience samples and existing studies. Hair samples were 

taken from the adult female caregiver in the home and from one child ten years of age or younger. The 

2 2 2 P A G E

highest levels of exposure to children occur in Eastern Europe and the lowest levels of exposure occur in 

rural areas of Southeast Asia. 

JOHN F. BANZHAF III, JD; 2004 

John F. Banzhaf is a Professor at George Washington University Law School. He initiated legal action 

that required the OSHA to propose a rule banning smoking in virtually all work places. Professor Banzhaf 

developed new legal approaches to protecting non-smokers from exposure to SHS, and educating the antismoking 

community about these approaches. These goals were accomplished by sponsoring the FAMRIfunded 

legal research and writing competition among law students to develop and research new ideas or 

approaches towards protecting non-smokers, and by holding an annual national conference to evaluate, 

improve and promote these and other new ideas related to protecting the public's health from exposure to 

SHS. 

GREGORY N. CONNOLLY, DMD, MPH; 2004 

Gregory Connolly became a Professor at the Harvard School of Public Health after an extensive career 

as Director of the Tobacco Control Program for the Massachusetts Department of Health. Dr. Connolly 

has been author and co-author of articles in publications detailing the effects of state, national, and 

international clean indoor air initiatives on the economy and health of hospitality workers. Dr. Connolly’s 

research examined the effect on air quality of the 2004 Massachusetts initiative banning smoking in all 

workplaces, including bars and restaurants, as well as the economic effect on the state’s bar and restaurant 

business, tourism, and lottery sales, and has replicated this research in other states that have adopted 

smoke-free practices. Additionally, he has led research regarding children’s exposure to SHS in automobiles 

and is working with colleagues at Harvard University to develop improved toxicological measures of SHS 

exposure among children. Another research study by Dr. Connolly in 2006 examined and compared 

indoor air quality in a global sample of smoke-free and smoking-permitted Irish pubs. The results of the 

study indicated that the level of air pollution inside Irish pubs located in smoke-free cities was 93% lower 

than the level found in pubs in smoke permitted cities. Dr. Connolly has conducted extensive training of 

public health officials, students, and scientists regarding SHS exposure including the use of the Tricor 

Systems, Incorporated (TSI) SidePak Aerosol Monitor for measuring SHS exposure in US cities and 

internationally. He has worked with scientists and public health students to measure and report the health 

risks of SHS exposure internationally, as well as a number of US states. The training and research was 

performed in collaboration with another Dr. William Cahan Professor, Michael Cummings, PhD. Dr. 

Connolly conducted SHS exposure training for Eastern European nations in August 2005 and similar 

training in Cyprus in February 2006 for Middle Eastern nations. 





study. Presented at the National Conference on Tobacco or Health. Chicago, IL, May 4-6, 2005. 








MARGARET R. SPITZ, MD, MPH; 2004 

Margaret Spitz is Chair of the Department of Epidemiology at the University of Texas M. D. Anderson 

Cancer Center. Dr. Spitz has conducted a strong and innovative molecular and genetic epidemiology 

program that combines laboratory studies with clinical research and is highly interactive and 

multidisciplinary. Her overall research goal was to further the understanding of the molecular mechanisms 

underlying individual differences in susceptibility to cancer caused by exposure to tobacco smoke and to 

extend the findings from the individual projects in FAMRI’s Center of Excellence at the Weizmann 

Institute. Dr. Spitz developed and tested a panel of in vitro functional assays for determining susceptibility 

to lung cancer, including the comet assay, telomere length measurements, cell cycle control, and DNA 

P A G E 2 2 3

epair capacity assays. Her collaboration with the FAMRI Center at the Weizmann Institute combined a 

basic science foundation with the rigor of high throughput assay development and validation to augment 

the molecular epidemiology undertakings. Rapid screening of individuals for risk using minimally invasive 

procedures will identify high-risk subgroups. 


El-Zein RA, Schabath MB, Etzel CJ, Lopez MS, Franklin JD, Spitz MR. Cytokinesis-blocked 

micronucleus assay as a novel biomarker for lung cancer risk. Cancer Res 2006;66:6449-6456. 

El-Zein R, Schabath MB, Etzel CJ, Lopez MS, Franklin JD, Spitz MR. The cytokinesis-blocked 

micronucleus assay as a novel biomarker for lung cancer risk. Abstract presented at American Association 

for Cancer Research, 97th Annual Meeting. Washington, DC 2006. 

Etzel CJ, Liu M, Spitz MR. Lung cancer risk factors in a minority population. Abstract presented at 

American Association for Cancer Research, 97th Annual Meeting. Washington, DC, 2006. 

Etzel CJ, Lu M, Merriman K, Liu M, Vaporacyan A, Spitz MR. An epidemiologic study of early onset lung 

cancer. Lung Cancer 2006;52:129-134. 

Gorlov IP, Amos C, Spitz M. Identification of a novel lung cancer candidate susceptibility gene using a 

familial aggregation approach. Abstract presented at American Association for Cancer Research, 97 th 

Annual Meeting. Washington, DC, 2006. 

Gorlova O, Zhang Y, Amos C, Spitz M. Aggregation of cancer among relatives of never smoking lung 

cancer patients Presented at the American Association for Cancer Research. Washington, DC, 2005. 

Gorlova OY, Zhang Y, Schabath MB, Lei L, Zhang Q, Amos CI, Spitz MR. Never smokers and lung 

cancer risk: A case-control analysis of epidemiological and environmental factors. Int J Cancer 

2006;118:1798-1804. 

Gu J, Gong Y, Huang M, Lu C, Spitz MR, Wu X. Polymorphisms of STK15 (Aurora-A) gene and lung 

cancer risk in Caucasians. Carcinogenesis 2007;28:350-355. 

Gu J, Spitz MR, Roth JA, Wu X. Aberrant promoter methylation profile associated with survival in patients 

with non-small cell lung cancer. Abstract presented at American Association for Cancer Research, 97 th 

Annual Meeting Washington, DC, 2006. 

Li G, Zhai X, Zhang Z, Chamberlain RM, Spitz MR, Wei Q. MDM2 gene promoter polymorphisms and 

risk of lung cancer: a case-control analysis. Carcinogenesis 2006;27:2028-2033. 

Lin X, Gu J, Lu C, Spitz MR, Wu X. Expression of telomere-associated proteins as prognostic markers for 

overall survival in patients with non-small cell lung cancer. Abstract presented at American Association 

for Cancer Research, 97th Annual Meeting Washington, DC, 2006. 

Lin X, Gu J, Lu C, Spitz MR, Wu X. Expression of telomere-associated genes as prognostic markers for 

overall survival in patients with non-small cell lung cancer. Clin Cancer Res 2006;12:5720-5725. 

Mahabir S, Spitz MR, Barrera SL, Beaver SH, Etzel C, Forman MR. Dietary zinc, copper and selenium 

and risk of lung cancer. Int J Cancer 2006;120:1108-1115. 

Schabath MB, Hernandez LM, Wu X, Pillow PC, Spitz MR. Dietary phytoestrogens and lung cancer risk. 

JAMA 2005;294:1493-1504. 

Schabath MB, Wei Q, Xifeng Wu X, Spitz MR. Prior respiratory disease, DNA repair capacity, and 

inflammation- related genotypes modify lung cancer risk. Abstract presented at American Association for 

Cancer Research, 97th Annual Meeting Washington, DC, 2006. 

Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LH, Spitz MR, Wei Q. Polymorphisms of methionine 

synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. 

Pharmacogenet and Genomics 2005;15:547-555. 

Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LH, Spitz MR, Wei Q. Sex differences in risk of lung cancer 

associated with methylene-tetrahydrofolate reductase polymorphisms. Cancer Epidemiol Biomarkers Prev 

2005;14:1477-1484. 

Wang L, Shi Q, Guo Z, Qiao Y, Spitz MR, Wei Q. A novel assay to measure the capacity to repair N7- 

guanine site-specific DNA damage. Abstract presented at American Association for Cancer Research, 

97 th Annual Meeting Washington, DC, 2006. 

Wu X, Huang M, Gu J, Amos CI, Shao L, Zhang Q, Spitz MR. DNA repair and cell cycle control 

pathways in lung cancer predisposition. Abstract presented at American Association for Cancer Research, 


Wu X, Lin J, Etzel CJ, Schabath MB, Gorlova OY, Zhang Q, Dong Q, Amos CI, Spitz MR. Interplay 

between mutagen sensitivity and epidemiological factors in modulating lung cancer risk. Abstract 

presented at American Association for Cancer Research, 97th Annual Meeting Washington, DC, 2006. 

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Yang H, Spitz MR, Liu J, Gu J, Lu C, Stewart DJ, Wu X. ATM haplotype-tagging SNPs predict non-small 

cell lung cancer risk in Caucasians. Abstract presented at American Association for Cancer Research, 


K. MICHAEL CUMMINGS, PhD; 2005 

Michael Cummings is Chairman of the Department of Health Behavior at Roswell Park Cancer Institute 

in Buffalo, New York. Dr. Cummings is widely recognized as one of the leading public health scholars in 

the field of tobacco control, and is a past member of the FAMRI Medical Advisory Board. He currently 

directs the operations of the New York State Smoker’s Quit line and directs the operations of an 

international research center devoted to evaluating the impact of approaches to tobacco control. He has 

published over 230 peer reviewed scientific papers most of which address the topic of tobacco and health. 

Dr. Cummings’s FAMRI project has two primary objectives: 1) to raise awareness of the benefits of 

smoke-free initiatives by carefully documenting the levels of indoor tobacco smoke pollution in common 

public venues in countries with and without means that protect the public from exposure to tobacco 

smoke pollution; and 2) to carefully document the history of scientific research on tobacco and health, 

especially as it relates to information about the heath risks of SHS exposure. This project has facilitated air 

monitoring studies in over 30 countries around the globe using a standardized data collection protocol. 

Dr. Cummings received the 2009 Luther L. Terry Award for Outstanding Research Contribution. 


Bauer JE, Hyland A, Li Q, Steger C, Cummings KM. A longitudinal assessment of the impact of 

smokefree worksite policies on tobacco use. Am J Public Health 2005;95:1024-1029. 

Borland R, Yong HH, Cummings KM, Hyland A, Anderson S, Fong GT. Determinants and consequences 

of smoke-free homes: findings from the International Tobacco Control (ITC) Four Country Survey. Tob 

Control 2006;15 Suppl 3:iii42-50. 

Borland R, Yong HH, Siahpush M, Hyland A, Campbell S, Hastings G, Cummings KM, Fong GT. 

Support for and reported compliance with smoke-free restaurants and bars by smokers in four countries: 

findings from the International Tobacco Control (ITC) Four Country Survey. Tob Control 2006;15 

Suppl 3:iii34-41. 



Cummings, KM. Exposure in western New York, 2003. Presented at the 10th Annual Society for Research 

on Nicotine and Tobacco Meeting. Scottsdale, AZ, Feb 18-21, 2004. 

Fong G, Hyland A, Hammond D, Borland R, Hastings G, Cummings KM, McNeil A, Anderson S. 

Changes in knowledge, attitudes, and behavior following the Irish Smoke-Free Law: findings from the 

ITC-Ireland/U.K. survey. Presented at the Society for Research on Nicotine and Tobacco. Prague, 

Czech Republic, Mar 20-23, 2005. 

Higbee C, Bauer JE, Cummings KM, Wieczorek W, Alford T, Hyland A. Avoidance of smoky 

establishments: findings from Erie and Niagara Counties in New York. J Public Health Manag Pract 

2004;10:508- 510. 

Hyland A, Higbee C, Bauer J, Giovino G, Wieczorek W, Alford T, Cummings KM. Non-smokers avoid 

smoky establishments: findings from Erie/Niagara Counties, NY. Presented at the National Conference 

on Tobacco or Health. Boston, Mass, Dec 10-12, 2003. 

Hyland A, Puli V, Cummings M, Sciandra R. New York’s smoke free regulations: effects on employment 

and sales in the hospitality industry. Cornell Hotel and Restaurant Administration Quarterly 2003;44:9- 

16. 

Hyland A, Travers M, Cummings KM. One Year After the New York State Clean Indoor Air Act: What’s 

Changed and What Hasn’t. Report prepared for Erie/Niagara Tobacco-Free Coalition, 2004. 










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RICHARD A. DAYNARD, JD, PhD; 2005 

Richard A. Daynard has made legal contributions to the field of tobacco research leading to the 

curtailing of SHS exposure worldwide. Dr. Daynard’s current research is based on critically important and 

time-sensitive issues stemming from the World Health Organization (WHO)-sponsored Framework 

Convention on Tobacco Control (FCTC) Treaty. This treaty, effective February 27, 2005, directs parties 

to “adopt and implement in areas of existing national jurisdiction as determined by national law and 

actively promote at other jurisdictional levels the adoption and implementation of effective legislative, 

executive, administrative, and/or other measures, providing for protection from exposure to tobacco 

smoke in indoor workplaces, public transport, indoor public places, and, as appropriate, other public 

places”. Currently, over 140 nations have ratified it. Dr. Daynard will focus on conducting research for 

non-governmental organizations (NGOs) in relevant countries to reduce exposure to SHS to the greatest 

extent possible. The results of these efforts should be a long-term reduction in disease caused by exposure 

to SHS worldwide, as well as reduced SHS exposure for Americans traveling abroad. This issue is of 

particular concern to flight attendants on international routes. 

WILLIAM GROSSMAN, MD; 2008 

William Grossman, a former member of FAMRI’s Medical Advisory Board, is Director of the Center for 

Prevention of Heart and Vascular Disease at UCSF where he is the Meyer Friedman Distinguished 

Professor of Medicine. Dr. Grossman’s FAMRI project has the primary objective of improving clinical 

attention to tobacco use and SHS exposure in Cardiology. Despite the major contribution of tobacco and 

SHS exposure to cardiovascular disease, cardiology training programs often do not provide comprehensive 

training in addressing tobacco use in clinical practice. His FAMRI Award will support the development 

and evaluation of an evidence-based model curriculum for improving clinical attention to tobacco use and 

SHS exposure in cardiology. The curriculum is being developed for cardiology fellows, faculty, house staff, 

and medical residents and will be evaluated at UCSF for impact on clinicians’ tobacco-related knowledge, 

attitudes, and behaviors from pre- to post-training and at 3 months post-training. The curriculum and 

supporting materials will be packaged and made available online for wide dissemination. The curriculum 

will be promoted at cardiology and graduate medical education scientific meetings and within scientific 

journals. The curriculum Web site will track use of the program through file downloads and surveys 

emailed to registrants. Ultimately, this research could lead to a model tobacco cessation curriculum that 

can be disseminated nationally and internationally and thereby effectively serve to improve clinical practice 

in addressing tobacco use and SHS exposure in cardiology. Work completed to date includes completion of 

the initial slide set (93 slides), supporting instructor notes, and clinician handouts (e.g., pharmacotherapy 

guide, counseling guide, etc.). Feedback on the slides will be gathered from a group of expert advisors. 

The initial training and evaluation at UCSF is planned for late spring 2009. The evaluation will include 

clinician-completed surveys and electronic chart review. The slides will be revised/updated as needed with 

plans to put them online for dissemination in Fall 2009. Evaluation of dissemination and use of the slides 

will be a continuous process. 

S. KATHERINE HAMMOND, PhD; 2008 

Katharine Hammond is a Professor of Environmental Health Sciences at the School of Health, 

University of California, Berkeley. Dr. Hammond plans to educate epidemiologists about the importance 

of tobacco exposure assessment and the health effects on flight attendants exposed to tobacco smoke in 

airline cabins. 

2 2 6 P A G E

FAMRI GRANTEE PORTAL 

FAMRI has dedicated a section of its Web site www.famri.org to all of the investigators that they have 

funded, which supports a search of abstracts of all FAMRI-funded research and has a forum where individuals 

can communicate with other grantees. A Grantee Portal Reference Guide is available on the Web site 

and can also be requested from famri@aibs.org . 

FAMRI encourages its grantees to use this helpful portal. 

P A G E 2 2 7

PERSONAL THOUGHTS FROM THE FLIGHT ATTENDANT 

MEMBERS OF THE BOARD OF TRUSTEES 

The Flight Attendant Members of the Board of Trustees share their perspective for some of the resesearch that 

FAMRI is funding. 

PATRICIA L. YOUNG 

Patricia L. Young, Flight Attendant Trustee, who retired from American Airlines 

after 37 years, continues to marvel at FAMRI’s accomplishments: 

I started my fight against tobacco in the summer of 1966 when the other nonsmoking 

flight attendants were telling me that they were told by their doctors 

that they had the lungs of smokers. Our flight attendants suffer and die from the 

same diseases and sicknesses that smokers do. I continue to be extremely disappointed 

and saddened that the health care professionals world wide, despite 

mounting evidence coming out every day regarding the dangers to non-smokers 

of exposure to SHS, still are not asking the most basic questions of their 

patients regarding this exposure. The addition of this issue to the FAMRI mission 

statement and the projects FAMRI is funding will result in an immense 

change in medical protocol. FAMRI’s Distinguished Professor, William 

Grossman, MD, University of California, San Francisco, has focused his award on 

effecting this change. By asking their patients the extremely important and substantive 

questions relating to exposure to SHS, the medical professionals will 

educate the world public, from the very small child to their elders, on the dangerous 

ramifications SHS has on their health and that of their children and 

pets. FAMRI funded a study conducted by Ronald M. Davis, MD, (deceased), 

former President of the American Medical Association and FAMRI Distinguished 

Professor for research and education for smoke-free pets and families. This study 

continues through his two colleagues Sharon Milberger, PhD and Amanda 

Holm, MPH, which is resulting in important findings on the health of pets living 

with smokers. 

FAMRI has reached breathtaking heights resulting from our investment in 

medicine and science; our future successes will be awe-inspiring and will continue 

to change our world for the better. 

LANI BLISSARD 

Lani Blissard, Flight Attendant Trustee, who retired from American Airlines 

after 36 years, has a sense of urgency about the medical conditions of the members 

of the flight attendant class: 

When we lost our beloved Bland Lane, it gave us an even greater realization of 

the high urgency of research leading to the treatment and cure of diseases suffered 

by non-smoking flight attendants damaged by SHS in pre-tobacco ban airline 

cabins. 

Exciting work is currently being done at our FAMRI Bland Lane COE at 

UCSF, where flight attendants are evaluated via sophisticated tests and guided 

for treatment. Studies there, such as those of Dr. Warren Gold and his team, 

have revealed pulmonary damage in the majority of F/As who flew for years in 

those smoky airline cabins. 

We seek and look forward to studies which could lead to actual cure of the 

serious SHS generated illnesses of our non smoking F/A class, including emphysema, 

cardiovascular disease and numerous inflammatory conditions. We are 

enthused with the wonderful scientists we have funded and look forward every 

day to the results of their work. 

2 2 8 P A G E

LEISA SUDDERETH 

Leisa Sudderth is a 24-year veteran currently flying with American Airlines. 

Non-smoking flight attendants are dying from or diagnosed with the diseases 

caused by their exposure to second hand tobacco smoke when smoking was permitted 

in airline cabins at alarming rates. FAMRI’s investment in scientific studies and 

Centers of Excellence are addressing this urgency through the development of early 

diagnostic techniques, treatments and searches for cures of these terrible illnesses. 

The current economic situation is taking its toll on scientific initiatives and discoveries 

as less money is available to fund innovative projects. FAMRI’s resources are 

not immune from the economic situation which makes achieving our goal more 

urgent. 

BLAND LANE, (1929-2007) 

Bland Lane, Flight Attendant Trustee, who retired from Pan American World 

Airways and United Airlines after 48 years of service, died unexpectedly on 

February 15, 2007. 

Included are remarks from Bland in previous years. 

Bland Lane was excited about the grant proposal of Mardi Crane-Godreau, PhD, 

FAMRI Grantee and member of the flight attendant class action: 

Dr. Crane-Godreau and I have similarities in our backgrounds in that we both 

flew as flight attendants for Pan American World Airways and we both suffer from 

diseases caused by second hand tobacco smoke exposure in airline cabins. Dr. 

Crane-Godreau left the U.S. flag carrier and changed from world traveler to a 

career in business and then, to scientific research to find answers for the injuries she 

sustained due to her exposure of second hand tobacco smoke in our work place. I 

applaud her hard work, determination, and tenacity in accomplishing her goals. I 

wish her much success toward a positive outcome in her research toward understanding 

the genetic changes in cells which when exposed to second hand tobacco 

smoke cause certain infections. My hope is she will provide a major contribution to 

the world’s health. 

FAMRI’s wish and goal for the future is for the success of each of our researchers 

in eradicating some of the diseases suffered by mankind today. 

P A G E 2 2 9

APPENDICES: LIST OF FAMRI GRANTEES 

List of FAMRI Grantees 2002 

AWARD INVESTIGATOR INSTITUTION TITLE 

CoE Benowitz, Neal L., MD University of California, San Francisco FAMRI Bland Lane Center of Excellence on Second Hand Smoke at UCSF 

CIA Antonia, Scott J. MD, PhD University of South Florida Development of a Tumor Vaccine for Lung Cancer 

CIA Bluestein, Danny, PhD State University of New York at Stony Brook Second Hand Tobacco Smoke Platelet Activation and Cardiovascular Risk 

CIA Califano, Joseph A., MD The Johns Hopkins University Chromosomal Instability in Head and Neck Cancer 

CIA Deftos, Leonard J. MD VA San Diego Healthcare System Nucleolar Expression of PTHrP and Outcome in Non-small Cell Lung Cancer 

CIA Deng, Xingming, MD, PhD University of Florida The Role of Bc12 in Nicotine-induced Survival Signaling and 

Chemoresistance in Human Lung Cancer Cells 

CIA Gartenhaus, Ronald B., MD University of Maryland Transformed Follicular Lymphoma: Smoke Related? 

CIA Grando, Sergei A., MD, PhD University of California, Davis Precocious Skin Aging due to Secondhand Smoke 

CIA Joad, Jesse P., MD University of California, Davis Second Hand Tobacco Smoke Worsens RSV Bronchiolitis by 

Cysteinyl Leukotriene 

CIA Kobzik, Lester, MD Harvard University Smoke and Susceptibility to Respiratory Infection 

CIA Lee, David J., PhD University of Miami Influence of Second Hand Tobacco Smoke in Youth 

CIA Levy, David T., PhD Pacific Institute for Research & Evaluation The Use of Simulation Models to Predict and Understand Public 

Health Problems 

CIA Meyerson, Matthew L., MD, PhD Harvard University LOH and Gene Expression Profiles in Lung Carcinoma 

CIA Pauly, John L., PhD Roswell Park Cancer Institute Functional Studies of Human Lung Macrophages 

CIA Pili, Roberto, MD The Johns Hopkins University Modulation of Tumor Response to Retinoids 

CIA Rodriguez, Ronald, MD, PhD The Johns Hopkins University Adenoviral Bladder Cancer Gene Therapy 

CIA Xiao, Lei, PhD University of Florida PKC-epsilon Expression on the Outcome of Chemotherapy 

YCSA Alani, Rhoda M., MD The Johns Hopkins University Inhibitors of Histone Acetyltransferases as Novel Therapies for HPVassociated 

Malignancies 

YCSA Al-Delaimy, Wael K., MD, PhD University of California, San Diego Risk of Coronary Heart Disease Among Women Exposed to Second 

Hand Tobacco Smoke 

YCSA Biswal, Shyam, PhD The Johns Hopkins University Lung Cancer Susceptibility and Chemoprevention 

YCSA Cairns Paul, PhD Fox Chase Cancer Center Early Detection of Cancer by Hypermethylation 

YCSA Chong, Rachel, MD The Johns Hopkins University Second Hand Tobacco Smoke and Thyroid Disease 

YCSA Franzmann, Elizabeth, MD University of Miami Markers and Mechanisms for Head and Neck Cancer 

YCSA Hyland, Andrew, PhD Roswell Park Cancer Institute Economic, Behavioral, and Disease Impact of Clean Air 

YCSA Laden, Francine, ScD Harvard University Second Hand Tobacco Smoke and Health in a Blue Collar Population 

YCSA Li, Daqing, MD University of Pennsylvania MRN-Targeted Chemosensitization for Oral Cancer 

YCSA Loeb, David M., MD, PhD The Johns Hopkins University The Role of WT1 in the Pathogenesis of Breast Cancer 

YCSA Miller, David P. Sc.D., S.M. Harvard University The Molecular Epidemiology of Second Hand Tobacco Smoke 

AssoCIAted with Lung Cancer 

YCSA Mishra, Archana, MD State University of New York at Buffalo Impact of Second Hand Tobacco Smoke on Respiratory Health of 

Non Smoking Adults 

YCSA Watkins, D. Neil, MBBS, PhD The Johns Hopkins University Cyclopamine Inhibits Hedgehog Signaling and Growth in Lung Cancer Cells 

WCDP Blum, Alan, MD University of Alabama A book documenting flight attendant exposure to second hand 

tobacco smoke in airline cabins 

WCDP Burns, David M., MD University of California, San Diego; Second Hand Tobacco Smoke in the Work Place 

Professor Emeritus 

WCDP Davis, Ronald, M., MD Henry Ford Health System Investigation of Airport Smoking Policies 

WCDP Glantz, Stanton A., PhD University of California, San Francisco Scientific Impact of Second Hand Tobacco Smoke 

WCDP Hecht, Steven S., PhD University of Minnesota Cancer Center Biomarkers of Tobacco-Specific Carcinogen Uptake 

WCDP Repace, James L., MSc Repace Associates, Inc. Scientific Study Regarding Second Hand Tobacco Smoke in the 

Hospitality Industry 

WCDP Rigotti, Nancy A., MD Massachusetts General Hospital Scientific Study of Tobacco Use Among Young Adults 

WCDP Siegel, Michael B., MD, MPH Boston University School of Public Health Study of Effects of Second Hand Tobacco Smoke on Workers and the Public 

2 3 0 P A G E



CIA Ball, Douglas W., MD The Johns Hopkins University Regulation of Non-small Cell Lung Cancer by Notch 

CIA Bero, Lisa A., PhD University of California, San Francisco Development of Smoking Restrictions on Airlines 

CIA De Marco, Teresa, MD University of California, San Francisco The Effect of Second Hand Tobacco Smoke on Exercise Capacity and 

Clinical Outcomes in Pulmonary Arterial Hypertension 

CIA Fleischmann, Kirsten E., MD, MPH University of California, San Francisco Passive Smoking and Outcomes in Congestive Heart Failure 

CIA Fomenkov, Alexey, PhD The Johns Hopkins University Role of EGRF and its Downstream Targets in Head and Neck Cancers 

of Smoking Patients 

CIA Fuchs, Ephraim J., MD The Johns Hopkins University Tumor Vaccine After Nonmyeloablative Allogeneic Stem Cell 

Transplantation for Kidney Cancer 

CIA Hamilos, Daniel L., MD Massachusetts General Hospital Pathogenesis of Chronic Sinusitis in Relationship 

to Tobacco Smoke Exposure 

CIA Kornberg, Lori, PhD University of Florida Adenoviral Gene Transfer of FRNK and p53 for Treatment of Head 

and Neck Cancer: In Vitro Studies 

CIA Lee, David J., PhD University of Miami Serum Cotinine and Middle Ear Disease in Children and Adolescents: 

The National Health and Nutrition Examination Survey III 

CIA Mahoney, Martin C., MD, PhD Roswell Park Cancer Institute Airway Resistance and Cytogenetic Abnormalities Associated with 

Tobacco Smoke Exposure 

CIA Massion, Pierre P., MD Vanderbilt University Identification of New Molecular Targets in Lung Cancer 

CIA Mirhashemi, Ramin, MD Torrance Memorial Medical Center Genetic Predisposition to Second Hand Tobacco Smoke in Cervical Diseases 

CIA Moreb, Jan S., MD University of Florida Role of ALDHs in the Pathogenesis and Biology of Lung Cancer 

CIA Narayan, Satya, PhD University of Florida Mechanisms of Secondhand Smoking-Induced Breast Carcinogenesis 

CIA Pearlman, Justin D., MD Dartmouth College Advanced Cardiovascular Imaging Center 

CIA Raman, Venu, PhD The Johns Hopkins University Deciphering Genetic Alterations Caused by Second Hand Tobacco 

Smoke Exposure in the Pathogenesis of Breast Cancer 

CIA Robbins, Richard A., MD Carl T. Hayden VA Medical Center Noninvasive Assessment of the Lower Respiratory Tract in Response 

to Second Hand Tobacco Smoke 

CIA Switzer, Paul, PhD Stanford University Quantifying Human Exposure to Second Hand Tobacco Smoke 

CIA Trink, Barry, PhD The Johns Hopkins University Cloning of a Putative Oncogene on 20q11 

CIA Wong, Brian J. F., MD, PhD University of California Irvine Optical Diagnosis of Early Laryngeal Cancer 

YCSA Barnes, Betsy J., PhD UMDNJ-New Jersey Medical School Role of IRF-5 as a Tumor Suppressor in Non-small Cell Lung Cancer 

YCSA Bhattacharya, Raka, PhD The Johns Hopkins University The Role of HMG-I/Y in the Pathogenesis of Lung Cancer 

YCSA Bunz, Fred, MD, PhD The Johns Hopkins University Roles of the Checkpoint Kinases in the Responses of Human Cancer 

Cells to DNA Damage 

YCSA Ferris, Robert L., MD, PhD University of Pittsburgh Apoptosis of Effector T Cells in Cancer: Implications for Immune Therapy 

YCSA Foronjy, Robert F., MD Columbia University The Effect of PLTP Induction in Smokers 

YCSA Horton, Maureen R., MD The Johns Hopkins University Matrix Induced Epithelial Activation in Bronchitis 

YCSA Hung, Chien-Fu, PhD The Johns Hopkins University Development of Novel Human Immunology Assays for Human HPV 

Vaccine Trials 

YCSA Jaimes, Edgar A., MD University of Alabama at Birmingham Mechanisms of Endothelial Dysfunction in Smokers 

YCSA Khan, Saeed R., PhD The Johns Hopkins University Novel Drug Development for Breast Cancer 

YCSA Park, Ben Ho, MD, PhD The Johns Hopkins University Estrogen Receptor Signaling in Normal and Cancerous Breast 

Epithelial Cells 

YCSA Peters, Edward S., DMD, ScD Louisiana State University Second Hand Tobacco Smoke and Head and Neck Cancer 

YCSA Saha, Debabrata, PhD University of Texas Southwestern COX-2 Regulation in Response to Combined Therapy 

YCSA Salihu, Hamisu M., MD, PhD University of South Florida Effect of Second Hand Tobacco Smoke on Fetal Body and Brain Size 

YCSA Walter, Robert E., MD, MPH Boston University Biomarkers of Chronic Obstructive Pulmonary Disease 

YCSA Winickoff, Jonathan P., MD, MPH Harvard University Changing Pediatric Practice to Address Second Hand Tobacco 

Smoke Exposure 

BDA Brown, Anthony, MS Roswell Park Cancer Institute Tobacco Institute and Council for Tobacco Research Collection Development 

P A G E 2 3 1

BDA Butter, Karen A., MLS University of California, San Francisco FAMRI-Guildford Digital Library of Documents 

WCDP Brandt, Allan M., PhD Harvard Medical School To Research History and Policy Studies in Tobacco Control 

WCDP Hurt, Richard D., MD Mayo Clinic To Produce a Health Assessment of Flight Attendants Previously 

Exposed to Secondhand Smoke 

WCDP Petty, Thomas L., MD Health One Alliance To Promote Knowledge about New Technologies and Approaches to 

the Early Diagnosis of Lung Cancer and Related Disorders 

WCDP Samet, Jonathan M., MD The Johns Hopkins University To research Reducing the Risks of Secondhand Smoke: A Global Approach 



11 Rotter, Varda, PhD Weizmann Institute of Science FAMRI Center of Excellence: CARE 

CIA Abraham, Theodore P. The Johns Hopkins University Peripheral Vascular Hemodynamics and Ventricular Mechanics in 

Passive Smokers 

CIA Altes, Talissa Ann, MD, MS University of Virginia A New Method to Detect Early Changes of Emphysema in Persons 

Exposed to Second Hand Cigarette Smoke 

CIA Arenberg, Douglas A., MD University of Michigan A Transgenic Animal Model to Control the Angiogenic Switch in 

Lung Cancer 

CIA Bennett, William P., MD, MS City of Hope Methylation in Lung Cancers of Smokers and Non-smokers 

CIA Bluestein, Danny, PhD State University of New York at Stony Brook Thrombogenic Effects of Smoke and Nicotine on Platelets and 

Endothelium 

CIA Carson, Johnny L., PhD University of North Carolina at Chapel Hill Clinical and Laboratory Studies of Human Nasal Epithelium 

CIA Cousins, Scott W., MD Duke University Inflammation, Smoking and Blindness from Ocular 

Neovascularization 

CIA D'Armiento, Jeanine, MD, PhD Columbia University Passive Smoke Exposures in Asthmatics: Relationship to Matrix 

Metalloproteases 

CIA Fletcher, Joel G., MD Mayo Clinic ECG-gated Multidetector CT of Aortic Distensibility 

CIA Fong, Yuman, MD Memorial Sloan-Kettering Cancer Center Early Detection and Screening of Smoking-related Cancers by use of 

Green Fluorescent Protein Expressing Herpes Simplex Virus 

CIA Gentile, Deborah, MD Allegheny-Singer Research Institute Ontogeny of Cytokine Immune Responses: Role of SHS 

CIA Gold, Mark S., MD University of Florida Second Hand Tobacco Smoke Awareness, Competency and Practice: 

Physicians and Medical Students 

CIA Hahn, Ellen J., DNS, RN University of Kentucky Reducing SHS: Cardiac and Asthma Outcomes 

CIA Ishov, Alexander M., PhD University of Florida Implication of Potential Tumor Suppression Function of DAXX in c- 

met Dependent Lung Malignancy 

CIA Jacobson, Francine L., MD, MPH Brigham & Women’s Hospital Risk Factors for Chronic Obstructive Pulmonary Disease 

CIA Kim, Jean, MD, PhD The Johns Hopkins University Epithelium and Immunomodulation in Chronic Rhinosinusitus 

CIA King, Landon S., MD The Johns Hopkins University Smoke-Induced Dysregulation of Airway Aquporins 

CIA Klareskog, Lars, MD, PhD Karolinska Institutet Tobacco-caused Rheumatoid Arthritis; Genes, Mechanisms and 

Specific Therapy 

CIA Lane, Andrew P., MD The Johns Hopkins University Chronic Sinusitis and the Airline Cabin Environment 

CIA Liu, Yijun, PhD University of Florida Functional MRI Investigation of Impaired Leptin Regulation due to 

Secondhand Smoking 

CIA Rocco, James W., MD, PhD Massachusetts General Hospital Targeting the Ink4a/Arf Locus in Head and Neck Cancer 

CIA Rudin, Charles, MD, PhD The Johns Hopkins University Small Molecule Inhibitors of Bcl-2 as Novel Therapeutics for Lung Cancer 

CIA Starcher, Barry C., PhD University of Texas Health Center at Tyler Passive Cigarette Smoke in the Pathogenesis of Skin Cancer 

CIA Stearman, Robert S., PhD University of Colorado Epigenetic Control of Human Prostacyclin Synthase 

CIA Su, Yunchao, MD, PhD Medical College of Georgia Effect of Side-Stream Cigarette Smoke on Lung Endothelial 

Angiogenesis Induced by Epidermal Growth Factor 

CIA Teret, Stephen P., JD, MPH The Johns Hopkins University Law and the Prevention of Tobacco-Related Disease 

CIA Wadler, Scott, MD Weill Cornell Medical Center Patterns of Gene Expression in Early Lung Lesions 

(deceased, project resumed by 

Lane, Maureen, PhD) 

CIA Wolf, Jeffrey S., MD University of Maryland Correlation of Chronic Sinusitis and Tobacco Smoke 

CIA Wong, Richard J., MD Memorial Sloan-Kettering Cancer Center Sensitivity of Tobacco-Induced Cancer to Herpes Viral Oncolysis 

CIA Xing, Michael Mingzhao, MD, PhD The Johns Hopkins University BRAF Mutation and Other Common Genetic and Epigenetic Alterations 

in Thyroid Cancer: Relationship with Smoking and Clinical Applications 

2 3 2 P A G E


CIA Zahnow, Cynthia A., PhD The Johns Hopkins University Activation of CUBGP1 in Breast by Second Hand Tobacco Smoke 

CIA Zhang, JianLiang, PhD University of Florida Environment Tobacco Smoke-induced Lung Cell Death via the Nitric 

Oxide-Cytochrome c Oxidase Signaling 

YCSA Bazarov, Alexy V., PhD University of California, San Francisco Combinatorial Treatment Modalities of Anti-Angiogenic and Anti-HIF 

in Invasive Breast and Brain Cancers 

YCSA Carraway, Hetty E., MD The Johns Hopkins University Promoter Hypermethylation as a Molecular Marker for Breast Cancer 

YCSA Cohen, Noam A., MD, PhD University of Pennsylvania Contribution of Second Hand Tobacco Smoke to Sinusitis 

YCSA Coldren, Christopher D., PhD University of Colorado Expression Profiling of Blood in Lung Cancer Chemoprevention 

YCSA Gorlova, Olga Y., PhD M. D. Anderson Cancer Center Second Hand Tobacco Smoke and Lung Cancer Risk 

YCSA Halmos, Balazs, MD Case Western Reserve University Development of Stem Cell Model Systems of Lung Cancer and 

Tobacco-Damaged Airway Epithelium 

YCSA Jin, Zhaohui, MD Harvard University The Role of BAD in Nicotine/NNK Signaling Pathways in Human 

Lung Cancer Cells 

YCSA Karhadkar, Sunil S., MBBS The Johns Hopkins University Hedgehog Signaling Link Cancer and Injury Repair in Bladder 

Epithelium 

YCSA Keshamouni, Venkateshwar, PhD University of Michigan PPAR Gamma in Tumorogenesis and Therapy of 

Non-small Cell Lung Cancer 

YCSA Lee, Byron K., MD University of California, San Francisco The Effect of Secondhand Smoking on the Risk of Developing Atrial 

Fibrillation in Patients with Pacemakers and Defibrillators 

YCSA Ling, Pamela M., MD University of California, San Francisco Reversing Tobacco Market Research on Young Adults 

YCSA Liuba, Petru, MD, PhD Lund University Impact of Passive Smoking on Early Atherosclerosis in Children with 

Type 1 Diabetes Mellitus (ImPasSE) 

YCSA McGlothlin, Dana P, MD University of California, San Francisco Cardiovascular Effects of Secondhand Smoke During Pregnancy 

YCSA McKinley, Sarah J., MD University of Colorado Aging and COPD: Cellular Senescence in Emphysema 

YCSA Romeo, Guilio R. Harvard University Mechanisms and Consequences of Profillin-1 Increase in Atherogenesis 

YCSA Shachaf, Catherine M., PhD Stanford University Targeting MYC for the Treatment of Lung Cancer 

YCSA Shenassa, Edmond D., ScD Brown University Exposure to Second Hand Tobacco Smoke and Infantile Colic 

YCSA Stabile, Laura A., PhD University of Pittsburgh Targeting the Estrogen Receptor for Lung Cancer Therapy 

YCSA Yu, Jian, PhD University of Pittsburgh Transcriptional Regulations of PUMA in Lung Cancer 

YCSA Zhang, Jin, PhD The Johns Hopkins University Molecular Mechanisms of Spatiotemporal Regulation of Leukocyte 

Chemotaxis and its Dysregulation Involved in Chronic Sinusitis 

YCSA Zhou, Wei, MD, PhD Harvard University Smoking, Polymorphisms, and Lung Cancer Prognosis 

WCDP Banzhaf, John F., JD George Washington University To research Legal Action and Education Against Tobacco Smoke Pollution 

WCDP Connolly, Gregory N., DMD, MPH Harvard School of Public Health Impact of state, National, and International Clear In-door Air Laws 

WCDP Spitz, Margaret, MD, MPH MD Anderson Cancer Center Genetic Susceptibility to Lung Cancer 



CoE Rudin, Charles, MD, PhD The Johns Hopkins University The Johns Hopkins FAMRI Center of Excellence 

CIA Baldwin, Brenda R. PhD The Johns Hopkins University A Role for Tobacco Carcinogens in Breast Cancer 

CIA Barlev, Nickolai A., PhD Tufts-New England Medical Center Hospitals The Role of Lysine Histone Methyltransferase Set 7/9 in Breast Cancer 

CIA Barry, William H., MD University of Utah Effects of Second Hand Tobacco Smoke on Susceptibility of 

Ventricular Myocytes to Ischemic Injury 

CIA Chu, Hong Wei, MD National Jewish Medical and Research Center Effects of Cigarette Smoke and Mycoplasma Pneumoniae on VEGF 

Expression by Human Primary Small and Large Airway Epithelial Cells 

CIA Datta, Pran K., PhD Vanderbilt University TGF-beta Signaling in Lung Cancer: A Therapeutic Target 

CIA Deng, Xingming, MD, PhD University of Florida Nicotine Regulation of Bax's Proapoptotic Function in Human Lung 

Cancer Cells 

CIA Denmeade, Samuel R., MD The Johns Hopkins University The Macronome as a Tool for Early Cancer Diagnosis 

CIA Edvinsson, Lars, MD, PhD Lund University Alterations in Expression of Vascular G-protein Coupled Receptors 

as a Novel Mechanism Responsible for Cardiovascular Morbidity by 

Cigarette Smoking 

CIA Ellenhorn, Joshua, MD City of Hope An MVA Vaccine Targeting p53 in Breast Cancer 

CIA Garofalo, Roberto P., MD University of Texas Medical Branch at Galveston Protein Fingerprint of Airway Inflammation Induced by Viral Infection 

and Environmental Tobacco Smoke Exposure 

P A G E 2 3 3


CIA Getzenberg, Robert H., PhD The Johns Hopkins University A Marker for Bladder Cancer in Involuntary Smokers 

CIA Grando, Sergei A., MD, PhD University of California Irvine Nicotinic Receptors Alter Gene Expression in Keratinocytes 

CIA Hanahan, Douglas, PhD University of California, San Francisco Enhancing Cisplatin Efficacy with a Copper Chelator 

CIA Hastings, Randolph H., MD, PhD Veterans Medical Research Foundation Effects of PTHrP on Lung Cancer Survival in Women 

CIA Hirshberg, Abraham, MD, DMD Tel Aviv University Development of a Noninvasive Diagnostic Method for Detecting 

Genetically Altered Cells Present in Oral Mucosa of High Risk 

Patients, etc. 

CIA Idell, Steven, MD, PhD University of Texas Health Center at Tyler PAI-1 Airway Remodeling in Passive Smoke Exposure 

CIA Lagercrantz, Hugo, MD, PhD Karolinska Institutet Causes of Perinatal and Infant Morbidity and Mortality Due to Fetal 

Nicotine Exposure 

CIA Li, Dean Y., MD, PhD University of Utah Treating Vascular Disease by Targeting Elastin Signaling 

CIA Li, Luyuan, PhD University of Pittsburgh Oncogenic Role of RHBDF1 in Breast Cancer 

CIA O’Neill, J. Timothy, PhD Uniformed Services University of the Health Sciences Carbon Monoxide Hypoxia in Tobacco Smoke Induced Disease 

CIA Pauly, John L., PhD Roswell Park Cancer Institute Comparative Studies of Human Buccal Cells of Smokers 

and Non-Smokers 

CIA Potter, David A., MD, PhD University of Minnesota Twin Cities Epoxygenase Mechanisms of Breast Cancer Progression 

CIA Ratovitski, Edward, PhD The Johns Hopkins University Functional Role CDC91L1-containing Complex in Human Bladder Cancers 

CIA Reisman, David N., MD, PhD University of Michigan The Impact of the SWI/SNF Complex in Cancer 

CIA Schiestl, Robert H., PhD University of California, Los Angeles Base Excision Repair in SHS Caused DNA Deletions and Cancer 

School of Medicine and Public Health 

CIA Schouenborg, Jens, MD Lund University Effects of Passive Smoking and Nicotine on the Development of 

CNS Body Image and Motor Skill 

CIA Seagrave, JeanClare, PhD Lovelace Respiratory Research Institute LDL Oxidation and Exposure to Second Hand Tobacco Smoke 

CIA Singh, Shashibhushan P., PhD Lovelace Respiratory Research Institute Role of ERK in AHR in Prenatal Tobacco Smoke Exposure 

CIA Vincek, Vladimir, MD, PhD University of Miami Tobacco Smoke and Gene Expression in Sinus Mucosa 

CIA Wong, Kwok-Kin, MD, PhD Dana Farber Cancer Institute Organismal Effect of Tobacco Smoke on Telomerase Null Mice 

CIA Zheng, Yun-Ling, MD, PhD, MPH Georgetown University Environmental and Genetic Risk Factors of Breast Cancer 

YCSA Bowler, Russell P., MD, PhD National Jewish Medical and Research Center Molecular Phenotype of Early Emphysema 

YCSA Carlisle, Diane, PhD Magee Women's Health Corporation Role of Nicotine in COPD Progression 

YCSA Curci, John A., MD Washington University Effect of Smoking on Model Abdominal Aortic Aneurysms 

YCSA Edwards, Michael G., PhD University of Colorado Peripheral Blood Mononuclear Cell Profiling in Tobacco Exposure: 

Susceptibility Markers for COPD 

YCSA Falta, Michael T, MD PhD University of Colorado Identification of Pathogenic CD4+ T Cells in the Lungs of Patients 

with Severe Emphysema 

YCSA Hazra, Saswati, PhD University of California, Los Angeles PPAR Gamma Agonist Mediated Suppression of PGE2 in Human NSCLC 

YCSA Kamat, Ashish M., MD University of Texas M. D. Anderson Cancer Center Markers of Response to Intravesical Bladder Cancer Therapy 

YCSA Lai, Stephen Y., MD, PhD University of Texas M.D. Anderson Cancer Center Erythropoietin Signaling in Head and Neck Cancer 

YCSA Lee, Andrew C., MD University of California, San Francisco Endothelial Progenitor Cell Number and Function, Inflammation, and 

Endothelial Dysfunction After Exposure to Second Hand Tobacco 

Smoke: a putative Mechanism of the Cardiovascular Complications 

of Tobacco Smoke 

YCSA Meeker, John D., ScD University of Michigan Maternal Exposure to Environmental Tobacco Smoke and Pregnancy 

Outcomes 

YCSA Shim, Yun M., MD University of Virginia Biology of IL-13 and 5-LO in the Pathogenesis of COPD 

YCSA Vassallo, Robert, MD Mayo Clinic Alterations in Dendritic Cell-Mediated Immunity Caused by Smoking 

YCSA Wilk, Jemma B., DSc Boston University Genetic Epidemiology of Pulmonary Function and COPD 

YCSA Yang, Jun, PhD The Johns Hopkins University HDGF, a New Potential Target for Breast Cancer Therapy 

BDA Lin, Yong Y., PhD and Turino, Gerald, MD St. Luke's-Roosevelt Hospital Center Elastin Degradation in Pulmonary Diseases 

WCDP Cummings, K. Michael, PhD, MPH Roswell Park Cancer Institute Adverse Impact of Second Hand Tobacco Smoke Exposure on Society 

WCDP Daynard, Richard A., JD, PhD Northeastern University School of Law Curtailing of Second Hand Tobacco Exposure Worldwide 

2 3 4 P A G E



CoE Klein, Jonathan, MD, MPH American Academy of Pediatrics The Julius B. Richmond MD Center of Excellence for Children 

CIA Becker, Patrice M., MD The Johns Hopkins University Neuropilin-1 and emphysema 

CIA Buka, Stephen, ScD Harvard School of Public Health Adult Health Consequences of Prenatal and Postnatal Second 

Hand Tobacco Smoke Exposure 

CIA Califano, Joseph A., MD The Johns Hopkins University Tobacco - Induced Mitochondrial Alterations in Upper 

Aerodigestive Mucosa 

CIA Canfield, Stephen M., MD, PhD Columbia University The Impact of Second Hand Tobacco Smoke on T Cell Immune 

Response: Implications for Upper and Lower Airways Disease 

CIA Castrillon, Diego H., MD, PhD University of Texas Southwestern Smoke and Early Menopause: Mechanisms and Model Systems 

CIA Davis, Ronald M., MD; Henry Ford Health System Research and Education on Smoke-free Air for Pets and Families 

(deceased, project resumed by 

Milberger, Sharon, ScD) 

CIA Gold, Mark S., MD University of Florida Second Hand Tobacco Smoke-Induced Heart and Brain Injury 

CIA Goldman, Radoslav, PhD Georgetown University Analysis of Serum Peptides Associated with Squamous Cell 

Carcinoma of the Head and Neck (HNSCC) 

CIA Groner, Judith A., MD Ohio State University Second Hand Tobacco Smoke and Cardiovascular Dysfunction in 

Children 

CIA Jaspers, Ilona, PhD University of North Carolina at Chapel Hill SHS and Influenza-Induced Responses in Nasal Epthelium 

CIA Lee, David J., PhD University of Miami Second Hand Tobacco Smoke and Worker Health 

CIA Mariani, Thomas J., PhD University of Rochester PPAR Gamma and Susceptibility to Smoke-induced COPD 

CIA Morgan, James P., MD, PhD Caritis St. Elizabeth’s Medical Center Exacerbation of Viral Myocarditis by Tobacco Smoke as a Cause 

of Heart Failure 

CIA Nakshatri, Harikrishna, PhD Indiana University Developing DMAPT, a NF-kappaB Inhibitor for Bladder Cancer 

CIA Navas-Acien, Ana, MD, PhD The Johns Hopkins University Second Hand Tobacco Smoke Exposure Among Bar And 

Nightclub Employees 

CIA Nelkin, Barry D., PhD The Johns Hopkins University The Role of CDK5 in Cancer and Metastasis 

CIA Ng, Shu-Wing, PhD Brigham and Women’s Hospital Antibodies for Smoking Related Mucinous Ovarian Cancer 

CIA Niedbala, R. Sam, PhD Lehigh University Detection of Passive Smoke Exposure in Children and Adults 

Using Oral Based Rapid Test Technology 

CIA Owen, Caroline A., MD, PhD Brigham and Women’s Hospital A Novel Anti-inflammatory Role for ADAM15 in Emphysema 

CIA Palmer, James N., MD University of Pennsylvania Second Hand Tobacco Smoke Exposure Increases Biofilms 

Formation and Subsequent Ciliary Dysfunction 

CIA Petrache, Irina, MD Indiana University Smoking Impairs Alpha1-antitrypsin's Pro-survival Effect in the Lung 

CIA Powell, Charles A., MD Columbia University Lung Adenocarcinoma Progression: Markers and Mediation by 

Cigarette Smoke Exposure 

CIA Powell, Jonathan D., MD, PhD The Johns Hopkins University A2a Receptor Antagonism as a Novel Means to Enhance Vaccine 

Therapy for the Treatment and Prevention of Breast Cancer 

CIA Prokhorov, Alexander V., University of Texas M. D. Anderson Second Hand Tobacco Smoke in Mexican American Households 

MD, PhD 

Cancer Center 

CIA Raez, Luis E., MD University of Miami Lung Cancer Immunotherapy 

CIA Raman, Venu, PhD The Johns Hopkins University Activation of DDX3 by Benzo[a]pyrene Diol Epoxide, a 

Component of Second Hand Tobacco Smoke in Transformation of 

Human Breast Cells: a Potential Mechanism for Neoplastic 

Transformation 

CIA Rigotti, Nancy A., MD Massachusetts General Hospital Household Smoking Bans: A Comprehensive Analysis 

CIA Salathe, Matthias, MD University of Miami Ciliary Dysfunction in SHS-induced Bronchitis 

CIA Schlosser, Rodney J. MD Charleston Research Institute Effects of Second Hand Tobacco Smoke and Sinonasal Immunity 

CIA Shams, Homayoun, DVM, PhD University of Texas Health Center at Tyler Second Hand Cigarette Smoke and Immunity to Tuberculosis 

CIA Shapiro, Steven D., MD University of Pittsburgh Elastin Fragment Inhibition as a Therapy for COPD 

CIA Singh, Bhuvanesh, MD, FACS Memorial Sloan-Kettering Cancer Center Functional Characterization of SCCRO 

CIA Soldin, Offie P., PhD Georgetown University Tobacco Smoke Exposure and Genetic Disposition Associations 

with Hormonal Changes in Women 

CIA Turchi, John J., PhD Indiana University School of Medicine Analysis of DNA Repair Capacity to Predict and Target 

Chemoresisitant Small Cell Lung Cancer 

CIA Wilder, Julie A., PhD Lovelace Respiratory Research Institute Environmental Tobacco Smoke Exacerbates Allergic Asthma 

P A G E 2 3 5


YCSA Alumkal, Joshi J., MD Oregon Health and Sciences Center DNA Methylation as a Predictor of Biochemical Relapse after 

Radical Prostatectomy and NKX3.1 Gene Silencing in Prostate 

Cancer: Importance and Mechanisms 

YCSA Bruijnzeel, Adriaan W., PhD University of Florida Childhood Second Hand Tobacco Smoke Exposure: Delayed 

Neuropsychiatric Effects 

YCSA Crane-Godreau, Mardi, PhD Dartmouth College Effect of Second Hand Tobacco Smoke on Respiratory and 

Reproductive Tract Epithelial Cell Production and Release of CCL20 

YCSA Cui, Zhiyong, PhD Dartmouth College A Disposable Device to Measure Secondhand Smoke Exposure 

YCSA Farassati, Faris, PhD, PharmD. University of Kansas Usurping Signaling Characteristics of Breast, Cervical and Prostate 

Cancer to Target Them With a 'Signal-Smart' Virus 

YCSA Heys, Jeffrey J., PhD Arizona State University Simulation of Second Hand Tobacco Smoke Deposition in the Airways 

YCSA Hoque, Mohammad O., DDS, PhD The Johns Hopkins University Genetic and Epigenetic Alterations in Bladder Cancer by Tobacco Smoke 

YCSA Hughes, Suzanne C., PhD, MPH San Diego State University PSE Rates and Correlates: Koreans/Korean Americans 

YCSA Im, Eunok, PhD University of California, Los Angeles Age-related Macular Degeneration 

YCSA Kassem, Nada, DrPH, MS, RN San Diego State University Hookah Use and Second Hand Tobacco Smoke 

YCSA Lavelle, James C., MD University of Colorado at Denver Cigarette Smoke and Mechanical Stretch in COPD 

and Health Sciences Center 

YCSA Levantini, Elena, PhD Beth Israel Deaconness Medical Center The Role of the Transcription Factor CEB/P alpha in Normal Lung 

Development and in Murine Models of Lung Cancer and Tobaccodamaged 

Airway Epithelium 

YCSA Marsit, Carmen J., PhD Brown University Role of SHS on Somatic Alterations in Bladder Cancer 

YCSA Martinez, Mark L., MD University of Utah Altered Gene Expression in Vascular Endothelial Cells in Response to 

Oxidative Stress from Environmental Tobacco Smoke 

YCSA Michel, Loren, MD Washington University Targeting the Trop-2 Receptor Pathway in Cancer 

YCSA Park, Ben Ho, MD, PhD The Johns Hopkins University Somatic Cell Knock-in of a Mutant K-ras Gene for Understanding 

and Targeting Ras-induced Cancers Related to Second Hand Tobacco 

Smoke 

YCSA Srisuma, Sorachai, MD, PhD Mahidol University, Bangok Serine Protease Inhibitor E2 and COPD 

YCSA Travers, Mark J., PhD Roswell Park Cancer Institute Advances in Monitoring Exposure to Second Hand Tobacco Smoke in 

the Air and in the Body 



CoE Henschke, Claudia, PhD, MD New York Hospital-Weill Cornell Medical Center Center for Early Detection of Second Hand Tobacco Smoke Diseases 

BLIDP Edvinsson, Lars Lund University Enhanced Expression of Vascular G-protein Coupled Receptors in 

Arterial Smooth Muscle Cells induced by Cigarette Smoke 

BDA Hildemann, Lynn M., PhD Stanford University Study in Human Exposure Analysis for Pollutants from Second Hand 

Tobacco Smoke 

CIA Antony, Veena B., MD University of Florida Second Hand Tobacco Smoke and Airway Infection 

CIA Avraham, Shalom MD, PhD Harvard University Role of Second Hand Smoke in Breast Cancer Angiogenesis and 

Metastasis 

CIA Ball, Douglas W., MD The Johns Hopkins University Regulation of Non-Small Cell Lung Cancer by Notch 

CIA Barrett, Edward G. PhD Lovelace Respiratory Research Institute Fetal-Postnatal Smoke Exposure: Response to RSV Infection 

CIA Bartlett, Donald Jr., MD Dartmouth College Second-Hand Tobacco Smoke and SIDS: a Laryngeal Connection? 

CIA Bernard, Hans-Ulrich PhD, MSc University of California, Irvine Synergy of HPVs and Tobacco Smoke in Cervical Cancer 

CIA Carson, Johnny L., PhD University of North Carolina at Chapel Hill Laboratory Studies of Human Nasal Epithelium 

CIA Chan, Sophia Siuchee PhD University of Hong Kong RCT of a Family Intervention to Reduce SHS Exposure in Children 

CIA Chen, Chang-Yan, MD, PhD Beth Israel Deaconness Medical Center Nicotine: Signaling and Mitogenesis in the Breast 

CIA Connolly, Gregory N., DMD, MPH Harvard School of Public Health Second Hand Tobacco Smoke Emissions and Reduced Exposure Products 

CIA Cutting, Garry R. MD The Johns Hopkins University The Effects of Secondhand Smoke on Cystic Fibrosis 

CIA Das, Salil K., Sc.D., D.Sc. Meharry Medical College Role of PBRs in Breast Cancer Induced by Secondhand Smoke 

CIA Fong, Yuman, MD Memorial Sloan-Kettering Cancer Center Detection of Premalignant Lesions in the Oral Cavity Induced by 

Tobacco Related Carcinogens 

CIA Foster, Charles B. , MD Cleveland Clinic Cigarette Smoke and Impaired Selenoprotein Production 

CIA Geller, Alan C. , MPH, RN Harvard University Second-Hand Smoke Counseling for Parents of Hospitalized 

Pediatric Patients 

2 3 6 P A G E


CIA Gold, Mark S., MD University of Florida Increasing Secondhand Smoke Awareness, Competency and 

Screening among Medical Professionals: Expanding the Medical 

Curriculum 

CIA Haley, Kathleen J., MD Harvard University Effects of Second-Hand Tobacco on the Immature Lung 

CIA Hyland, Andrew, PhD Roswell Park Cancer Institute Secondhand Smoke Global Research Network 

CIA Inana, George, MD, PhD University of Miami Gene Profiling Second Hand Smoke and Macular Degeneration 

CIA Lane, Andrew P., MD The Johns Hopkins University Tobacco Smoke Exposure, Innate Immunity, and Chronic Sinusitis 

CIA Larsson, Lennart P. PhD Lund University Tobacco Smoke Endotoxin 

CIA LeMaitre ,Vincent, PhD Columbia University Nicotine and the Pathobiology of Aneurysm 

CIA Luo, Hongbo R. PhD Harvard University Reduced Neutrophil Death in Tobacco-induced COPD 

CIA Martin, Stuart S. PhD University of Maryland How Second-Hand Smoke Affects Breast Tumor Dormancy in the Lung 

CIA McGrath-Morrow, Sharon A. MD The Johns Hopkins University Second-Hand Smoke and Neonates and Predisposition to COPD 

CIA Milberger, Sharon, Sc.D. Henry Ford Health System Prevalence of Smoke-Free Campus Policies in U.S. Hospitals and 

Best Practices for Policy Implementation 

CIA Ratner, Adam J., MD, MPH Columbia University Suppression of Airway Immunity by Secondhand Smoke 

CIA Slingerland, Joyce MD, PhD University of Miami Targeting the SRC Oncogene in Breast Cancer Therapy 

CIA Stroud, Laura R., PhD The Miriam Hospital, Brown University Maternal Smoking: Fetuses in Withdrawal? 

CIA Taylor, Rodney J. MPH, MD University of Maryland Evaluating CD137 as a Novel Treatment in a New Tobacco- 

Exacerbated Model of Chronic Sinusitis 

CIA Tesfaigzi, Yohannes, PhD Lovelace Respiratory Research Institute Goblet Cell Hyperplasia in Chronic Bronchitis 

CIA Trink, Barry, PhD The Johns Hopkins University The GPI Transamidase Complex Subunits as Oncogenes in Bladder Cancer 

CIA Wang, Hong-Gang , PhD The Pennsylvania State University Nicotine Induced Src Signaling in Lung Metastasis 

CIA Valacchi, Giuseppe, PhD University of Siena Does Second Hand Cigarette Smoke (SCS) Modulate Vitamin E 

Uptake in Lung Tissue? 

CIA Vandivier, R. William, MD University of Colorado Aging & COPD: Phagocyte Function in the Pathogenesis of Emphysema 

CIA Van Winkle, Laura S., PhD University of California, Davis SHS and Sex Differences in Airway Development 

CIA Wong, Brian J. F., MD, PhD University of California, Irvine Medical Center Screening and Diagnosis of Laryngeal Cancer with OCT 

CIA Wong, Richard J. MD Memorial Sloan-Kettering Cancer Center Selective Herpes Viral Targeting of Tobacco-Related Cancers 

CIA Wu, T. John, PhD Uniformed Services University of the Health Sciences Second Hand Smoke as an Endocrine Disruptor 

CIA Yolton, Kimberly, PhD Cincinnati Children's Hospital Tobacco Smoke and Early Human Neurobehavior 

CIA Zhang, JianLiang, PhD University of Florida Exhaled Smoke-Induced Lung Endothelial Apoptosis via 

Peroxynitrite-Bax Signaling 

YCSA Akulapalli, Sudhakar, PhD Boys Town National Research Hospital Regulation of Tumor Angiogenesis by Combostatin 

YCSA Burkard, Mark E. MD, PhD University of Wisconsin Chemical Genetic Validation of Polo-like Kinase-1 as a Breast 

Cancer Drug Target 

YCSA Calfee, Carolyn, MD University of California, San Francisco Impact of Tobacco Smoke Exposure on Acute Lung Injury 

YCSA Di Cello, Francescopaolo, PhD The Johns Hopkins University Secondhand Tobacco Smoke and HMG-IY in Breast Cancer 

YCSA Erb, Teresa M., MD Magee Women's Health Corporation Effects of Second Hand Tobacco Smoke on Placental Stem Cell Differentiation 

YCSA Ezzie, Michael E., MD Ohio State University The Role of Thrombospondin-1 in Emphysema 

YCSA Guerrero-Plata, Maria Antonieta, PhD University of Texas Medical Branch at Galveston Innate Immunity and Tobacco Smoke 

YCSA Guo, Zhongmin .MD, PhD Indiana University Roles of DNA Promoter Hypermethylation in Head and Neck Cancer 

Cisplatin Resistance 

YCSA Hann, Christine L. MD, PhD The Johns Hopkins University Using Novel Tumor Models and Novel Therapeutics to Define Tumor 

Progenitors in Small Lung Cancer 

YCSA Hartney, John M., PhD University of Colorado Influence of Arhgef1 on Pulmonary Immunity 

YCSA Hunter, Terri B. PhD H. Lee Moffitt Cancer Center Combination Ad.p53-DC Immunotherapy/Chemotherapy for SCLC 

YCSA Hurley, Paula J., PhD The Johns Hopkins University Optimizing Therapy of Smoking-Related Cancers by Modulating 

Nucleotide Metabolism 

YCSA Jeyaseelan, Sambithamby, Louisiana State University CXCL5 is Central to Cigarette Smoke-Induced Neutrophil Influx 

DVM, PhD 

YCSA Juergens, Rosalyn, MD The Johns Hopkins University Targeting Epigenetic Changes in Metastatic Lung Cancer 

YCSA Kim, Myoung Sook PhD The Johns Hopkins University Epigenetic Alterations in Progression of Esophageal Squamus Cell 

Carcinoma by Tobacco Smoking 

YCSA Lauring, Josh MD, PhD The Johns Hopkins University Functional Analysis of the MMSET Oncogene in Translocation 4;14 

Multiple Myeloma 

YCSA Lee, Walter T., MD Duke University Optimizing Fusion Hybrids for Cancer Immunotherapy 

P A G E 2 3 7


YCSA McClean, Michael , Sc.D. Boston University Secondhand Tobacco Smoke and Alcohol in Head and Neck Cancer 

YCSA Park, Jong-In, PhD Medical College of Wisconsin MEK-Induced Growth Arrest in Small Cell Lung Cancer Cells 

YCSA Reynolds, Paul R., PhD University of Utah RAGE-Mediated Effects of Pulmonary Inflammation and Emphysema 

YCSA Rhee, Sang Hoon, PhD University of California, Los Angeles Innate Immune Response and Intestinal Inflammation 

YCSA Seiwert, Tanguy Y., MD University of Chicago The Receptor Tyrosine Kinase c-MET as a Novel Therapeutic Target 

in Head and Neck Cancer 

YCSA Sharma, Sanjai, MD West Los Angeles VA Medical Center Role of Egr3 in Smoking Induced Cancer 

YCSA Singh, Anju, PhD The Johns Hopkins University Developing NRF2 Inhibitors for Cancer Chemotherapy 

YCSA Spanier, Adam J., MD, MPH Cincinnati Children's Hospital Low Level Prenatal Tobacco Exposure and Infant Wheeze 

YCSA Uchio, Edward, M. MD Yale University Spectral and Spatial Analysis of Urine Cytology 

YCSA Wilson, Andrew A. , MD Boston University Cell-Based Therapy for Cigarette Smoke-Related Lung Disease 

YCSA Zhai, Rihong MD, PhD Harvard University Smoking-Gene-Environment Interactions in Esophageal Adenocarcinoma 

YCSA Zhao, Feng, PhD Duke University Small Diameter Blood Vessel Regeneration by Biomimetic Engineering 



CoE Benowitz, Neal L., MD University of California, San Francisco FAMRI Bland Lane Center of Excellence on Second Hand Tobacco 

Smoke at UCSF (Renewal) 

BDA Yedgar, Saul, PhD Hebrew University of Jerusalem Clinical Phase I/IIa Trial for Testing the Efficacy of MRX-4 

in Allergic Rhinitis 

CIA Abdullah, Abu S., MD, Boston University Reducing Second Hand Tobacco Smoke Exposure 

PhD, MPH, MFPH 

Among Young Children 

CIA Alpert, Hillel R., BSc, SM Harvard School of Public Health Second Hand Tobacco Smoke Exposure and Pediatric Illness in the US 

CIA Balmes, John, MD and University of California, San Francisco Second Hand Tobacco Smoke and Sinusitis: Effect of Sidestream 

Shusterman, Dennis, MD, MPH 

Smoke on Sinus Ostial Patency 

CIA Biswal, Shyam, PhD The Johns Hopkins University Targeting NRF2 for Intervening Emphysema 

CIA Briegel, Karoline J., PhD University of Miami Miller School of Medicine Role of Transcription Factor TBX2 in Breast Cancer 

CIA Bunz, Fred MD, PhD The Johns Hopkins University Targeting the ATR Kinase in Second Hand Tobacco Smoke-Related Cancers 

CIA Casola, Antonella, MD University of Texas Medical Branch at Galveston Tobacco Smoke and Oxidative Stress in RSV Bronchiolitis 

CIA Chan, Annie W., MD Massachusetts General Hospital Mechanisms of Environmental Tobacco Smoke-Induced Nervous 

System Malformations and Cancers 

CIA Chu, Hong Wei, MD National Jewish Medical and Research Center Host Defence Functions of Airway Epithelial Cells in COPD 

CIA Connolly, Gregory N., DMD, MPH Harvard School of Public Health Smoke-free Air Laws, Exposure and Health in Adolescents 

CIA Dai, Zhenhua, MD, PhD University of Texas Health Center at Tyler Second Hand Tobacco Smoke, Immunity and Allograft Rejection 

CIA Deng, Xingming, MD, PhD University of Florida Development of Structure-Based Small Molecule Anti-lung Cancer 

Drug(s) by Targeting Bax 

CIA Foronjy, Robert F., MD Columbia University Redox Regulation of Smoke Induced Inflammation 

CIA Gabrielson, Kathleen L., DVM, PhD The Johns Hopkins University Role of Heat Shock Protein 90 in Tobacco Smoke-induced Heart Disease 

CIA Gartenhaus, Ronald B., MD University of Maryland Translational Control and Breast Cancer Development 

CIA Gillespie, M. Boyd, MD Charleston Research Institute Second Hand Tobacco Smoke Exacerbation of Allergic Rhinitis 

CIA Gilley, David P., PhD Indiana University Telomere Dysfunction and Breast Cancer Detection 

CIA Hamilos, Daniel L., MD Massachusetts General Hospital Pathogenesis of Chronic Rhinosinusitis in Relation to Second Hand 

Cigarette Smoke and Abnormal Epithelial Innate Immunity 

CIA Heston, Warren D. W., PhD Cleveland Clinic Cigarette Smoke Impairment of Bladder Cancer Treatment 

CIA Hsieh, Jer-Tsong, PhD University of Texas Southwestern Small Peptide Therapy on Metastatic Prostate Cancer 

CIA Hyland, Andrew, PhD Roswell Park Cancer Institute A Multiple Stakeholder Study Regarding the Impact of Second Hand 

smoke in Multiunit Housing 

CIA Jaimes, Edgar A., MD University of Alabama at Birmingham Role of Nicotine as Mediator of the Effects of Tobacco in the 

Progression of Chronic Kidney Disease 

CIA Jiang, Feng, MD, PhD University of Maryland Early Detection of Lung Cancer in African Americans Exposed to 

Second Hand Smoke 

CIA Kajon, Adriana Elisa, PhD Lovelace Respiratory Research Institute Second Hand Tobacco Smoke Exposure and Susceptibility to 

Respiratory Viral Infection 

2 3 8 P A G E


CIA Krug, Lee M., MD Memorial Sloan-Kettering Cancer Center Tetravalent Vaccine Against SCLC: A Pilot Trial 

CIA Kogevinas, Manolis, MD, PhD University of Crete Fetal and Infant Exposure to SHS and its Role in Chronic Disease 

CIA LeVan, Tricia D., PhD University of Nebraska Haemophilus influenzae Tolerance: A Mechanism for Chronic 

Colonization in COPD 

CIA Maitra, Anirban, MBBS The Johns Hopkins University Inhibition of Hedgehog Signaling by Cyclopamine Prodrug for 

Prostate Cancer 

CIA Marin-Castano, Maria University of Miami Role of Smoking in Age-Related Macular Degeneration 

CIA Martin, Kathleen A., PhD Dartmouth College Effects of Second Hand Cigarette Smoke Exposure on Adinopectin, 

mTOR, and Vascular Disease 

CIA Narayan, Satya, PhD University of Florida Mechanism of Second Hand Cigarette Smoke-induced 

Transformation of Normal Human Breast Epithelial Cells 

CIA O'Neill, J. Timothy, PhD Uniformed Services University of the Health Sciences Perinatal Nicotine, Carbon Monoxide and Neurodevelopment 

CIA Patz, Samuel, PhD Brigham & Women's Hospital, Inc. Noninvasive Measurement of Alveolar Surface Area 

CIA Pearse, David B., MD The Johns Hopkins University Role of Cyclic Guanosine Monophosphate in Tobacco Smokeinduced 

Lung Endothelial Dysfunction and Emphysema 

CIA Prakash, Y. S., MD, PhD Mayo Clinic Neurotrophins in Cigarette Smoke Induced Airway Hyperreactivity 

CIA Pritsos, Chris A., PhD University of Nevada, Reno Air Filtration Systems, Second Hand Tobacco Smoke 

and Respiratory Disease 

CIA Rosser, Charles J., MD University of Florida Genomic Analysis of Urine to Detect Bladder Cancer 

CIA Saha, Debabrata PhD University of Texas Southwestern Modulation of Stereotactic Body Radiation Therapy to Improve 

Therapeutic Ratio 

CIA Springer, Matthew L., PhD University of California, San Francisco Long-Term Vascular Effects of Second Hand Tobacco Smoke 

CIA Su, Yunchao, MD, PhD Medical College of Georgia Side-stream Tobacco Smoke and Nitric Oxide Modification and 

Calpains in Airway Epithelial Repair 

CIA Taraseviciene-Stewart, Laimute, PhD National Jewish Medical and Research Center Immune Responses to Second Hand Cigarette Smoke Exposure 

CIA Tyagi, Shivraj, PhD Brigham & Women's Hospital, Inc. The Role of Bronchio-Alveolar Stem Cells in Cigarette Smoke- 

Related Emphysema 

CIA van der Vliet, Albert, PhD University of Vermont Tobacco Aldehydes and Allergic Airway Inflammation 

CIA Wang, Bingcheng, PhD Case Western Reserve University EphA2 Kinase as a Target for Treatment and Early Detection of Lung Cancer 

CIA Wang, Zhaoxi, MD, PhD Harvard School of Public Health Smoking, Polymorphisms, and Lung Cancer Prognosis 

CIA Winickoff, Jonathan P., MD, MPH Massachusetts General Hospital Evaluating Online Clinical Office-Systems Training to Address 

Second Hand Tobacco Smoke Exposure of Children 

CIA Wu Wenxin, PhD University of Oklahoma Health Sciences Center Cigarette Smoke Exposure and Influenza Virus Infection in Human Lung 

CIA Zahnow, Cynthia A., PhD The Johns Hopkins University Second Hand Tobacco Smoke and its Role in Breast Cancer 

YCSA Bansal-Travers, Maansi, PhD; Roswell Park Cancer Center Evaluating the Characteristics that Influence Persuasiveness of 

Second Hand Tobacco Smoke Advertisements 

YCSA Barkley-Elliman, Laura, PhD National University of Ireland, Galway Tolerance of Tobacco Smoke-Induced DNA Damage in Lung 

YCSA Basseres, Daniela S., PhD University of North Carolina at Chapel Hill Therapeutic Targets in K-Ras-Induced Lung Cancer 

YCSA Begum, Shahnaz, MBBS, PhD The Johns Hopkins University Allelic Imbalance and miRNA Regulation by Tobacco Smoke in NSCLC 

YCSA Benarafa, Charaf, DVM, PhD Immune Disease Institute Role of SERPINB1 in Cigarette Smoke-induced Defective 

Antimicrobial Defense 

YCSA Chan, Timothy A., MD, PhD Memorial Sloan-Kettering Cancer Center Discovery and Characterization of Novel Tumor Suppressor Genes in 

Breast Cancer Using Genome-wide Genetic and Epigenetic Analysis 

and Development of Molecular Markers for High-risk Patients with 

Tobacco Exposure 

YCSA Chatterjee, Aditi, PhD The Johns Hopkins University The Effect of Adenylate Kinase 3 (AK3) on Tobacco Smoke-induced 

Cisplatin Resistance in Bladder Cells 

YCSA Damico, Rachel, MD, PhD The Johns Hopkins University Regulators of Cigarette-induced Endothelial Cell Apoptosis 

YCSA Herynk, Matthew H., PhD University of Texas M. D. Anderson Cancer Center Gender Differences in the Efficacy of Antiangiogenic Therapies: The 

Role of EGFR/Estrogen Receptor Interactions in NSCLC 

YCSA Jukosky, James A., PhD Dartmouth College The Influence of Second Hand Cigarette Smoke on the Innate 

Immune Function of Nasal Epithelial Cells 

YCSA Kachhap, Sushant K., PhD The Johns Hopkins University NDRG1 Modulation to Decrease Prostate Cancer Invasion 

YCSA Levy, Douglas, PhD Harvard Medical School Second Hand Tobacco Smoke, Pediatric Healthcare Use, and Spending 

YCSA Pan, Quintin, PhD Ohio State University Development of PKC epsilon Inhibitors for Treating Head and Neck Cancer 

P A G E 2 3 9


YCSA Peacock, Craig D., PhD The Johns Hopkins University Hedgehog Signaling in Small Cell Lung Cancer Stem Cells 

YCSA Rosen, Laura J., PhD Tel Aviv University Well-baby Clinic-based Intervention 

YCSA Sebrié, Ernesto, MD, MPH Roswell ParkCancer Institute Health Impact Study of Smokefree Policies in Latin America 

YCSA Selaru, Florin M., MD The Johns Hopkins University Gastric Cancer: Molecular Pathogenesis and Biomarker Discovery 

YCSA Serafini, Paolo, PhD University of Miami Miller School of Medicine Use of PDE5 Inhibitors for the Immune Therapy of HNSCC 

YCSA Sidhaye, Venkataramana, MD The Johns Hopkins University Effects of Cigarette Smoke on Airway Epithelial Barrier Function 

YCSA Vigodner, Margarita, PhD Stern College, Yeshiva University Second Hand Tobacco Smoke as a Potential Cause of 

Spermatogenic Failures and Male Infertility 

YCSA Woodworth, Bradford A., MD University of Alabama at Birmingham Reversal of Tobacco-Related Chronic Sinusitis 

YCSA Zemans, Rachel L., MD National Jewish Medical and Research Center Synergistic Effects of Cigarette Smoke and PMNs in COPD 

YCSA Zhou, Qun, MD, PhD The University of Maryland Targeting Nrf2/ARE by HDAC Inhibition in Breast Cancer 

WCDP Grossman, William, MD University of California, San Francisco Health Care Professionals asking the Right Questions Re SHS 

WCDP Hammond, S. Katherine, PhD University of California, Berkeley Assessment of FlightAttendants’ Exposure to Second Hand 

Tobacco Smoke and Epidemiologic Studies 



CoE Rotter, Varda, PhD Weizmann Institute of Science CARE, Center for Advanced Research on Lung Cancer Renewal 

BDA Rotter, Varda, PhD, Rudin, Weizmann Institute of Science, The Johns Hopkins Inter-Center Collaboration--Multi-Modality Approach to Risk 

Charles, MD, University Medical Center, New York Hospital- Assessment, Early Detection and Prognosis of Lung Cancer 

Henschke, Claudia, PhD, MD Weill Cornell Medical Center 

CIA Al-Delaimy, Wael K., MD, PhD University of California, San Diego Hair and Toenail Nicotine Levels in the Population 

CIA Borchers, Michael T., PhD University of Cincinnati Cytotoxic T Cell Expansions in Smoke-Induced Lung Disease 

CIA Choi, Augustine M. K., MD Brigham & Women's Hospital Autophagy in COPD 

CIA Cohen, Noam A., MD, PhD Philadelphia Research & Education Foundation Tobacco Mediated Sinonasal Ciliary Dysfunction 

CIA Deng, Xingming, MD, PhD University of Florida Mcl-1 is a Novel Signaling Target of Nicotine in Human Lung 

Cancer Cells 

CIA DiDonato, Joseph, PhD Cleveland Clinic Smoking and the Pathogenesis of Asthma 

CIA Elias, Jack A., MD Yale University Cigarettes and RIG-like Helicase Innate Immunity 

CIA Fan, Z. Hugh, PhD University of Florida Analyzer for Detecting Secondhand Smoke Exposure 

CIA Forteza, Rosanna Malbran, MD University of Miami Second Hand Smoke-Induced Asthma Exacerbations 

CIA Fregien, Nevis L., PhD University of Miami Molecular Control of Ciliated Cell Maintenance 

CIA Hong, Jun-Yan, PhD University of Medicine and Dentistry of New Jersey CYP2A13: A New Link Between Smoking and Breast Cancer 

CIA Jaspers, Ilona, PhD The Hamner Institute SHS and Influenza-Induced Immune Responses 

CIA Kim, Young J., MD, PhD The Johns Hopkins University STAT3 and the Tumor Microenvironment in Head and Neck Cancer 

CIA Klareskog, Lars, MD, PhD Karolinska Institutet Investigation of Active and Second Hand Tobacco Smoke as 

Triggers of Arthritis 

CIA Lee, David J., PhD University of Miami Secondhand Smoke: Prevalence, Validation & Effects 

CIA Lee, Janet, MD University of Pittsburgh Lung Activation of CX3CK1 by Second Hand Smoke Exposure 

CIA Lee, Patty J., MD Yale University TLR-Mediated Emphysema: Role of Aging and Gender 

CIA Ling, Pamela M., MD, MPH University of California, San Francisco Bar Interventions to Decrease Young Adult Smoking 

CIA Mishra, Neerad C., PhD Lovelace Respiratory Research Institute Effects of Prenatal CS Exposure on Allergic Asthma 

CIA Netto, George, MD The Johns Hopkins University Methylation Markers of Bladder Cancer Recurrence 

CIA Ratovitski, Edward A., PhD The Johns Hopkins University Inflammatory Role of LKB1 Tumor Suppressor in Lung Cancer 

CIA Rigotti, Nancy A., MD Massachusetts General Hospital Hospitalization for Coronary Heart Disease: A Time to Address 

SHS Exposure 

CIA Shetty, Sreerama, PhD University of Texas Health Center at Tyler Regulation of Tobacco Smoke Induced Airway Injury 

CIA Soldin, Offie P., PhD Georgetown University Tobacco Smoke Exposure Associations with Hormonal Changes 

and the Risk of Spontaneous Abortion 

CIA Tuder, Rubin M., MD University of Colorado Role of Adiponectin in the Protection of Emphysema 

CIA Warner, David, MD Mayo Clinic Reducing Smoke Exposure in Children Facing Surgery 

CIA Welt, Corrine, MD Massachusetts General Hospital Gene/Tobacco Interactions and Ovarian Function 

YCSA Cavallari, Jennifer, Sc.D., CIH Harvard School of Public Health Cardiovascular Effects of SHS in Construction Workers 

YCSA Christoforou, Nicolas, PhD Duke University Engineered Cardiac Patch with Cardiac Progenitors 

2 4 0 P A G E


YCSA Dasgupta, Piyali, PhD Joan C. Edwards School of Medicine Nicotine/Acetylcholine Signaling in Lung Cancer 

at Marshall University 

YCSA Dela Cruz, Charles S., MD, PhD Yale University Mechanisms of Synergy Between Cigarette Smoke and RSV 

YCSA Höti, Naser Uddin, PhD The Johns Hopkins University Generation of Optimized Prostate Specific CRAd Virus 

YCSA Kosmider, Beata, PhD National Jewish Medical and Research Center Human Alveolar Type II Cell Injury by Cigarette Smoke 

YCSA Monzon-Medina, Maria E., PhD University of Miami Epithelial Barrier Disruption in Chronic Bronchitis 

YCSA Seng, Seyha, PhD Beth Israel Deaconess Medical Center Effects of Second Hand Smoking on Development of 

Neurodegenerative Signs 

YCSA Thimmulappa, Rajesh, PhD The Johns Hopkins University NRF2 - A Therapeutic Target for COPD Exacerbation 

YCSA Toonkel, Rebecca, MD Columbia University Inflammation and Stem Cells in Smoke Induced Lung Cancer 

YCSA Vij, Neeraj, PhD The Johns Hopkins University Mechanism of Proteasomal Pathway in COPD and Emphysema 

YCSA Wang, Alice, MD Boston University School of Medicine Smoking and Intrauterine Growth Restriction 

P A G E 2 4 1

APPENDICES: ACRONYMS 

The following is a list of acronyms that are used in the research synopses of FAMRI-funded work. 

AMA 

ASBMB 

BDA 

BLIDP 

CD 

CDC 

CIA 

CoE 

COPD 

CT 

DNA 

FAMRI 

FASEB 

FDA 

HFHS 

HNSCC 

IELCAP 

American Medical Association 

American Society for Biochemistry and Molecular Biology 

Board Designated Award 

Bland Lane International Distinguished Professor 

Clusters of Differentiation; proteins expressed on the cell surface 

of lymphocytes as they mature 

Centers for Disease Control 

Clinical Innovator Award 

Center of Excellence 

Chronic obstructive pulmonary disease 

Computed tomography 

Deoxyribonucleic acid 

Flight Attendant Medical Research Institute 

Federation of American Societies for Experimental Biology. 

Food and Drug Administration 

Henry Ford Health System 

Head and neck squamous cell carcinoma 

International Early Lung Cancer Action Program 

IL- 

JHMI 

JHU 

MRI 

mRNA 

NIH 

NSCLC 

OSHA 

PCR 

RNA 

RT-PCR 

SCC 

SCLC 

SHS 

TNF 

UCSF 

WCDP 

YCSA 

Interleukin 

Johns Hopkins Medical Institutions 

Johns Hopkins University 

Magnetic resonance imaging 

Messenger RNA 

National Institutes of Health 

Non-small cell lung cancer 

Occupational Safety and Health Administration 

Polymerase chain reaction 

Ribonucleic acid 

Real-time polymerase chain reaction 

Squamous cell carcinoma 

Small cell lung cancer 

Second hand tobacco smoke 

Tumor necrosis factor 

University of California San Francisco 

William Cahan Distinguished Professor 

Young Clinical Scientist Award 

APPENDICES: SUPPORTED PUBLICATIONS AND MEETING ABSTRACTS 

Abrams S, Mahoney M, Hyland A, Cummings KM. 

Clean indoor air laws protect hospitality workers: 

evidence from New York State, 2005. Presented 

at the National Conference on Tobacco or 

Health. Chicago, IL, May 4-6, 2005. 

Abrams SM, Mahoney MC, Hyland A, Cummings 

KM, Davis W, Song L. Early evidence on the 

effectiveness of clean indoor air legislation in 

New York state. Am J Public Health 

2006;96:296-298. 

Abrams SM, Mahoney MC, Hyland A, Cummings 

KM. A cross-sectional study of secondhand 

smoke exposure in western New York, 2003. 

Presented at the 10th Annual Society for 

Research on Nicotine and Tobacco Meeting. 

Scottsdale, AZ, Feb 18-21, 2004. 

Abukhdeir A, Vitolo M, Argani P, De Marzo AM, 

Karakas B, Konishi H, Gustin J, Lauring J, Garay 

J, Pendleton C, Konishi Y, Blair BG, Brenner K, 

Garrett-Mayer E, Carraway H, Bachman KE, 

Park BH. Tamoxifen stimulated growth of breast 

cancer due to p21 loss. Proc Natl Acad Sci U S A 

2008;105(1):288-293. 

Abukhdeir AM, Blair BG, Brenner K, Karakas B, 

Konishi H, Lim J, Sahasranaman V, Huang Y, 

Keen J, Davidson N, Vitolo MI, Bachman KE, 

Park BH. Physiologic estrogen receptor alpha 

signaling in non-tumorigenic human mammary 

epithelial cells. Breast Cancer Res Treat 

2006;99(1):23-33. 

Abukhdeir AM, Vitolo MI, Argani P, De Marzo 

AM, Karakas B, Konishi H, Gustin JP, Lauring J, 

Garay JP, Pendleton C, Konishi Y, Blair BG, 

Brenner K, Garrett-Mayer E, Carraway H, 

Bachman KE, Park BH. Tamoxifen-stimulated 

growth of breast cancer due to p21 loss. Proc 

Natl Acad Sci U S A 2008;105:288-293. 

Abuzeid W, Khan K, Jiang X, Cao X, O’Malley BW, 

Li D. DNA damage signaling pathway as a treatment 

target for HNSCC. Presented at the 

American Academy of Otolaryngol Head Neck 

Surg Meeting. San Diego, CA, 2007. 

Abuzeid W, Khan K, Paulson DP, Jiang X, Araki K, 

Reddy N, Jungreis DB, Zhang J, Lapidus RG, 

O’Malley BW, Li D. Dual disruption” therapy for 

head and neck cancer: targeting DNA repair 

pathways to induce cancer cell death. Presented 

at the American Head and Neck Surgery Society. 

San Francisco, CA, 2008. 

Abuzeid W, Khan K, Paulson DP, Jiang X, Araki K, 

Reddy Ni, Jungreis DB, Zhang J, Lapidus RG, 

O’Malley BW, Li D. Disruption of DNA repair 

pathways: chemoradiation-free treatment for cancer. 

Presented at the American Association of 

Cancer Research Meeting. San Diego, CA 2008. 

Abuzeid W, Shi G, Rhee J, Carney J, O’Malley BW, 

Li D. Mutant Rad50-mediated cisplatin 

chemosensitization for the treatment of human 

head and neck cancer. Presented at the American 

Association of Cancer Research Meeting. Los 

2 4 2 P A G E

Angeles, CA, 2007. 

Adar S, Livneh Z. Translesion DNA synthesis across 

non-DNA segments in cultured human cells. 

DNA Repair 2006;5:479-490. 

Adusumilli PS, Chan MK, Ben-Porat L, Mullerad 

M, Stiles BM, Tuorto S, Fong Y. Citation characteristics 

of basic science research publications in 

general surgical journals. J Surg Res 

2005;128(2):168-173. 

Adusumilli PS, Chan MK, Chun YS, Hezel M, 

Chou TC, Rusch VW, Fong Y. Cisplatin-induced 

GADD34 up regulation potentiates oncolytic 

viral therapy in the treatment of malignant pleural 

mesothelioma. Cancer Biol Ther 

2006;5(1):48-53. 

Adusumilli PS, Chan MK, Hezel M, Yu Z, Stiles 

BM, Chou TC, Rusch VW, Fong Y. Radiationinduced 

cellular DNA damage repair response 

enhances viral gene therapy efficacy in the treatment 

of malignant pleural mesothelioma. Ann 

Surg Oncol 2007;14(1):258-269. 

Adusumilli PS, Eisenberg DP, Chun YS, Ryu KW, 

Ben-Porat L, Hendershott KJ, Chan MK, Huq 

R, Riedl CC, Fong Y. Virally directed fluorescent 

imaging improves diagnostic sensitivity in the 

detection of minimal residual disease after potentially 

curative cytoreductive surgery. J Gastrointest 

Surg 2005;9(8):1138-1147. 

Adusumilli PS, Eisenberg DP, Stiles BM, 

Hendershott KJ, Stanziale SF, Chan MK, Hezel 

M, Huq R, Rusch VW, Fong Y. Virally-directed 

fluorescent imaging (VFI) can facilitate endoscopic 

staging and minimally invasive cancer surgery. 

Surg Endosc 2006;13(1):53-64. 

Adusumilli PS, Stiles BM, Chan MK, Chou TC, 

Wong RJ, Rusch VW, Fong Y. Radiation therapy 

potentiates effective oncolytic viral therapy in the 

treatment of lung cancer. Ann Thorac Surg 

2005;80(2):409-417. 

Adusumilli PS, Stiles BM, Chan MK, Eisenberg DP, 

Yu Z, Stanziale SF, Huq R, Wong RJ, Rusch VW, 

Fong Y. Real-time diagnostic imaging of tumors 

and metastases by use of a replication-competent 

herpes vector to facilitate minimally-invasive 

oncological surgery. FASEB J 2006;20(6):726- 

728. 

Adusumilli PS, Stiles BM, Chan MK, Mullerad M, 

Eisenberg DP, Ben-Porat L, Huq R, Rusch VW, 

Fong Y. Imaging and therapy of malignant pleural 

mesothelioma using replication-competent 

herpes simplex viruses. J Gene Med 

2006;8(5):603-615. 

Ahn CA, Lathers D, Wise SK, Mulligan R, 

Schlosser RJ. Quantification of dendritic cells in 

chronic rhinosinusitis. Presented at the Annual 

American Academy of Otolaryngology - Head 

and Neck Surgery Meeting. Washington DC, 

Sept 16-19, 2007. 

Alani RM, Silverthorn CF, Orosz K. Tumor angiogenesis 

in mice and men. Cancer Biol Ther 

2004;3:41-42. 

Albers A, Abe K, Hunt J, Wang J, Lopez-Albaitero 

A, Schaefer C, Gooding W, Whiteside TL, 

Ferrone S, DeLeo A, Ferris RL. Antitumor 

activity of human papillomavirus type 16 E7- 

specific T cells against virally infected squamous 

cell carcinoma of the head and neck. Cancer Res 

2005;65:11146-11155. 

Albers A, Biener L, Siegel M, Cheng D, Rigotti 

NA. Impact of parental home smoking policies 

on policy choices of independently living young 

adults. Tob Control 2009. 

Albers A, Siegel MB, Cheng DM, Rigotti NA, 

Biener L. Effect of local restaurant and bar 

smoking regulations on secondhand smoke 

exposure among Massachusetts adults. Am J 

Public Health 2004;94:1959-1964. 

Albers AB, Siegel M, Cheng D, Biener L, Rigotti 

NA. Household smoking bans and adolescent 

anti-smoking attitudes and smoking initiation: 

findings from a longitudinal study of a 

Massachusetts youth cohort. Am J Public Health 

2008;98:1886-1893. 

Albers AB, Siegel M, Cheng DM, Biener L, Rigotti 

NA. Relation between local restaurant smoking 

regulations and attitudes towards the prevalence 

and social acceptability of smoking: a study of 

youths and adults who eat out predominantly at 

restaurants in their town. Tobacco Control 

2004;13:347-355. 

Albers AE, Ferris RL, Kim GG, Chikamatsu K, 

DeLeo AB, Whiteside TL. Immune responses to 

p53 in patients with cancer: enrichment in 

tetramer+ p53 peptide-specific T cells and 

regulatory CD4+CD25+ T cells at tumor sites. 

Cancer Immunol Immunother 2005;54:1072- 

1081. 

Al-Delaimy WK, Stampfer MJ, Manson JE, Willett 

WC. Toenail nicotine levels as predictors of 

coronary heart disease among women. Am J 

Epidemiol 2008;167:1342-1348. 

Al-Delaimy WK, Willett WC. Measurement of 

Tobacco Smoke exposure: comparison of toenail 

nicotine biomarkers and self-reports. Cancer 


Aldonyte R, Brantly M, Block E, Patel J, Zhang J. 

Matrix metalloproteinase-2 is responsible for 

nuclear matrix degradation in cigarette smoke 

induced apoptosis in pulmonary artery endothelial 

cells. Proceedings of the American Thoracic 

Society 2006; 3:A681. 

Aldonyte R, Hutchinson ET, Jin B, Brantly M, 

Block ER, Patel J, Zhang J. Endothelial alpha-1- 

antitrypsin attenuates cigarette smoke induced 

P A G E 2 4 3

apoptosis. COPD. c2008;5:153-162. 

Aldonyte R, Jin B, Brantly M, Block E, Patel J, 

Zhang J. Alpha-1-antitrypsin uptake and antiapoptotic 

effect in pulmonary artery endothelial 

cells is down regulated by blockage of VEGF R2. 

Proc of the Am Thor Soc 2006;3:A305. 

Aldonyte R, Jin B, Brantly M, Block E, Patel J, 

Zhang, J, Multi-tasking of major human antiprotease: 

alpha-1-antitrypsin is up taken by lung 

endothelial cells and ameliorates cigarette smokeinduced 

apoptosis. Presented at The 4th General 

Meeting of the International Proteolysis Society 

2005. 

Alexander GR, Wingate MS, Salihu H, Kirby RS. 

Fetal and neonatal mortality risks of multiple 

births. Obstet Gynecol Clin North Am 2005;32:1- 

16. 

Alexander MR, Salihu HM, Dwight RJ. Survival of 

triplets born to United States teenagers. Am J 


Alio AP, Salihu HM. Maternal determinants of 

pediatric preventive care utilization among blacks 

and whites. J Natl Med Assoc 2005;97:792-797. 

Aliyu MH, Jolly PE, Ehiri J, Salihu HM. High parity 

and adverse birth outcomes. Exploring the 

maze. Birth 2005;32:45-59. 

Aliyu MH, Salihu HM, Keith LG, Ehiri JE, Islam 

MA, Jolly PE. Extreme parity and risk of stillbirth. 



MA, Jolly PE. High parity and fetal morbidity 

outcomes. Obstet Gynecol 2005;105:1045-1051. 


MA, Jolly PE. Trends in birth across high parity 

groups by race/ethnicity and maternal age in the 

United States. J Natl Med Assoc 2005;97:799- 

804. 

Allison EM, Paszkiewicz GM, Timm E, 

Podniesinski E, Wallace PK, Pauly JL. Phenotypic 

analysis of surface membrane antigens of fluorescent 

human lung macrophages (‘smoker cells’) 

from surgically excised lung tissues of patients 

with lung cancer. Presented at the Annual 

FAMRI Meeting. Miami, FL, May 12-14, 2004. 

Alpert H. Factors associated with youth support of 

public smoking bans in developing countries 

worldwide: Results from the Global Youth 

Tobacco Survey. Presented at 14th World 

Conference on Tobacco or Health, Mumbai, 

India, March 8-11, 2009. 

Alpert H. Manipulation of free nicotine and its 

dosing to target high risk groups. presented at 

the cigarette industry’s entry into the smokeless 

tobacco market: research and policy questions 

and concerns. Meeting at Harvard School of 

Public Health. Boston, MA, July 10, 2008. 

Alpert H. Role of the secondary school 

environment on secondhand smoke exposure 

among Cypriot youth. Presented at 14th World 

Conference on Tobacco or Health. Mumbai, 

India, March 8-11, 2009. 

Alpert H. Youth attitudes and public smoking ban 

policies in developing countries worldwide: 

Results from the global youth tobacco survey. 

Presented at 14th World Conference on Tobacco 

or Health. Mumbai, India, March 8-11, 2009. 

Alpert HR, Carpenter CM, Travers MJ, Connolly 

GN. Environmental and economic evaluation of 

the Massachusetts Smoke-Free Workplace Law. J 

Community Health 2007;32:269-281. 

Alpert HR, Connolly G, Rosen LJ. Freedom from 

tobacco. Israel Med Assoc J 2008;10:92. 

Alpert HR, Connolly GN, Koh H. After the master 

settlement agreement: Targeting and exposure of 

youth to magazine tobacco advertising. Health 

Affairs 2008;27(6)503-512. 

Alpert HR., Spalletta R, Connolly GN, O’Connor 

RJ. Recent advances in cigarette ignition 

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Yue W, Dacic S, Sun Q, Landreneau R, Guo M, 

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Zarek PE, HuangCT, Lutz ER, Kowalski J, Horton 

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Zhai R, Liu G, Asomaning K, Su L, Kulke MH, 

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Zhai R, Liu G, Zhou W, Su L, Heist RS, Lynch TJ, 

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lung cancer. Clin Cancer Res 2008;14: 612-617. 

Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren 

YR, Rey S, Hammers H, Chang D, Pili R, Dang 

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Presented at The Sixth Meeting on Programmed 

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Zhang J, Block ER, Patel JM. Bax nitration and 

oligomerization promotes Bax insertion into 

mitochondria and release of cytochrome c, 2006. 

Presented at The International Cell Death 

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Zhang J, Block ER, Patel JM. Cigarette smokeinduced 

upregulation of ET-1 expression is associated 

with extracellular signal-regulated kinase 

1/2 (Erk1/2) phosphorylation/activation of vascular 

endothelial zinc finger 1 (Vezf1), 2006. 

Presented at Evolution of Pulmonary 

Hypertension: Emerging Diseases and Novel 

therapeutics Meeting. The National Institute of 

Health, Bethesda, MD, Dec 7-8, 2006. 

Zhang J, Bruesewitz M, Primak A, Fletcher JG, 

McCollough CH. Partial reconstructions in 

multidetector row CT (MDCT), 2005. 

Presented at the Radiological Society of North 

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Program. Chicago IL, Nov, 2005. 

Zhang J, Fletcher JG, Bruesewitz M, Primak A, 

McCollough CH. Inaccuracies in the 

measurement of object size and attenuation 

resulting from partial scan reconstruction 

artifacts, 2005. Presented at the Radiological 

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Annual Meeting Program. Chicago, IL, Nov, 

2005. 

Zhang J, Fletcher JG, Primak A, McCollough CH. 

Variation in the measurement of object size and 

attenuation using partial scan reconstruction 

algorithms in cardiac CT, 2005. Presented at the 

Sixth International Conference on Cardiac 

Computed Tomography Sponsored by 

Massachusetts General Hospital and Harvard 

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Zhang J, Fletcher JG, Raghavan, Araoz P, Vrtiska 

TJ, McCollough CH. Validation of vessel 

distensibility measurement using ECG-gated 

MDCT, 2005. Presented at the Radiological 

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2005. 

Zhang J, Jin B, Mohammed KA, Block ER, Patel 

JM, Antony VB. Cigarette smoke-enhanced lung 

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with S-nitrosylation and inhibition of mitochondrial 

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2 8 6 P A G E

the American Thoracic Society 2005; 2:A136. 

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is associated with PI3K signaling in cultured 

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Zhang J, Narayan VM, Block ER, Patel JM. 

Peroxynitrite-induced Bax nitration and 

oligomerization promote Bax insertion into 

mitochondria and release of cytochrome c, 2007. 

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pathways by destabilizing EGFR mRNA in ERnegative 

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Zhou W, Suk R, Liu G, Park S, Neuberg DS, Wain 

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Vitamin D is associated with improved survival in 

early-stage non-small cell lung cancer patients. 


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P A G E 2 8 7

APPENDICES: INDEX BY AUTHOR 

Abdullah, Abu S 238 

Abraham, Theodore P 232 

Akulapalli, Sudhakar 57, 109, 237, 261 

Al-Delaimy, Wael K 135, 219, 230, 240, 243, 274 

Alani, Rhoda 230 

Alani, Rhoda M 230 

Alpert, Hillel R 238 

Altes 166, 232 

Altes, Talissa 232 

Alumkal, Joshi J 236 

Antony, Veena 49, 52, 146, 236, 251, 286 

Arenberg, Douglas A 232 

Avraham, Shalom 236 

Ball, Douglas W 231, 236 

Balmes, John 238 

Bansal-Travers, Maansi 239 

Banzhaf, John F 223, 233 

Barkley-Elliman, Laura 115, 239 

Barlev, Nickolai A 80, 233 

Barnes, Betsy J 231 

Barrett, Edward G 51, 91, 236 

Barry, William H 233 

Bartlett, Donald 236 

Basseres, Daniela S 239 

Bauer, John A 16 

Becker, Patrice M 68, 129, 149, 235, 261 

Begum, Shahnaz 239 

Benarafa, Charaf 239 

Bennett, William P 232 

Benowitz, Neal L 230, 238 

Bernard, Hans-Ulrich 236 

Bero, Lisa A 231 

Best, Dana 43 

Bhattacharya, Raka 78, 123, 231, 252 

Biswal, Shyam 230, 238 

Blissard, Lani 13, 228 

Bluestein, Danny 230, 232 

Blum, Alan 230 

Bowler, Russell 234 

Brandt, Allan M 232 

Briegel, Karoline J 76, 238 

Brown, Anthony 231 

Bruijnzeel, Adriaan W 184, 185, 236 

Buka, Stephen L 189, 200, 235, 265 

Bunz, Fred 231, 238 

Burkard, Mark E 78, 237, 248, 273 

Burns, David M 217, 230, 292 

Butter, Karen 177, 232 

Cairns, Paul 97 

Calfee, Carolyn 237 

Califano, Joseph A 230, 235 

Canfield, Stephen M 235 

Carlisle, Diane L 155 

Carraway, Hetty E 233 

Carson, Johnny L 232, 236 

Casola, Antonella 238 

Castrillon, Diego H 130, 195, 235, 260 

Chan, Annie W 238 

Chan, Sophia Siuchee 190, 236 

Chan, Timothy 239 

Chatterjee, Aditi 59, 63, 64, 84, 94, 239, 251, 284 

Chen, Chang-Yan 72, 236 

Chong, Rachel Ying Vun 36, 196, 230, 274 

Chu, Hong Wei 233, 238 

Cohen, Noam A 233, 240 

Coldren, Christopher D 233 

Cole, Phillip 37 

Connolly, Gregory 233, 236, 238 

Cousins, Scott W 232 

Crane-Godreau 17, 18, 179, 229, 236, 251, 284 

Cui, Zhiyong 236 

Cummings, K. Michael 234 

Cutting, Garry R. 236 

D'Armiento, Jeanine M. 56, 145, 146, 232, 253, 254, 262, 272, 

277, 283 

Dai, Zhenhua 238 

Damico, Rachel 239 

Dannenberg, Andrew 46 

Das, Salil K. 75 

Datta, Pran 233 

Davis, Ronald M. 2, 17, 217, 228 

Daynard, Richard A. 226, 234 

De Marco, Teresa 25, 140, 231, 249 

Deftos, Leonard 119, 230, 248, 257, 272, 281 

Deng, Xingming 230, 233, 238, 240 

Denmeade, Samuel R., 66, 124, 129, 167, 233, 256, 263 

Di Cello, Francescopaolo 237 

Edvinsson, Lars 233, 236 

Edwards, Michael G. 89, 156, 234, 241, 246 

Eisner, Mark 28 

Ellenhorn, Joshua 233 

Erb, Teresa M 237 

Ezzie, Michael E. 159, 237 

Falta, Michael 234 

Farassati, Faris 236 

Ferris, Robert L. 85, 94 

Fleischmann, Kirsten 231 

Fletcher, Joel 232 

Fomenkov, Alexey 231 

Fong, Yuman 232, 236 

Foronjy, Robert F 231, 238 

Foster, Charles B 236 

Franzmann, Elizabeth 230 

Fuchs, Ephraim J 231 

Gabrielson, Kathleen L 238 

Garofalo, Roberto P 233 

Gartenhaus, Ronald B 230, 238 

Geller, Alan C 236 

Gentile, Deborah A 194, 232 

Getzenberg, Robert H 234 

Gillespie, M. Boyd 238 

Gilley, David P 238 

2 8 8 P A G E

Glantz, Stanton A 230 

Gold, Mark S 232, 235, 237 

Gold, Warren M 29 

Goldman, Radoslav 235 

Gonzalez-Burchard, Esteban 27 

Gorlova, Olga Y 233 

Gottlieb, Mark 42, 45, 156, 162, 255, 282 

Grando, Sergei A 230, 234 

Groner, Judith 235 

Grossman, William 240 

Guerrero-Plata, Maria Antonieta 192, 237, 249, 256 

Guo, Zhongmin 237 

Hahn, Ellen J 232 

Haley, Kathleen J 237 

Halmos, Balazs 233 

Hamilos, Daniel L 231, 238 

Hammond, S. Katherine 240 

Hanahan, Douglas 234 

Hann, Christine L 237 

Hartney, John M 237 

Hazra, Saswati 234 

Hecht, Steven S 230 

Henschke, Claudia I 46, 47 

Herynk, Matthew H 239 

Heston, Warren D. W 238 

Heys, Jeffrey J 236 

Hirshberg, Abraham 234 

Holtgrave, David 39 

Hoque, Mohammad O 236 

Horton, Maureen 231 

Hsieh, Jer-Tsong 238 

Hughes, Suzanne C 236 

Hung, Chien-Fu 231 

Hunter, Terri B 237 

Hurley, Paula J 237 

Hurt, Richard D 232 

Hyland, Andrew 230, 237, 238 

Idell, Steven 234 

Im, Eunok 236 

Inana, George 237 

Ishov, Alexander M 232 

Jacobson, Francine L 232 

Jaimes, Edgar A 231, 238 

Jaspers, Ilona 235, 240 

Jeyaseelan, Sambithamby 237 

Jiang, Feng 238 

Joad, Jesse P 230 

Juergens, Rosalyn 237 

Jukosky, James A 239 

Kachhap, Sushant K 239 

Kajon, Adriana Elisa 238 

Kamat, Ashish 234 

Karhadkar, Sunil S 233 

Kassem, Nada 236 

Keshamouni, Venkateshwar 233 

Khan, Saeed R 231 

Kim, Jean 232 

Kim, Myoung Sook 237 

King, Landon S 232 

Klareskog, Lars 232, 240 

Klein, Jonathan D 41, 44 

Kobzik, Lester 230 

Kogevinas, Manolis 239 

Kornberg, Lori J 95, 231, 263 

Krug, Lee M 239 

Laden, Francine 230 

Lagercrantz, Hugo 234 

Lai, Stephen Y 234 

Lane, Andrew P 232, 237 

Lane, Bland 13, 14, 25, 29, 44, 216, 228, 229, 230, 238, 242 

Lane, Maureen 232 

Larsson, Lennart P 237 

Lauring, Josh 237 

Lavelle, James C 236 

Lee, Byron K 233 

Lee, David J 230, 231, 235, 240 

Lee, Walter T 237 

LeMaitre, Vincent 56, 136, 145, 237, 253, 254 

LeVan, Tricia D 239 

Levantini, Elena 236 

Levy, Douglas 239 

Li, Daqing 230 

Li, Dean Y 234 

Li, Luyuan 234 

Lin, Yong Y 234 

Ling, Pamela 233, 240 

Liu, Jun 37 

Liu, Yijun 232 

Liuba, Petru 233 

Livneh, Zvi 31, 34, 243, 245, 266, 272 

Loeb, David M 230 

Luo, Hongbo R 237 

Mahoney, Martin 231 

Maitra, Anirban 239 

Marin-Castano, Maria 239 

Marsit, Carmen J 236 

Martin, Kathleen A 239 

Martin, Stuart S 237 

Martinez, Mark L 236 

Massion, Pierre P 231 

Max, Wendy 29 

McClean, Michael 238 

McGrath-Morrow, Sharon A 237 

Meeker, John D 234 

Meyers, Caren 39 

Meyers, David 37 

Meyerson, Matthew 230 

Michel, Loren 236 

Milberger, Sharon 235, 237 

Miller, David P 230 

Mirhashemi, Ramin 231 

Mishra, Archana 230 

Moreb, Jan 231 

Morgan, James P 235 

Movsisyan, Narine 40 

Nakshatri, Harikrishna 235 

Narayan, Satya 231, 239 

Navas-Acien, Ana 235 

Nelkin, Barry 235 

Ng, Shu-Wing 235 

Niedbala, R. Sam 235 

O'Neill, J. Timothy 234, 239 

Oren, Moshe 31, 32, 33, 245, 269, 274, 286 

Owen, Caroline A 235 

P A G E 2 8 9

Palmer, James N 235 

Pan, Quintin 239 

Park, Ben-Ho 68, 129 

Park, Jong-In 238 

Patz, Samuel 239 

Pauly, John L 230, 234 

Peacock, Craig D 240 

Pearlman, Justin D 231 

Pearse, David B 239 

Peters, Edward 231 

Petrache, Irina 235 

Petty, Thomas L 232 

Pili, Roberto 230 

Potter, David A 234 

Powell, Jonathan D 235 

Prakash, Y. S 239 

Pritsos, Chris A 239 

Prokhorov, Alexander V 235 

Rade, Jeffrey 40 

Raman, Venu 231, 235 

Ratner, Adam J 237 

Ratovitski, Edward 234, 240 

Rechavi, Gideon 31, 32, 34, 285 

Redberg, Rita 26, 29, 255, 258 

Reisman, David N 234 

Repace, James 230 

Reynolds, Paul R 238 

Rhee, Sang Hoon 238 

Rigotti, Nancy 230, 235, 240 

Robbins, Richard A 231 

Rocco, James W 232 

Rodriguez, Ronald 230 

Rogers, Richard J 141 

Rosen, Laura 240 

Rosser, Charles J 239 

Rudek, Michelle A 35, 38, 82, 113, 256, 261, 275 

Rudin, Charles M 35, 36, 113, 121, 232, 233, 240, 257, 261, 275 

Saha, Debabrata 231, 239 

Salihu, Hamisu M 231 

Samet, Jonathan 232 

Schlosser, Rodney J 235 

Schouenborg, Jens 234 

Seagrave, JeanClare 234 

Sebrié, Ernesto 240 

Selaru, Florin M 240 

Serafini, Paolo 240 

Shachaf, Catherine M 233 

Shams, Homayoun 235 

Shapiro, Steven D 235 

Sharma, Sanjai 238 

Shim, Yun M 234 

Shusterman, Dennis 238 

Sidhaye, Venkataramana 240 

Sidransky, David 3, 13 

Siegel, Michael B 230 

Singh, Anju 238 

Singh, Bhuvanesh 235 

Singh, Shashibushan P 198 

Slingerland, Joyce 237 

Soldin, Offie P 235, 240 

Spanier, Adam 238 

Spitz, Margaret R 223 

Springer, Matthew L 239 

Srisuma, Sorachai 236 

Stabile, Laura A 233 

Starcher, Barry 232 

Stearman, Robert S 232 

Stewart, Michael 47 

Stillman, Frances 40 

Stroud, Laura 237 

Su, Yunchao 232, 239 

Subbaramaiah, Kotha 47 

Suddereth, Leisa 229 

Switzer, Paul 231 

Tanski, Susanne E 45 

Taraseviciene-Stewart, Laimute 239 

Taylor, Rodney J 237 

Teret, Stephen P 232 

Tesfaigzi, Yohannes 237 

Travers, Mark J 236 

Trink, Barry 231, 237 

Turino, Gerald 234 

Tyagi, Shivraj 239 

Valacchi, Giuseppe 237 

van der Vliet, Albert 239 

Van Winkle, Laura S 237 

Vandivier, R. William 237 

Vassallo, Robert 234 

Vigodner, Margarita 240 

Vincek, Vladimir 234 

Wadler, Scott 232 

Walter, Robert E 231 

Wang, Hong-Gang 237 

Watkins, D. Neil 230 

Watkins, D. Neil, 230 

Weitzman, Michael 45 

Wilder, Julie A 235 

Wilk, Jemma B 234 

Wilson, Andrew A 238 

Winickoff, Jonathan P 231, 239 

Wolf, Jeffrey S 232 

Wong, Brian J. F 231, 237 

Wong, Kwok-Kin 234 

Wong, Richard J 232, 237 

Woodworth, Bradford A 240 

Wu, Wenxin 154 

Xiao, Lei 230 

Xing, Michael M 134 

Yang, Jun 234 

Yankelevitz, David F 46, 47, 122, 264 

Yedgar, Saul 238 

Yolton, Kimberly 237 

Young, Patricia L 13, 228 

Yu, Jian 233 

Zahnow, Cynthia 233, 239 

Zemans, Rachel L 240 

Zhai, Rihong 238 

Zhang, Jianliang 233, 237 

Zhang, Jin 233 

Zhao, Feng 238 

Zheng, Yun-Ling 234 

Zhou, Qun 240 

Zhou, Wei 233 

2 9 0 P A G E

APPENDICES: INDEX BY SUBJECT 

Acute Lung Injury 48, 100, 104, 237, 248, 254, 268, 278, 291 

Airway Diseases 48, 54, 56, 291 

Arthritis 38, 57, 209, 232, 240, 262, 267, 272, 291 

Author Index 291 

Blissard, Lani 13, 228, 288, 291 

Board Designated Awards 14, 291 

Cahan, William 2, 14, 216, 223, 242 

Cancer, Bladder 18, 19, 58, 59, 60, 61, 62, 63, 64, 96, 97, 98, 167, 

230, 234, 235, 236, 237, 238, 239, 240, 248, 251, 252, 256, 258, 

267, 272 

Cancer, Breast 19, 37, 59, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 

75, 76, 77, 78, 79, 80, 81, 82, 124, 128, 129, 191, 230, 231, 233, 

234, 235, 236, 237, 238, 239, 240, 242, 250, 251, 252, 259, 270, 

271, 278, 279, 284, 287 

Cancer, Cervical 19, 82, 83, 236, 248 

Cancer, Chemotherapeutic Agents 58, 291 

Cancer, Gastric 84, 240 

Cancer, Head and Neck 13, 31, 34, 63, 81, 84, 85, 86, 87, 88, 89, 

90, 91, 93, 94, 95, 96, 97, 107, 184, 230, 231, 232, 234, 237, 238, 

239, 240, 242, 245, 251, 254, 262, 264, 265, 271, 272, 274, 275, 

277, 278, 280, 291 

Cancer, Kidney 97, 98, 231, 246, 248, 252 

Cancer, Lung 30, 31, 32, 33, 34, 35, 36, 38, 39, 46, 47, 49, 63, 77, 

78, 91, 92, 95, 98, 99, 100, 101, 102, 103, 104, 105, 107, 108, 

109, 110, 111, 112, 113, 114, 115, 117, 118, 119, 120, 121, 122 

Cancer, Lymphoma 12, 37, 107, 121, 124, 125, 230, 291 

Cancer, Multiple 125, 130, 291 

Cancer, Ovarian 131, 235, 291 

Cancer, Prostate 19, 37, 63, 66, 119, 130, 131, 132, 133, 134, 167, 

238, 239, 246, 248, 254, 263, 272, 291 

Cancer, Thyroid 81, 85, 88, 94, 126, 128, 134, 135, 232, 258, 259, 

265, 266, 273, 275, 281, 285, 291 

Cardiovascular 12, 16, 17, 25, 26, 28, 46, 47, 54, 135, 136, 137, 

138, 140, 141, 143, 165, 174, 189, 196, 197, 205, 206, 214, 215, 

216, 217, 218, 226, 228, 230, 231, 233, 234, 235, 240, 246, 252, 

255, 256, 265, 273, 291 

Chronic Kidney Disease 143, 144, 206, 238, 291 

Commonly Used Acronyms 291 

COPD 20, 21, 22, 25, 26, 27, 28, 36, 46, 49, 50, 55, 100, 112, 144, 

145, 146, 147, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 

159, 160, 161, 162, 165, 193, 200, 213, 222, 233, 234, 235, 236, 

237, 238, 239, 240, 241, 242, 244, 247, 252, 253, 254, 261, 266, 

267, 271, 280, 281, 282, 291 

Davis, Ronald M 235, 288, 291 

Diagnostic Techniques 102, 162, 164, 229, 291 

Disease Prevention 12, 41, 167, 175, 217, 291 

Distinguished Professors †160, 216, 291 

Education 14, 17, 25, 29, 30, 41, 44, 45, 47, 167, 176, 181, 217, 

219, 222, 226, 228, 233, 235, 240, 291 

Expanding Grantees Research Capabilities Through 

Preservation of Tobacco Disease Documents 177, 291 

Exposure to Second Hand Tobacco Smoke 12, 14, 17, 45, 117, 

136, 172, 178, 188, 202, 229, 231, 233, 234, 236, 291 

FAMRI Award Categories 14, 291 

FAMRI Centers of Excellence 25, 44, 291 

FAMRI Grantee Portal 227, 291 

FAMRI Supported Publications and Meeting Abstracts 291 

Geographic Distribution 15, 291 

Highlighted Research 291 

Hormonal Changes from Tobacco Exposure 189, 291 

Immune Function Impacted by Tobacco Smoke 191, 194, 291 

Infectious Diseases 50, 194, 195, 291 

Lane, Bland 13, 14, 25, 29, 44, 216, 228, 229, 230, 238, 242, 289, 

291 

List of FAMRI Grantees 230, 231, 232, 233, 235, 236, 238, 240, 

291 

Menopause 21, 65, 195, 235, 253, 291 

Neurobehavioral Consequences of Tobacco Exposure 195, 

196, 291 

Peer Reviewed Awards 14, 291 

Personal Thoughts from the Flight Attendant Members of the 

Board of Trustees 228, 291 

Pregnancy and Perinatal Effects from Tobacco Exposure 197, 

204, 291 

Research Summaries 291 

Richmond, Julius B 2, 12, 13, 41, 44, 187, 217, 235, 265, 291 

Sinusitis 23, 154, 181, 183, 205, 206, 207, 208, 209, 210, 211, 212, 

217, 222, 231, 232, 233, 237, 238, 240, 291 

Skin and Second Hand Smoke 212, 291 

Spermatogenesis 22, 213, 291 

Suddereth, Leisa 229, 290, 291 

Vision 3, 36, 214, 215, 264, 291 

Young, Patricia L 13, 228, 290, 291 

P A G E 2 9 1

NOTES: 

2 9 2 P A G E

NOTES: 

P A G E 2 9 3

ATTRIBUTION 

FLIGHT ATTENDANT MEDICAL RESEARCH INSTITUTE 

2009 COMPENDIUM 

The Trustees of FAMRI acknowledge and thank the following individuals for their work in producing FAMRI’s 

fourth edition of its Compendium containing a crystallized description of the work FAMRI funds and its impact. 

SCIENTIFIC EDITOR 

David M. Burns, MD, Professor Emeritus, University of San Diego 

AMERICAN INSTITUTE OF BIOLOGICAL SCIENCES 

EDITORS 

Margaret Chamberlin, PhD 

Nicole Reynolds, MS 

EDITORIAL STAFF 

Afton Carpenter, BS 

Tina Rosenthal, MHS 

David Irwin, PhD 

2 9 4 P A G E

2009 FAMRI MONOGRAPH: PREVENTION, TREATMENT AND CURE OF DISEASES CAUSED FROM EXPOSURE TO TOBACCO SMOKE

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