SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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I N T R O D U C T I O N A N D P R O G R E S S R E P O R T 

T A B L E O F C O N T E N T S 

INTRODUCTION AND 

PROGRESS REPORT 

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LEADERSHIP 

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MULTIDISCIPLINARY RESEARCH 

PROGRAMS 

Cancer Prevention and 1 

Control Program 

Clinical Oncology Research Program 33 

Tumor Cell Biology Program 65 

Tumor Immunology Program 103 

Viral Oncology Program 129 

SHARED RESOURCES 

Analytical Imaging Core 143 

Biostatistics 145 

Cell Purification and Banking Facility 146 

Clinical Research Services Resource 147 

DNA Core Facility 148 

EDITOR 

W. Jarrard Goodwin, M.D., F.A.C.S. 

Director, University of Miami 

Sylvester Comprehensive Cancer Center 

PRODUCTION COORDINATION 

Office of Research Administration 

Office of Marketing and Communications 

Sabia Communications 

Flow Cytometry Resource 149 

Gene Knockout and Transgene Facility 150 

Histology Research Lab Core 151 

Informatics 152 

Molecular Analysis Core 153 

Population Research Core 154 

PUBLICATIONS 155 

GLOSSARY 191 

UM/Sylvester Comprehensive Cancer Center Scientific Report 2004




I N T R O D U C T I O N A N D 

P R O G R E S S R E P O R T 


Director, University of Miami Sylvester Comprehensive Cancer Center 

INTRODUCTION 

Since publishing our last Scientific Report in 

2002, much has changed at the University of 

Miami Sylvester Comprehensive Cancer Center. 

We have recruited more than 25 new faculty 

members, most of whom are physician-scientists, 

reflecting our commitment to translational 

research. Our Institutional Review Board has 

approved and opened 160 therapeutic clinical trials. 

We have strengthened our five multidisciplinary 

research programs and opened new shared 

resources, most notably the Population Research 

Core that supports population-based cancer 

prevention and control research at UM/Sylvester. 

With assistance from the Population Research 

Core, we are increasing the diversity of clinical 

trial participants to represent the racial, ethnic, 

and socioeconomic composition of South 

Florida’s diverse and unique community. Much 

of this has been done under the thoughtful leadership 

of Joseph D. Rosenblatt, M.D., associate 

director, clinical and translational research, and 

the several senior scientists he’s already brought 

to South Florida. Dr. Rosenblatt joined the 

University of Miami School of Medicine in 2001 

as division chief of Hematology-Oncology. 

His presence can be felt everywhere. 

UM/Sylvester’s Best Friend 

Many of you may have known or heard about Jay 

W. Weiss, whom we often describe as the “best 

friend UM/Sylvester will ever have.” As chairman 

of the board of governors, Jay led UM/Sylvester 

during its most challenging years, and did so with 

integrity, tenacity, and grace. Jay’s vision and 

leadership continually invigorated and inspired us 

to reach new heights. To Jay, who lost his battle 

with cancer earlier this year, and the many others 

who continue to support UM/Sylvester each and 

every day, we dedicate this report. As we continue 

our quest to cure cancer and to ensure the best 

possible quality of life for those suffering from 

this disease, we know we do so with the support 

of many friends and colleagues. During the past 

two years, UM/Sylvester has been the proud recipient 

of nearly $56 million in cancer-related 

research grants and more than $17 million in 

philanthropy (to support research). We continually 

are expanding our research and clinical facilities 

and planning for the day when we can start 

building much-needed new infrastructure. 

Cancer Incidence and Death Rates 

Despite all the success we’ve had as a nation and 

the important research that’s underway across 

the globe, cancer remains a threat to this society. 

According to the American Cancer Society, 1.3 

million new cancer cases will be reported this 

year, and Florida stands second only to California, 

projecting more than 96,000 new cancer 

cases in 2004. But we have made progress, which 

I highlight below. According to the Annual 

Report to the Nation, 1 Americans’ risk of getting 

and dying from cancer continues to decline 

and survival rates for many cancers continue 

to improve: 

• Both overall observed cancer incidence rates 

and death rates from all cancers combined have 

dropped. 

• We’ve seen the first ever drops in lung cancer 

incidence rates in women. 

• The percentage of patients who have survived 

more than five years post-diagnosis has 

increased in the past two decades. 

UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 

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• Among men, cancer incidence rates have 

recently declined for seven of the top 15 cancer 

sites: lung, colon, oral cavity, leukemia, stomach, 

pancreas, and larynx. 

• In addition to lung cancer, incidence rates 

among women also have declined in: colon, 

cervix, pancreas, ovary, and oral cavity cancers. 

• Childhood cancers have shown some of the 

largest improvements in cancer survival during 

the past 20 years. 

• There are, however, wide variations in survival 

associated with race and ethnicity; in every 

racial and ethnic population, with the exception 

of Asian/Pacific Islander women, the risk of 

cancer death from all cancer sites combined was 

higher than the risk of death for non-Hispanic 

white patients. 

The State of Florida, the citizens of South 

Florida, and the University of Miami are investing 

heavily in translational research—with ideas 

flowing from the laboratory bench to the patient’s 

bedside and back again—which is the essence 

of a comprehensive cancer center, the essence of 

UM/Sylvester. I am proud to tell you about the 

important translational research underway at 

UM/Sylvester and the equally important basic 

science and cancer prevention and control 

research that undergirds and strengthens our 

efforts. 

PROGRESS REPORT 

Scientists at UM/Sylvester are grouped into 

five multidisciplinary research programs that 

reflect our strengths and our priorities—Cancer 

Prevention and Control, Clinical Oncology Research, 

Tumor Cell Biology, Tumor Immunology, 

and Viral Oncology. Our scientists work within 

the established research programs and with physicians 

in UM/Sylvester’s 15 multidisciplinary, sitebased 

oncology groups. Together we design and 

conduct the clinical trials necessary to test the 

value of new prevention, screening, diagnosis, 

and treatment protocols. Examples of significant 

research currently taking place at UM/Sylvester 

are included in this report, which is organized 

by multidisciplinary research program. We 

also have provided descriptions of each of our 

shared resources and a list of publications by 

author. Several research projects of particular 

note are highlighted here: 

Research Highlights 

Note: More information also can be found at 

www.sylvester.org. 

• UM/Sylvester is expanding the use of a vaccine 

for patients with non-small cell lung cancer. 

It now will be administered to two new groups 

of patients: those who have surgery to remove 

lung tumors and those who complete their 

first cycle of standard chemotherapy. The lung 

cancer vaccine was developed by Eckhard R. 

Podack, M.D., Ph.D., UM/Sylvester’s Associate 

Director, Basic Science and Chairman of 

Microbiology and Immunology, and has been 

available in research protocols at UM/Sylvester 

for more than three years. UM/Sylvester is the 

only facility in the United States that does immunotherapy 

using the B7.1 vaccine for lung 

cancer. Luis Raez, M.D., F.A.C.P., asssitant 

professor of Medicine and Epidemiology and 

Public Health, administered the vaccine to 19 

people who had an expected survival of less 

than six months; six or them are still diseasefree 

and three have surpassed the three-year 

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mark with no sign of relapse. This disease is 

lethal and the average survival for this diagnosis 

is less than one year. The results of the threeyear 

study were published on July 15 in the 

Journal of Clinical Oncology. 

• A study just published in the New England Journal 

of Medicine could have huge implications 

for the thousands of children diagnosed with 

cancer every year, raising hope they can avoid 

potentially fatal cardiac problems caused by 

their treatment. Steven E. Lipshultz, M.D., 

professor and chairman of Pediatrics at the University 

of Miami School of Medicine, is the lead 

author of the study, which reveals that using a 

heart-protective drug dexrazoxane (under the 

brand name Zinecard) before chemotherapy 

sharply lowered the amount of heart damage. 

The drug works by soaking up spare iron in the 

blood that normally would bind with the chemotherapy 

drug to produce compounds known 

to destroy heart muscle. The study, which began 

in 1995, tracked 200 childhood leukemia 

patients in the United States and Canada for 

three years. 

• Howard T. Petrie, Ph.D., professor of Microbiology 

and Immunology at the University of 

Miami School of Medicine, has identified a 

key step in the path that stem cells take in 

supporting the body’s immune system. His 

work was published in the June 16 issue of the 

journal Immunity. Finding a way to cultivate 

T-cell growth could lead to new therapies that 

strengthen the immune system in patients with 

a variety of illnesses. 

• A seven-year international study revealed that 

less-invasive laparoscopic surgery for colon 

cancer is just as effective as traditional open 

surgery when performed by an experienced surgeon—but 

with faster recovery times and fewer 

complications. Three UM/Sylvester colorectal 

surgeons were involved in the study, published 

in the New England Journal of Medicine in May 

2004—Michael D. Hellinger, M.D., F.A.C.S., 

F.A.S.C.R.S., division chief of Colon and Rectal 

Surgery at the University of Miami School of 

Medicine; Laurence R. Sands, M.D., F.A.C.S., 

F.A.S.C.R.S., and Rene F. Hartmann, M.D., 

F.A.C.S., F.A.S.C.R.S. The study compared 

patient outcomes at three and five years after 

surgery and found no significant difference in 

recovery, relapse, or survival between the two 

techniques. 

• Izidore Lossos, M.D., associate professor of 

Medicine, is the lead author of a landmark 

lymphoma study published in April 2004 in 

the New England Journal of Medicine. The study 

identifies six genes that can predict whether a 

patient’s lymphoma will respond to standard 

treatment. This finding by researchers at the 

University of Miami School of Medicine, 

Stanford University School of Medicine, and 

Applied Biosystems could result in the first 

gene-based screening to identify people who 

need aggressive therapy. 

• Glen N. Barber, Ph.D., professor of Microbiology 

and Immunology and co-leader of the Viral 

Oncology Program at UM/Sylvester, is conducting 

research into using the tumor destroying 

properties of viruses for therapeutic purposes. 

This research has focused on a recombinant 

vesicular stomatitis virus (VSV) that expresses 

virus-like particles (VLP). VLP may be used 

for immunizing, preventing, or treating viral 

infections. Dr. Barber has demonstrated the 

feasibility of generating large amounts of VLP, 

including human T-lymphotropic virus, type 1 

and human papilloma virus-like particles using 

VSV, which is innocuous in humans. Furthermore, 

he has shown that the VLP can be delivered 

to dendritic cells, which in turn process 

and present antigens. This approach may lead 

to novel immunization and treatment modalities 

for a variety of viral infections and new 

approaches to cancer. 

• UM/Sylvester has opened a phase II clinical 

trial to investigate a novel treatment for metastatic 

melanoma. Pegylated arginine deiminase 

(ADI-PEG) is an amino acid enzyme inhibitor, 

which interferes with the ability of melanoma 

tumor cells to proliferate. Lynn G. Feun, M.D., 


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professor of Medicine at the University of 

Miami School of Medicine, is leading the 

investigation. ADI-PEG is a targeted approach 

to fighting cancer, which focuses on enzymes 

that are very common in all melanoma cell 

lines. ADI-PEG attaches to arginine, an amino 

acid in the blood, which malignant tumor cells 

rely on to grow. The ADI-PEG degrades the 

arginine, making it impossible for the cancer 

to synthesize and use. This has significant advantages 

over previous treatments. Because 

this treatment is not chemotherapy, it can be 

administered as an outpatient treatment with 

a single weekly injection, rather than requiring 

a hospital stay or a long infusion. 

• Sheldon Greer, Ph.D., professor of Microbiology 

and Immunology at the University of 

Miami School of Medicine, has made many 

important discoveries in the course of his distinguished 

scientific career. An experimental 

radiosensitizer developed by Dr. Greer will 

shortly enter a phase I clinical trial for head 

and neck cancer patients. Cytochlor, developed 

by Dr. Greer and NCI-approved for patient 

trials to be conducted by Luis E. Raez, M.D., 

F.A.C.P., enters tumor cells and renders them 

much more susceptible to low-dose radiation. 

This enables a much higher success rate against 

cancer cells and the potential for reducing 

patient side effects. 

• Theodore J. Lampidis, Ph.D., professor of Cell 

Biology and Anatomy, has discovered one way 

to attempt to tackle the problem of targeting 

non-dividing tumor cells that are resistant to 

chemotherapy and/or radiation. He has 

found that slow dividing cells located in the 

middle of the tumor grow under low oxygen 

conditions (hypoxia) and differ in their metabolism 

of glucose from normal cells in the body. 

To exploit this difference, he has shown that by 

simply using a false sugar—2-Deoxyglucose 

(2-DG)—instead of glucose, the slow growing 

tumor cells take up more 2-DG than the slow 

growing normal cells and consequently starve to 

death. Luis E. Raez, M.D., F.A.C.P., and Shou- 

Ching Tang, M.D., Ph.D., have initiated the 

first clinical trials in lung cancer patients using 

this highly novel approach. 

• A unique peptide (IEP11) was defined by 

Diana M. Lopez, Ph.D., professor of Microbiology 

and Immunology and leader of UM/Sylvester’s 

Tumor Immunology Program. This 

peptide appears to elicit a powerful immune 

response in mice that have been injected with 

various types of tumor cells. Subsequent studies 

indicate that those animals that were “IEP11 

immunized” were found to form tumors at a 

greatly reduced rate. This suggests that the 

peptide could serve as an adjuvant treatment to 

enhance many cancer vaccine therapies in the 

treatment of a variety of tumor types. Viragen, 

a new biotechnology company located in 

Plantation, Florida, will collaborate with the 

University’s team to develop the peptide for 

use in human clinical trials. 

• Azorides Morales, M.D., chairman of Pathology 

at the University of Miami School of Medicine, 

has devised a way to use microwave radiation 

to reduce tissue pathology processing from 

one day to about one hour. The Jackson Health 

System and UM/Sylvester are the only institutions 

in the world offering this technique. This 

is not frozen section pathology, but accelerated 

tissue processing patented by the University of 

Miami, which may revolutionize the way tissues 

are processed, while allowing pathologists to 

extract vital molecular information in ways not 

previously possible. 

• Eckhard R. Podack, M.D., Ph.D., has developed 

a new antibody that can be used to target 

Hodgkin’s and non-Hodgkin’s lymphoma cells. 

The development of this novel antibody called 

SGN30, which identifies a protein on the surface 

of the cancer cells and “labels” the cells 

with an antibody therapy, allows the immune 

system to target them for destruction. This is a 

more “intelligent” treatment and should have 

fewer side effects than with traditional chemotherapy. 

Joseph D. Rosenblatt, M.D., and 

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Hugo F. Fernandez, M.D., have initiated 

a clinical trial using SGN30 in lymphoma 

patients. UM/Sylvester has collaborated 

with Seattle Genetics to further the investigation 

of SGN30. 

• The future of cancer treatment also may use 

vaccines to boost the immune system so it 

recognizes and kills cancer cells. Luis E. Raez, 

M.D., F.A.C.P., and Richard J. Thurer, M.D., 

are among the physicians working with 

UM/Sylvester physician-scientist Eckhard R. 

Podack, M.D., Ph.D., to develop several new 

revolutionary vaccines for the treatment of 

lung cancer. This approach also may lead to 

vaccines for other cancers. Dr. Thurer is a professor 

of Surgery and director of the Thoracic 

Surgery Section. 

• Joseph D. Rosenblatt, M.D., UM/Sylvester’s 

Associate Director, Clinical and Translational 

Research and Division Chief of Hematology- 

Oncology, opened a phase I clinical trial of a 

novel combination therapy for patients with 

certain types of leukemia and lymphoma. 

The idea of this trial is to use an antibody, 

which has had some success in the treatment 

of these disorders, and to try and augment the 

effects of that antibody in combination with 

interleukin-2 (IL-2). Campath-1H, also called 

alemtuzumab, is an approved form of treatment 

for patients with efractory/relapsed B-cell 

chronic lymphocytic leukemia, T-prolymphocytic 

leukemia, and cutaneous T-cell lymphomas 

(Sezary syndrome). By using IL-2 and 

alemtuzumab in combination it may hasten 

the return of the immune system to normal 

by enhancing the recovery of T cells and 

reducing post-treatment infectious complications. 

The idea of combining these two drugs 

was developed by Dr. Rosenblatt, Edgardo 

Santos, M.D., and their colleagues in the 

department of Medicine at the University of 

Miami School of Medicine. 

• Joseph D. Rosenblatt also is leading studies 

related to the development of novel immunotherapeutic 

and gene therapy strategies for 

human malignancy. Dr. Rosenblatt and 

Khaled Tolba, M.D., assistant professor of 

Medicine, have studied the ability of gene 

therapy “vectors” derived from herpes simplex 

virus called HSV amplicons to augment the 

immune response to tumors. Together with 

Seung-Uon Shin, Ph.D., an expert in antibody 

engineering, Dr. Rosenblatt’s laboratory has 

developed a variety of antibody fusion proteins 

with potential utility in human malignancy. 

These include fusions with immune effector 

molecules such as T-cell costimulatory ligands, 

and/or molecules that can recruit immune cells 

such as chemokines. Dr. Shin also is studying 

a fusion of anti-tumor antibody with an antiangiogenic 

agent called endostatin, which 

improves upon the performance of either an 

anti-her2/neu antibody or endostatin alone 

in the setting of breast cancer in preclinical 

tumor models. 

• Joyce M. Slingerland, M.D., Ph.D., professor 

of Medicine, is directing research efforts in 

breast cancer and also serves as director of the 

Braman Family Breast Cancer Institute at 

UM/Sylvester, a multidisciplinary translational 

research institute devoted to advancing research 

in cancer prevention, diagnosis, and treatment. 

Dr. Slingerland is a recognized authority on cell 

cycle regulation in relation to breast cancer, 

with particular emphasis on the p27 cell cycle 

regulator. She heads a major laboratory effort 

and has continued to recruit key individuals 

to increase expertise in the areas of molecular 

pathology, epidemiology, and clinical trials in 

breast cancer. 


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National Cancer Institute Designation 

I am pleased to tell you that UM/Sylvester will 

seek National Cancer Institute designation in 

2005. Comprised of a distinguished group of 

physicians and scientists, the External Advisory 

Committee has visited UM/Sylvester twice 

within the past year to evaluate the progress in 

our multidisciplinary research programs and 

research initiatives. They were highly complimentary 

of UM/Sylvester’s continuing efforts and 

recommended application for the NCI-Comprehensive 

Cancer Center designation next year. 

The EAC will meet with us again during the 

fall of 2004; their advice and assistance has been 

invaluable. 

Research is curing cancer, and to further 

achieve that goal, UM/Sylvester continues to 

build upon its excellent multidisciplinary research 

programs and shared resources already in place. 

We are especially invested in the development of 

home grown clinical trials based on science and 

technology developed at the University of Miami. 

We continue working to bring research discoveries 

from the laboratory bench to the patient bedside 

more quickly than ever before. 

In Closing 

These are exciting times at UM/Sylvester, and 

I am proud to be part of such a dynamic and 

dedicated team. Together with support from our 

senior vice president for medical affairs and dean 

of the school of medicine, John G. Clarkson, 

M.D., and University of Miami President Donna 

E. Shalala, Ph.D., we take steps toward winning 

the war against cancer every day. We also work 

very hard to ensure the best possible quality of 

life for our patients. But we must continue to 

do more. 

I hope you find this report interesting and 

inspiring. I want to assure you that UM/Sylvester, 

South Florida’s only university-based cancer center, 

is making a difference in the lives of South 

Florida citizens and that we are committed to 

this noble cause. 

Thank you for your time and attention. 


Director 

University of Miami 

Sylvester Comprehensive Cancer Center 

1 NCI: http://www.cancer.gov and the SEER Homepage: http://www.seer.cancer.gov. Click on “1975-2001 Report to the Nation.” 

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L E A D E R S H I P 


U N I V E R S I T Y O F M I A M I 

Donna E. Shalala, Ph.D. 

President 

U N I V E R S I T Y O F M I A M I S C H O O L O F M E D I C I N E 

John G. Clarkson, M.D. 

Senior Vice President for Medical Affairs and Dean 

John M. Deeley 

Vice President for Administration, Operations and Planning 

Minor W. Anderson 

Associate Vice President for Medical Affairs and Managing Director, University of Miami 

Medical Group 

U M / S Y L V E S T E R C O M P R E H E N S I V E C A N C E R C E N T E R 

As of year end, FY 2004 

EXECUTIVE COMMITTEE 


Director 

Michael H. Antoni, Ph.D. 

Associate Director, 

Cancer Prevention and Control 

Dido Franceschi, M.D. 

Division Chief, Informatics 

Kelvin P. Lee, M.D. 

Program Co-Leader, 

Clinical Oncology Research 

Joseph A. Lucci, III, M.D. 

Director, Clinical Research Services Resource 

Arnold M. Markoe, M.D., Sc.D. 

Professor and Chairman, Radiation Oncology 

Eckhard R. Podack, M.D., Ph.D. 

Associate Director, Basic Science 

Robert S. Powell, M.Ed. 

Associate Director, Administration 

Joseph D. Rosenblatt, M.D. 

Associate Director, 

Clinical and Translational Research 

James J. Schlesselman, Ph.D. 

Division Chief, Biostatics 

Joyce M. Slingerland, M.D., Ph.D. 

Director, Braman Family Breast Cancer Institute 

at UM/Sylvester 


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MULTIDISCIPLINARY RESEARCH 

PROGRAM LEADERSHIP 


Cancer Prevention and Control Program 



Clinical Oncology Research Program 

Kermit L. Carraway, Ph.D. 

Tumor Cell Biology Program 

Diana M. Lopez, Ph.D. 

Tumor Immunology Program 

William J. Harrington, Jr., M.D. 

Glen N. Barber, Ph.D. 

Viral Oncology Program 

SHARED RESOURCE LEADERSHIP 

Alberto Pugliese, M.D. 

Beata R. Frydel, Ph.D. 

Analytical Imaging Core 


Biostatistics 


Cell Purification and Banking Facility 


James D. Hanlon, Jr., R.N. 

Clinical Research Services Resource 

Rudolf K. Werner, Ph.D. 

DNA Core Facility 

Richard L. Riley, Ph.D. 

Flow Cytometry Resource 

Thomas R. Malek, Ph.D. 

Gene Knockout and Transgene Facility 

Carol K. Petito, M.D. 

Histology Research Lab Core 


Informatics 

Roland Jurecic, Ph.D. 

Molecular Analysis Core 


Dorothy F. Parker, M.H.S. 

Population Research Core 

SCIENTIFIC STEERING COMMITTEE 

Eckhard R. Podack, M.D., Ph.D., Chair 

Microbiology and Immunology 


Psychology 




Cell Biology and Anatomy 

Murray P. Deutscher, Ph.D. 

Biochemistry and Molecular Biology 

Marilyn Stern Emas, M.Ed. 

Development 

Lora E. Fleming, M.D., Ph.D., M.P.H., M.Sc. 

Epidemiology and Public Health 


Otolaryngology 


Clinical Research Services Resource 


Medicine 

Judith B. Hayden, M.B.A. 

Marketing and Communications 

Denise M. Korniewicz, D.N.Sc., R.N., F.A.A.N. 

Nursing 

David J. Lee, Ph.D. 




Robert B. Levy, Ph.D. 


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Obstetrics and Gynecology 

Gary S. Margules, Ph.D. 

Technology Transfer 

Robert S. Powell, M. Ed. 

Administration 


Medicine 

Antonieta Sauerteig, M.S. 

Research Administration 



Joyce M. Slingerland, M.D., Ph.D. 

Medicine 

Richard Spring 

UM/Sylvester Board of Governors 

BOARD OF GOVERNORS 

Joaquin F. Blaya, Chair 

Rose Ellen Greene, Vice Chair 

Thomas B. Levinson, Vice Chair 

Diane Abrams 

William H. Allen, Jr. 

Minor Anderson 

Cynthia L. Augustyn, J.D. 

Jose P. Bared 

Gloria Berkowitz 

Norman L. Braman 

Minette Brown 

John G. Clarkson, M.D. 

Diane M. Cook 

John M. Deeley 

Denny Feinsilver 

Michael B. Fernandez 

Thomas J. Fitzpatrick 

Bernard J. Fogel, M.D. 

Gail Gidney 


Mark Halpern 

Peggy Hollander 

Mark Levitats 

Alan S. Livingstone, M.D., F.A.C.S. 

Jayne S. Malfitano 

George Mencio, Jr. 

Eugene K. Montoya 

Marvin O’Quinn 

Dennis Patin, M.D. 

Nilda P. Peragallo, Dr.P.H., R.N., F.A.A.N. 


Joan Scheiner 

John Schulte 

Anne Smith, R.N., M.B.A. 

Richard Spring 

David L. Stansberry, M.S. 

Barbara Weintraub 


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EXTERNAL ADVISORY COMMITTEE 

Albert F. LoBuglio, M.D. 

Evalina B. Spencer Professor of Oncology 

University of Alabama at Birmingham 

Director, UAB Comprehensive Cancer Center 

David W. Golde, M.D. 

Enid A. Haupt Chair of Hematologic Oncology 

Memorial Sloan-Kettering Cancer Center 

Head, Laboratory of Molecular and Cellular 

Hematology 

Harvey Herschman, Ph.D. 

Director for Basic Research 

Professor, Department of Biological Chemistry 

Professor, Department of Pharmacology 

UCLA-Jonsson Comprehensive Cancer Center 

Paul B. Jacobsen, Ph.D. 

Professor of Psychology and Oncology 

University of South Florida 

Program Leader, Psychosocial and Palliative 

Care Program 

Program Leader, Health Outcomes and Behavior 

H. Lee Moffitt Cancer Center & Research Institute 

James J. Mulé, Ph.D. 

Associate Center Director, Translational Science and 

Technology Development 

Michael McGillicuddy Endowed Chair, Melanoma 

Research and Treatment 

H. Lee Moffitt Cancer Center & Research Institute 

Joyce C. Niland, Ph.D. 

Chair and Professor, Division of Information 

Sciences 

Director, Department of Biostatistics 

City of Hope National Medical Center 

Paul Okunieff, M.D. 

Chair and Philip Rubin Professor of Radiation 

Oncology 

University of Rochester 

Max S. Wicha, M.D. 

Director, University of Michigan Cancer Center 

Distinguished Professor of Oncology 

University of Michigan Cancer Center 

James F. Lynch, M.B.A. 

Vice President, Hospital and Medical Science 

Administration 

Fox Chase Cancer Center 

Nancy Mueller, Sc.D. 

Professor of Epidemiology 

Associate Director for Population Sciences 

Dana-Farber/Harvard Cancer Center 

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C A N C E R P R E V E N T I O N A N D C O N T R O L P R O G R A M 

C A N C E R P R E V E N T I O N A N D 

C O N T R O L P R O G R A M 

PROGRAM LEADER 


Professor of Psychology 

DESCRIPTION OF PROGRAM 

The Cancer Prevention and Control Program 

is composed of 23 faculty members in nine 

different departments at the University of Miami. 

The program, which builds on earlier work, 

includes research in cancer etiology, prevention, 

early detection, education/outreach, cancer 

genetics, quality of life, survivorship, psychoneuroimmunology, 

and biobehavioral 

interventions. 

Specific studies underway at this time 

include the use of tobacco, assessment of quality 

of life among persons who have been treated for 

cancer, stress management intervention in persons 

recently diagnosed with cancer, investigations 

of cancer incidence in Florida, outreach 

to Hispanic populations, and implementation 

of cancer control strategies. 

The projects performed by members of the 

Cancer Prevention and Control Program vary 

substantially. Some are purely behavioral or psychosocial 

in their aims; others examine neuroendocrine 

and immunological mechanisms relevant 

for disease promotion and/or progression. Most 

of these projects entail collaboration among behavioral 

scientists, surgeons, and oncologists. 

Others involve collaboration among psychologists, 

epidemiologists, immunologists, biochemists, 

and other biomedical scientists. 

GOALS OF PROGRAM 

1) Determine the predictors of cancer risk behavior 

in vulnerable populations and then develop 

and evaluate culturally competent interventions 

to prevent cancer in clinical and community 

populations. 

2) Develop and evaluate psychosocial interventions 

designed to reduce stress, enhance quality 

of life, and improve compliance as well as 

other health-related behaviors and biological 

processes associated with health outcomes. 

3) Examine the interactive effects of stress, behavior, 

and psychosocial components on neuroendocrine 

and immune function in cancer 

patients and in at-risk populations. Determine 

how these vary across sites, gender, age, race/ 

ethnicity, and prognostic variables. 

4) Better understand the risk factors for recurrence, 

enhancing quality of life, the role of the 

family in survival, preventing second malignancies 

and the sequelae of cancer treatment, 

and gain a better understanding of potential 

psychosocial influences on biological processes 

that may be involved in cancer recurrence. 

5) Develop and evaluate methods of disseminating 

cancer information and education for 

diverse communities. 

PARTICIPANTS 

Antoni, Michael H., Ph.D. 

Psychology 

Armstrong, F. Daniel, Ph.D. 

Pediatrics 

Baumbach-Reardon, Lisa L., Ph.D. 

Pediatrics 

Blomberg, Bonnie B., Ph.D. 


Carver, Charles S., Ph.D. 

Psychology 

Fleming, Lora E., M.D., Ph.D., M.P.H., M.Sc. 


UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 1


Fletcher, Mary Ann A., Ph.D. 


Goodman, Kenneth W., Ph.D. 

Medicine 

Goodwin, W. Jarrard, M.D., F.A.C.S. 


Ironson, Gail H., M.D., Ph.D. 

Psychology 

Kirsner, Robert S., M.D. 

Dermatology and Cutaneous Surgery 

Kumar, Mahendra, Ph.D. 

Psychiatry and Behavioral Sciences 

Lechner, Suzanne C., Ph.D. 


Lee, David J., Ph.D. 


Levis-Dusseau, Silvina, M.D. 

Medicine 

McCoy, Clyde B., Ph.D. 


Penedo, Frank J., Ph.D. 

Psychology 

Roos, Bernard A., M.D. 

Medicine 

Schlesselman, James J., Ph.D. 


Schneiderman, Neil, Ph.D. 

Psychology 

Shor-Posner, Gail S., Ph.D. 


Twiggs, Leo B., M.D. 

Obstetrics and Gynecology 

Wilkinson, James D., M.D., M.P.H. 


HIGHLIGHTS 

Breast Cancer 

African-American women with pre-menopausal 

breast cancer have characteristic mutations and 

polymorphic variants not observed in Caucasians. 

In addition, the frequency of BRCA1 and 

BRCA2 germ-line “deleterious” mutations is 

much less than that observed in Caucasians. 

Overall, breast cancer in African-American 

women occurs at a younger age, is more often 

estrogen receptor negative, and more frequently 

exhibits aggressive biological behaviors. 

Breast Cancer Screening 

After controlling for demographic variables traditionally 

related to breast cancer screening rates, 

there are ethno-regional differences in breast cancer 

screening and Pap smear practices among Cubans, 

Mexican-Americans, Puerto Ricans, Central 

Americans, and South Americans across the United 

States. Social integration appears to influence 

participation in cancer screening among Hispanic 

women. The modest effect is not universal across 

Hispanic groups and is stronger for Pap smear 

than for mammography screening behavior. 

Florida Comprehensive Cancer Control 

Initiative 

The Florida Comprehensive Cancer Control Initiative 

(FCCCI) was established in October 2000 

as the result of a federal appropriation and funding 

from the CDC’s Comprehensive Cancer 

Control Program. The CDC’s funding ended in 

June 2003, but the program continues as a departmental 

resource for expanding UM/Sylvester’s 

community-based cancer control research program. 

During the two and one-half years the FCCCI 

was funded by CDC, it established four regional 

cancer control collaboratives that cover the entire 

state of Florida. Each collaborative engaged in a 

strategic planning process and developed a comprehensive 

cancer control plan for their respective 

regions (http://fccci.med.miami.edu). More than 

200 individuals and 100 organizations participated 

in the planning process, which has been 

integrated into the state’s cancer control planning 

2 



activities. The regional collaboratives form a 

unique infrastructure that continues under the 

leadership of cancer centers and universities: 

UM/Sylvester is the lead agency for the Southeast 

Regional Collaborative; the H. Lee Moffitt Cancer 

Center and Research Institute is sponsoring 

the Southwest Regional Collaborative; the M.D. 

Anderson Cancer Center in Orlando is sponsoring 

the Northeast Regional Collaborative; and 

the Northwest Regional Collaborative is led by a 

collaborative effort involving Florida State University, 

Florida A&M University, and the Coastal 

Cancer Information Service Partnership Program. 

Membership in the regional collaboratives, implementation 

of the regional plans, and integration 

into state activities, are ongoing. 

In addition to establishing the collaboratives 

and developing the regional plans, the FCCCI 

has conducted the following pilot studies: 

• Telephone survey on attitudes and barriers to cancer 

screening and education—a random statewide 

phone survey that asked participants their reasons 

for obtaining or not obtaining specific 

cancer screening tests and information about 

cancer. 

• Miami-Dade Cancer Prevention Project—addresses 

cancer disparities in the Haitian-American 

community in north Miami-Dade County, 

which has a high percentage of late stage diagnoses 

for breast, cervical, prostate, colorectal, 

and lung cancers. 

• Sun protection in Miami-Dade County public 

schools—a survey in elementary and middle 

public schools to determine current policies and 

procedures for protecting students and staff 

from sun exposure and skin cancer risk. 

• Small area analysis of cancer and demographic 

data for Miami-Dade County (funded by an 

American Cancer Society Florida Division 

grant; Robert S. Kirsner, M.D., is the principal 

investigator)—developed a methodology to 

correlate late stage diagnosis with sociodemographic 

variables and identify geographic areas 

of the county at greatest need of interventions 

to reduce late diagnosis. 

Head and Neck Cancer 

Supplemental beta-carotene has no significant 

effect on second head and neck cancer mortality 

or lung cancer mortality. 

Hepatocellular Carcinoma 

Florida Blacks and Hispanics are at significantly 

increased risk for hepatocellular carcinoma (HCC) 

incidence when compared with Whites from 

Florida. These results have implications for preventive 

HCC recommendations in growing racial 

and ethnic subpopulations in the United States. 

Hodgkin’s Disease 

The incidence of Hodgkin’s and non-Hodgkin’s 

lymphoma is significantly higher among Florida’s 

Hispanic children, with 30 percent increased relative 

risk, compared to White non-Hispanics. 

Black children have significantly decreased incidence 

and risk. Results for lymphoid leukemia 

were similar. Incidence of lymphoma in Florida’s 

Hispanic children (primarily those of Cuban and 

Central American origin) differ from similar reports 

from Texas and California, where Hispanics 

are primarily of Mexican origin. 

Tobacco Use 

Results of the evaluation of Florida’s Tobacco Pilot 

Program show that there has been a decrease 

in the prevalence of smoking among middle and 

high school students by approximately 40 percent 

and 18 percent, respectively, statewide since 

1988. Exposure to tobacco use prevention education 

has been associated with lower proportions 

of youth who smoke, as has been the intensity of 

law enforcement efforts. Evaluation of the media 

campaign shows an association between more 

recall of anti-tobacco messages and less tobacco 

use. Further, when anti-tobacco community partnerships/coalitions 

were most active, there were 

greater decreases in youth tobacco use than when 

the activities were less active. 

Cigarette smoking may be a gateway drug to 

illegal drug use. Persons who had smoked cigarettes 

were far more likely to use cocaine, heroin, 

crack, and marijuana. 



MICHAEL H. ANTONI, PH.D. 


DESCRIPTION OF RESEARCH 

Dr. Antoni’s research interests over the past 

decade have focused on examining the effects 

of stressors and stress management interventions 

on the adjustment to, and physical course 

of, diseases such as breast cancer, cervical cancer, 

prostate cancer, chronic fatigue syndrome, and 

HIV infection. He also has examined some of the 

psychobiological mechanisms that might explain 

ways in which stressful events and psychosocial 

interventions contribute to the adjustment to, 

and physical course of, these diseases looking specifically 

at psychological intervening variables 

(stress appraisal processes, coping behaviors, and 

social resources) and biological/physiological variables 

(endocrine and immune system functioning). 

For the past four years, Dr. Antoni has been 

funded by the NCI through a five-year P50 Center 

for Psycho-Oncology Research (CPOR) grant, 

which conducts bio-psychosocial research on the 

inter-relationships between cognition, emotions, 

biological processes, and physical health in the 

context of several cognitive-behavioral stress 

management (CBSM) randomized clinical trials. 

Populations include those at high risk for cancer 

and those dealing with cancer diagnoses including 

cervical neoplasia, breast cancer, and prostate 

cancer. The grant includes funding for four clinical 

trials, five core laboratories dedicated to providing 

psychosocial and biological mechanism 

and outcome data, as well as statistical/data management 

for the four clinical trials. A number of 

UM/Sylvester investigators including those from 

the departments of Microbiology and Immunology, 

Psychology, and Medicine, have ongoing 

pilot studies designed to elaborate on biopsychosocial 

pathways being explored in the 

CPOR parent trials. 

Generally speaking, most of Dr. Antoni’s research 

efforts have focused on using information 

derived from studies examining the effects of field 

and laboratory stressors to develop stress reduction 

interventions that are specifically tailored to 

the disease-related issues, educational levels, and 

cultural characteristics of the target groups. This 

has resulted in the development of treatment 

manuals used for conducting intervention 

groups, which are in turn used to test the efficacy 

of treatment programs in the context of randomized 

clinical trials. In addition to testing the efficacy 

of these interventions in homogeneous 

populations, this program also will conduct 

generalizability studies designed to see how well 

the interventions work in diverse patients groups 

(e.g., inner city HIV+ women at risk for cervical 

cancer and Spanish-speaking breast cancer patients). 

The overarching goal is to develop theoretically 

driven and empirically supported 

psychosocial interventions with utility for secondary 

and tertiary prevention in persons diagnosed 

and treated for cancer. 

SELECTED PUBLICATIONS 

2002 

Antoni, MH, Cruess, DG, Klimas, N, Maher, K, 

Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G, 

Schneiderman, N, and Fletcher, MA. Stress management 

and immune system reconstitution in 

symptomatic HIV-infected gay men over time: 

effects on transitional naïve T cells 

(CD4(+)CD45RA(+)CD29(+)). American Journal 

of Psychiatry 159:143-45, 2002. 

Knippels, HM, Goodkin, K, Weiss, JJ, Wilkie, 

FL, and Antoni, MH. The importance of cognitive 

self-report in early HIV-1 infection: validation 

of a cognitive functional status subscale. 

AIDS 16:259-67, 2002. 

Culver, JL, Arena, PL, Antoni, MH, and Carver, 

CS. Coping and distress among women under 

treatment for early stage breast cancer: comparing 

African Americans, Hispanics and non-Hispanic 

Whites. Psycho-oncology 11:495-504, 2002. 

4 



Cruess, S, Antoni, MH, Hayes, A, Penedo, F, 

Ironson, G, Fletcher, MA, Lutgendorf, S, and 

Schneiderman, N. Changes in mood and depressive 

symptoms and related change processes 

during cognitive behavioral stress management 

in HIV-Infected Men. Cognitive Therapy and 

Research 26:373-392, 2002. 

Kumar, M, Kumar, AM, Waldrop, D, Antoni, 

MH, Schneiderman, N, and Eisdorfer, C. The 

HPA axis in HIV-1 infection. Journal of Acquired 

Immune Deficiency Syndromes 31 

Supplement 2:S89-93, 2002. 

2003 

Antoni, MH. Stress management and psychoneuroimmunology 

in HIV infection. CNS 

Spectrums 8:40-51, 2003. 

Perna, FM, Antoni, MH, Baum, A, Gordon, P, 

and Schneiderman, N. Cognitive behavioral 

stress management effects on injury and illness 

among competitive athletes: a randomized clinical 

trial. Annals of Behavioral Medicine 25:66- 

73, 2003. 

Antoni, MH. Psychoneuroendocrinology and 

psychoneuroimmunology of cancer: Plausible 

mechanisms worth pursuing? Brain, Behavior and 

Immunity 17 (1 Supplement):S84-91, 2003. 

Antoni, MH and Pitts, M. Journal of Psychosomatic 

Research, special issue. Journal of Psychosomatic 

Research 54:179-83, 2003. 

Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher, 

MA, Klimas, N, Duran, R, Ironson, G, and 

Schneiderman, N. Sleep disturbance mediates the 

association between psychological distress and 

immune status among HIV-positive men and 

women on combination antiretroviral therapy. 

Journal of Psychosomatic Research 54:185-89, 

2003. 

Pereira, DB, Antoni, MH, Danielson, A, Simon, 

T, Efantis-Potter, J, Carver, CS, Duran, RE, 

Ironson, G, Klimas, N, Fletcher, MA, and 

O’Sullivan, MJ. Stress as a predictor of symptomatic 

genital herpes virus recurrence in women 

with human immunodeficiency virus. Journal of 

Psychosomatic Research 54:237-44, 2003. 

Petronis, VM, Carver, CS, Antoni, MH, and 

Weiss, S. Investment in body image and psychosocial 

well-being among women treated for early 

stage breast cancer: partial replication and extension. 

Psychology & Health 18:1-13, 2003. 



Ironson, G, Klimas, N, and O’Sullivan, MJ. Life 

stress and cervical squamous intraepithelial lesions 

in women with human papillomavirus and 

human immunodeficiency virus. Psychosomatic 

Medicine 65:427-34, 2003. 

Weiss, JL, Mulder, CL, Antoni, MH, De 

Vroome, EM, Garssen, B, and Goodkin, K. Effects 

of a supportive-expressive group intervention 

on long-term psychosocial adjustment in 

HIV-infected gay men. Psychotherapy and Psychosomatics 

72:132-40, 2003. 

McGregor, BA, Antoni, MH, Boyers, A, Alferi, 

SM, Blomberg, BB, and Carver, CS. Cognitive 

behavioral stress management increases benefit 

finding and immune function among women 

with early stage breast cancer. Journal of Psychosomatic 

Research 54:1- 8, 2003. 

Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas, 

NG, Fletcher, MA, Antoni, MH, LeBlanc, WG, 

and Schneiderman, N. Psychological distress is 

associated with decreased memory helper T-cell 

and B-cell counts in pre-AIDS HIV seropositive 

men and women but only in those with low viral 

load. Psychosomatic Medicine 65:627-35, 2003. 

O’Cleirigh, C, Ironson, G, Antoni, MH, 

Fletcher, MA, McGuffey, L, Balbin, E, 

Schneiderman, N, and Solomon, G. Emotional 

expression and depth processing of trauma and 

their relation to long-term survival in patients 

with HIV/AIDS. Journal of Psychosomatic Research 

54:225-35, 2003. 



Robbins, M, Szapocznik, J, Tejeda, M, Samuels, 

D, Ironson, G, and Antoni, MH. The protective 

role of the family and social support network in a 

sample of HIV+ African American women: 

results of a pilot study. Journal of Black Psychology 

29:17-37, 2003. 

Lechner, SC, Antoni, MH, Lydston, D, 

LaPerriere, A, Ishii, M, Devieux, J, Ironson, G, 

Schneiderman, N, Brondolo, E, Tobin, J, and 

Weiss, S. Cognitive-behavioral interventions improve 

quality of life in women with AIDS. Journal 

of Psychosomatic Research 54: 253-261, 

2003. 

Lechner, SC, Zakowski, SG, Antoni, MH, 

Greenhawt, M, Block, K, and Block, P. Do 

sociodemographic and disease-related factors influence 

benefit-finding in cancer patients? 

Psycho-oncology 12: 491-499, 2003. 

Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I, 

Carver, CS, Antoni, MH, Roos, BA, and 

Schneiderman, N. Perceived stress management 

skill mediates the relationship between optimism 

and positive mood following radical prostatectomy. 

Health Psychology 22:220-2, 2003. 

Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, 

MH, Malow, R, Costa, P, and Schneiderman, N. 

Personality, quality of life and HAART adherence 

among men and women living with HIV/AIDS. 


2003. 

Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J, 

Antoni, MH, Ironson, G, Malow, R, and 

Schneiderman, N. Coping and psychological distress 

among symptomatic HIV+ men who have 

sex with men. Annals of Behavioral Medicine 

25:203-13, 2003. 

HIGHLIGHTS/DISCOVERIES 

• Life stress and stress management in the promotion 

of human papillomavirus to cervical neoplasia— 

researchers have been investigating the interaction 

of viral and psychosocial risk factors for 

cervical cancer among African American 

women who are co-infected with HIV-1 and 

high versus low-risk human papillomavirus 

(HPV) types. One study specifically examines 

the relationships between life stress, pessimism, 

emotional expression, natural killer cell cytotoxicity 

(NKCC), and cytotoxic-suppressor 

T cells, and the development of squamous 

intraepithelial lesions (SIL) and cervical carcinoma 

in women co-infected with HIV and one 

or more HPV types. Dr. Antoni’s laboratory 

recently found that elevated life stress predicts 

greater promotion and persistence of SIL, 

greater numbers of genital herpes virus outbreaks, 

and greater declines in NK cell percentages 

over a one-year prospective period in 

women co-infected with HIV and HPV. The 

reductions in NK percentage appeared to explain 

the association between elevated life stress 

and SIL promotion. This work led to one of the 

projects in the CPOR, which evaluates the effects 

of CBSM intervention on distress, quality 

of life, NK cells, and their cytotoxicity, and the 

promotion of SIL and indices of clinical disease 

progression in HIV+HPV+ women. 

• Psychosocial intervention after surgery for breast 

cancer—the laboratory has an NCI-funded 

project titled “Facilitating Positive Adaptation 

in Women with Breast Cancer,” which examines 

the effects of group-based CBSM intervention 

on psychosocial adjustment in 200 

early-stage breast cancer patients in the weeks 

following surgery. Pilot work over the prior year 

established an immunologic battery for this 

study, which includes lymphoproliferative responses 

to CD3 crosslinking and associated 

Th1- and Th2-like cytokine production, and 

cytokine-stimulated NKCC to K562 targets 

and breast-cancer related cell lines. This work 

also showed that women assigned to CBSM 

showed increases in positive growth and opti- 

6 



mism and a decreased prevalence of clinical depression, 

decreases in plasma cortisol, and increases 

in lymphocyte proliferative responses to 

anti-CD3 crosslinking. 

• International breast cancer research—additional 

work with the Helen Dowling Institute in 

Rotterdam, Holland, focused on developing 

new assessment strategies for measuring emotional 

expression patterns and acute responses 

to emotionally-arousing laboratory challenges 

in breast cancer patients and how these change 

during the course of psychotherapy. They are 

collecting data for a Dutch Cancer Foundation 

(NKB)-funded study titled “Effects of group 

psychotherapy compared with group support in 

patients with early-stage breast cancer,” which is 

modeled after the recently funded NCI study 

noted above. These researchers found evidence 

that psychosocial intervention reduced cortisol 

levels and modulated the NK cell response to 

laboratory challenges. 

• Psychosocial intervention after adjuvant therapy 

for breast cancer—together with a team led by 

Gail H. Ironson, M.D., Ph.D., and Ron E. F. 

Durán, Ph.D., the CPOR is investigating the 

effects of CBSM in a randomized trial among 

women who completed adjuvant therapy for 

breast cancer within the last year. Preliminary 

results suggest that the intervention produces 

similar psychological and physiological effects 

to those observed in women receiving CBSM 

shortly after surgery. 

• Psychosocial intervention after surgery for prostate 

cancer—together with a team led by Neil 

Schneiderman, Ph.D., and Frank J. Penedo, 

Ph.D., the CPOR is investigating the effects of 

CBSM in a randomized trial among men recently 

undergoing surgery for early-stage prostate 

cancer. Preliminary results suggest that the 

intervention is successful in increasing quality 

of life in this population. Studies now are underway 

examining the biological changes that 

may occur concurrently with these quality of 

life improvements. 

F. DANIEL ARMSTRONG, PH.D. 

Professor of Pediatrics 


Dr. Armstrong’s major interests in cancer 

research are in the areas of neurocognitive 

late effects in children treated for brain tumors 

and acute lymphocytic leukemia, quality of life 

assessment in childhood cancer, interventions for 

cognitive late effects in childhood cancer survivors, 

and health behavior outcomes in long-term 

survivors of childhood cancer. 


2002 

Lemanek, KL, Brown, RT, Armstrong, FD, 

Hood, C, Pegelow, CH, and Woods, G. Dysfunctional 

eating patterns and symptoms of pica in 

children and adolescents with sickle cell disease. 

Clinical Pediatrics 41:493-500, 2002. 

Perrin, E and the Committee on Psychosocial 

Aspects of Child and Family Health, American 

Academy of Pediatrics. (Armstrong, FD, co-author), 

Technical Report: Co-parent or secondparent 

adoption by same-sex parents. Pediatrics 

109:341-344, 2002. 

2003 

Thompson, RJ, Jr., Armstrong, FD, Link, CL, 

Pegelow, CH, Moser, F, and Wang, W. A prospective 

study of the relationship over time of behavior 

problems, intellectual functioning, and family 

functioning in children with sickle cell disease: 

a report from the Cooperative Study of Sickle 

Cell Disease. Journal of Pediatric Psychology 

28:59-65, 2003. 



LISA L. BAUMBACH-REARDON, PH.D. 

Associate Professor of Pediatrics 


Dr. Baumbach’s laboratory is involved in 

breast cancer research focusing on a better 

understanding of the genetic basis of breast cancer 

in African-American women. The laboratory 

is completing two major projects. The first is the 

development of a specific BRCA1 and BRCA2 

mutation/variants panel for women of African 

ancestry with either breast cancer or a significant 

family history of breast/ovarian cancer. Development 

of such a panel will allow its incorporation 

into clinical practice with clear improvement 

of genetic counseling for this minority and 

underserved population. Based on their preliminary 

data, supplemented with a thorough review 

of all published English literature, the laboratory 

has identified 13 reported mutations and 13 reported 

unclassified variants in BRCA1, and six 

mutations and ten variants in BRCA2 in African 

Americans. Some of these genetic changes are 

specific to an individual; others are recurrent in 

the African Americans studied. A screening panel 

for such BRCA1 and BRCA2 mutations/variants 

will be designed to develop an efficient assay for 

eventual use in clinical practice. 

The second project, which complements the 

first, is a genome-wide analysis of all genetic 

changes in breast cancer tissues collected from 

African-American patients. These studies will use 

state-of-the art technology of DNA microarray 

analysis. The combined information from these 

studies will provide significant new insights into 

the genetic basis of African-American breast cancer, 

thus providing important new information 

regarding diagnosis and possible therapies. 


• Identified 13 reported mutations and 13 reported 

unclassified variants in BRCA1, and six 

mutations and 10 variants in BRCA2 in African 

Americans. 

• Made significant progress in the development of 

the mutation screening panel-streamlined 

methodology for mutation detection. 

• Filed for a patent to protect information related 

to the development of the mutation screening 

panel, through the University of Miami Office 

of Technology Transfer. 

• Conducted further detection and population 

screening for African-American BRCA1 and 

BRCA2 missense mutations. 

BONNIE B. BLOMBERG, PH.D. 

Professor of Microbiology and Immunology 


Research in Dr. Blomberg’s laboratory focuses 

on two projects. One of these projects 

involves basic research on the molecular regulation 

of B lymphopoiesis in mice. Generation of 

B lymphocytes is important in cancer patients 

receiving bone marrow as well as in the normal 

production of the humoral (antibody) response. 

Aged humans and other mammals have a poorer 

immune response to pathogens. 

In collaboration with Richard L. Riley, 

Ph.D., in the department of Microbiology and 

Immunology, Dr. Blomberg has shown that aged 

mice, those greater than or equal to about 80 

percent of their full life span, have a substantial 

decrease in the number of precursor B lymphocytes 

as well as the amount of the precursor B-cell 

receptor (preBCR) including the surrogate light 

chain (SLC)g5 and VpreB. Their data indicate 

that this affects the antibody V H 

repertoire at the 

pre-B cell level, i.e., before antigen selection. 

8 



More recent data indicate that the transcription 

factor, E2A, is reduced in not only precursor B 

cells but also in mature B cells in peripheral 

lymphoid organs in aging, leading to defects in 

Ig class switch and humoral immunity. Current 

studies will reveal the molecular and cellular 

causes of these defects in the aged humoral 

immune response and attempt to reverse these 

defects. These studies are important for cancer 

for two reasons: 1) the depressed immune 

response seen in aged humans likely contributes 

to increased susceptibility to cancer, and 2) bone 

marrow transplantation given to many types of 

cancer patients requires generation of mature 

B lymphocytes from the precursors in the bone 

marrow. Knowledge about the cellular and 

molecular requirements for B lymphopoiesis 

in young and aged individuals should lead to 

improvements in the humoral immune system 

of cancer patients. 

Another project in Dr. Blomberg’s laboratory 

involves clinical research with breast cancer patients. 

In collaboration with Michael H. Antoni, 

Ph.D., and Charles S. Carver, Ph.D., in the department 

of Psychology, Sharlene Weiss, Ph.D., 

in the department of Medicine, and members of 

the Cancer Prevention and Control Program at 

UM/Sylvester, Dr. Blomberg’s laboratory is 

measuring the status of various immune parameters 

in patients in response to psychosocial intervention 

(e.g., group therapy, stress reduction). 

Preliminary experiments have shown that intervention 

patients have an improved immune 

response as seen by the ability of their T cells 

to proliferate in response to an antigen-specific 

receptor stimulus (anti-CD3). Current studies are 

measuring T, natural killer (NK), and lymphokine-activated 

killer (LAK) cytotoxic function 

as well as potential TH1/TH2 differences by 

cytokine production resulting from T-cell stimulation. 

These studies are important to allow optimal 

immune response in cancer patients, which 

will better detect/destroy residual cancer and 

allow for better patient survival. 


2002 

Jin, Y, Fuller, L, Carreno, M, Esquenazi, V, 

Blomberg, BB , Wei, YT, Ciancio, G, Burke, GW 

3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional 

and phenotypic properties of peripheral T 

cells anergized by autologous CD3(+) depleted 

bone marrow cells. Human Immunology 63:567- 

75, 2002. 

Burke, GW, Ciancio, C, Blomberg, BB , Rosen, 

A, Suzart, K, Roth, D, Kupin, W, Esquenazi, V, 

and Miller, J. Randomized trial of three different 

immunosuppressive regimens to prevent chronic 

renal allograft rejection. Transplantation Proceedings 

34:1610-11, 2002. 

Blomberg, BB , Mathew, J, Fainman, H, Hussini, 

S, Carreno, M, Hnatyszyn, H, Garcia-Morales, 

R, Fuller, L, Vallone, T, Rosen, A, Esquenazi, V, 

Ricordi, C, Tzakis, A, and Miller, J. Human bone 

marrow cells retrovirally transduced with the allogeneic 

class II gene, HLA-DR3beta, down regulate 

anti-allogeneic responses of autologous 

lymphoid cells. Human Immunology 63:S19, 

2002. 

2003 

Mathew, JM, Blomberg, BB , Fuller, L, Burke, 

GW, Ciancio, G, Kenyon, N, Ricordi, C, Tzakis, 

AG, Esquenazi, V, and Miller, J. A novel microcell-mediated 

lympholytic assay for the evaluation 

of regulatory cells in human alloreactive 

CTL responses. Journal of Immunological Methods 

272:67-80, 2003. 

Blomberg, BB , Hussini, S, Fainman, H, Mathew, 

JM, Hernandez, A, Carreno, M, Hnatyszyn, HJ, 

Garcia-Morales, R, Fuller, L, Rosen, A, Ricordi, 

C, Tzakis, A, Miller, J, and Esquenazi, V. 

Retroviral transduction of an allogeneic class II 

gene into human bone marrow down regulates 

allo-immune reactivity. Human Immunology 

64:S128, 2003. 



Hernandez, A, Lindner, I, Blomberg, BB, 

Hussini, S, Burger, M, Mathew, JM, Carreno, M, 

Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A, 

Lee, KP, Miller, J, and Esquenazi, V. Suppression 

of allogeneic T cell proliferation through blocking 

of NF-KB in the differentiation process of 

human dendritic cells. Human Immunology 

64:S128, 2003. 

Mathew, JM, Alvarez, S, Vallone, T, Blomberg, 

BB, Joshua, M, and Esquenazi, V. A human- 

SCID-mouse-islet transplant model for the evaluation 

of the regulatory activity of donor bone 

marrow cells. Human Immunology 64:S7, 2003. 

Van Der Put, E, Sherwood, EM, Blomberg, BB, 

and Riley, RL. Aged mice exhibit distinct B cell 

precursor phenotypes differing in activation, proliferation, 

and apoptosis. Experimental Gerontology 

38:1137-47, 2003. 

Frasca, D, Nguyen, D, Van Der Put, E, Riley, 

RL, and Blomberg, BB. The Age-related decrease 

in E47 DNA-binding does not depend on increased 

Id inhibitory proteins in bone marrowderived 

B cell precursors. Frontiers in Bioscience 

8:A110-16, 2003. 

Frasca, D, Nguyen, D, Riley, RL, and Blomberg, 

BB. Effects of aging on proliferation and E47 

transcription factor activity induced by different 

stimuli in murine splenic B cells. Mechanisms of 

Ageing and Development 124:361-69, 2003. 


BB. Decreased E12 and/or E47 transcription factor 

activity in the bone marrow as well as in the 

spleen of aged mice. Journal of Immunology 

170:719-26, 2003. 

Frasca, D, Van der Put, E, Riley, RL, and 

Blomberg, BB . Reduced Ig class switch in aged 

mice correlates with decreased E47 and activation-induced 

cytidine deaminase. Journal of Immunology 

172:2155-62, 2003. 


SM, Blomberg, BB , and Carver, CS. Cognitive 




Research 54:1- 8, 2003. 


• Compromised humoral immune response in 

aged individuals may be at least partially explained 

by antibody V H 

repertoire differences at 

the pre-B cell level (before antigen selection). 

• Decreased transcription factor E2A is important 

for decreased Ig class switch and optimal humoral 

immunity. 

• Demonstrated improved immune response in 

breast cancer patients after psychosocial intervention. 

CHARLES S. CARVER, PH.D. 



Dr. Carver’s cancer-related research concerns 

the role of psychosocial variables in cancer 

morbidity and quality of life in cancer patients, 

in terms of emotional disturbance, psychosexual 

disturbance, and disruption of normal life activities. 

He is interested in the influences of vulnerability 

and resilience factors such as personality 

and perceptions of availability of social support. 

Dr. Carver also is interested in coping processes 

of various sorts and their influence on adaptation 

to diagnosis and treatment of cancer. Over time, 

his work has expanded to include studies of quality 

of life among long-term survivors of cancer 

and studies of relations between psychosocial 

variables at diagnosis and recurrence over the 

years following treatment (PI, Quality of Life 

in Adult Cancer Survivors, NCI grant R01- 

CA78995). Dr. Carver is a collaborator in 

research that provides cancer patients with 

psychosocial interventions—ten-week group 

10 



sessions in cognitive-behavioral stress management—and 

examines effects of those interventions 

over the subsequent year. His first study on 

that topic examined only psychosocial outcomes 

(PI, Adjustment to Breast Cancer Among Younger 

Women, NCI grant R01- CA64710). Pilot data 

collected in that study, however, have led to further 

work in which he and his colleagues also are 

examining the impact of the intervention on immune 

function (Co-PI, Facilitating Positive Adaptation 

to Breast Cancer, NCI grant 

R01-CA64710). 


2002 

Perczek, RE, Burke, MA, Carver, CS, Krongrad, 

A, and Terris, MK. Facing a prostate cancer diagnosis: 

who is at risk for increased distress? Cancer 

94:2923-29, 2002. 



treatment for early stage breast cancer: Comparing 

African Americans, Hispanics, and non-Hispanic 

Whites. Psycho-oncology 11:495-504, 

2002. 

2003 














Medicine 65:427-34, 2003. 






Research 54:1-8, 2003. 

Carver, CS, Lehman, JM, and Michael, HA. Dispositional 

pessimism predicts illness. Journal of 

Personality and Social Psychology 84:813-21, 

2003. 













• Completed interviews with 90 cancer survivors, 

while working toward the development of a 

measure of psychosocial adjustment aimed 

specifically at cancer survivors. The interview 

phase was followed by an item-development 

phase. The items were then tested on another 

sample of cancer survivors, resulting in a measure 

termed the Quality of Life in Adult Cancer 

Survivors (QLACS). 

• Investigated ethnic differences in reactions to 

the cancer experience. One study found that 

Hispanic women reported a variety of more 

intense concerns of several sorts than did non- 

Hispanic Whites or Blacks, along with greater 

levels of distress. Concerns about existential 

issues, sexuality, and rejection from others all 

played roles in predicting various aspects of 

quality of life in this study. Two other studies 

determined that Hispanic and African-American 

women use more religious coping than do 

non-Hispanic White women. Non-Hispanic 

White women, it was found, use more humor. 



• Studied a sample of low socioeconomic status 

(SES) Hispanic breast cancer patients. This 

study, led by Dr. Carver’s colleague, Susan 

Alferi, Ph.D., found substantial differences 

between women who identified themselves as 

Catholic and those who identified themselves 

as fundamentalist Christians. Among the 

Catholic women, greater involvement in 

religious coping was related to greater emotional 

distress. Among the other women the 

opposite pattern emerged. Clearly, the effect 

of religious involvement varies with the nature 

of the religious involvement. 

• Examined the effects of early portions of the 

experience on the quality of life of long-term 

survivors (five years or more). This research has 

found that higher levels of distress during the 

period surrounding treatment related strongly 

to higher levels of distress five to 15 years later. 

One of these studies also found that women 

who reported finding benefit in the cancer experience 

during the first year post-treatment 

had better emotional quality of life four to 

seven years later. 

LORA E. FLEMING, M.D., PH.D., M.P.H., 

M.Sc. 

Professor of Epidemiology 

and Public Health 


Dr. Fleming’s research interests are focused in 

occupational and environmental medicine 

and epidemiology. She is the only board-certified 

and licensed occupational and enviromental 

medicine physician and epidemiologist in South 

Florida. 

Dr. Fleming has performed funded research 

on the health effects of methyl mercury contamination 

in the Everglades (Agency for Toxic Substances 

and Disease Registry and the Florida 

Department of Health (FDOH)); a study of fumigation 

workers with the National Institute of 

Occupational Safety and Health (NIOSH); a 

study of pesticide levels and Parkinson’s disease 

(University of Miami Glaser Award); an evaluation 

of reported health effects of the fumigant 

Benlate (FDOH); an evaluation of the human 

health effects of hazardous waste incineration 

(Florida Department of Environmental Protection); 

an evaluation of the occupational health 

effects of solid waste work (Center for Solid and 

Hazardous Waste); back injury prevention in 

firefighters (FDOH); several studies on the human 

health effects of the marine toxin diseases 

(National Institute of Environmental Health Sciences, 

CDC, and the FDOH); a NIOSH Career 

Development Award studying the chronic health 

effects of a large cohort of licensed Florida pesticide 

applicators; and has recently finished a large 

cohort study of certified Florida firefighters 

funded by NIOSH. 

Dr. Fleming is associate director of the 

NIEHS Marine and Freshwater Biomedical Sciences 

Center at the University of Miami and director 

of outreach and education at the center. 

She serves and has served on numerous task 

forces and committees, including the Florida 

Birth Defects Registry, Florida Harmful Algal 

Bloom Taskforce, and the Florida Pesticide Advisory 

Committee. 

Cancer-Related Activities 

At UM/Sylvester, Dr. Fleming is the director of 

research and project director for the Florida Cancer 

Data System (FCDS), Florida’s incident tumor 

registry. As part of her work with FCDS, Dr. 

Fleming interacts with investigators, students, and 

FCDS personnel to increase research opportunities 

and educational outreach at the FCDS. With 

her colleagues, Dr. Fleming has investigated the 

cancer experience of Florida’s Hispanic population, 

the risk of subsequent cancers among persons with 

ovarian cancer, the risk of cancer among Florida’s 

children, and the stage at which poor women in 

Florida present for diagnosis of breast cancer. 

Based on her research, which focuses on the 

human health effects of marine and freshwater 

toxins, Dr. Fleming has studied the possible asso- 

12 



ciation between blue green algal toxins in drinking 

water and the risk of hepatocellular carcinoma 

in Florida. 

With NIOSH funding, Dr. Fleming has assisted 

Fangchao Ma, M.D., and other colleagues 

to examine the cancer risks associated with 

firefighting in Florida. A retrospective cohort 

study was conducted among 34,796 male and 

2,017 female firefighters certified between 1972 

and 1999. Age- and gender-specific cancer incidence 

rates in the general Florida population 

were used as comparisons in calculating the standardized 

incidence ratios (SIR). A total of 1,032 

cases of cancer among Florida firefighters (970 

male and 52 female) were identified by linkage 

with the FCDS as of December 31, 1999. The 

overall risk of cancer among male firefighters was 

significantly lower compared to that of the general 

Florida population (age adjusted SIR=0.84; 

95 perecent CI=0.79-0.90) as well as for cancers 

of buccal (0.67; 0.47-0.91), stomach (0.50; 0.25- 

0.90), lung (0.65; 0.54-0.78), and brain (0.58; 

0.31-0.97). Significantly increased cancer incidence 

was observed among male firefighters for 

bladder (1.29; 1.01-1.62), testes (1.60; 1.20- 

2.09), and thyroid cancers (1.77; 1.08-2.73). Female 

firefighters had significantly increased 

overall risk (1.63; 1.22-2.14), and increased incidence 

for thyroid cancers (3.97; 1.45-8.65) and 

Hodgkin’s disease (6.25; 1.26-18.26). 


2002 

Dewailly, E, Furgal, C, Knap, A, Galvin, J, 

Baden, D, Bowen, B, Depledge, M, Duguay, L, 

Fleming, LE, Ford, T, Moser, F, Owen, R, Suk, 

WA, and Unluata, U. Indicators of ocean and 

human health. Canadian Journal of Public 

Health 93: S34-8, 2002. 

Grant, P, Skinner, HG, Fleming, LE, and Bean, 

JA. Influence of structured encounter forms on 

documentation by community pediatricians. 

Southern Medical Journal 95:1026-31, 2002. 

Knap, A, Dewailly, E, Furgal, C, Galvin, J, 

Baden, D, Bowen, RE, Depledge, M, Duguay, L, 


WA, and Unluata, U. Indicators of ocean health 

and human health: developing a research and 

monitoring framework. Environmental Health 

Perspectives 110:839-45, 2002. 

Zhou, O, Shimoda, H, Gao, B, Oh, S, Fleming, 

LE, and Yue, G. Materials science of carbon 

nanotubes: fabrication, integration, and properties 

of macroscopic structures of carbon 

nanotubes. Accounts of Chemical Research 

35:1045-53, 2002. 

Wilkinson, JD, Wohler-Torres, B, Trapido, E, 

Fleming, LE, MacKinnon, J, and Peace, S. Cancer 

among Hispanic women in South Florida: an 

18-year assessment: a report from the Florida 

Cancer Data System. Cancer 95:1752-58, 2002. 

2003 

Oberstein, EM, Fleming, LE, Gomez-Marin, O, 

and Glassberg, MK. Pulmonary Lymphangioleiomyomatosis 

(LAM): Examining Oral Contraceptive 

Pills and the Onset of Disease. Journal 

of Women’s Health (Larchmont) 12:81-5, 2003. 

Entzel, PP, Fleming, LE, Trepka, MJ, and 

Squicciarini, D. The health status of newly 

arrived refugee children in Miami-Dade County, 

Florida. American Journal of Public Health 

93:286-8, 2003. 

Fleming, LE, Gomez-Marin, O, Zheng, D, Ma, 

F, and Lee, D. National Health Interview Survey 

mortality among US farmers and pesticide applicators. 

American Journal of Industrial Medicine 

43:227-33, 2003. 

Varela, JE, Gomez-Marin, O, Fleming, LE, and 

Cohn, SM. The risk of death for Jehovah’s Witnesses 

after major trauma. Journal of Trauma 

54:967-72, 2003. 




• Research on human health effects of marine and 

freshwater toxins—blue green algae, or 

cyanobacteria, are microorganisms at the base 

of the food and oxygen chain. The blue green 

algae easily grow in fresh water reservoirs, sometimes 

producing large amounts of toxins. These 

natural toxins can be carcinogenic and have 

been associated with an increased risk of liver 

cancer in animals and humans in China; furthermore, 

normal drinking water treatment 

does not completely remove these toxins. 

Therefore, using the technology of geographic 

information systems (GIS) to store, analyze, 

and display the data, Dr. Fleming and her colleagues 

showed that there may be an increased 

risk of liver cancer in Florida for persons living 

near surface water treatment plants with possible 

blue green algal toxin contamination. This 

study was performed in collaboration with the 

FCDS, the University of Miami NIEHS Marine 

and Freshwater Biomedical Sciences Center, 

and the Rosenstiel School of Marine and 

Atmospheric Sciences, as well as the St. Johns 

River Management District. Funding for this 

study was provided by the Florida Harmful Algal 

Bloom Taskforce at the Florida Marine Research 

Institute. 

• Examination of the cancer risks associated with 

firefighting in Florida—this study did not find 

evidence of an excess risk of lung or brain cancer 

in firefighters as documented in prior mortality 

studies. The study does, however, suggest 

that a significantly increased risk of bladder 

cancer among male firefighters might be related 

to occupational exposure, rather than tobacco 

use. This is the largest known study of 

firefighters to date. 

MARY ANN A. FLETCHER, PH.D. 



Dr. Fletcher is interested in studying immunologic 

changes during stress management in 

breast cancer and cervical neoplasia. She has collaborated 

with Michael H. Antoni, Ph.D., Gail H. 

Ironson, M.D., Ph.D., and Neil Schneiderman, 

Ph.D., for the past 17 years on NIH-funded 

projects examining the immunological effects of 

stress management in persons with HIV infection, 

women at risk for cervical cancer, and 

women undergoing treatment for early-to-midstage 

breast cancer. 

Dr. Fletcher is the director of the E.M. 

Papper Laboratory of Clinical Immunology. This 

laboratory has been an important core facility for 

mind-body research at the University of Miami 

for many years. Much of their research has been 

cancer related. Currently, the laboratory supports 

the P50 Center for Psycho-Oncology Research 

(CPOR), which is assessing the effects of cognitive-behavioral 

stress management (CBSM) on 

both psychological and biological parameters in 

patients with breast cancer and prostate cancer 

and with cervical hyperplasia. The laboratory 

functions as a Biological Assessment Core to 

coordinate the collection, storage, and assaying 

of immune indices of cytotoxic and helper cell 

function (cytokine-stimulated natural killer cytotoxicity 

(NKCC), ELISPOT, quantitative flow 

cytometric measurement of surface and intracellular 

molecules, including activation and differentiation 

markers as well as cytokines, perforin, and 

granzymes). By ELISA assays, the laboratory 

measures Th1 (g-IFN, IL-2, IL-12), Th2 (IL-4, 

IL-5, IL-6, and IL-10), and proinflamatory (IL-1, 

IL-6, and TNF-α) cytokines as well as receptors 

of these cytokines in body fluids and lymphocyte 

culture supernatants. Standardized assays are used 

for soluble markers of disease activity (CA 15.3, 

PSA, VEGF, etc.) in blood samples collected 

from cancer patients and controls. 

14 




2002 






effects on transitional naive T cells 


of Psychiatry 159:143-45, 2002. 

2003 








2003. 















O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher, 

MA, McGuffey, L, Balbin, E, Schneiderman, N, 

and Solomon, G. Emotional expression and 

depth processing of trauma and their relation to 

long-term survival in patients with HIV/AIDS. 


2003. 


• Dr. Fletcher’s primary areas of focus include 

examining quantitative indices of lymphocyte 

subpopulations and qualitative indices of function 

including NKCC and IgG antibodies to 

latent herpes viruses, and how these respond to 

stressors and stress management interventions 

in these populations. 

• Her laboratory currently is exploring the mechanics 

of cytotoxicity (e.g., perforin and 

granzyme production) and how these relate to 

psychosocial factors via hypothalamic pituitary 

adrenal hormone changes. 

KENNETH W. GOODMAN, PH.D. 

Associate Professor of Medicine 


Work on ethics and evidence-based practice 

constitutes a natural extension of efforts to 

explore ethical issues in health informatics, epidemiology, 

and public health. The University of 

Miami’s reputation as a leader in under-addressed 

areas of clinical and research ethics continues to 

expand. The University continues to work on 

issues in the use of information technology, especially 

in public health. Moreover, the University’s 

ethics programs include international research 

ethics among the core foci, even as the University 

continues work on end-of-life care, environmental 

health and ethics, and genetics. Efforts to develop 

ethics curricula for scientists and others 

continue. 

Dr. Goodman is director of the University of 

Miami’s Bioethics Program, director of clinical and 

research ethics education at UM/Sylvester, and 

vice chair of UM/Sylvester’s Bioethics Committee. 




2002 

Green, RM, DeVries, KO, Bernstein, J, 

Goodman, KW, Kaufmann, R, Kiessling, AA, 

Levin, SR, Moss, SL, and Tauer, CA. Overseeing 

research on therapeutic cloning: a private ethics 

board responds to its critics. Hastings Center Report 

32:27-33, 2002. 

2003 

Markovitz, BP and Goodman, KW. Case reports 

on the web redux: confidentiality still in jeopardy. 

Proceedings of the AMIA Annual Symposium 

926, 2003. 

W. JARRARD GOODWIN, M.D., F.A.C.S. 

Professor of Otolaryngology 


Dr. Goodwin’s research focuses on the prevention 

and treatment of squamous cell carcinoma 

(SCCA) of the upper aerodigestive tract. 

Cancer Prevention and Control 

Dr. Goodwin has had a long-term interest in the 

potential of several micronutrients to inhibit the 

development of these cancers. Currently, various 

aspects of an extensive database from a phase III 

chemo-prevention trial, investigating the activity 

of beta-carotene, are being analyzed and published. 

He also is collaborating with investigators 

at the University of Florida on an NCI-funded 

oral cavity cancer control project. Disparities in 

mortality and stage at time of presentation for 

under-served populations is a developing interest. 

Quality of Life 

In addition, Dr. Goodwin studies the impact of 

treatment decisions on the quality of life experienced 

by patients with head and neck cancer. 

Current studies include collaborative investigations 

of speech and swallowing function following 

various treatment interventions. Working 

with Frank J. Penedo, Ph.D., he also is interested 

in the effect of stress and depression on survival 

and quality of life in this group of patients. 

Therapy 

Finally, Dr. Goodwin is actively involved in clinical 

trials studying the effect of P-53 gene therapy, 

alone and in combination with chemotherapy, for 

recurrent cancers of the oral cavity, pharynx, and 

larynx. 


2003 

Civantos, FJ, Gomez, C, Duque, C, Pedroso, F, 

Goodwin, WJ, Weed, DT, Arnold, D, and 

Moffat, F. Sentinel node biopsy in oral cavity 

cancer: correlation with PET scan and immunohistochemistry. 

Head & Neck 25:1-9, 2003. 

Franzmann, EJ, Schroeder, GL, Goodwin, WJ, 

Weed, DT, Fisher, P, and Lokeshwar, VB. Expression 

of tumor markers hyaluronic acid and hyaluronidase 

(HYAL1) in head and neck tumors. 

International Journal of Cancer 106:438-45, 

2003. 


• Established, as one of the first investigators, the 

efficacy of selenium and retinoic acid in inhibiting 

carcinogenesis in an animal tumor model 

relevant to SCCA of the upper aerodigestive 

tract. 

• Published definitive outcomes studies analyzing 

the results of salvage treatment for recurrent 

cancer of the upper aerodigestive tract and for 

the treatment of Stage IV cancer. 

16 



GAIL H. IRONSON, M.D., PH.D. 



Predictors of Long-Term Survivorship 

Dr. Ironson’s work focuses on identifying psychosocial 

characteristics of persons who become 

long-term survivors of HIV and cancer. 

Psychosocial Interventions to Improve 

Survivorship 

Parallel work by Dr. Ironson’s colleagues is evaluating 

the effects of interventions designed to 

boost emotional awareness and expression, build 

social support, and benefit breast cancer survivors 

and HIV-infected persons. This work is funded 

by two NIH/NIMH R01’s and an NCI P50. 


2002 








of Psychiatry 159:143-5, 2002. 

Ironson, G, Freund, B, Strauss, JL, and Williams, 

J. Comparison of two treatments for traumatic 

stress: a community-based study of EMDR and 

prolonged exposure. Journal of Clinical Psychology 

58:113-28, 2002. 

Ironson, G, Solomon, GF, Balbin, EG, 

O’Cleirigh, C, George, A, Kumar, M, Larson, D, 

and Woods, TE. The Ironson-Woods Spirituality/ 

Religiousness Index is associated with long survival, 

health behaviors, less distress, and low cortisol 

in people with HIV/AIDS. Annals of 

Behavioral Medicine 24:34-48, 2002. 

Freedland, KE, Skala, JA, Carney, RM, 

Raczynski, JM, Taylor, CB, Mendes De Leon, 

CF, Ironson, G, Youngblood, ME, Rama 

Krishnan, KR, and Veith, RC. The Depression 

Interview and Structured Hamilton (DISH): Rationale, 

development, characteristics, and clinical 

validity. Psychosomatic Medicine 64:897-905, 

2002. 

2003 








2003. 


LaPerriere, A, Ishii, M, Devieux, J, Stanley, H, 

Ironson, G, Schneiderman, N, Brondolo, E, 

Tobin, JN, and Weiss, S. Cognitive-behavioral 

interventions improve quality of life in women 

with AIDS. Journal of Psychosomatic Research 

54:253-61, 2003. 







2003. 
















Medicine 65:427-34, 2003. 



Schneiderman, N. Coping and Psychological 

Distress Among Symptomatic HIV+ Men Who 

Have Sex With Men. Annals of Behavioral Medicine 

25:203-13, 2003. 


• Identified in her long-term survivorship studies 

a number of cognitive appraisal, emotional expression, 

and spiritual-related predictors that 

characterize HIV and cancer populations. 

• Used this information to relate these psychosocial 

characteristics to relevant physiological 

indicators (e.g., cortisol and natural killer cell 

toxicity (NKCC)) that may explain their association 

with extended survival and optimal 

health outcomes. 

ROBERT S. KIRSNER, M.D. 

Associate Professor of Dermatology and 

Cutaneous Surgery 


Dr. Kirsner’s research interests encompass skin 

cancer, health services research, and epidemiology. 

Specifically, he focuses on primary and 

secondary prevention of skin cancer. With regard 

to primary prevention efforts, his laboratory is 

evaluating the policies and procedures in the Miami-Dade 

County school system related to sun 

protection and studying the attitudes and behaviors 

of Hispanic students toward skin cancer prevention. 

His research will evaluate predictors of a 

school-based education program aimed at skin 

cancer education. Dr. Kirsner’s research efforts 

18 

regarding secondary prevention is aimed at determining 

prevalence of screening being performed 

in various settings, patient preferences regarding 

screening, and predictors of when skin cancer 

screening will occur. Dr. Kirsner’s work in health 

services research is aimed at determining the role 

of a health care delivery system for outcomes for 

skin cancer and other screenable cancers such as 

breast, colon, and cervical cancer. Researchers in 

this laboratory also are evaluating the effect of 

poverty and access to cancer-related services on 

cancer outcomes. Finally, Dr. Kirsner’s interest in 

epidemiology has focused on the role of ultraviolet 

light in the development and mortality of skin 

cancer and lymphoma. 


2002 

Kirsner, RS , Fastenau, J, Falabella, A, Valencia, I, 

Long, R, and Eaglstein, WH. Clinical and economic 

outcomes with graftskin for hard-to-heal 

venous leg ulcers: a single-center experience. Dermatologic 

Surgery 28:81-82, 2002. 

Federman, DG, Kravetz, JD, and Kirsner, RS . 

Skin cancer screening by dermatologists: prevalence 

and barriers. Journal of the American Academy 

of Dermatology 46:710-14, 2002. 

Federman, DG and Kirsner, RS . The patient 

with skin disease: an approach for nondermatologists. 

Ostomy/Wound Management 48:22-8; 

quiz 29-30, 2002. 

Harrison-Balestra, C, Eaglstein, WH, Falabela, 

AF, and Kirsner, RS . Recombinant human platelet-derived 

growth factor for refractory nondiabetic 

ulcers: a retrospective series. Dermatologic 

Surgery 28:755-59; discussion 759-60, 2002. 

Sullivan, TP, Elgart, GW, and Kirsner, RS . Pemphigus 

and smoking. International Journal of 

Dermatology 41:528-30, 2002. 

Sullivan, TP and Kirsner, RS . Surgical pearl: 

punch technique to improve granulation over 

exposed tendons in chronic wounds. Journal of 

the American Academy of Dermatology 47:439- 

40, 2002. 



Trent, JT and Kirsner, RS. Diagnosing necrotizing 

fasciitis. Advances In Skin & Wound Care 

15:135-38, 2002. 

Zacur, H and Kirsner, RS. Debridement: Rationale 

and Therapeutic Options. Wounds 14:2E- 

7E, 2002. 

2003 

Kirsner, R. New approaches to a timeless dilemma. 

Ostomy/Wound Management 49:12-14, 

2003. 

Li, J, Zhang, YP, and Kirsner, RS . Angiogenesis 

in wound repair: angiogenic growth factors and 

the extracellular matrix. Microscopy Research 

and Technique 60:107-14, 2003. 

Trent, JT, Kirsner, RS , Romanelli, P, and Kerdel, 

FA. Analysis of intravenous immunoglobulin for 

the treatment of toxic epidermal necrolysis using 

SCORTEN: The University of Miami Experience. 

Archives of Dermatology 139:39-43, 2003. 

Trent, JT and Kirsner, RS . Wounds and malignancy. 

Advances in Skin & Wound Care 16:31- 

34, 2003. 

Jacob, SE, Lodha, R, Cohen, JJ, Romanelli, P, 

and Kirsner, RS . Paraneoplastic eosinophilic 

fasciitis: a case report. Rheumatology International 

23:262-4, 2003. 

Martin, LK and Kirsner, RS . Ulcers caused by 

bullous morphea treated with tissue-engineered 

skin. International Journal of Dermatology 

42:402-04, 2003. 

Ayyalaraju, RS, Finlay, AY, Dykes, PJ, Trent, JT, 

Kirsner, RS , and Kerdel, FA. Hospitalization for 

severe skin disease improves quality of life in the 

United Kingdom and the United States: a comparative 

study. Journal of American Academy of 

Dermatology 49:249-54, 2003. 

Banta, MN, Eaglstein, WH, and Kirsner, RS . 

Healing of refractory sinus tracts by dermal matrix 

injection with Cymetra. Dermatologic Surgery 

29:863-66, 2003. 

Geren, SM, Kerdel, FA, Falabella, AF, Kirsner, 

RS. Infliximab: A treatment option for ulcerative 

pyoderma gangrenosum. Wounds 15:49-53, 

2003. 

Kirsner, RS . Infection and Intervention. Wounds 

15:127-28, 2003. 


• Found that differences in the stage of melanoma 

between patients enrolled in fee for 

service compared to HMO is related to patient 

access. 

• Described the correlation between melanoma 

in Black and Hispanic patients with UV exposure 

(the first to do so), suggesting a rationale 

of skin cancer prevention in darkly pigmented 

populations. 

• Established that a history of skin cancer is the 

most important predictor for determining 

whether a patient will have skin cancer screening 

performed by his primary care provider. 

MAHENDRA KUMAR, PH.D. 

Professor of Psychiatry and 

Behavioral Sciences 


Dr. Kumar is the director of the Molecular 

Neuroendocrinology and Neurotransmitters 

Laboratory in the department of Psychiatry and 

Behavioral Sciences at the University of Miami. 

He has been a close collaborator with Michael H. 

Antoni, Ph.D., Gail H. Ironson, M.D., Ph.D., 

and Neil Schneiderman, Ph.D., over the past 15 

years in various research investigations including 

most recently, the Center for Psycho-Oncology 

Research (CPOR), funded by the NCI. Dr. Kumar 

conducts several neuroendocrinological protocols 

within the CPOR and is responsible for carrying 

out all the required assays to understand the mediating 

effects of stress hormones on health and 

immunological indices during cognitive-behavioral 

stress management (CBSM) intervention. 




2002 








of Psychiatry 159:143-5, 2002. 









MH, Schneiderman, N, and Eisdorfer, C. 

The HPA axis in HIV-1 infection. Journal of 

Acquired Immune Deficiency Syndromes 31 

Supplement 2:S89-93, 2002 

2003 

Mitchell, A and Kumar, M. Psychological coping 

and cancer. Search strategy used is inadequate. 

British Medical Journal 326:598; author reply 

598, 2003. 


• Made available urinary, blood, and salivary cortisol 

measurements that help in the understanding 

of the acute and more enduring effects of 

this form of stress management on different 

cancer populations studied at UM/Sylvester. 

• Installed a real time polymerase chain reaction 

(PCR) facility, which has been used to quantify 

viral loads for HPV 16 and 18 sub-strains in 

HIV+ women at-risk for cervical neoplasia in 

one CPOR project. In fact, viral loads samples 

have been obtained from the participants. 

SUZANNE C. LECHNER, PH.D. 

Assistant Professor of Psychiatry and 

Behavioral Sciences 


Dr. Lechner’s research in psycho-oncology 

focuses on two different themes: positive 

adaptation to breast cancer and the causes of late 

presentation to clinic following the detection of a 

breast cancer symptom. With regard to the first, 

Dr. Lechner is involved in clinical trials and correlational 

research studies to examine how people 

adjust to illness, and whether there are variables 

that can predict which patients will adapt well 

and which will require psychotherapeutic intervention. 

Within the context of all of these studies, 

she is interested in the complex relationships 

between positive adjustment and psychosocial 

and immunological/endocrine variables. The 

laboratory’s ongoing clinical intervention studies 

are examining the effects of a ten-week cognitivebehavioral 

stress management (CBSM) intervention 

versus a one-day stress management seminar 

on immunological, endocrine, and psychological 

outcomes for women with early stage breast cancer. 

In addition, Dr. Lechner is the primary investigator 

of another ongoing correlational research 

study, funded by the American Psychological Association 

Division 38, which will examine the 

correlates and consequences of benefit-finding 

(i.e., the belief that having cancer has led to positive 

life changes, such as better relationships with 

family and friends, a stronger sense of self-efficacy, 

and personal strength and redirected 

priorities). 

Dr. Lechner’s research also focuses on another 

topic: delayed presentation to clinic following 

the detection of a breast cancer symptom. 

Early detection and treatment has been shown to 

result in a significant reduction in breast cancer 

mortality. In spite of the importance of early detection, 

some women delay seeking consultation 

after they detect a suspicious breast cancer symp- 

20 



tom, such as a palpable breast lump or nipple 

discharge. Women who delay in seeking medical 

advice are more likely to present with advanced 

disease, thus limiting available treatment options 

and substantially impacting mortality. Previous 

studies have indicated that breast cancer patients 

who delayed as long as three to six months had 

poorer prognoses than those who sought treatment 

within three months of symptom detection. 

The reasons for delayed presentation are not well 

understood, but may include such factors as 

symptom-related information, sociodemographic 

variables, ethnicity-related factors (e.g., fatalism), 

attitudes and beliefs of the person’s social network 

or religion, psychological attributes, and knowledge-related 

factors. The percentage of women 

who present to the clinic with late stage breast 

cancer in the metropolitan Miami-Dade area is 

disproportionate to state and national averages, 

leading to the hypothesis that late presentation 

may be a significant health problem in this geographical 

area. 


2003 






of Psychosomatic Research 54:253-61, 2003. 





Psycho-oncology 12:491-99, 2003. 


Development of Benefit-Finding in Cancer 

Survivors 

One study examined patients’ perceptions that 

having cancer led to positive life changes, or 

benefit-finding, e.g., improved relationships, 

enhanced appreciation of life, increased resilience, 

and self-reliance. The laboratory investigated 

the relationship between benefit-finding and 

sociodemographic (e.g., gender, age, marital 

status, education, and income) and diseaserelated 

variables (e.g., severity of disease, or 

cancer stage, or time since diagnosis). 

• As hypothesized, benefit-finding was greater in 

younger patients, and also differed by stage of 

disease in a curvilinear fashion. Individuals with 

Stage II disease had significantly higher benefitfinding 

scores than those with Stage IV or Stage 

I cancer. 

• Time since diagnosis and treatment status 

(i.e., currently in treatment, completed treatment, 

or no treatment) were not related to 

benefit-finding. 

• Findings suggest that stage of disease is an important 

factor to consider when investigating 

positive perceptions of disease in individuals 

with cancer. 

Another study examined whether various 

measures of positive thinking (i.e., Life Orientation 

Test-Revised for Optimism) and found 

meaning (Benefit-Finding Scale) measured over a 

one-year period following surgery for early stage 

breast cancer were associated with adjustment 

(i.e., Profile of Mood States, Quality of Life 

(QOL), and CES-Depression). 

• Controlling for baseline levels of adjustment, 

greater optimism at one-year follow-up was associated 

with concurrent higher vigor, better 

QOL, fewer depressive symptoms, less anxiety, 

depression, anger, and fatigue. 

• One-year follow-up benefit-finding was correlated 

with concurrent higher vigor, better QOL, 

fewer depressive symptoms, and less anxiety 

when baseline adjustment scores were controlled. 



• Findings suggest that maintaining a positive 

attitude may relate to psychological well-being 

over the year post surgery. 

An additional study revealed that there were 

complex relationships between benefit-finding 

and coping over the one-year period following 

surgery for early stage breast cancer. 

• During the early period of dealing with the diagnosis 

of and treatment for breast cancer, for 

example, benefit-finding is associated with 

greater positive reframing, religious coping, selfdistraction, 

substance use, examining emotions, 

and seeking less social support. By mid-treatment 

(three months later), active coping and 

religious coping were important correlates of 

benefit-finding, while after treatment completion 

(six months), higher benefit-finding was 

related to greater active coping, examining emotions, 

seeking social support, religious coping, 

and reduced use of acceptance coping. However, 

by one year after surgery, greater benefitfinding 

was associated with using positive 

reframing and planning coping strategies. 

• Thus, effective coping strategies early on may be 

those that help women modulate their emotions 

and maintain hope. Later on, the most 

effective strategies appear to be those that help 

them move on and plan for the future. 

• The research outcome suggests that finding 

benefits in cancer may be differentially related 

to the coping strategies women employ at different 

points during the treatment trajectory, 

which may have important implications for tailoring 

psychosocial interventions across medical 

treatment. 

DAVID J. LEE, PH.D. 

Associate Professor of Epidemiology and 

Public Health 


Dr. Lee is a chronic disease epidemiologist 

with a long-standing interest in the prevalence 

of, and morbidities associated with, sensory-related 

diseases and impairments. In the past 

two years, he has published findings that examined 

cancer mortality risk in community-residing 

adults with visual impairment and glaucoma. Previous 

research has suggested an association between 

cancer risk and eye disease. Dr. Lee and his 

colleagues found, however, that detection bias, in 

part, might be responsible for this association. 

Their findings were of sufficient merit to warrant 

publication of an accompanying editorial by a 

leading ophthalmic epidemiologist. 

Dr. Lee entered the field of tobacco control 

research in 2000, where he now devotes 60 percent 

of his research efforts. Since this career shift, 

he has served as co-investigator of the Florida 

Youth Cohort Study that is following a sample of 

Florida adolescents in order to monitor changes 

in tobacco-related attitudes/beliefs and behaviors. 

He also is the lead author on three papers reporting 

results from this work. Dr. Lee also is the 

principal investigator of two Flight Attendant 

Medical Research Institute (FAMRI)-funded 

grants to study the influence of second-hand 

smoke on the health of adolescents. Using 

UM/Sylvester developmental funds, Dr. Lee 

fielded a school-based pilot study in 2004 that 

examined second-hand smoke exposure and cancer 

risk factors in an ethnically diverse group of 

middle-school students. Findings from this study 

will be used to develop an intervention designed 

to reduce cancer risk factors in this population. 

It will be submitted for possible funding to the 

NCI in February 2005. 

22 



Dr. Lee also has developed an interest in the 

identification of cancer risk factors in adults. For 

example, he recently co-authored a paper examining 

cancer mortality risk in pesticide applicators. 

He served as the dissertation chair for a project 

examining cancer risk in Florida firefighters. Two 

papers examining cancer mortality and cancer 

incidence in this occupational group are presently 

under peer review. In 2003, Dr. Lee and his colleagues 

published a lead article in the journal 

Ophthalmology examining the association between 

glaucoma and cause-specific mortality including 

cancer. Dr. Lee’s most recent tobacco-related 

publication focused on trends in smoking rates 

among 209 of the largest worker groups in the 

United States. This paper was published in the 

Journal of Occupational and Environmental 

Medicine in 2004. 

A novel non-nicotine replacement therapy 

smoking cessation strategy for older adults with 

chronic disease, including cancer patients, is 

presently under review by the NCI. A cognitive 

behavioral smoking cessation program directed 

at military recruits prior to entry into basic 

training is also under review at the Department 

of Defense. 


2002 

Lee, DJ, Gomez-Marin, O, Lam, BL, and Zheng, 

DD. Visual acuity impairment and mortality in 

U.S. adults. Archives of Ophthalmology 

120:1544-50, 2002. 

Lee, DJ, Trapido, E, and Rodriguez, R. Self-reported 

school difficulties and tobacco use among 

fourth- to seventh-grade students. Journal of 

School Health 72:368-73, 2002. 

2003 


F, and Lee, DJ. National Health Interview Survey 

mortality among U.S. farmers and pesticide 

applicators. American Journal of Industrial 

Medicine 43:227-33, 2003. 

Lee, DJ, Gomez-Marin, O, Ma, F, and Lam, BL. 

Uncorrected binocular distance visual acuity 

impairment and survival: The National Health 

and Nutrition Examination Survey I. Ethnicity 

and Disease 13:485-91, 2003. 

Lee, DJ, Trapido, E, and Rodriguez, R. Secondhand 

smoke and earaches in adolescents: The 

Florida Youth Cohort Study. Nicotine and Tobacco 

Research 5:1-4, 2003. 


• Demonstrated an association between exposure 

to second-hand smoke and self-reported earaches 

in adolescents, which is novel in that 

these associations have typically been reported 

in younger children and infants. The two 

FAMRI-funded studies will help to determine if 

biologically confirmed exposure to second-hand 

smoke is related to both reported earaches and 

clinically confirmed indicators of middle ear 

problems. 

SILVINA LEVIS-DUSSEAU, M.D. 

Professor of Medicine 


For the last ten years, Dr. Levis-Dusseau, director 

of the Osteoporosis Center, a joint venture 

between the University of Miami School of 

Medicine and the Miami Veterans Administration 

Medical Center, has been conducting clinical 

trials testing the effectiveness of different drugs in 

the treatment of osteoporosis. Currently, she is 

conducting an NIH-sponsored trial that will 

evaluate the effectiveness of estrogens derived 

from soy in preventing menopausal symptoms 

and bone loss. Her research interests also include 

improving muscle function and bone mass in 

elderly individuals with vitamin D deficiency. 

Dr. Levis-Dusseau has collaborated with Bernard 

A. Roos, M.D., Michael H. Antoni, Ph.D., and 

Neil Schneiderman, Ph.D., for the past three 



years to conduct a clinical trial testing the effects 

of low-dose estrogen treatment on quality of life, 

osteoporosis risk, and other physical indicators in 

men who had undergone androgen deprivation 

therapy for metastatic prostate cancer. This 

project is funded by the NCI as part of the 

Center for Psycho-Oncology Research (CPOR), 

which is directed by Michael H. Antoni, Ph.D. 


2002 

Levis, S, Quandt, SA, Thompson, D, Scott, J, 

Schneider, DL, Ross, PD, Black, D, Suryawanshi, 

S, Hochberg, M, and Yates, J. Alendronate reduces 

the risk of multiple symptomatic fractures: 

results from the fracture intervention trial. Journal 

of the American Geriatric Society 50:409-15, 

2002. 

2003 

Hernandez-Cassis, C, Vogel, CK, Hernandez, TP, 

Econs, MJ, Iglesias, M, Iglesias, A, Levis, S, 

Roos, BA, Howard, GA, and Gamarra, AI. Autosomal 

dominant hyperostosis/osteosclerosis with 

high serum alkaline phosphatase activity. Journal 

of Clinical Endocrinology & Metabolism 

88:2650-55, 2003. 


• Discovered that vitamin D deficiency in South 

Florida residents is higher than expected: approximately 

25 percent in young adults and 30 

percent in the elderly. 

FRANK J. PENEDO, PH.D. 

Assistant Professor of Psychology 

Psycho-Oncology, Psychology of Aging and 

Immunosenescence in Chronically Ill Older 

Adults 

Within the fields of health psychology and behavioral 

medicine, cancer and the human immunodeficiency 

virus (HIV) have provided unique 

opportunities to evaluate the role of psychosocial 

factors in disease acquisition and progression 

among various populations. Part of Dr. Penedo’s 

research is examining the role of psychosocial factors 

such as stress, coping, and personality style in 

psychological distress and physical health status 

in three specific populations: 1) HIV+ ethnically 

diverse men who have sex with men (MSM) and 

heterosexual older men with a history of substance 

use, 2) men treated with radical prostatectomy 

or radiation for localized prostate cancer, 

and 3) men and women diagnosed with Stages I- 

III of head and neck cancer. 

Dr. Penedo’s research with these chronic disease 

groups is focused primarily on evaluating the 

efficacy of group- and individual-based stress 

management interventions on reducing distress 

and improving quality of life (QOL) and physical 

health status among older cancer or HIV populations 

(50 years and older). Dr. Penedo is particularly 

interested in how psychosocial factors such 

as stress, coping, and personality style may interact 

with health behaviors (e.g., treatment adherence), 

neuroendocrine function, and the agerelated 

decrements in immune function (i.e., 

immuno-senescence) seen in older populations. 

More specifically, he is interested in how stress 

and other psychosocial factors may interact with, 

and exacerbate, age-related decrements in immune 

function on the one hand, and disease 

progression in older cancer and HIV populations 

on the other. 

Several of the research questions involved in 

Dr. Penedo’s work aim to answer: 1) whether psychosocial 

factors impact neuroendocrine and immune 

parameters in chronically ill older adults 

(e.g., Does psychological stress-related activation 

24 



of the HPAC-axis lead to suppressed immunity, 

particularly shifts in specific T-cell and cytokine 

subpopulations and angiogenic factors?), 2) the 

extent to which age-related decrements in immunity 

can be exacerbated (or buffered) by psychosocial 

factors (e.g., Are there protective 

psychosocial factors such as coping repertoires or 

personality styles that may buffer the effects of 

distress on immune function or age-related decrements 

in immunity? Can psychosocial interventions 

modify these factors in an aim to sustain or 

enhance immunity as well as ameliorate disease 

progression?), and 3) the clinical implication of 

the impact of psychosocial factors on neuroendocrine 

and immune function in older chronically 

ill populations (e.g., What is the clinical significance—disease 

progression, improved physical 

health status—of the relationship between 

psychosocial factors and neuroendocrine and 

immune function in older adults?). 

In an effort to answer these questions, 

Dr. Penedo is involved in several biopsychosocial 

HIV and cancer studies evaluating the role of 

psychosocial factors and psychosocial interventions 

on QOL, immune function, and health 

status. 


2003 







Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M, 

Malow, R, Costa, P, and Schneiderman, N. Personality, 

quality of life and HAART adherence 



2003. 






25:203-13, 2003. 

BERNARD A. ROOS, M.D. 



Dr. Roos’ current clinical research involves 

adult stem cells as well as hormone and exercise 

therapy in men and women, particularly frail 

elderly. One project is directed at the role of estrogen 

in the aging male and the other on the 

restorative effects of resistance exercise in frail 

elderly. In addition, there are several major research 

and training initiatives in geriatrics. 


2002 

Yang, ES, Maiorino, CA, Roos, BA, Knight, SR, 

and Burnstein, KL. Vitamin-D mediated growth 

inhibition of an androgen-ablated LNCaP cell 

line model of human prostate cancer. Molecular 

and Cellular Endocrinology 186:69–79, 2002. 

D’Ippolito, G, Schiller, PC, Balkan, W, Roos, 

BA, and Howard, GA. Cooperative anabolic actions 

of HGF and 1,25-dihydroxyvitamin D 3 

in 

osteoblastic differentiation of human vertebral 

marrow stromal fibroblasts. Bone 31:269–75, 

2002. 

Perez-Stable, CM, Schwartz, GG, Farinas, A, 

Finegold, M, Binderup, L, Howard, GA, and 

Roos, BA. The Gγ/T-15 transgenic mouse model 

of androgen-independent prostate cancer: target 

cells of carcinogenesis and the effect of the vitamin 

D analog EB 1089. Cancer Epidemiology, 

Biomarkers and Prevention 1555–63, 2002. 



Signorile, JF, Carmel, MP, Czaja, SJ, Asfour, SS, 

Morgan, RO, Khalil, TM, Ma, F, and Roos, BA. 

Differential increases in average isokinetic power 

by specific muscle groups of older women due to 

variations in training and testing. Journal of Gerontology: 

Medical Sciences 57:M683–M690, 

2002. 

Signorile, JF and Roos, BA. Resistance training 

for power, strength, and functionality: a longterm 

prescription. American Journal of the Medical 

Sciences 398-402, September/October, 2002. 

2003 






of Clinical Endocrinology & Metabolism 

88:2650-55, 2003. 








• The laboratory’s research on exercise and nutrition 

continues to improve the prescription of 

exercise and nutrition in the frail and vulnerable 

elderly. They have completed preliminary studies 

of a speed-training method to improve mobility 

that revealed a special role for neural 

coordination. Important physical function correlates 

with vitamin deficiency, and a clinical 

trial has demonstrated the effects of correcting 

vitamin deficiency on the mobility of older 

persons. 

• Osteoporosis therapy approaches have emerged 

from studies of normal human stem cells and 

studies of artificial matrix that can support their 

growth and mineralization. Researchers in Dr. 

Roos’ laboratory have discovered a unique combination 

of matrix, hormones, vitamins, and 

growth factors that promotes the maturation 

and growth of stem cells that forms bone in tissue 

culture and in animal transplants. Tissue 

engineering approaches also are being examined 

as they address the many safety issues that will 

ultimately allow the application of these new 

technologies to persons with osteoporosis. 

• Hormonal changes in aging individuals continue 

to offer the opportunity—through hormone 

replacement therapy—to slow the aging 

process. Following up on earlier studies of sex 

hormone deficiency and concerns over the 

many diverse complications of sex hormone 

replacement, researchers in this laboratory have 

begun to evaluate various nutritional supplements 

such as soy protein chemicals that can act 

as sex hormone replacements without causing 

increased risk of cancer. Moreover, the initial 

studies of vitamins in aging persons have been 

completed, reporting that 20 percent of older 

ambulatory South Floridians are vitamin D 

deficient. Planning for several studies to assess 

the dose and effects of successful vitamin D 

replacement in older persons is underway. The 

initial focus is on benefits of vitamin D replacement 

on gait, balance, and other mobilityrelated 

factors. 

• New hormonal interventions that can improve 

the mood of men undergoing hormone-deprivation 

therapy for advancing prostate cancer are 

now being examined. The laboratory, through 

an NCI-funded study, will aim to demonstrate 

that low-dose estrogen replacement might benefit 

men with prostate cancer. Similar studies 

based on the use of estrogen-like nutritional 

compounds, such as soy isoflavones, also are 

being considered. 

26 



NEIL SCHNEIDERMAN, PH.D. 



Dr. Schneiderman’s research focuses on improving 

the quality of life (QOL) in men 

who have undergone radical prostatectomy or 

beam radiation treatment for localized prostate 

cancer. As project leader of a study titled “Cognitive-Behavioral 

Stress Management and Prostate 

Cancer” on Center Grant P50 CA84944 (under 

Michael H. Antoni Ph.D.’s direction as principal 

investigator), Dr. Schneiderman’s laboratory is 

conducting studies comparing a ten-week cognitive-behavioral 

stress management (CBSM) 

program versus a one-day CBSM seminar. They 

are examining QOL indicators and immune 

system status (e.g., natural killer cell cytotoxicity 

(NKCC)) throughout a 12-month follow-up 

period. 


2002 








of Psychiatry 159:143-45, 2002. 





(Supplement 2):S89-93, 2002. 

Williams, R, Schneiderman, N, Relman, A, and 

Angell, M. Resolved: psychosocial interventions 

can improve clinical outcomes in organic disease—rebuttals 

and closing arguments. Psychosomatic 

Medicine 64:564-67, 2002. 

Williams, RB and Schneiderman, N. Resolved: 

psychosocial interventions can improve clinical 

outcomes in organic disease (pro). Psychosomatic 

Medicine 64:552-57, 2002. 

Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB, 

Evans, JD, McDonald, PA, and Schneiderman, 

N. Hemodynamic response patterns: responder 

type differences in reactivity and recovery. Psychophysiology 

39:739-46, 2002. 

2003 





trial. Annals of Behavioral Medicine 25:66- 

73, 2003. 



Schneiderman, N. Sleep disturbance mediates 

the association between psychological distress and 




2003. 




associated with decreased memory helper T cell 

and B cell counts in pre-AIDS HIV seropositive 









2003. 














2003. 






25:203-13, 2003. 







Berkman, LF, Blumenthal, J, Burg, M, Carney, 

RM, Catellier, D, Cowan, MJ, Czajkowski, SM, 

DeBusk, R, Hosking, J, Jaffe, A, Kaufmann, PG, 

Mitchell, P, Norman, J, Powell, LH, Raczynski, 

JM, and Schneiderman, N. Enhancing Recovery 

in Coronary Heart Disease Patients Investigators 

(ENRICHD). Effects of treating depression and 

low perceived social support on clinical events 

after myocardial infarction: the Enhancing Recovery 

in Coronary Heart Disease Patients 

(ENRICHD) Randomized Trial. Journal of the 

American Medical Association 289:3106-16, 

2003. 

Watkins, LL, Schneiderman, N, Blumenthal, JA, 

Sheps, DS, Catellier, D, Taylor, CB, and 

Freedland, KE; ENRICHD Investigators. Cognitive 

and somatic symptoms of depression are associated 

with medical comorbidity in patients 

after acute myocardial infarction. American Heart 

Journal 146:48-54, 2003. 

Fernander, AF, Durán, REF, Saab, PG, Llabre, 

MM, and Schneiderman, N. Assessing the reliability 

and validity of the John Henry Active 

Coping Scale in an urban sample of African 

Americans and White Americans. Ethnicity & 

Health 8:147-61, 2003. 


Evans, JD, McDonald, PAG, and Schneiderman, 

N. Hemodynamic response patterns: Responder 


39:739-46, 2003. 


• Maintaining an optimistic outlook is associated 

with greater NKCC by way of greater emotional 

expression. 

• Perceived stress management skills mediate 

improvements in mood and QOL during the 

CBSM intervention. 

• Intervention-related gains in QOL may be 

paralleled by gonadal hormone (testosterone) 

changes. 

GAIL S. SHOR-POSNER, PH.D. 

Professor of Psychiatry and Behavioral 

Sciences 


Dr. Shor-Posner is funded by the NCI as part 

of the Women’s Intervention Nutrition 

Study (WINS). She received this funding for the 

Low Fat Diet and Breast Cancer Recurrence/Outcome 

Trial. The goal of this multi-site project is 

to determine whether a program of dietary fat 

intake reduction, provided in addition to defined 

adjuvant therapy, will effectively prolong diseasefree 

survival for patients between 48 and 78 years 

of age with early stage breast cancer. The study is 

ongoing, and a proposal has been submitted for 

continuation until 2007. 

28 



Dr. Shor-Posner is the principal investigator 

of the Fogarty International Center (FIC) AIDS 

and TB International Training and Research Program, 

funded by the NIH/FIC. The AIDS training 

curriculum is an international program 

designed to contribute to research capacity building 

in targeted developing countries, to facilitate 

the ability of scientists/clinicians to slow HIV-1 

disease progression, prevent maternal-to-child 

transmission, and enhance survival. This program 

also seeks to provide training to qualified health 

professionals from two countries that are currently 

experiencing the most dramatic increases 

in TB and multi-drug resistant TB (MDR-TB) 

in the Americas, Honduras, and the Dominican 

Republic. 

Dr. Shor-Posner also is the mentor of Florida 

Department of Health-funded research titled, 

“Pulmonary Complications in Tobacco Users Infected 

With the Human Immunodeficiency Virus: 

Therapeutic Implications.” This proposal is 

for evaluation of the frequency of tobacco use 

among HIV+ individuals hospitalized at Jackson 

Memorial Hospital and the impact of tobacco use 

on the risk of developing lower respiratory infections. 

Additionally, Dr. Shor-Posner is the nutrition 

director of the NIH-funded General Clinical 

Research Center (GCRC). The GCRC, while 

located in several locations, functions as a single 

integrated department/unit with single program 

leadership and coordination. This clinical research 

infrastructure provides a conduit for the 

enhancement of multi-specialty projects. 


2002 

Miguez-Burbano, MJ, Pineda-Medina, L, 

Lecusay, R, Page, JB, Castillo, G, Burban, X, 

Rodriguez, A, Rodriguez, N, and Shor-Posner, 

G. Continued high risk behaviors in HIV infected 

drug abusers. Journal of Addictive Diseases 

21:67-80, 2002. 

Shor-Posner, G , Miguez, MJ, Pineda, LM, 

Rodriguez, A, Ruiz, P, Castillo, G, Burban, X, 

Lecusay, R, and Baum, M. Impact of selenium 

status on the pathogenesis of mycobacterial disease 

in HIV-1-infected drug users during the era 

of highly active antiretroviral therapy. Journal of 

Acquired Immune Deficiency Syndromes 

29:169-73, 2002. 

Miguez-Burbano, MJ, Burbano, X, Rodriguez, A, 

Lecusay, R, Rodriguez, N, and Shor-Posner, G . 

Development of thrombocytosis in HIV+ drug 

users: impact of antiretroviral therapy. Platelets 

13:183-85, 2002. 

Miguez, MJ, Burbano, X, Archer, H, and 

Shor-Posner, G . Limited impact of highly active 

antiretroviral therapy in thrombocytopenia. 

Journal of Acquired Immune Deficiency 

Syndromes 30:260-61, 2002. 

Miguez-Burbano, MJ, Navas, R, Forero, MG, 

Burbano, X, Rodriguez, N, and Shor-Posner, G . 

Evaluation of HIV prevention and counseling 

practices of obstetrician/gynecologists in Bogota, 

Colombia: impact on women’s knowledge and 

risk practices. AIDS Education and Prevention 

14:72-80, 2002. 

Shor-Posner, G , Lecusay, R, Morales, G, Campa, 

A, and Miguez-Burbano, MJ. Neuroprotection in 

HIV-positive drug users: implications for antioxidant 

therapy. Journal of Acquired Immune Deficiency 

Syndromes 31 Supplement 2:S84-88, 

2002. 

Burbano, X, Miguez-Burbano, MJ, McCollister, 

K, Zhang, G, Rodriguez, A, Ruiz, P, Lecusay, R, 

and Shor-Posner, G . Impact of a selenium 

chemoprevention clinical trial on hospital admissions 

of HIV-infected participants. HIV Clinical 

Trials 3:483-91, 2002. 

Shor-Posner, G , Lecusay, R, Miguez-Burbano, 

MJ, Morales, G, and Campa, A. Neuroprotection 

in HIV+ drug users: implications for antioxidant 


Syndromes 31:S84-S88, 2002. 



2003 

Miguez-Burbano, MJ, Archer, H, Rodriguez, M, 

and Shor-Posner, G . Discontinuation of secondary 

prophylaxis and the risk of Pneumocystis 

carinii pneumonia. AIDS 17:140-41, 2003. 

Shor-Posner, G , Lecusay, R, Miguez, MJ, 

Moreno-Black, G, Zhang, G, Rodriguez, N, 

Burbano, X, Baum, M, and Wilkie, F. Psychological 

burden in the era of HAART: impact of 

selenium therapy. International Journal of Psychiatry 

in Medicine 33:55-69, 2003. 

Miguez, MJ, Shor-Posner, G , Morales, G, 

Rodriguez, A, and Burbano, X. HIV treatment in 

drug abusers: impact of alcohol use. Addiction 

Biology 8:33-37, 2003. 

Miguez-Burbano, MJ, Burbano, X, Ashkin, D, 

Pitchenik, A, Allan, R, Pineda, L, Rodriguez, N, 

and Shor-Posner, G . Impact of tobacco use on 

the development of opportunistic respiratory 

infections in HIV seropositive patients on 

antiretroviral therapy. Addiction Biology 

8:39-43, 2003. 

Perez-Then, E, Peña, R, Tavarez-Roja, M, Peña, 

C, Quiñonez, S, Buttler, M, Ammann, A, 

Hernandez, W, Goyanes, M, Miguez, MJ, Shor- 

Posner, G, and PMTCT Group. Preventing 

mother-to-child HIV transmission in a developing 

country: the Dominican Republic experience. 

Journal of Acquired Immune Deficiency Syndromes 

34:506-11, 2003. 

LEO B. TWIGGS, M.D. 

Professor and Associate Dean of Women’s 

Health, Interim Chairman of Obstetrics and 

Gynecology, and Medical Director, Institute 

for Women’s Health 


Dr. Twiggs, who also is the Dean of Women’s 

Health at the University of Miami School of 

Medicine, has tested the efficacy of a vaccine for 

human papillomavirus (HPV) as a method of 

controlling the risk of cervical cancer. He also 

collaborates with Michael H. Antoni, Ph.D., and 

Mary Josephine O’Sullivan, M.D., to conduct 

studies of the effects of stressors and stress management 

on health behaviors and cervical neoplasia 

in women co-infected with HIV and HPV. 


2002 

Wright, TC Jr., Cox, JT, Massad, LS, Twiggs, 

LB, and Wilkinson, EJ. ASCCP-Sponsored Consensus 

Conference. 2001 Consensus Guidelines 

for the management of women with cervical cytological 

abnormalities. Journal of the American 

Medical Association 287:2120-29, 2002. 

2003 

Wright, TC Jr., Cox, JT, Massad, LS, Carlson, J, 

Twiggs, LB , and Wilkinson, EJ. American Society 

for Colposcopy and Cervical Pathology 2001 

consensus guidelines for the management of 

women with cervical intraepithelial neoplasia. 

American Journal of Obstetrics and Gynecology 

189:295-304, 2003. 

30 




• Cancer control research—The Institute for 

Women’s Health has an active cancer control 

research program. Dr. Twiggs, Timothy De 

Santis, M.D., and Nahida Chakhtoura, M.D., 

have been collaborating with two medical device 

companies utilizing spectroscopic measures 

in cervical precursors in an effort to diagnose 

and prevent cervical cancer. This collaboration 

in an Institutional Review Board (IRB)- 

approved research setting resulted in the 

evaluation of more than 300 women with 

abnormal Pap smears in three separate clinical 

research protocols. 

JAMES D. WILKINSON, M.D., M.P.H. 

Associate Professor of Epidemiology and 

Public Health 


Dr. Wilkinson’s research focuses on epidemiological 

studies of cancer examining differential 

cancer risks among U.S. Hispanics for both 

adults and children. The results of this research 

are intended to better inform cancer control and 

prevention efforts in Florida among various subpopulations. 

Currently, Dr. Wilkinson is part of a 

collaborative team, led by investigators from the 

International Agency for Research on Cancer, to 

study prostate cancer genetics in Cuban men, 

comparing populations from Havana and Miami. 

An application for project funding to the NCI is 

planned for 2004. 


2002 


Fleming, LE, MacKinnon, J, Voti, L, and Peace, 

S. Cancer trends among Hispanic men in South 

Florida, 1981-1998. Cancer 94:1183-90, 2002. 







• Florida’s Hispanic children have a 30 percent 

increased risk of lymphoma and lymphoid leukemia 

compared to non-Hispanic White children. 

• Cancer incidence is decreased for both Hispanic 

men and women in South Florida compared to 

non-Hispanic Whites. 

• Lung cancer is now the third most common 

cancer among Hispanic women in South 

Florida. 

• Similarly, cancer mortality is decreasing among 

the Hispanic and non-Hispanic populations of 

South Florida. 



32 


C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M 

C L I N I C A L O N C O L O G Y R E S E A R C H 

P R O G R A M 



Professor of Medicine and Division Chief of Hematology-Oncology 

PROGRAM CO-LEADER 


Associate Professor of Microbiology and Immunology 

PROGRAM DESCRIPTION 

The Clinical Oncology Research Program 

(CORP) is composed of 23 faculty members 

as well as associate faculty members from accross 

the University of Miami School of Medicine. Faculty 

are specifically selected for their involvement 

in research that has significant translational potential 

and may lead to improvements in cancer 

prevention, diagnosis, and treatment. Program 

members must have peer-reviewed cancer-related 

research funding or be newly recruited investigators 

with the potential to apply for and receive 

funding. Associate program members generally 

are clinical faculty who are selected based on 

significant involvement in the overall clinical 

research effort at the University, such as involvement 

in clinical trials and/or correlative studies. 

The program was organized in January 2003 

to address the need for a broad-based clinical 

research program distinct from the four multidisciplinary 

research programs at the University 

of Miami Sylvester Comprehensive Cancer Center. 

Nearly half of the program members are 

newly recruited faculty. 


The overall goal of the CORP is to translate 

findings from UM/Sylvester’s basic research 

programs into new therapeutic, diagnostic, and/ 

or prognostic interventions, as well as develop 

novel and innovative clinical trials. 

Specific goals include: 

1) Translating UM/Sylvester’s basic science efforts 

into the clinical arena. This includes the preclinical 

and clinical development of novel diagnostic 

and therapeutic strategies and their 

implementation in the form of clinical protocols 

by CORP investigators. 

2) Integrating clinical research efforts across 

departmental lines. This includes support for 

site-based disease approaches encompassing 

tissue procurement for analysis and validation, 

improved mechanisms for tissue preservation 

to facilitate analysis of gene expression, 

proteomics, and coordination of efforts 

involving basic scientists, surgical staff, 

and pathologists. 

3) Developing the institutional intramural trial 

portfolio in an effort to provide novel clinical 

options for UM/Sylvester patients and to 

develop pilot phase I/II trials for subsequent 

validation in the cooperative group setting. 



Several shared interests connect researchers 

and create natural liaisons with other UM/Sylvester 

programs. Areas of interest include: 

• Development of gene and cellular therapies for 

cancer. 

• Development of novel pharmacological agents 

and/or combinations. 

• Identification of new prognostic and/or therapeutic 

targets. 

• Creation of mechanisms for tissue procurement 

and/or correlative studies. 

CORP members are involved in the development 

and management of several shared resources 

including Clinical Research Services; tumor banks 

and databases for breast cancer, and more recently, 

lymphoma; and a Cell Banking and Purification 

Facility for the study of hematological malignancies. 

The CORP also serves as the major access 

point to the University of Miami’s general clinical 

research center for clinical oncology research. 

The CORP meets on a monthly basis and 

invites investigators from other multidisciplinary 

research programs to share findings in a group 

forum designed to foster translation and application 

to the clinical arena. Recent CORP initiatives 

include the testing of a locally developed 

antibody to CD30 for treatment of Hodgkin’s 

and non-Hodgkin’s lymphomas, testing of novel 

genetically engineered lung cancer vaccines in 

phase I/II trials, novel radio-sensitizers, identification 

of new molecular prognostic factors in lymphoma 

and breast cancer, and the targeting of 

non-dividing anaerobic tumor cells using glycolytic 

inhibitors. The CORP continues to promote 

the identification and adaptation of promising 

strategies developed by UM/Sylvester basic scientists 

for clinical application. 

PARTICIPANTS 

Benedetto, Pasquale W., M.D. 

Medicine 

Feun, Lynn G., M.D. 

Medicine 

Ganju-Krishan, Awtar, Ph.D. 

Radiation Oncology 

Greer, Sheldon, Ph.D. 


Koniaris, Leonidas G., M.D., F.A.C.S. 

Surgery 

Lampidis, Theodore J., Ph.D. 


Lee, Kelvin P., M.D. 


Lipshultz, Steven E., M.D. 

Pediatrics 

Lokeshwar, Balakrishna L., Ph.D. 

Urology 

Lokeshwar, Vinata B., Ph.D. 

Urology 

Lossos, Izidore, M.D. 

Medicine 

Milikowski, Clara, M.D. 

Pathology 

Raez, Luis E., M.D., F.A.C.P. 

Medicine 

Rocha Lima, Caio Max S., M.D. 

Medicine 

Rosenblatt, Joseph D., M.D. 

Medicine 

Savaraj, Niramol, M.D. 

Medicine 

Singal, Rakesh, M.D. 

Medicine 

Slingerland, Joyce M., M.D., Ph.D., F.P.R.C.(C) 

Medicine 

Soloway, Mark S., M.D. 

Urology 

34 



Tang, Shou-Ching, M.D., Ph.D. 

Medicine 

Tolba, Khaled A., M.D. 

Medicine 

Vincek, Vladimir, M.D., Ph.D. 

Pathology 

Wolfson, Aaron H., M.D. 

Radiation Oncology 

LYNN G. FEUN, M.D. 



Dr. Feun’s research focuses on developing 

novel treatment strategies for patients with 

melanoma, liver cancer, and brain tumors. 


2002 

Feun, L, Modiano, M, Lee, K, Mao, J, Marini, A, 

Savaraj, N, Plezia, P, Almassian, B, Colacino, E, 

Fischer, J, and MacDonald, S. Phase I and pharmacokinetic 

study of 3-aminopyridine-2- 

carboxaldehyde thiosemicarbazone (3-AP) using a 

single intravenous dose schedule. Cancer Chemotherapy 

and Pharmacology 50:223-29, 2002. 

Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG, 

Xu, R, Xu, J, and Savaraj, N. Procollagen-like 

protein as a molecular target in the treatment of 

primary brain tumor. ScientificWorldJournal 

2:125-26, 2002. 

Feun, LG, Savaraj, N, Hurley, J, and Marini, A. 

Phase II trial of Paclitaxel and Dacarbazine with 

filgrastim administration in advanced malignant 

melanoma. Cancer Investigation 20:357-61, 

2002 

study comparing combined treatment with histamine 

dihydrochloride plus interleukin-2 versus 

interleukin-2 alone in patients with metastatic 

melanoma. Journal of Clinical Oncology 20:125- 

33, 2002 

2003 

Feun, LG, O’Brien, C, Molina, E, Rodriguez, M, 

Jeffers, L, Schiff, ER, Marini, A, Savarj, N, and 

Ardalan, B. Recombinant leukocyte interferon, 

doxorubicin, and 5FUDR in patients with hepatocellular 

carcinoma-a phase II trial. Journal of 

Cancer Research and Clinical Oncology 129:17- 

20, 2003 

Prados, MD, Schold, SC JR SC, Fine, HA, 

Jaeckle, K, Hochberg, F, Mechtler, L, Fetell, MR, 

Phuphanich, S, Feun, L, Janus, TJ, Ford, K, and 

Graney, W. A randomized, double-blind, placebo-controlled, 

phase II study of RMP-7 in 

combination with carboplatin administered intravenously 

for the treatment of recurrent malignant 

glioma. Journal of Neuro-Oncology 5:96-110, 

2003 

Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L, 

Donnelly, E, Solomon, J, Sundaram, M, Feun, 

LG, and Savaraj, N. Phase II study of vinorelbine 

with low dose prednisone in the treatment of 

hormone-refractory metastatic prostate cancer. 

Oncology Reports 10:885-89, 2003 

Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT, 

Lampidis, T, Robles, C, Furst, AJ, and Feun, LG. 

Overexpression of mutated MRP4 in cisplatin 

resistant small cell lung cancer cell line: collateral 

sensitivity to azidothymidine. International Journal 

of Oncology 23:173-79, 2003 

Agarwala, SS, Glaspy, J, O’Day, SJ, Mitchell, M, 

Gutheil, J, Whitman, E, Gonzalez, R, Hersh, E, 

Feun, LG, Belt, R, Meyskens, F, Hellstrand, K, 

Wood, D, Kirkwood, JM, Gehlsen, KR, and 

Naredi, P. Results from a randomized phase III 




• Collaborated on a phase I trial of arginine 

deiminase in melanoma with promising results. 

A phase II protocol currently is under development. 

• Developed a phase I clinical trial for patients 

whose brain tumors expressed a procollagenlike 

protein, based on Dr. Feun and Niramol 

Savaraj, M.D.’s in vitro discovery that this 

protein may predict clinical response to vitamin 

D therapy. This trial has been approved by the 

Institutional Review Board (IRB); the Investigational 

New Drug (IND) application is under 

review by the Food and Drug Administration 

(FDA). 

AWTAR GANJU-KRISHAN, PH.D. 

Professor of Radiation Oncology 


Most of Dr. Krishan’s current research 

focuses on: 

• Monitoring of nuclear hormone receptor expression 

in human breast and prostate tumors. 

Dr. Krishan has developed flow cytometric 

methods for determining estrogen, androgen, 

and vitamin D receptor expression in archival 

human tumors. These methods recently have 

been used to determine expression in human 

male and female breast tumors and prostate 

tumors. 

• Evaluating a novel apoptosis assay with antibodies 

to ssDNA using flow cytometry; Dr. 

Krishan and Oscar Frankfurt, Ph.D., (University 

of Miami) have been studying the use of a 

novel method for discriminating between 

apoptotic and the necrotic cells by laser flow 

cytometry, which was recently published. 

• Evaluating tumor cells in body fluids using high 

resolution flow cytometry; Dr. Krishan and his 

colleagues have recently developed a high resolution 

flow cytometer with funding from NASA 

and the American Cancer Society (ACS). This 

instrument can measure nuclear volume and 

thus discriminate between normal and tumor 

cells. Supported by an exploratory grant from 

the NIH-NCI, they are currently examining the 

potential of this technique for detecting occult 

tumor cells in body fluids from cancer patients. 

• Studying androgen receptor expression in human 

prostate tumors; Dr. Krishan and May 

Abdel-Wahab, M.D., Ph.D., have used flow 

cytometric methods to correlate receptor expression 

with clinical response in patients on 

the Radiation Therapy Oncology Group’s 

(RTOG) study of radiation and hormone 

therapy in prostate cancer patients. 

• Evaluating DNA aneuploidy and S-phase fraction 

as indicators of response to chemoradiotherapy 

in patients with invasive cervical 

carcinoma; Dr. Krishan, Aaron H. Wolfson, 

M.D., and Daniel Estape, M.D., are involved 

in this project, which is funded by the RTOG 

and seeks to use high-resolution flow cytometry 

for the analysis of aneuploidy and cell cycle distribution 

in human cervical cancer under a 

University of Miami IRB-approved protocol. 

• Organizing annual Indo-U.S. workshops in 

cytomics. These workshops include six to ten 

U.S. faculty members along with their Indian 

counterparts, who teach the latest methods in 

flow cytometry in India. Up to 50 researchers 

attend these workshops, and so far, four workshops 

have been held in research institutes/ 

universities in Chandigarh, Hyderabad, Jammu, 

and Bombay. 

36 




2002 

Krishan, A. Flow cytometric monitoring of hormone 

receptor expression in human solid tumors. 

Proceedings of SPIE 4622: 211-17, 2002. 

Arya, P, Andritsch, IH, and Krishan, A. Androgen 

receptor expression in archival human breast 

tumors. Methods in Cell Science 24:61-64, 2002. 

Krishan, A. Flow cytometric monitoring of drug 

resistance in human tumor cells. Methods in Cell 

Science 24:55-60, 2002. 

Thomas, RA, Krishan, A, and Brochu, M. High 

resolution flow cytometric analysis of electronic 

nuclear volume and DNA content in normal and 

abnormal human tissue. Methods in Cell Science 

24:11-18, 2002. 

Adiga, SK, Andritsch, IH, Rao, RV, and Krishan, 

A. Androgen receptor expression and DNA content 

of paraffin-embedded archival human prostate 

tumors. Cytometry 50:25-30, 2002. 

2003 

Frankfurt, OS and Krishan, A. Apoptosis-based 

drug screening and detection of selective toxicity 

to cancer cells. Anticancer Drugs 14:555-61, 

2003. 

Frankfurt, OS and Krishan, A. Microplate 

screening for apoptosis with antibody to singlestranded 

DNA distinguishes anticancer drugs 

from toxic chemicals. Journal of Biomolecular 

Screening 8:185-90, 2003. 

Frankfurt, OS and Krishan, A. Apoptosis enzyme-linked 

immunosorbent assay distinguishes 

anticancer drugs from toxic chemicals and predicts 

drug synergism. Chemico-biological Interactions 

145:89-99, 2003. 



Science 24:55-60, 2003. 

Abdel-Wahab, M, Krishan, A, Milikowski, C, 

Wahab, AA, Walker, G, and Markoe, A. Androgen 

receptor antigen density and S-phase fraction 

in prostate cancer: a pilot study. Prostate Cancer 

and Prostatic Disease 6:294-300, 2003. 


• Developed Krishan’s propidium iodide/hypotonic 

citrate method for rapid determination of 

cellular DNA content and cell cycle traverse. 

This method is universally used for rapid cell 

cycle analysis by flow cytometry. 

• Developed flow cytometric assays for drug 

transport and efflux. This rapid method is now 

universally used as a functional assay for drug 

resistance. 

• Developed flow cytometric methods for rapid 

determination of nuclear hormone receptor expression 

in human archival tumors. 

• Developed the NASA/ACS flow cytometer, 

which now is sold by NPE Systems Inc., as a 

commercial unit for rapid determination of 

cellular volume and DNA content. 

SHELDON GREER, PH.D. 



Dr. Greer’s laboratory has developed a drug 

that selectively radiosensitizes human tumors. 

The drug is 5-chloro-2'-deoxycytidine 

(cytochlor). When it is coadministered with 

tetrahydrouridine (H 4 

U), an inhibitor of its preliminary 

systemic deamination before it reaches 

the tumor site, it has been shown to be efficacious 

versus seven rodent tumors and seven human 

tumors in nude mice. For example, with a 

rodent mammary adenocarcinoma, 80 percent 

cures were obtained with weight loss no greater 

than that obtained with radiation alone. This was 

confirmed by an independent blind study. Similar 

response was obtained with human tumors, 



which included two prostatic tumors, three head 

and neck tumors, a glioblastoma, a lung tumor, 

and a breast tumor. 

Cytochlor has resulted in a three-fold dose 

increase effect, meaning that a dose of 70 Gy is 

equivalent to a dose of 210 Gy to the tumor 

without damage to underlying tissue. The success 

of the radiosensitizer can be understood in view 

of several biochemical studies that show: 1) 99 

percent of the cells of a human prostate tumor 

and a head and neck tumor incorporated the 

radiosensitizer into DNA, 2) 40 percent of thymine 

was replaced by 5-chlorouracil in DNA of 

tumor cells, 3) all tumors obtained from patients 

with head and neck tumors had elevated levels 

over that of normal tissue of one of the two enzymes, 

which anabolize cytochlor to become a 

radiosensitizer, and 50 percent of patients had 

elevations of both enzymes (averaging greater 

than 10-fold), 4) 5-chlorouracil derived from 

cytochlor is not removed from DNA as is 5- 

iodoruacil (the first generation radiosensitizer), 5) 

5-CldUMP derived from cytochlor inhibits 

thymidylate synthetase as effectively as 

FdUMP—this prevents the formation of TTP, 

the competitor to the incorporation of CldUTP, 

and 6) CldUTP activates dendritic cell (DC) 

kinase, the enzyme responsible for the first step 

in the anabolism of cytochlor. 

Studies commissioned by the NCI have 

shown that cytochlor did not display any clinical 

signs of toxicity to primates when given the drug 

five days per week for three weeks. No toxicity 

was seen in mice and dogs where it was shown 

that H 4 

U extended the half life and increased the 

selectivity of cytochlor. The drug is awaiting IND 

approval by the FDA and will be tested in a phase 

I clinical trial at UM/Sylvester in patients with 

squamous cell carcinoma (SCCA) of the oropharynx 

and oral cavity. 

Dr. Greer also has discovered an approach to 

tumors that arise or are successful as a result of 

gene silencing. These include tumors due to the 

silencing of genes, encoding tumor suppressor 

genes, repair enzymes, migration suppressor glycoproteins 

such as cadherin, estrogen receptors, 

enzymes protecting cells, oxidative damage, antiangiogenesis 

factors, and factors that prevent the 

tumors from being controlled by the patient’s 

immune system. The drug, called zebularine, can 

be administered orally and is non-toxic. The NCI 

has ordered the development of this drug after 

studies in nude mice showed its effectiveness. 

The drug also has the potential to be utilized in 

patients with abnormal globin gene expression 

(hemoglobinopathies) and abnormalities in the 

immune system. 


2003 

Cheng, JC, Matsen, CB, Gonzales, FA, Ye, W, 

Greer, S, Marquez, VE, Jones, PA, and Selker, 

EU. Inhibition of DNA methylation and reactivation 

of silenced genes by zebularine. Journal of 

the National Cancer Institute March 5; 95:399- 

409, 2003. 


• Developed and tested cytochlor, in collaboration 

with the NCI, which is now under review 

by the FDA for clinical application and testing. 

• Developed zebularine in cooperative studies 

including the University of Oregon, the University 

of Southern California, the NIH, and the 

University of Miami. Zebularine is approved for 

further development by the NIH. 

• Developed an approach for chemotherapy or 

radiation therapy based on the enzymatic profile 

of human tumors and adjacent normal tissue 

with respect to four enzymes involved in 

nucleic acid metabolism. The study requires a 

small amount of biopsy material. The approach 

is novel in that it involves several (nine) antimetabolites 

including cytochlor and zebularine, 

which have never been used in humans. The 

novel approach also involves gene therapy combined 

with radiation therapy, allowing greater 

selectivity than gene therapy combined with 

chemotherapy because of the very nature of 

external beam radiation therapy. 

38 



LEONIDAS G. KONIARIS, M.D., F.A.C.S. 

Associate Professor of Surgery 


Dr. Koniaris’ research concentrates on the 

mechanism of growth control and deregulation 

in vivo in the gastrointestinal (GI) tract and 

breast. In particular, he has focused on the role of 

two secreted factors—interleukin-6 (IL-6) and 

macrophage inflammatory cytokine-1 (MIC-1). 

IL-6 is a pro-inflammatory cytokine essential 

in normal liver homeostasis. Investigators in the 

laboratory have recently demonstrated that IL 

functions as a growth factor for hepatocytes 

through an apparent direct mechanism that does 

not involve activation of cMET or epidermal 

growth factor (EGF). Subsequent work has demonstrated 

that this mitogenic response is associated 

with profound anti-apoptotic activity. Other 

work from the laboratory has examined how the 

IL-6 response affects insulin signaling and contributes 

to the hepatocellular dysfunction seen in 

chronic liver disease. In addition, they are examining 

the effects of IL-6 on hepatocellular carcinoma 

with collaborators at the University of 

North Carolina. 

MIC-1 is a divergent member of the transforming 

growth factor-beta (TGF-β) superfamily 

of growth and differentiation factors. MIC-1 

strongly has been implicated in the pathogenesis 

of both colorectal and prostate cancers and may 

have a potent anti-tumor function. The laboratory 

has examined the expression of MIC-1 and 

found it to be an immediate early response to a 

variety of organ injuries and exposures to carcinogens. 

They have generated MIC-1 null mice and 

are examining their propensity to the development 

of liver, colorectal, breast, and prostate 

cancers. 


2002 

Barreiro, CJ, Lillemoe, KD, Koniaris, LG, Sohn, 

TA, Yeo, CJ, Coleman, J, Fishman, EK, and 

Cameron, JL. Diagnostic laparoscopy for 

periampullary and pancreatic cancer: what is the 

true benefit? Journal of Gastrointestinal Surgery 

6:75-81, 2002. 

Kovach, SJ, Hendrickson, RJ, Cappadona, CR, 

Schmidt, CM, Groen, K, Koniaris, LG, and 

Sitzmann, JV. Cryoablation of unresectable pancreatic 

cancer. Surgery 131:463-64, 2002. 

Sayeed, S, Koniaris, LG , and Papadakos, PJ. Image 

of the month. Acute respiratory distress syndrome. 

Archives of Surgery 137:491-92, 2002. 

Abt, PL, Halaby, I, Schoeniger, LO, and 

Koniaris, LG. Intrahepatic gas. Journal of the 

American College of Surgeons 195:129, 2002. 

Cirillo, RL Jr. and Koniaris, LG. Detecting blunt 

pancreatic injuries. Journal of Gastrointestinal 

Surgery 6:587-98, 2002. 

Hendrickson, RJ, Koniaris, LG, Kovach, SJ, and 

Johnson, JA. Gamma probe-confirmed 

laparoscopic accessory splenectomy. Surgical Endoscopy 

16:1364, 2002. 

Hendrickson, RJ, Koniaris, LG, Schoeniger, LO, 

Strang, J, Killackey, MA, and Peacock, JL. Small 

bowel obstruction due to a paracolonic retroperitoneal 

hernia. American Journal of Surgery 

68:756-58, 2002. 

Sayeed, S, Koniaris, LG , Kovach, SJ, and 

Hirokawa, T. Torsion of a wandering spleen. Surgery 

132:535-36, 2002. 

Ognibene. SJ, Koniaris. LG, Pegoli, W Jr., and 

Drugas, GT. Intraoperative colonic lavage in a 

premature infant: a case report. Journal of Pediatric 

Surgery 37:1645-47, 2002. 



Price, JA, Kovach, SJ, Johnson, T, Koniaris, LG , 

Cahill, PA, Sitzmann, JV, and McKillop, IH. Insulin-like 

growth factor I is a comitogen for hepatocyte 

growth factor in a rat model of 

hepatocellular carcinoma. Hepatology 36:1089- 

97, 2002. 

Hendrickson, RJ, Koniaris, LG, Jiang, S, 

Waldman, D, Massey, HT, and Sitzmann, JV. 

Purposeful delay in the repair of a traumatic left 

common carotid pseudoaneurysm in a bovine 

aortic arch presenting as a widened mediastinum. 

Journal of Trauma 53:1166-69, 2002. 

Sitzmann, JV and Koniaris, LG. Intra-arterial 

hepatic catheterization and pump placement. 

Operative Techniques in General Surgery 4:99- 

110, 2002 

Zimmers, TA, Davies, MV, Koniaris, LG, 

Haynes, P, Tomkinson, KN, McPherron, AC, 

Wolfman, NM, and Lee SJ. Cachexia induced 

by systemic myostatin administration in mice. 

Science 296:1486-88, 2002. 

2003 

Koniaris, LG. Induction of MIC-1/growth differentiation 

factor-15 following bile duct injury. 

Journal of Gastrointestinal Surgery 7:901-5, 

2003. 

Koniaris, LG, Seibel, JA, Geschwind, JF, and 

Sitzmann, JV. Can ethanol therapies injure the 

bile ducts? Hepato-gastroenterology 50:69-72, 

2003. 

Hendrickson, RJ, Diaz, AA, Salloum, R, and 

Koniaris, LG. Benign rectal ulcer: an underground 

cause of inpatient lower gastrointestinal 

bleeding. Surgical Endoscopy17:1759-65, 2003. 

Koniaris, LG, Schoeniger, LO, Kovach, S, and 

Sitzmann, JV. The quick, no-twist, no-kink portal 

confluence reconstruction. Journal of the 

American College of Surgeons 196:490-94, 2003. 

Schoeniger, LO, Bankey, P, Drugas, GT, and 

Koniaris, LG. Optimal closure of the complex 

abdomen. Archives of Surgery 138:458, 2003. 

Koniaris. LG, Drugas. G, Katzman. PJ, and 

Salloum, R. Management of gastrointestinal lymphoma. 

Journal of the American College of Surgeons 

197:127-41, 2003. 

Koniaris, LG, Wilson, S, Drugas, G, and 

Simmons, W. Capnographic monitoring of ventilatory 

status during moderate (conscious) sedation. 

Surgical Endoscopy 17:1340, 2003. 

Koniaris, LG, McKillop, IH, Schwartz, SI, and 

Zimmers, TA. Liver regeneration. Journal of the 


Zimmers, TA, McKillop, IH, Pierce, RH, Yoo, 

JY, and Koniaris, LG. Massive liver growth in 

mice induced by systemic interleukin 6 administration. 

Hepatology 38:326-34, 2003. 

Senn, JJ, Klover, PJ, Nowak, IA, Zimmers, TA, 

Koniaris, LG, Furlanetto, RW, and Mooney, RA. 

Suppressor of cytokine signaling-3 (SOCS-3), a 

potential mediator of interleukin-6-dependent 

insulin resistance in hepatocytes. Journal of Biological 

Chemistry 278:13740-46, 2003. 

Klover, PJ, Zimmers, TA, Koniaris, LG, and 

Mooney, RA. Chronic exposure to interleukin-6 

causes hepatic insulin resistance in mice. Diabetes 

52:2784-89, 2003. 

THEODORE J. LAMPIDIS, PH.D. 

Professor of Cell Biology and Anatomy 


Dr. Lampidis’ research has evolved from his 

preliminary work on the physiology and 

pharmacology of cultured cardiac cells. A video/ 

electronic-computerized system was developed to 

monitor cardiac cell function in vitro. Using pulsating 

myocardial cells as a model, he focused on 

why the widely used anti-tumor agent, Adriamycin, 

affected the hearts of patients treated with this 

drug. This initial idea led Dr. Lampidis to study 

drug selectivity between certain types of tumor 

and normal cells and the chemical requirements 

40 



of anti-cancer drugs for reduced cardiotoxicity 

and increased tumoricidal potency. 

Dr. Lampidis’ efforts then turned toward 

understanding the mechanisms of drug resistance 

to mitochondrial agents such as rhodamine 123 

and the structure/function requirements of various 

chemotherapeutic agents for recognition by 

p-glycoprotein (Pgp)-mediated multiple drug 

resistance (MDR). Molecular and immunochemical 

probes of MDR and other cellular 

resistance mechanisms (i.e., multi-drug resistance-related 

protein), were developed to detect 

and study these phenomena. He and his colleagues 

found that chemical charge and lipophilicity 

play critical roles in determining 

whether anticancer drugs are recognized by tumor 

cells expressing these MDR mechanisms. 

As an outcome of their studies on mitochondrial 

agents, these researchers realized that tumor 

cells treated with the uncoupling agent, rhodamine 

123, were strikingly similar to the poorly oxygenated 

cancer cells located at the inner core of solid 

tumors. In both conditions, the cells rely exclusively 

on anaerobic metabolism for survival. 

Moreover, cells in the center of a tumor divide 

more slowly than outer-growing aerobic cells and 

consequently are more resistant to standard chemotherapeutic 

agents, which target the more 

rapidly dividing cells. Thus, by the nature of their 

slow growth, these tumor cells exhibit a form of 

MDR, which contributes significantly to chemotherapy 

failures in the treatment of solid tumors. 

Anaerobiosis, however, also provides a natural 

window of selectivity for agents that interfere 

with glycolysis. This concept forms the basis for 

Dr. Lampidis’ current initiative of exploiting the 

natural selectivity that inhibitors of glycolysis 

should have for hypoxic cells that are slowly 

growing at the inner core of solid tumors. His 

background and work on mitochondrial localizing 

drugs and MDR uniquely position him to 

stimulate new initiatives in this promising area of 

research. 

A long-term goal for Dr. Lampidis is the addition 

of the appropriate glycolytic inhibitors 

(which are presently being designed and synthesized) 

to current clinical protocols, which may 

significantly improve the success rate of cancer 

chemotherapy. Moreover, studying how tumor 

cells react to combinations of oxidative phosphorylation 

and glycolytic inhibitors could lead to 

the design of future novel approaches to more 

successfully treat cancer. 


2002 

Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ . 

Hypoxia increases tumor cell sensitivity to glycolytic 

inhibitors: a strategy for solid tumor therapy 

(Model C). Biochemical Pharmacology 64:1745- 

51, 2002. 

2003 

Savaraj N, Wu, C, Wangpaichitr, M, Kuo, MT, 

Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L. 




of Oncology 23:173-79, 2003. 

Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and 

Lampidis, TJ . Multidrug resistance correlates 

with overexpression of Muc4 but inversely with 

P-glycoprotein and multidrug resistance related 

protein in transfected human melanoma cells. 

Biochemical Pharmacology 65:1419-25, 2003. 


• In osteosarcoma, wild type (wt) cells treated 

with agents that inhibit mitochondrial oxidative 

phosphorylation (OXPHOS) by interacting 

with complexes I, III, and V of the electron 

transport chain in different ways—rhodamine 

123 (Rho-123), rotenone, oligomycin, and antimycin 

A—all of the agents were found to hypersensitize 

wt cells to the glycolytic inhibitors 

2-deoxyglucose (2-DG) and oxamate. 



• In ρ 0 cells that have lost their mitochondrial 

DNA and therefore cannot undergo OXPHOS, 

cells were found to be ten and 4.9 times more 

sensitive to 2-DG and oxamate, respectively, 

than wt cells. 

• Lactic acid levels, which are a measure of 

anaerobic metabolism, were found to be greater 

than three times higher in ρ 0 than in wt cells. 

Moreover, when wt cells were treated with rho 

123, lactic acid amounts increased as a function 

of increasing rho 123 doses. Under similar rho 

123 treatment, ρ 0 cells did not increase their 

lactic acid levels. These data confirm these different 

cell models are similarly sensitive to glycolytic 

inhibitors due to their dependence on 

anaerobic metabolism. 

• These results suggest that inner core tumor cells 

are more dependent on glycolysis than outer 

growing aerobic cells, which provides a window 

of selectivity that can be exploited therapeutically. 

Thus, glycolytic inhibitors could be used 

to specifically target the hypoxic slow-growing 

cells of solid tumors and thereby increase the 

efficacy of current chemotherapeutic and irradiation 

protocols designed to kill rapidly-dividing 

cells. Moreover, glycolytic inhibitors could 

be particularly useful in combination with antiangiogenic 

and anti-hypoxic inducible factor 

(HIF) agents, which a priori, should make tumors 

more anaerobic. 

• Recently, Dr. Lampidis has provided proof of 

principle in two animal models of human cancer 

(non-small cell lung and osteosarcoma) that 

the addition of the glycolytic inhibitor 2-DG 

(which targets the slowly growing hypoxic cells 

of a tumor), increases the efficacy of standard 

chemotherapeutic agents (which target the rapidly 

growing aerobic cells) in reducing tumor 

size and prolonging survival. In collaboration 

with Threshold Pharmaceuticals, the NCI, and 

UM/Sylvester, they have received FDA approval 

and are now nearing the first human trials testing 

his strategy. 

KELVIN P. LEE, M.D. 

Associate Professor of Microbiology 

and Immunology 


Research in Dr. Lee’s laboratory focuses on 

the cells and molecules that play central roles 

in initiating the adaptive immune response. 

Understanding these interactions is essential for 

developing effective immune-based therapies 

against cancer. At the cellular level, they are 

specifically studying the dendritic cells (DC), 

which are thought to be the most important professional 

antigen presenting cell (APC). Because 

DC monitor the local environment for immunologic 

“danger” signals and control what antigens 

are presented to T cells to activate them, they are 

positioned to regulate the initiation of immune 

responses. Their work has examined how DC 

arise from hematopoietic progenitors and their 

intracellular/genetic characteristics. Dr. Lee and 

his colleagues have previously reported that activation 

of the protein kinase C (PKC) intracellular 

signal transduction pathway in human hematopoietic 

CD34 + stem cells causes direct differentiation 

to a pure population of DC. Thus, PKC 

signaling specifically triggers the DC differentiation 

“program” in these cells. Additionally, specific 

isoforms of PKC appear to regulate specific 

aspects of DC differentiation. Ongoing studies 

are seeking to completely characterize the components 

of the PKC signaling pathway and what 

genetic events are triggered by this signal. 

From a translational standpoint, researchers 

in Dr. Lee’s laboratory have found that in addition 

to normal cells, PKC activation can drive 

DC differentiation in acute and chronic myeloid 

leukemic blasts. Because these “leukemic” DC 

retain the ability to activate T cells and are endogenously 

loaded with leukemia antigens, they 

potentially can be used as “cellular” anti-leukemia 

vaccines by re-infusion back into patients. This 

work aims to bring this approach to clinical trials. 

In addition to the DC studies, a clinical trial 

(headed by Dr. Lee) and basic laboratory research 

42 



currently are looking at novel agents against 

multiple myeloma (MM). The NCI-sponsored 

phase I/II clinical trial is examining arsenic trioxide 

+ ascorbic acid in the treatment of refractory/ 

relapsed MM. Initial results demonstrate that this 

combination is effective against myeloma that is 

resistant to standard chemotherapy (including 

thalidomide) with acceptable toxicity. The laboratory 

component of these studies seeks to understand 

how arsenic kills myeloma, how ascorbic 

acid potentiates that killing, how myeloma cells 

become resistant to arsenic, and which host 

(i.e., patient) factors may help the myeloma 

survive in the bone marrow. 


2002 

Gray Parkin, K, Stephan, RP, Apilado, RG, Lill- 

Elghanian, DA, Lee, KP, Saha, B, and Witte, PL. 

Expression of CD28 by bone marrow stromal 

cells and its involvement in B lymphopoiesis. 

Journal of Immunology 169:2292-302, 2002. 

Baumgartner, R, Durant, P, van Gessel, Y, 

Chattopadhyay, S, Beswick, RL, Tadaki, DK, 

Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence 

for the requirement of T cell costimulation 

in the pathogenesis of natural Pneumocystis 

carinii pulmonary infection. Microbial Pathogenesis 

33:193-201, 2002. 

Strbo, N, Yamazaki, K, Lee, KP, Rujkavina, D 

and Podack, ER. Heat shock fusion protein 

gp96-Ig mediates strong CD8 CTL expansion 

in vivo. American Journal of Reproductive Immunology 

48:220-25, 2002. 

2003 

Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and 

Harlan, DM. Porcine CD80: cloning, characterization, 

and evidence for its role in direct human 

T-cell activation. Xenotransplantation 10: 252- 

58, 2003. 

Lindner. I, Kharfan-Dabaja, M, Ayala. E, 

Kolonias, D, Cejas, P, and Lee, KP. Induced differentiation 

of chronic myelogenous leukemia to 

dendritic cells down-regulates BCR-ABL gene 

expression. Journal of Immunology 171:1780-91, 

2003. 

McCafferty-Grad, J, Bahlis, NJ, Krett, N, Reis, I, 

Lee, KP, and Boise, LH. Arsenic trioxide utilizes 

caspase dependent and caspase independent 

death pathways in myeloma cells. Molecular Cancer 

Therapeutics 2:1155-64, 2003. 


• Direct activation of PKC causes normal human 

hematopoietic CD34 + stem cells to differentiate 

into DC. 

• PKC activation causes many myeloid leukemias 

to differentiate into immunologically functional 

“leukemic” DC. These cells have potential utility 

as “cellular” anti-leukemia vaccines. 

• Specific intracellular signaling pathways downstream 

of PKC activation control specific aspects 

of DC differentiation. 

• Arsenic trioxide + ascorbic acid is an effective 

combination in the treatment of refractory/relapsed 

myeloma. 

Bahlis, NJ, McCafferty-Grad, J, Jordan- 

McMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M, 

Eckman, J, Goodman, M, Fernandez, HF, Boise, 

LH, and Lee, KP. Feasibility and correlates of 

arsenic trioxide combined with ascorbic acid-mediated 

depletion of intracellular glutathione for 

the treatment of relapsed/refractory multiple myeloma. 

Clinical Cancer Research 8:3658-68, 

2002. 



STEVEN E. LIPSHULTZ, M.D. 

Professor and Chairman of Pediatrics 


Dr. Lipshultz’s research focuses on the prevention 

of cardiomyopathy and heart failure 

in children and young adults. He developed 

the National Heart, Lung, and Blood Institute 

(NHLBI)-sponsored Pediatric Cardiomyopathy 

Registry (PCMR) to better understand genetic 

and metabolic cardiomyopathies; the NHLBI 

P2C2 HIV study to better understand infectious 

and inflammatory cardiomyopathies; and the 

NCI Dana-Farber Cancer Institute childhood 

leukemia and NCI Children’s Oncology Group 

childhood cancer survivor cohorts to better understand 

toxic cardiomyopathies from 

anthracycline chemotherapy and mediastinal irradiation. 

Further understanding of clinical phenotypes, 

human syndrome delineation, 

epidemiology, and the natural history of these 

pediatric diseases has resulted from these cohorts. 


2002 

Lipshultz, SE, Lipsitz, SR, Sallan, SE, Simbre, 

VC 2nd, Shaikh, SL, Mone, SM, Gelber, RD, 

and Colan, SD. Long-term enalapril therapy for 

left ventricular dysfunction in doxorubicintreated 

survivors of childhood cancer. Journal of 

Clinical Oncology 20:4517-22, 2002. 

Harmon, WG, Dadlani, GH, Fisher, SD, and 

Lipshultz, SE. Myocardial and pericardial disease 

in HIV. Current Treatment Options in Cardiovascular 

Medicine 4:497-509, 2002. 

Lipshultz, SE, Giantris, AL, Lipsitz, SR, Kimball, 

Dalton V, Asselin, BL, Barr, RD, Clavell, LA, 

Hurwitz, CA, Moghrabi, A, Samson, Y, Schorin, 

MA, Gelber, RD, Sallan, SE, and Colan, SD. 

Doxorubicin administration by continuous infusion 

is not cardioprotective: the Dana-Farber 91- 

01 Acute Lymphoblastic Leukemia protocol. 

Journal of Clinical Oncology 20:1677-82, 2002. 

2003 

Zareba, KM and Lipshultz, SE . Cardiovascular 

complications in patients with HIV infection. 

Current Infectious Disease Reports 5:513-20, 

2003. 

Constine, LS, Hinkle, AS, French, CA, 

Kozlowski, AM, Proukou, C, Lipsitz, SR, Miller, 

TL, Vermilion, RP, Rifai, N, and Lipshultz, SE. 

Radiation-associated risk factors for premature 

cardiovascular disease in childhood cancer survivors 

include accelerated atherosclerosis. International 

Journal of Radiation Oncology Biology 

Physics 57(2 Supplement):S199-200, 2003. 

Adams, MJ, Lipshultz, SE, Schwartz, C, Fajardo, 

LF, Coen, V, and Constine, LS. Radiation-associated 

cardiovascular disease: manifestations and 

management. Seminars in Radiation Oncology 

13:346-56, 2003. 

Lipshultz, SE, Fisher, SD, Lai, WW, and Miller, 

TL. Cardiovascular risk factors, monitoring, and 

therapy for HIV-infected patients. AIDS 17 

Supplement 1:S96-122, 2003. 

Fisher, SD, Bowles, NE, Towbin, JA, and 

Lipshultz, SE. Mediators in HIV-associated cardiovascular 

disease: a focus on cytokines and 

genes. AIDS 17 Supplement 1:S29-35, 2003. 

Lipshultz, SE, Somers, MJ, Lipsitz, SR, Colan, 

SD, Jabs, K, and Rifai, N. Serum cardiac troponin 

and subclinical cardiac status in pediatric 

chronic renal failure. Pediatrics 112:79-86, 2003. 

Al-Attar, I, Orav, EJ, Exil, V, Vlach, SA, and 

Lipshultz, SE. Predictors of cardiac morbidity 

and related mortality in children with acquired 

immunodeficiency syndrome. Journal of the 

American College of Cardiology 41(9):1598-605, 

2003. 

Benun, J, Fisher, SD, Orav, EJ, Schwartz, ML, 

Exil, V, Messere, C, and Lipshultz, SE . Cardiac 

management by pediatricians versus pediatric cardiologists 

in an inpatient academic center. American 

Heart Journal 145:424-9, 2003. 

44 



Dadlani, GH, Harmon, WG, Simbre II, VC, 

Tisma-Dupanovic, S, and Lipshultz, SE . 

Cardiomyocyte injury to transplant: pediatric 

management. Current Opinion in Cardiology 

18:91-7 (Review), 2003. 

Adams, MJ, Hardenbergh, PH, Constine, LS, 

and Lipshultz, SE . Radiation-associated cardiovascular 

disease. Critical Reviews in Oncology/ 

Hematology 45:55-75 (Review), 2003. 

BALAKRISHNA L. LOKESHWAR, PH.D. 

Associate Professor of Urology 


Dr. Lokeshwar’s research focuses on the 

mechanism of prostate cancer metastasis and 

its control by novel chemotherapeutic drugs. For 

the last several years, Dr. Lokeshwar’s laboratory 

has focused on extracellular matrix degradation 

and tumor metastasis. His laboratory has studied 

the regulation of a class of basement membrane 

matrix degrading enzymes called the matrix 

metalloproteinases (MMPs) in prostate cancer. 

Using cancer cell cultures established from 

human prostate tumor tissues obtained after 

prostatectomy, they showed that an imbalance 

exists between the levels of MMPs (overproduction) 

and their natural inhibitors (underproduction) 

in invasive prostate cancer cells. Based on 

this finding, they developed a hypothesis that a 

novel approach to control metastatic cancer is 

to correct the imbalance either by inhibition of 

secretion of MMPs or by increasing the extracellular 

levels of their endogenous inhibitor. 

Since several small synthetic inhibitors of 

MMPs exist, they tested the usefulness of the inhibitors 

using the criteria of oral bioavailability, 

systemic toxicity, and ability to target bone metastasis. 

In their search for a suitable inhibitor, 

Dr. Lokeshwar’s laboratory tested a series of synthetic 

tetracycline analogues, which were shown 

to possess a strong anti-collagenase activity with 

little or no antibiotic activity. Researchers tested 

eight different chemically modified tetracyclines 

(CMTs) and found one of them, 6-deoxy, 6- 

demethyl, 4-dedimethylamino tetracycline 

(CMT-3, COL-3, now termed Metastat R by 

CollaGenix Pharmaceuticals, Newtown, Pennsylvania), 

to be the most promising. Oral dosing 

with this analogue to rats and mice-bearing metastatic 

prostate tumors reduced tumor growth and 

metastasis, with no measurable systemic toxicity. 

Furthermore, prophylactic dosing of animals with 

the drug significantly reduced the incidence of 

tumor at the site of tumor cell injection. Their 

demonstration of a highly antimetastatic and antitumor 

activity of CMT-3 in a rat prostate tumor 

model led to its phase I clinical trial by the 

Developmental Therapeutics Program of the NCI 

(NCI-DTP). In the recently concluded human 

clinical phase I trial of CMT-3, the NCI-DTP 

recommended CMT-3 for phase II and phase III 

in patients with soft tissue sarcoma and advanced 

metastatic tumors. The University of Miami and 

the State University of New York at Stony Brook 

have jointly obtained a use patent on this drug. 

This finding also has generated a wide interest in 

the use of CMT-3 among many investigators 

within and outside the University of Miami, including 

a new patent issued to the University for 

the treatment of corneal ulceration in patients 

with meibomian gland disease, also called ocular 

rosacea. Dr. Lokeshwar’s current research focuses 

on identifying novel plant products that have 

been used as folk medicine and identifying novel 

combination therapies for advanced hormonerefractive 

prostate cancer. 

In a related development, COL-3 is undergoing 

a phase III clinical trial against HIVinduced 

Karposi’s sarcoma. Twenty centers 

nationwide are engaged in this trial, headed by 

Dr. Bruce DeZube of New England Deaconess 

Hospital, Boston. 




2002 

Dursun, D, Wang, M, Monroy, D, Li, DQ, 

Lokeshwar, BL , Stern, M, and Pflugfelder, SC. 

Experimentally induced dry eye produces ocular 

surface inflammation and epithelial disease. Advances 

in Experimental Medicine and Biology 

506:647-55, 2002. 


Lokeshwar, BL , Stern,ME, and Pflugfelder, SC. 

A mouse model of keratoconjunctivitis sicca. Investigative 

Ophthalmology & Visual Science 

43:632-38, 2002. 

Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block, 

NL, and Golub, LM. Inhibition of cell proliferation, 

invasion, tumor growth and metastasis by 

an oral non-antimicrobial tetracycline analog 

(COL-3) in a metastatic prostate cancer model. 


2002. 

Whitlatch, LW, Young, MV, Schwartz, GG, 

Flanagan, JN, Burnstein, KL, Lokeshwar, BL , 

Rich, ES, Holick, MF, and Chen, TC. 25- 

Hydroxyvitamin D-1alpha-hydroxylase activity is 

diminished in human prostate cancer cells and is 

enhanced by gene transfer. Journal of Steroid Biochemistry 

and Molecular Biology 81:135-40, 

2002. 

2003 

Chen, TC, Holick, MF, Lokeshwar, BL , 

Burnstein, KL, and Schwartz, GG. Evaluation of 

vitamin D analogs as therapeutic agents for prostate 

cancer. Recent Results in Cancer Research 

164:273-88, 2003. 

Dandekar, DS, Lokeshwar, VB, Cevallos- 

Arellano, E, Soloway, MS, and Lokeshwar, BL . 

An orally active Amazonian plant extract (BIRM) 

inhibits prostate cancer growth and metastasis. 

Cancer Chemotherapy and Pharmacology 52:59- 

66, 2003. 


• Demonstrated that an imbalance exists between 

the levels of MMPs (overproduction) and their 

natural inhibitors (underproduction) in invasive 

prostate cancer cells. 

• Identified a novel, chemically modified nonantimicrobial 

tetracycline (CMT-3) as an effective 

anti-metastatic drug with potential to treat 

prostate cancer metastatic to bone. The NCI 

has completed the phase I trial of this drug and 

is awaiting further trials. Other novel agents are 

being tested in Dr. Lokeshwar’s laboratory, not 

only for controlling cancer, but also other 

chronic diseases such as chronic ocular surface 

inflammation. Dr. Lokeshwar’s research has 

brought in one patent to the University of 

Miami jointly with the State University of 

New York at Stony Brook. Meanwhile, two 

patents are pending on the new application of 

his research findings. 

• Identified a potential application of CMT to 

treat the meibomian gland dysfunction that 

leads to the ocular rosacea. This was done in 

collaboration with Stephen C. Pflugfelder, 

M.D., Baylor College of Medicine, Houston, 

Texas. 

Li de, Q, Shang, TY, Kim, HS, Solomon, A, 

Lokeshwar, BL , and Pflugfelder, SC. Regulated 

expression of collagenases MMP-1, -8, and -13 

and stromelysins MMP-3, -10, and -11 by human 

corneal epithelial cells. Investigative Ophthalmology 

& Visual Science 44:2928-36, 2003. 

46 



VINATA B. LOKESHWAR, PH.D. 



Dr. Lokeshwar’s research focuses on understanding 

the mechanism of cancer progression 

and tumor angiogenesis. Recent advances in 

cancer research have elucidated that the components 

of extracellular matrix (ECM) and ECMdegrading 

enzymes play a crucial role in 

regulating both the metastatic progression of localized 

tumors and tumor angiogenesis. Using 

bladder and prostate cancer model systems, she 

and her colleagues are trying to understand how 

ECM affects tumor metastasis and angiogenesis. 

Work in Dr. Lokeshwar’s laboratory demonstrates 

that an ECM component, hyaluronic acid 

(HA, which is a glycosaminoglycan), and its degrading 

enzyme, hyaluronidase (HAase), are 

closely associated with the biology of cancers of 

the bladder and prostate. They observed that elevated 

urinary HA and HAase levels are diagnostic 

indicators of bladder cancer and its grade, 

respectively. This finding has led to the development 

of a simple, noninvasive, highly sensitive, 

and specific urine test (HA-HAase test; 90 percent 

accuracy) for detecting bladder cancer and 

monitoring its recurrence. 

Dr. Lokeshwar’s research on prostate cancer 

showed that immunohistochemical localization 

of both HA and HAase in prostate cancer tissues 

is greater than 85 percent accurate in predicting 

prognosis for prostate cancer patients and is 

better than CD44v6 and microvessel density. 

Furthermore, both HAase and the HA-HAase 

combination are independent predictors of 

prognosis. Thus, use of these markers in biopsy 

specimens may help clinicians to make individualized 

treatment decisions and improve patients’ 

prognosis. 

In their efforts to understand the function of 

tumor-derived HAase, the researchers purified 

and cloned the first tumor-derived HAase. They 

have demonstrated that this tumor-derived 

HAase degrades tumor-associated HA into small 

angiogenic fragments, which then interact with a 

HA receptor, RHAMM, on endothelial cells. The 

HA fragments and RHAMM interaction on the 

cell surface induces signaling events, resulting in 

the stimulation of endothelial cell functions such 

as proliferation through the mitogen-activated 

protein kinase (MAPK). Endothelial cell proliferation 

is of key importance in tumor angiogenesis. 

Their recent work, using an antisense cDNA 

transfection strategy, demonstrates that tumorderived 

HAase is necessary for tumor growth and 

muscle invasion of bladder tumors. This is an 

important finding since 60 percent of bladder 

cancer patients with muscle invasive disease die 

within five years. 

Currently, Dr. Lokeshwar’s research efforts 

focus on the following areas. First, researchers are 

comparing the efficacy of the HA-HAase test 

with other FDA-approved bladder tumor markers 

for monitoring bladder cancer recurrence. Second, 

they are testing the potential of HAase and 

HA-HAase to predict prognostic potential using 

prostate biopsy specimens. Thirdly, they are 

investigating the functions of HAase and HAsynthase 

enzymes in bladder and prostate cancer 

growth and progression. 


2002 

Lokeshwar, VB and Soloway, MS. Re: Urine 

based markers of urological malignancy. Journal 

of Urology 167:1406-07, 2002. 

Lokeshwar, VB , Schroeder, GL, Selzer, MG, 

Hautmann, SH, Posey, JT, Duncan, RC, Watson, 

R, Rose, L, Markowitz, S, and Soloway, MS. 

Bladder tumor markers for monitoring recurrence 

and screening comparison of hyaluronic 

acid-hyaluronidase and BTA-Stat tests. Cancer 

95:61-72, 2002. 

Ekici, S and Lokeshwar, VB . Mesane tumoru 

belirleyicileri ve HA-HAase testi. Uroloji Bulteni 

13:133-40, 2002. 



Lokeshwar, VB , Schroeder, GL, Carey, RI, 

Soloway, MS, and Iida, N. Regulation of hyaluronidase 

activity by alternative mRNA splicing. 

Journal of Biological Chemistry 277:33654-63, 

2002. 

2003 

Dandekar, DS, Lokeshwar, VB , Cevallos- 

Arellano, E, Soloway, MS, and Lokeshwar, BL. 




66, 2003. 

Simon, MA, Lokeshwar, VB , and Soloway, MS. 

Current bladder cancer tests: unnecessary or beneficial? 

Critical Reviews in Oncology/Hematology 

47:91-107, 2003. 


Weed, DT, Fisher, P, and Lokeshwar, VB . Expression 




2003. 

Posey, JT, Soloway, MS, Ekici, S, Sofer, M, 

Civantos, F, Duncan, RD, and Lokeshwar, VB. 

Evaluation of the prognostic potential of hyaluronidase 



2002. 


• Developed the HA-HAase urine test, a noninvasive 

test that is about 90 percent accurate 

in detecting bladder cancer and monitoring its 

recurrence. 

• Established that HA and HAase are greater than 

85 percent accurate prognostic indicators for 


• Demonstrated the function of tumor-derived 

HAase in bladder tumor growth and muscle 

invasion. 

IZIDORE LOSSOS, M.D. 



By examining gene expression profiles in diffuse 

large B-cell lymphomas (DLBCL) and 

applying a pattern recognition algorithm-termed 

hierarchical clustering, Dr. Lossos’ laboratory 

identified at least two molecularly distinct forms 

of the disease. These were defined by specific 

gene expression signatures: germinal center (GC) 

B cell-like DLBCL characterized by expression of 

genes normally expressed in GC B cells, and having 

a significantly better overall survival than the 

activated B cell (ABC)-like DLBCL characterized 

by expression of genes normally induced during 

in vitro activation of B cells. Discovery of new 

DLBCL tumor categories with distinct outcomes 

by gene expression data suggested that 

lymphomagenesis mechanisms involved in the 

establishment or progression of these tumors may 

be distinct. Indeed, researchers in this laboratory 

and others have demonstrated that: 1) the 

t(14;18)(q32;q21) translocation involving the 

bcl-2 gene and the amplification of the c-rel locus 

on chromosome 2p are detected exclusively in 

GCB-like DLBCL; 2) the mutational machinery 

introducing somatic mutations into Ig genes is 

active in all GCB-like DLBCL but not in the majority 

of ABC-like DLBCL tumors, and 3) the 

ABC-like DLBCL cell lines demonstrate high 

expression of NF-κB target genes and have constitutive 

activity of I-κB kinase complex (IKK) 

that is not observed in the GCB-like DLBCL cell 

lines. Inhibition of IKK by dominant negative 

forms of IκKβ was cytotoxic to ABC-like but not 

to GCB-like DLBCL cell lines. The latter study 

demonstrated that NF-κB pathway is a potential 

new therapeutic target in ABC-like DLBCL. 

However, specific pathways active in GCB-like 

DLBCL have not yet been characterized. 

Analysis of the relative prognostic contribution 

of the individual genes comprising the expression 

signatures defining these two DLBCL 

subgroups demonstrated that expression of only 

48 



some of these genes significantly correlates with 

DLBCL survival. An expressed sequence tag (EST) 

that the laboratory named human germinal 

center-associated lymphoma (HGAL) (UniGene 

cluster 49614 -Clone 814622,GI:2210537) was 

identified as a best predictor of DLBCL survival. 

The predictive power of HGAL was International 

Prognostic Indicator (IPI) independent, as demonstrated 

by multivariate analysis including components 

of the IPI. Furthermore, the prognostic 

power of HGAL expression in predicting survival 

was also shown when its expression was considered 

as a continuous variable demonstrating 

direct correlation between higher levels of its 

expression and longer survival. Higher HGAL 

expression in ABC-like DLBCL still predicted 

better overall survival. There was no difference in 

the complete response rates between patients with 

high and low HGAL expression, thus suggesting 

that high HGAL expression was associated with 

either better response to salvage treatment or 

lower relapse rates due to more complete tumor 

cell eradication or effective immunological 

surveillance. 

The laboratory has cloned the full-length 

cDNA of this EST from both sorted GC lymphocytes 

and from the Ramos cell line and 

termed the gene human germinal center-associated 

lymphoma (HGAL) (GenBank accession 

number AF521911). HGAL is located on chromosome 

3q13. Comparison of the genomic sequence 

to the cDNA sequence revealed that 

HGAL spans 11kb. Recognition of a Kozak sequence 

and search for the longest open reading 

frame (ORF) led to the identification of a putative 

ORF extending from exon 1 to exon 6 and 

encoding a 178 amino acid protein, with 51 percent 

identity to the murine M17 protein that is 

expressed in GC lymphocytes. The HGAL gene 

product had a hydrophilic profile with no predicted 

transmembrane domain and lacked a nuclear localization 

sequence. HGAL contains a modified 

immunoreceptor tyrosine-based activation motif 

termed ITAM (D/EX 7 

D/EX 2 

YX 2 

LX 7 

YX 2 

L) that 

plays a role in signal transduction in B and T 

lymphocytes. HGAL is not expressed in nonlymphoid 

tissues but is expressed at high levels 

only in GC lymphocytes, at intermediate levels in 

memory B cells, and at relatively low levels in 

peripheral blood B cells. In tumors, its expression 

is high in follicular lymphoma tumors, low in 

chronic lymphocytic leukemia cells, and heterogeneous 

in DLBCL specimens. Thus, HGAL expression 

may correlate with specific stages of 

B-cell differentiation, especially the GC stage. 

The function of HGAL in normal lymphocytes 

and the reason its expression in DLBCL 

correlates with better DLBCL outcome, are 

not known. Whether the improved survival of 

patients with high HGAL-content tumors is 

attributed to specific function of this gene or 

is a marker of important biologic characteristic 

of the tumor is unknown. Researchers in Dr. 

Lossos’ laboratory are currently investigating 

these questions. 


2002 

Lossos, IS , Or, R, Ginzburg, V, Christensen, 

TG, Mashriki, Y, and Breuer, R. Cyclosporin 

A upmodulates bleomycin-induced pulmonary 

fibrosis in BALB/c mice. Respiration 69:344-49, 

2002. 

Auffermann-Gretzinger, S, Lossos, IS , Vayntrub, 

TA, Leong, W, Grumet, FC, Blume, KG, 

Stockerl-Goldstein, KE, Levy, R, and Shizuru, 

JA. Rapid establishment of dendritic cell chimerism 

in allogeneic hematopoietic cell transplant 

recipients. Blood 99:1442-48, 2002. 

Bokstein, F, Lossos, A, Lossos, IS, and Siegal, T. 

Central nervous system relapse of systemic non- 

Hodgkin’s lymphoma: results of treatment based 

on high-dose methotrexate combination chemotherapy. 

Leukemia & Lymphoma 43:587-93, 

2002. 



Huang, JZ, Sanger, WG, Greiner, TC, Staudt, 

LM, Weisenburger, DD, Pickering, DL, Lynch, 

JC, Armitage, JO, Warnke, RA, Alizadeh, AA, 

Lossos, IS , Levy, R, and Chan, WC. The 

t(14;18) defines a unique subset of diffuse large 

B-cell lymphoma with a germinal center B-cell 

gene expression profile. Blood 99:2285-90, 2002. 

Lossos, IS , Thorstenson, YR, Wayne, TL, Oefner, 

PJ, Levy, R, and Chu, G. Mutation of the ATM 

gene is not involved in the pathogenesis of either 

follicle center lymphoma or its transformation to 

higher-grade lymphoma. Leukemia & Lymphoma 

43:1079-85, 2002. 

Lossos, IS , Alizadeh, AA, Diehn, M, Warnke, R, 

Thorstenson, Y, Oefner, PJ, Brown, PO, 

Botstein, D, and Levy, R. Transformation of follicular 

lymphoma to diffuse large-cell lymphoma: 

Alternative patterns with increased or decreased 

expression of c-myc and its regulated genes. Proceedings 

of the National Academy of Sciences 

USA 99:8886-91, 2002. 

Lossos, IS , Warnke, R, and Levy, R. BCL-6 

mRNA expression in higher grade transformation 

of follicle center lymphoma: correlation with somatic 

mutations in the 5' regulatory region of the 

BCL-6 gene. Leukemia 16:1857-62, 2002. 

Lossos, IS , Natkunam, Y, Levy, R, and Lopez, 

CD. Apoptosis stimulating protein of p53 

(ASPP2) expression differs in diffuse large B-cell 

and follicular center lymphoma: correlation with 

clinical outcome. Leukemia & Lymphoma 

43:2309-17, 2002. 

2003 

Lossos, IS , Alizadeh, AA, Rajapaksa, R, 

Tibshirani, R, and Levy, R. HGAL is a novel 

interleukin-4-inducible gene that strongly predicts 

survival in diffuse large B-cell lymphoma. 

Blood 101:433-40, 2003. 

Lossos, IS , Czerwinski, DK, Wechser, MA, and 

Levy, R. Optimization of quantitative real-time 

RT-PCR parameters for the study of lymphoid 

malignancies. Leukemia 17:789-95, 2003. 

Martinez-Climent, JA, Alizadeh, AA, Segraves, R, 

Blesa, D, Rubio-Moscardo, F, Albertson, DG, 

Garcia-Conde, J, Dyer, MJ, Levy, R, Pinkel, D, 

and Lossos, IS . Transformation of follicular lymphoma 

to diffuse large cell lymphoma is associated 

with a heterogeneous set of DNA copy 

number and gene expression alterations. Blood 

101:3109-17, 2003. 

Akasaka, T, Lossos, IS , and Levy, R. BCL6 gene 

translocation in follicular lymphoma: a harbinger 

of eventual transformation to diffuse aggressive 

lymphoma. Blood 102:1443-48, 2003. 

Lossos, IS and Levy, R. Diffuse large B-cell lymphoma: 

insights gained from gene expression profiling. 

International Journal of Hematology 

77:321-29, 2003. 

Lossos, IS and Levy, R. Higher grade transformation 

of follicular lymphoma: phenotypic tumor 

progression associated with diverse genetic lesions. 

Seminars in Cancer Biology 13:191-202, 

2003. 

Lossos, IS , Akasaka, T, Martinez-Climent, JA, 

Siebert, R, and Levy, R. The BCL6 gene in B-cell 

lymphomas with 3q27 translocations is expressed 

mainly from the rearranged allele irrespective of 

the partner gene. Leukemia 17:1390-97, 2003. 

Do, B, Lossos, IS , Thorstenson, Y, Oefner, PJ, 

and Levy, R. Analysis of FAS (CD95) gene mutations 

in higher-grade transformation of follicle 

center lymphoma. Leukemia & Lymphoma 

44:1317-23, 2003 

Lossos, IS , Akasaka, T, and Levy, R. Multiple 

BCL6 translocation partners in individual cases 

of gastric lymphoma. Blood 102:1931-32, 2003. 

50 



CLARA MILIKOWSKI, M.D. 

Associate Professor of Pathology 


Since 1993, the Cooperative Breast Cancer 

Tissue Resource (CBCTR) has provided 

breast cancer tissue to researchers for the study of 

clinical markers of tumor prognosis and the 

evaluation of promising diagnostic tests based on 

these markers. It is a centrally administered repository 

of archival breast cancer tissues with associated 

clinical and outcome data to meet this 

need, and it is comprised of four sites in the 

United States—the University of Miami, Fox 

Chase Cancer Center, Kaiser-Permanente (Portland, 

Oregon), and Washington University (St. 

Louis, Missouri). These four institutions are geographically 

dispersed, offer significantly different 

clinical resources to the CBCTR, and have gathered 

their breast cancer cases from widely different 

clinical settings, which together parallel SEER 

data for breast cancer. 

Each site identified, segregated, and cataloged 

the specimens for the CBCTR locally. Selected 

clinical and outcome data obtained from 

its local hospital tumor registry are associated 

with each case. The combined clinical and outcome 

data from all four sites, stored centrally by 

Information Management Services (IMS), in addition 

to the tissue specimens stored at each site, 

constitute the “virtual tissue resource” of the 

CBCTR. IMS has used this material to prepare a 

searchable database for the CBCTR online, at 

http://www-cbctr.ims.nci.nih.gov/. Here, investigators 

can search the CBCTR material to determine 

if the specimens are adequate for use in 

their research. If investigators feel the resource 

meets their needs, instructions for application for 

these tissues are available on the same web site. 

The CBCTR currently has a “progression 

array,” which was designed by an NCI statistician 

who calculated the type and number of specimens 

that would be required to produce an array 

whose statistical power had already been calculated. 

Each of the sites has contributed to this 

[tissue micro-] array. 


2002 

Regev, A, Berho, M, Jeffers, LJ, Milikowski, C, 

Molina, EG, Pyrsopoulos, NT, Feng, ZZ, Reddy, 

KR, and Schiff, ER. Sampling error and 

intraobserver variation in liver biopsy in patients 

with chronic HCV infection. American Journal 

of Gastroenterology 97:2614-18, 2002. 

2003 


Abdel-Wahab, A., Walker, G, and Markoe, A. 

Androgen receptor antigen density and S-phase 

fraction in prostate cancer: a pilot study. Prostate 

Cancer and Prostatic Diseases 6:294-300, 2003. 

Fishman, JE, Milikowski, C, Ramsinghani, R, 

Velasquez, MV, and Aviram, G. US-guided coreneedle 

biopsy of the breast: how many specimens 

are necessary? Radiology 226:779-82, 2003. 

Pasquale, M and Milikowski, C . Three millimeter 

apocrine adenoma in a man: Case report and 

review of the literature. Archives of Pathology & 

Laboratory Medicine 127:1498-500, 2003. 

LUIS E. RAEZ, M.D., F.A.C.P. 

Assistant Professor of Medicine 


Dr. Raez’s research focuses on translational 

research in the areas of lung cancer, head 

and neck cancer, and the development of clinical 

trials with novel compounds for these diseases. 

Dr. Raez is the principal investigator in two 

phase-I trials that are developing allogeneic tumor 

cancer vaccines for lung cancer patients 

(both of them engineered at the University of 

Miami by Eckhard R. Podack, M.D., Ph.D.). 

Now that the first trial with the co-stimulatory 

molecule B7.1 (CD 80) has been successfully 

completed, he has developed a phase II clinical 

trial with the same vaccine to vaccinate patients 

with minimal disease with the goal to prevent 

relapse. Patients treated in the first phase I clini- 



cal trial with the B7.1 vaccine were incurable and 

had an expected survival of less than six months. 

Due to the therapy, however, 30 percent of the 

patients achieved disease stabilization or response 

and at least three patients now have survived for 

more than two years, with a median survival of 

18 months for the whole group. Dr. Raez will 

begin the phase I trial with the allogeneic tumor 

vaccine gp-96 for patients with lung cancer soon 

after FDA approval. This vaccine is more immunogenic 

than the B7.1 used before. In mice, it 

has been shown to have a stronger immune response. 

Due to his gp-96 vaccine project and the 

success of the B7.1 vaccine, Dr. Raez was granted 

a “Research Career Development Award” in 2002 

by the American Society of Clinical Oncology 

(ASCO) with funds to support his research for 

three years. 

Dr. Raez and his colleagues recently received 

Cancer Therapy Evaluation Program (CTEP) 

approval for a phase I clinical trial with a new 

drug called cytochlor (NSC 371331), a potent 

radiation sensitizer, which was discovered by 

Sheldon Greer, Ph.D., at the University of Miami. 

Dr. Raez and Dr. Greer will treat patients 

with radiation therapy with the goal to improve 

response and prevent relapse. Dr. Raez also was 

awarded the 2002-2003 Stanley J. Glaser Foundation 

Biomedical Research Award and funding 

for the cytochlor project. Additionally, CTEP has 

approved the project and will provide funding 

and drug production for its development. 

Dr. Raez also works with Theodore J. 

Lampidis, Ph.D., in developing the first phase I 

trial in humans with the combination of 2-DG 

with chemotherapy. 2-DG has a novel mechanism 

of action focused in the destruction of slowgrowing 

cells in the core of the tumors where 

conventional chemotherapy and radiation have 

not worked, which already has been proven by 

Dr. Lampidis’ research. Dr. Raez also has been 

trying to find the prognostic role of c-Kit, Bag-1, 

and CEACAM-1 in lung cancer, trying to correlate 

it with clinical responses and survival. 

Dr. Raez also has initiated several important 

clinical trials with new compounds for lung and 

head and neck cancers with Cpt-11, oxaliplatin, 

capecitabine, and Velcade, among others. 


2003 

Santos, ES, Raez, LE, Salvatierra, J, 

Morgensztern, D, Shanmugan, N, and Neff, GW. 

Primary hepatic non-Hodgkin’s lymphomas: a 

case report and review of the literature. American 

Journal of Gastroenterology (Review) 98:2789- 

93, 2003. 

Raez LE, Cassileth, PA, Schlesselman, JJ, 

Padmanabhan, S, Fisher, EZ, Baldie, PA, Sridhar, 

K, and Podack , ER. Induction of CD8 T-cell-Ifngamma 

response and positive clinical outcome 

after immunization with gene-modified allogeneic 

tumor cells in advanced non-small-cell lung 

carcinoma. Cancer Gene Therapy 10:850-58, 

2003. 

Santos, ES, Raez, LE, Kharfan-Dabaja, MA, 

Angulo, J, Restrepo, A, and Byrnes, JJ. Survival 

of renal allograft following de novo hemolytic 

uremic syndrome after kidney transplantation. 

Transplantation Proceedings 35:1370-74, 2003. 

52 



CAIO MAX S. ROCHA LIMA, M.D. 



Dr. Rocha Lima’s research focuses on developing 

novel treatments in patients with cancer 

(mainly lung cancer and gastrointestinal malignancies). 

Researchers in his laboratory work to identify 

prognostic factors in patients with cancer. 

They also are cooperating in the development of 

molecular finger-printing for gastrointestinal cancer 

patients. They are studying 33,000 genes in 

pancreatic cancer and colorectal cancer as an attempt 

to identify different gene expression patterns 

(tumor phenotype) and their correlation 

with overall survival, benefit to different types of 

treatment, and tumor aggressiveness. The investigators 

also are working to identify chromosomes 

alleles related to drug metabolism from buffy coat 

(leucocytes) and correlating with chemotherapy 

toxicity. 


2002 

Rocha Lima, CM, Herndon, JE 2nd, Kosty, M, 

Clamon, G, and Green, MR. Therapy choices 

among older patients with lung carcinoma: an 

evaluation of two trials of the Cancer and Leukemia 

Group B. Cancer 94:181-87, 2002. 

Rocha Lima, CM, Savarese, D, Bruckner, H, 

Dudek, A, Eckardt, J, Hainsworth, J, Yunus, F, 

Lester, E, Miller, W, Saville, W, Elfring, GL, 

Locker, PK, Compton, LD, Miller, LL, and 

Green, MR. Irinotecan plus gemcitabine induces 

both radiographic and CA 19-9 tumor marker 

responses in patients with previously untreated 

advanced pancreatic cancer. Journal of Clinical 

Oncology 20:1182-91, 2002. 

Rocha Lima, CM and Centeno, B. Update on 

pancreatic cancer. Current Opinion in Oncology 

14:424-30, 2002. 

Rocha Lima, CM and Joppert, MG. 

Topoisomerase I-based nonplatinum combinations 

in non-small-cell lung cancer. Oncology 

(Huntington) 16:25-31, 2002. 

Freitas, JR and Rocha Lima, CM. Therapy of 

advanced non-small-cell lung cancer with 

irinotecan and gemcitabine in combination. 

Clinical Lung Cancer 4 (Supplement 1): S26-90, 

2002. 

2003 

Coutinho, AK and Rocha Lima, CM. Metastatic 

colorectal cancer: systemic treatment in the new 

millennium. Cancer Control 10:224-38, 2003. 

Rocha Lima, CM and Chiappori, A. Treatment 

of relapsed small-cell lung cancer—a focus on the 

evolving role of topotecan. Lung Cancer 40:229- 

36, 2003. 

Bhargava, P, Jani, CR, O’Donnel, JL, Stuart, KE, 

and Rocha Lima, CM. Gemcitabine and 

irinotecan in locally advanced or metastatic 

biliary cancer. Oncology 17: 23-26, 2003. 

Chiappori, AA and Rocha Lima, CM. New 

agents in the treatment of small-cell lung cancer: 

focus on gemcitabine. Clinical Lung Cancer 4 

(Supplement 2): S56-63, 2003. 

Simon, GR, Ruckdeschel, JC, Williams, C, Cantor, 

A, Chiappori, A, Rocha Lima, CM, Antonia 

S, Haura, E, Wagner, H, Robinson, L, Sommers, 

E, Alberts, M, and Bepler, G. Gefitinib (ZD1839) 

in previously treated advanced non-small-cell 

lung cancer: experience from a single institution. 

Cancer Control 10:388-95, 2003. 

Rocha Lima, CM, Leong, SS, Sherman, CA, 

Perkel, JA, Putman, T, Safa, AR, and Green, MR. 

Irinotecan and gemcitabine in patients with solid 

tumors: phase I trial. Oncology (Huntington) 

16:19-24, 2002. 




Novel treatments with the following agents were 

designed and tested clinically by Dr. Rocha Lima: 

• IrinoGem (gemcitabine and irinotecan in combination) 

for pancreatic cancer and lung cancer 

(both small and non-small cell lung cancer). 

• DocGem in lung cancer. 

• ETopoTax in small cell lung cancer. 

His clinical efforts with the agent IrinoGem 

resulted in establishing it as a new clinical treatment 

option for pancreatic cancer. 

JOSEPH D. ROSENBLATT, M.D. 

Professor of Medicine and 

Division Chief of Hematology-Oncology 


Dr. Rosenblatt’s research focuses on the development 

of novel immune therapy and gene 

therapy strategies for cancer. Current research has 

focused on the potential role of recruitment of 

immune effector cells, using the local elaboration 

of both constitutive and inflammatory chemokines, 

such as secondary lymphoid chemokine (SLC), 

DC-CK1 and/or RANTES respectively, on the 

development of an anti-tumor response. Chemokine 

delivery has been investigated alone, or in combination 

with, expression of the costimulatory ligands 

CD80 (B7.1) or CD40L. Several delivery strategies 

have been investigated including the use of retroviral 

vectors, and/or the use of herpes simplex virus (HSV) 

amplicon vectors in several murine tumor models. 

Preliminary results suggest that the recruitment 

of naïve T cells using SLC is a particularly effective 

means of enhancing the anti-tumor immune 

response, particularly when combined with CD40Linduced 

co-stimulation. This strategy is being 

formally investigated using the OT-1 transgenic 

mouse model, which has a constitutively expressed 

T-cell receptor with defined anti-ovalbumin specificity 

and the murine tumors expressing the target 

ovalbumin antigen, for effects on tumor-induced 

tolerance and the development of systemic immunity. 

In a separate effort, the utility of HSV-derived 

helper virus-free amplicons is being tested 

for efficacy in augmenting the immunogenicity 

and antigen-presenting capability of fresh chronic 

lymphocytic leukemia cells (CLL). Both CD40L 

and CD80, and/or the tumor necrosis factor (TNF) 

ligand family member LIGHT have been targeted 

to fresh CLL cells using the helper free HSV 

amplicons. Results suggest the augmented ability 

of such CLL cells to present antigen in an allogeneic 

mixed-lymphocyte-tumor cell reaction, and/ 

or to serve as stimulatory cells for the derivation 

of autologous cytolytic T cells in vitro without 

deleterious effects on MHC-I expression is seen 

with HSV helper virus-containing preparations. 

A novel means of immune effector molecule 

delivery, which combines the antigen binding 

capabilities and localization characteristics of antibodies 

with the local delivery of a co-stimulatory 

molecule, anti-angiogenic peptide, or a chemokine, 

also is under investigation. Antibody fusion 

proteins targeting the human breast and ovarian 

cancer her2/neu antigen, linked to the extracellular 

domains of the B7.1 and/or 41BB-L 

costimulatory ligands, have been synthesized and 

their in vitro ability to bind to cognate antigenic 

targets and to deliver a local co-stimulatory signal 

has been documented. Additional fusions currently 

being developed in the laboratory include 

fusion of the anti-angiogenic peptide endostatin 

to anti-her2/neu antibody sequences, as well as 

fusion of the inflammatory chemokine RANTES. 

Selective targeting of immune effector cells using 

both local chemokine vector administration or 

antibody-fusion protein administration is being 

evaluated further. 

A novel antibody-fusion that targets delivery 

of endostatin to the site of her2/neu-expressing 

tumors has also been synthesized in collaboration 

with Seung-Uon Shin, M.D., and shows excellent 

efficacy in preclinical models. This fusion appears 

to substantially improve the results obtained with 

either antibody or endostatin alone. 

Currently, Dr. Rosenblatt’s laboratory is 

studying efficacy using a novel B-cell deficient 

mouse model, which allows testing of antibody 

54 



fusion protein targeting to xenogeneic (e.g., CEA, 

her2/neu) antigens, while preserving T-cell 

immune-effector functions. The B-cell deficient 

model also has demonstrated T-cell responses to 

tumor and may be better than those seen in the 

immunocompetent mouse. The laboratory is 

currently investigating the reasons for altered 

responses in the absence of B cells, and the possibility 

of applying this approach to clinically using 

antibody depletion of B cells with rituximab. 

Dr. Rosenblatt and his colleagues also have 

collaborated with the laboratory of Vicente 

Planelles, Ph.D., at the University of Utah, on 

developing several new approaches to HIV-1 gene 

therapy. These include the use of mutated tRNA LYS3 

primers, which can anneal to the sequences other 

than primer-binding sequences on the HIV-1 

genome, or tRNA LYS3 mutated in adenosine residue 

A58, which prevents normal methylation of 

the adenosine residue and disrupts proper termination 

of the nascent reverse transcript, thereby 

inhibiting completion of HIV-1 reverse transcription 

in model systems. Other investigations have 

centered on the effects of defective HIV-1 derived 

vectors on HIV-1 spread in culture. Recent experiments 

have demonstrated that efficient trafficking 

of defective HIV-1 vectors is observed 

in vitro following superinfection with wild type 

HIV-1 and that such trafficking results in a 

marked inhibition of wild type viral spread. 


2002 

Lancet, JE, Rosenblatt, JD , and Karp, JE. 

Farnesyltransferase inhibitors and myeloid malignancies: 

phase I evidence of Zarnestra activity in 

high-risk leukemias. Seminars in Hematology 

39:31-35, 2002. 

Tolba, KA, Bowers, WJ, Muller, J, Housekneckt, 

V, Giuliano, RE, Federoff, HJ, and Rosenblatt, 

JD. Herpes simplex virus (HSV) amplicon-mediated 

codelivery of secondary lymphoid tissue 

chemokine and CD40L results in augmented antitumor 

activity. Cancer Research 62:6545-51, 

2002. 

Rosenblatt, JD , Shin, SU, Nechustan, H, Yi, 

KH, and Tolba, K. Potential role of chemokines 

in immune therapy of cancer. Israel Medical Association 

Journal 4:1054-59, 2002. 

Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE, 

Kipps, TJ, Federoff, HJ, and Rosenblatt, JD . 

HSV amplicon-mediated delivery of LIGHT enhances 

the antigen-presenting capacity of chronic 

lymphocytic leukemia. Molecular Therapy 6:455- 

63, 2002. 

Andela, VB, Rosenblatt, JD , Schwarz, EM, 

Puzas, EJ, O’Keefe, RJ, and Rosier, RN. Synergism 

of aminobisphosphonates and farnesyl 

transferase inhibitors on tumor metastasis. Clinical 

Orthopaedics 397:228-39, 2002. 

2003 

Khorana, AA, Rosenblatt, JD , Sahasrabudhe, 

DM, Evans, T, Ladrigan, M, Marquis, D, Rosell, 

K, Whiteside, T, Phillippe, S, Acres, B, Slos, P, 

Squiban, P, Ross, M, and Kendra, K. A phase I 

trial of immunotherapy with intratumoral adenovirus-interferon-gamma 

(TG1041) in patients 

with malignant melanoma. Cancer Gene Therapy 

10:251-9, 2003. 

Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ, 

O’Keefe, RJ, Rosenblatt, JD, and Rosier, RN. 

The mevalonate synthesis pathway as a therapeutic 

target in cancer. (Review) Clinical Orthopaedics 

415 (Supplement):S59-66, 2003. 

Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A, 

Lu, C, McNair, C, Abboud, CN, and Rosenblatt, 

JD. Effects of the farnesyl transferase inhibitor 

R115777 on normal and leukemic hematopoiesis. 

Leukemia 17:1806-12, 2003. 

Rosenblatt, JD and Harrington, WJ Jr. Leukemia 

and myelopathy: the persistent mystery of pathogenesis 

by HTLV-I/II. Cancer Investigation 

21:323-24, 2003. 




• Developed novel antibody-chemokine and antibody-costimulatory 

ligand fusion proteins with 

dual function and preserved targeting capabilities. 

• Developed a novel strategy for gene therapy of 

HIV-1 using mutations introduced into the 

tRNA LYS3 primer. 

• Demonstrated the potential role for HSV 

amplicon vectors in gene therapy of malignancy, 

particularly CLL. 

• Demonstrated the use of trafficking and inhibition 

by defective HIV-1 as a novel approach to 

HIV-1 gene therapy. 

• Demonstrated the utility of combining 

chemokine delivery with costimulatory ligands 

in augmenting mouse response to tumors. 

NIRAMOL SAVARAJ, M.D. 

Adjunct Professor of Medicine 


Molecular Mechanism of Drug Resistance in 

Small Cell Lung Cancer 

Small cell lung cancer (SCLC) usually responds 

to chemotherapy, but relapse is inevitable. Although 

several new chemotherapeutic agents have 

shown activity in SCLC, salvage therapy is still 

poor. Research in Dr. Savaraj’s laboratory focuses 

on identifying the mechanisms of drug resistance 

in SCLC and developing approaches to overcome 

them. 

Since the combination of VP-16 and 

cisplatin is the most commonly used regimen in 

treating SCLC, the laboratory has studied the 

mechanism(s) of resistance of these two agents. 

They have established two pairs of cisplatin resistant 

sublines (SR-2 and BC), one VP-16 resistant 

subline (BV), one MRP1 (SCLCA), and one P- 

gp (SCLCR) resistant subline from two parental 

lines (SCLC1 and SCLCB). These cell lines were 

used to study the mechanism(s) of resistance in 

SCLC. Using cDNA subtraction and microarray, 

the laboratory has found that both cisplatin resistant 

cell lines overexpressed three families of 

cDNAs, the MMP family, DNA damage and repair 

proteins, and proteins involved in translation. 

The specific genes that were consistently 

elevated were elongation factor and ribosomal 

protein. Since rapamycin or its analog CCI-779 

can inhibit translation of the mRNA encoding 

elongation factor, they have investigated whether 

these analogs could reverse cisplatin drug resistance. 

Dr. Savaraj and her colleagues found that 

all cell lines were sensitive to rapamycin and 

CCI-779 with the ID 50 

ranged from 0.05-0.1µg/ 

ml. Furthermore, at 0.01µg/ml both drugs could 

also restore cisplatin sensitivity, and could completely 

restore VP-16 sensitivity in BV cell line. 

Neither rapamycin nor CCI-779 is able to reverse 

P-gp1 or MRP1 resistance. 


2002 

Feun, LG, Modiano, M, Lee, K, Mao, J, Marini, 

A, Savaraj, N, Plezia, P, Almassian, B, Colacino, 

E, Fischer, J, and MacDonald, S. Phase I and 

pharmacokinetic study of 3-aminopyridine-2- 







primary brain tumor. ScientificWorldJournal. 

2:125-26, 2002. 





2002. 

56 



Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ. 




51, 2002. 

2003 


Jeffers, L, Schiff, ER, Marini, A, Savaraj, N, and 



carcinoma-A phase II trial. Journal of 


20, 2003. 


Donnelly, E, Solomon, J, Sundaram, M, Feun, L, 

and Savaraj, N. Phase II study of vinorelbine 



Oncology Report 10:885-89, 2003. 


Lampidis, TJ, Robles, C, Furst, AJ, and Feun, 

LG. Overexpression of mutated MRP4 in 

cisplatin resistant small cell lung cancer cell line: 

Collateral sensitivity to azidothymidine. International 

Journal of Oncology 23:173-9, 2003. 


Lampidis, TJ. Multidrug resistance correlates 





RAKESH SINGAL, M.D. 



Dr. Singal’s research focuses on the mechanisms 

that inactivate certain tumor-suppressor 

genes in prostate cancer. A common mode of 

such inactivation involves a modification (methylation) 

in DNA. By understanding how genes are 

silenced, treatments can be developed to activate 

them and thereby prevent the development and/ 

or progression of prostate cancer. Researchers in 

Dr. Singal’s laboratory also are studying methylation 

of selected genes as a diagnostic and prognostic 

marker in prostate cancer. 

The present screening techniques for prostate 

cancer are very inefficient, and two out of three 

patients undergo prostate biopsy to detect cancer 

unnecessarily. Cancer patients often have a small 

amount of DNA circulating in their serum, 

thought to be released from the cancer cells. 

Dr. Singal’s laboratory has shown that certain 

methylated genes are present at a substantially 

higher percentage in prostate cancer tissue compared 

to benign prostatic conditions. Researchers 

are investigating if these methylated genes can 

be detected in serum DNA in patients with prostate 

cancer. If so, this test can be used as a part 

of prostate cancer screening, saving unnecessary 

prostate biopsies. 

DNA methylation plays a role during development 

by regulating gene expression. Another 

project in Dr. Singal’s laboratory focuses on understanding 

the role of methylation in regulating 

the expression of genes responsible for hemoglobin 

synthesis. Understanding the contribution of 

methylation to globin gene expression and the 

mechanisms involved will lead to the development 

of safe and effective therapies for globin 

gene disorders like thalassemia and sickle cell 

anemia. 




2002 

Singal, R, vanWert, JM, and Ferdinand, L Jr. 

Methylation of alpha-type embryonic globin gene 

alpha pi represses transcription in primary erythroid 

cells. Blood 100:4217-22, 2002. 

Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and 

Ginder, GD. Methylation of promoter proximal 

transcribed sequences of an embryonic globin 

gene inhibits transcription in primary erythroid 

cells and promotes formation of a cell type-specific 

methyl cytosine binding complex. Journal of 

Biological Chemistry 277:1897-1905, 2002. 

Noss, KR, Singal, R, and Grimes, SR. Methylation 

state of the prostate specific membrane antigen 

(PSMA) CpG island in prostate cancer cell 

lines. Anticancer Research 22:1505-11, 2002. 

2003 

Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal, 

R, and Gill, S. Gynecomastia attributable to human 

chorionic gonadotropin-secreting giant cell 

carcinoma of lung. Endocrinology Practices 

9:233-35, 2003. 

JOYCE M. SLINGERLAND, M.D., PH.D., 

F.P.R.C.(C) 



Dr. Slingerland’s research investigates how 

cancers escape negative growth controls. Following 

her discovery of a key inhibitor of cell 

cycle progression, p27, Dr. Slingerland and her 

colleagues went on to demonstrate that p27 levels 

are reduced in up to 60 percent of common human 

cancers (breast, prostate, lung, ovarian, and 

others), in association with poor patient prognosis. 

Dr. Slingerland showed that the therapeutic 

effect of antiestrogens in breast cancer requires 

the cyclin-dependent kinase (cdk) inhibitors p21 

and p27 to mediate growth arrest. Oncogenic 

activation of mitogenic signaling via the mitogenactivated 

protein kinase (MAPK) pathway deregulates 

p27 function, causing tamoxifen 

resistance in breast cancer. She provided key insights 

demonstrating the role of cell cycle inhibitors 

p15 and p27 as mediators of G1 arrest by 

transforming growth factor-beta (TGF-β) and 

demonstrated that cancer cells lose responsiveness 

to this growth inhibitory cytokine through loss or 

deregulation of p27. In a recent publication, her 

laboratory demonstrated that checkpoint loss 

during cancer progression makes p27 an essential 

mediator of arrest. They also showed that functional 

inactivation of p27 in human cancers can 

either occur through accelerated p27 degradation 

or through altered p27 phosphorylation leading 

to p27 mislocalization. The laboratory recently 

showed that activation of mitogenic signaling via 

the receptor tyrosine kinases and the phosphoinositol 

3’ kinase pathway alters p27 phosphorylation 

and function and the protein accumulates 

in the cytoplasm away from its targets in the 

nucleus. This work links oncogene activation 

with loss or inactivation of the cell cycle inhibitor, 

p27, elucidating a major mechanism of loss 

of growth control in cancer progression. 

Dr. Slingerland’s laboratory also is investigating 

the cause of aggressive estrogen receptor negative 

(ER-) breast cancers. Her group has found 

that oncogenic receptor tyrosine kinase and cSrc 

activation may not only activate mitogenic signaling 

leading to aggressive proliferation, but also 

lead to loss of detectable ER protein in ER negative 

(ER-) breast cancers. One third of newly diagnosed 

breast cancers are ER- and have a poor 

prognosis. Investigation of the mechanisms underlying 

the loss of ER expression showed that all 

of 70 primary ER- breast cancers expressed ER 

mRNA. Src or proteasome inhibition increased 

ER levels, and Src transfection stimulated both 

ligand activated ER transcriptional activity and 

ER proteolysis. Cotransfection of Her2 and Src 

reduced ER levels further. ER- primary breast 

cancers and cell lines showed increased Src activity 

compared to ER+ cancers and cell lines, and 

58 



the ER protein half-life was reduced in ERbreast 

cancer lines. These data support a model 

in which Her2 and cSrc cooperate with liganded 

ER to promote both ER dependent transcription 

and transcription linked ER proteolysis. 


2002 

Donovan, JC, Rothenstein, JM, and Slingerland, 

JM. Non-malignant and tumor-derived cells differ 

in their requirement for p27Kip1 in transforming 

growth factor-beta-mediated G1 arrest. 


2002. 

Lian, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R, 

Connor, MK, Han, K, Lee, JH, Ciarallo, S, 

Catzavelos, C, Beniston R, Franssen, E, and 

Slingerland, JM . PKB/Akt phosphorylates p27, 

impairs nuclear import of p27 and opposes p27- 

mediated G1 arrest. Nature Medicine 8:1153-60, 

2002. 

Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH, 

Kotchetkov, R, Sandhu, C, Milic, A, and 

Slingerland, JM . Altered p27(Kip1) phosphorylation, 

localization, and function in human epithelial 

cells resistant to transforming growth 

factor beta-mediated G(1) arrest. Molecular and 

Cellular Biology 22:2993-3002, 2002. 

2003 

Connor, MK, Kotchetkov, R, Cariou, S, Resch, 

A, Lupetti, R, Beniston, RG, Melchior, F, 

Hengst, L, and Slingerland, JM . CRM1/Ranmediated 

nuclear export of p27(Kip1) involves a 

nuclear export signal and links p27 export and 

proteolysis. Molecular Biology of the Cell 

14:201-13, 2003. 

Liang, J and Slingerland, JM . Multiple Roles of 

the PI3K/PKB (Akt) Pathway in cell cycle progression. 

Cell Cycle 2:339-45, 2003. 

MARK S. SOLOWAY, M.D. 

Professor and Chairman of Urology 


Much of the work in the University of 

Miami’s department of Urology is devoted 

to better understanding the role of surgery in 

treating prostate, bladder, and kidney cancers. 

The department has established a rather unique 

database of more than 1,300 men who have had 

radical prostatectomy performed by one surgeon 

and their pathology has been read by one pathologist. 

Through the efforts of devoted researchers, 

they have reported on the relationship 

between a number of clinical and pathologic risk 

factors, e.g., positive surgical margin location, 

seminal vesicle invasion, and risk of relapse. This 

is critical when counseling patients regarding diagnosis, 

follow-up schedule and, most importantly, 

the need and type of additional treatment. 

Researchers in Dr. Soloway’s laboratory have 

introduced the concept of local anesthesia for 

prostate biopsies. This has the potential to benefit 

more than 500,000 men annually in the United 

States who undergo this otherwise rather painful 

procedure. More than 13 randomized studies 

confirm the researchers’ observation of the benefit 

of a periprostatic nerve block prior to ultrasound 

guided prostate biopsies. 

In an effort to minimize the morbidity of 

radical retropubic prostatectomy, Dr. Soloway has 

taken steps to enhance recovery without sacrificing 

cancer control. To this end, he has reported 

his results with nerve sparing, the omission of a 

pelvic drain, and the use of a cell saver to obviate 

the need for an allogeneic transfusion. 

In collaboration with Gaetano Ciancio, 

M.D., professor of Surgery and Urology, they 

have carefully detailed their surgical approach to 

large kidney tumors. They have adapted techniques 

developed for liver transplantation to reduce 

the morbidity and mortality related to 

surgery of large renal tumors, many of which involve 

extension into the vena cava. 



Lastly, Dr. Soloway’s interest in bladder cancer 

continues. He has published the first article 

detailing the growth pattern of low-grade bladder 

tumors. Using a cohort of patients with lowgrade 

Ta tumors who were observed by periodic 

endoscopy, they were able to emphasize the safety 

of carefully monitoring such tumors to obviate 

the morbidity and cost of frequent outpatient 

surgery. 


2002 



of Urology 167:1406-07, 2002. 

Lokeshwar, VB, Schroeder, GL, Selzer, MG, 






95:61-72, 2002. 

Lokeshwar, VB, Schroeder, GL, Carey, RI, 




2002. 

2003 

Simon, MA, Lokeshwar, VB, and Soloway, MS. 



47:91-107, 2003. 


Civantos, F, Duncan, RC, and Lokeshwar, VB. 

Evaluation of the prognostic potential of hyaluronic 

acid and hyaluronidase (HYAL1) for prostate 

cancer. Cancer Research 63:2638-44, 2003. 

SHOU-CHING TANG, M.D., PH.D. 



BAG-1 is a recently identified anti-apoptotic 

protein that binds to Bcl-2, hepatocyte, and 

platelet-derived growth factor receptors, enhancing 

their inhibition of apoptosis. It also binds to 

heat shock proteins, RAF-1 serine/threonine kinase, 

and hormone receptors and modulates their 

functions. Researchers in Dr. Tang’s laboratory 

detected the presence of one new BAG-1 isoform, 

p29. They showed that the four BAG-1 isoforms 

are localized differentially in subcellular compartments 

and in various tissues, suggesting that they 

perform different functions. They recently demonstrated 

that each BAG-1 isoform has a differing 

ability to inhibit apoptosis induced by various 

apoptosis-inducing agents. On the other hand, 

antisense against BAG-1 sensitized cells to 

apoptosis was induced by various chemotherapeutic 

agents. More significantly, these researchers 

observed the overexpression of BAG-1 in the 

majority of breast and lung cancer patients and 

its prognostic value. In addition, they observed 

the coexpression of BAG-1 with Bcl-2, p53, and 

estrogen receptor/progesterone receptor (ER/PR) 

in breast cancer tissues. They have isolated the 

BAG-1 promoter region and noted its up-regulation 

by the mutant p53. The laboratory also has 

raised monoclonal antibodies against individual 

BAG-1 isoforms, allowing for clinical correlation 

of BAG-1 expression and disease course. Current 

research at the basic molecular biology level involves 

the study of BAG-1 expression control and 

its interaction with other cellular proteins, including 

Bcl-2, ER/PR, and hsp to explore how 

BAG-1 inhibits apoptosis. At the clinical research 

level, research involves the development of BAG- 

1 Mab and antisense in the prognosis and prediction 

to treatment response in a variety of solid 

tumors. 

60 




2002 

Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X, 

Pater, A, and Liepins, A. The alkaloid sanguinarine 

is effective against multi-drug resistance in 

human cervical cells via bimodal cell death. Biochemical 

Pharmacology 63:1415-21, 2002. 

Ding, Z, Green, AG, Yang, X, Chernenko, G, 

Tang, S-C, and Pater, A. Retinoic acid inhibits 

telomerase activity and downregulates expression 

but does not affect splicing of hTERT: correlation 

with cell growth rate inhibition in an in vitro 

cervical carcinogenesis/multidrug-resistance 

model. Experimental Cell Research 272:185-91, 

2002. 


Chernenko, G, Pater, A, and Liepins, A. The alkaloid 

sanguirine is effective against multidrug 

resistance in human cervical cells via bimodal cell 

death. Biochemical Pharmacology 63:1415-21, 

2002. 

Tang, S-C. BAG-1, an anti-apoptotic tumor 

marker. (Invited Review) IUBMB Life 53:99- 

105, 2002. 

Chen, J, Chernenko, G, Xiong, J and Tang, S-C. 

Distinct BAG-1 isoforms have different antiapoptotic 

functions in BAG-1-transfected C33A 

human cervical carcinoma cell line. Oncogene 

21:7050-59, 2002. 

2003 

Tang, S-C. Differential anti-apoptotic function 

of BAG-1 isoforms in human malignancy. Recent 

Research and Development in Biophysics and 

Biochemistry 3:427-44, 2003. 


• Cloned mouse and human BAG-1 genes and its 

promoter. 

• Discovered the mechanism by which four BAG- 

1 isoforms are generated. 

• Discovered the possible prognostic value of 

BAG-1 in breast and lung cancer. 

• Generated BAG-1-isoform-specific Mab’s 

(patent pending). 

• Generated BAG-1 antisense cDNA and siRNA. 

• Discovered BAG-1’s involvement in chemotherapy 

resistance. 

• Developed Eastern Cooperative Oncology 

Group (ECOG) protocol using BAG-1 as predictive 

marker in the treatment of NSCLC. 

KHALED A. TOLBA, M.D. 



During the past five years, Dr. Tolba has been 

developing immunotherapeutic strategies for 

B-cell hematologic malignancies, with particular 

interest in chronic lymphocytic leukemia (CLL). 

CLL is the most common leukemia in the Western 

hemisphere. As a relatively slow-progressing 

tumor with readily accessible tumor cells, it offers 

an opportunity to develop and test immunotherapeutic 

interventions. A number of profound 

immunologic deficiencies affecting both the B 

and T-cell responses, however, have posed a challenge 

to immune therapy of CLL. 

The laboratory has co-developed and 

adapted the use of herpes simplex virus (HSV) 

amplicons for gene transduction of CLL cells. 

Using CD40L as an effector molecule, they have 

shown robust induction of co-stimulatory molecules 

on transduced and bystander cells and in 

roughly one-third of tested patients demonstrated 

the capacity to generate cytotoxic T lymphocytes 

(CTL) activity. This capacity to elicit autologous 

CTL response, however, was not universal as 

more than half the patients tested failed to mount 



such a response despite adequate up-regulation 

of costimulatory signal on both transduced and 

bystander CLL cells. In addition to being a 

highly efficient gene transfer vector, herpes simplex 

virus (HSV)-based amplicons possess the 

capacity to engage and activate different elements 

of the innate immune system. Currently, the 

laboratory is studying various aspects of HSV 

amplicon/innate immune interaction and how 

this might influence the outcome of an adaptive 

anti-tumor immune response. 

Immune therapeutic strategies targeting the 

innate immune system might offer an alternative 

pathway to bypass inherent CD8 + T-cell defects, 

and effectively mount a systemic anti-tumor immune 

response. Dr. Tolba and his colleagues are 

currently exploring how HSV amplicon interacts 

with the family of toll-like (TL) receptors and 

up-regulates NKG2D ligands on target cells. 


2002 


Kipps, TJ, Federoff, HJ, and Rosenblatt, JD. 

Herpes simplex virus (HSV)-amplicon-mediated 

delivery of LIGHT enhances the antigen-presenting 

capacity of chronic lymphocytic leukemia. 

Molecular Therapy 6:455-63, 2002. 







2002. 

Rosenblatt, JD, Shin, SU, Nechustan, H, Yi, 

KH, and Tolba, KA. Potential role of 

chemokines in immune therapy of cancer. Israel 

Medical Association Journal 4:1054-59, 2002. 

VLADIMIR VINCEK, M.D., PH.D. 



Progress in the understanding of molecular 

events involved in the development and progression 

of human disease is revolutionizing the 

way diseases are diagnosed and treated. Physicians 

and scientists now are harnessing the power of 

molecular techniques to diagnose and prognosticate 

pathologic disorders. Furthermore, it is now 

possible to direct therapeutic agents to specific 

products expressed by diseased cells without affecting 

normal tissues. On the other hand, while 

standard histopathologic methods maintain tissue 

architecture for morphologic assessment, they do 

not preserve macromolecules. The extraction of 

nucleic acids from formaldehyde-fixed, paraffinembedded 

tissue, the most widely available material 

for clinical studies, is a notoriously unreliable 

and irreproducible process. Therefore, macromolecules 

usually are extracted from fresh or snapfrozen 

tissue specimens. Fresh or frozen tissue 

specimens, however, are of limited value for the 

assessment of histomorphology and cannot be 

utilized for long-term retrospective studies. Similarly, 

currently available tissue preservatives that 

protect nucleic acids cause considerable damage 

to the cell and tissue architecture and render 

them unsuitable for histomorphologic evaluation. 

Current studies in this laboratory show that 

it is feasible to simultaneously protect histomorphology 

and the integrity of macromolecules in 

fixed and processed tissue. The UMFIX reagent, 

developed in collaboration with other members 

of the Department of Pathology, seems to provide 

enormous advantage over the conventional fixation 

methods in allowing diagnosis, prognostication, 

and identification of treatment targets in 

patient samples. 

62 




2002 

Malek, TR, Yu, A, Vincek, V, Scibelli, P, and 

Kong, L. CD4 regulatory T cells prevent lethal 

autoimmunity in IL-2Rbeta-deficient mice. Implications 

for the nonredundant function of IL-2. 

Immunity 17:167-78, 2002. 

Morales, A, Essenfeld, H, Dubane, C, Vincek, V, 

and Nadji, M. Continuous-specimen-flow, highthroughput, 

1-hour tissue processing. Archives of 

Pathology & Laboratory Medicine 126:584-90, 

2002. 

2003 

Vincek, V, Knowles, J, and Nassiri, M. p63 

mRNA expression in normal human tissue. Anticancer 

Research 23:3945-48, 2003. 

Vincek, V, Nassiri, M, Knowles, J, Nadji, M, and 

Morales, AR. Preservation of tissue RNA in normal 

saline. Laboratory Investigation 83:137-38, 

2003. 

Jacob, SE, Nassiri, M, Kerdel, FA, and Vincek, V. 

Rapid measurement of multiple cytokines in psoriasis 

patients and correlation with disease severity. 

Mediators of Inflammation 12:309-13, 2003. 

Adkins, B, Bu, Y, Vincek, V, and Guevara, P. 

The primary responses of murine neonatal lymph 

node CD4 + cells are Th2-skewed and are sufficient 

for the development of Th2-biased memory. 

Clinical & Developmental Immunology 10:43- 

51, 2003. 

Vincek, V, Nassiri, M, Nadji, M., and Morales, 

AR. A novel tissue preservative that protects macromolecules 

(DNA, RNA, protein) and 

histomorphology in clinical samples. Laboratory 

Investigation 83:1-9, 2003. 

Jacob, SE, Berman, B, Nassiri, M, and Vincek, V. 

Topical application of imiquimod 5% cream to 

keloids alters expression genes associated with 

apoptosis. British Journal of Dermatology 149:1- 

4, 2003. 


• Patent pending for alcohol-based UMFIX preservative 

that preserves histomorphology and 

macromolecules. 



64 


T U M O R C E L L B I O L O G Y P R O G R A M 






The Tumor Cell Biology Program currently 

comprises 28 faculty members in 11 different 

departments at the University of Miami 

School of Medicine. Faculty members are chosen 

based on the potential of their research to contribute 

to important aspects in the understanding 

of cancer cell biology. Faculty members must have 

peer-reviewed cancer related research funding in 

a field aligned with the scientific goals of the program 

or be newly recruited faculty investigators. 


The overall goal of the Tumor Cell Biology Program 

is to develop knowledge in the area of cell 

biology that can be applied to translational research 

on neoplastic disease. The focus of the individual 

studies varies widely, from gene therapy 

to the ultrastructural analyses of protein; however, 

all investigators are involved in cutting-edge 

research using the developing methods of molecular 

biology and cell structural analysis to ask 

questions important to tumor cell biology. 

The specific aims of the program are to: 

1) Understand how genetic information is maintained, 

transferred, and translated into functional 

cell proteins, a fundamental issue 

throughout the history of cancer research. 

2) Determine how tumor cells interact with other 

cells and their environment, particularly the 

molecular species and associations that favor or 

disfavor those interactions. This issue is critically 

important for understanding metastasis 

of tumors, the process that usually determines 

mortality of cancer patients. 

3) Determine how signaling pathways and 

molecules transmit and integrate information, 

which determines cell fate, including cell structure 

and function. Included in such analyses are 

the mechanisms by which the molecular components 

of signaling and metabolic pathways 

are localized in cells to perform their particular 

roles. 

All of these questions and approaches are important 

to understanding how tumor cells behave 

and determining whether specific tumor cell 

behaviors can be exploited in combating cancer. 

Developing such translational applications is the 

ultimate goal of the Tumor Cell Biology 

Program. 

PARTICIPANTS 

Burnstein, Kerry L., Ph.D. 

Molecular and Cellular Pharmacology 

Carraway, Kermit L., Ph.D. 


Deutscher, Murray P., Ph.D. 


D’Urso, Gennaro, Ph.D. 


Fletcher, Terace M., Ph.D. 


Franzmann, Elizabeth J., M.D. 


Han, Zhiyong, Ph.D. 

Biology 

Harris, Thomas K., Ph.D. 


King, Mary Lou, Ph.D. 




Lampidis, Theodore J., Ph.D. 


Li, Jie, M.D., Ph.D. 

Dermatology and Cutaneous Surgery 

Liu, Chia-Yang, Ph.D. 

Ophthalmology 

Lokeshwar, Balakrishna L., Ph.D. 

Urology 

Lokeshwar, Vinata B., Ph.D. 

Urology 

Malhotra, Arun, Ph.D. 


Mayeda, Akila, Ph.D. 


Moraes, Carlos T., Ph.D. 

Neurology 

Perez, Aymee, Ph.D. 


Salas, Pedro J. I., M.D., Ph.D. 


Shonukan, Oluwatoyin, M.D. 

Medicine 

Singal, Rakesh, M.D. 

Medicine 

Slingerland, Joyce M., M.D., Ph.D., F.P.R.C. (C) 

Medicine 

Verde, Fulvia, Ph.D. 


Weed, Donald T., M.D., F.A.C.S. 


Welsh, Catherine F., M.D. 

Medicine 

Werner, Rudolf K., Ph.D. 


Wyche, James, Ph.D. 

Biology 

Zimmers, Teresa A., Ph.D. 

Surgery 


• MUC4 expression potentiates the phosphorylation/activation 

of the ErbB2 and ErbB3 tyrosine 

kinase receptors induced by neuregulin, 

providing a mechanism by which MUC4 may 

contribute to tumor progression through 

changes in cell signaling pathways (K. Carraway). 

• MUC4 in mammary gland is regulated at the 

post-transcriptional level by extracellular matrix 

(basement membrane) and by transforming 

growth factor-beta. Responses to both of these 

are known to change during breast cancer progression 

(K. Carraway). 

• MUC4 overexpression increases primary tumor 

growth in nude mice, acting as an antiapoptotic 

agent in the growing tumors and in 

cell culture (K. Carraway). 

• MUC4 regulates the localization of the receptor 

tyrosine kinase ErbB2 in polarized epithelial 

cells (K. Carraway). 

• Vitamin D inhibits the cell cycle by promoting 

nuclear exclusion of cyclin dependent kinase 2, 

opening new avenues for prostate cancer 

therapy. Regulation of cdk2 localization represents 

a new regulatory paradigm in G1 to S- 

phase progression (K. Burnstein). 

• Pol ε is required for initiation of DNA replication, 

suggesting that it provides multiple functions 

in promoting DNA replication, one of 

which is to facilitate assembly of the DNA replication 

initiation complex (G. D’Urso). 

• Discovery of a new endoribonuclease, RNase G 

(M. Deutscher). 

• Oligoribonuclease is an essential component of 

mRNA degradation (M. Deutscher). 

• Development of an efficient, cell-free translation 

system for mammalian cells (M. 

Deutscher). 

• Discovery of CD44v3-containing isoforms in 

head and neck squamous cell tumor tissues and 

cell lines (E. Franzmann). 

66 



• Development of a novel thermodynamically 

balanced inside-out method of polymerase 

chain reaction (PCR)-based synthesis to generate 

codon-optimized human kinase genes 

(T. Harris). 

• VegT, a T-box transcription factor, is essential 

for three important steps in development (M. 

L. King). 

• Glycolytic inhibitors can be used to specifically 

target the hypoxic slow-growing cells of solid 

tumors and thereby increase the efficacy of current 

chemotherapeutic and irradiation protocols 

designed to kill rapidly dividing cells (T. 

Lampidis). 

• In osteosarcoma, the addition of the glycolytic 

inhibitor 2-Deoxyglucose (2-DG) increases the 

efficacy of Adriamycin in reducing tumor size 

and prolonging survival (T. Lampidis). 

• In non-small cell lung cancer, the addition of 2- 

DG increases the effectiveness of taxol (T. 

Lampidis). 

• Microvascular endothelial cells produce two 

extracellular matrix proteins, laminin-8 and 

laminin-10, which play important roles in tumor 

angiogenesis (J. Li). 

• Discovery of an imbalance between the levels of 

matrix metalloproteinases (MMPs) (overproduction) 


in invasive prostate cancer cells (B. 

Lokeshwar). 

• Identification of a novel chemically modified 

non-antimicrobial tetracycline (COL-3) as an 

effective anti-metastatic drug with the potential 

to treat prostate cancer metastatic to bone; 

completion of NCI phase I trial of this drug (B. 

Lokeshwar). 

• Development of the HA-HAase urine test, a 

non-invasive test that is about 90 percent accurate 

in detecting bladder cancer and monitoring 

its recurrence (V. Lokeshwar). 

• Development of HA and HAase tests that are 

greater than 85 percent accurate prognostic 

indicators for prostate cancer (V. Lokeshwar). 

• Demonstration of the function of tumor-derived 

HAase in bladder tumor growth and 

muscle invasion (V. Lokeshwar). 

• Splicing activator RNPS1 is incorporated in the 

early splicing complex, stimulating formation of 

the ATP-dependent splicing complex, and subsequently 

increasing generation of both intermediate 

and final spliced products (A. Mayeda). 

• Cells with defective mitochondrial respiration 

can be more resistant to cell death, which might 

explain the presence of mtDNA mutations in 

some cancers (C. Moraes). 

• Mitochondrial defects stimulate the production 

of metalloproteases, which in turn promotes 

tissue invasion (C. Moraes). 

• Up-regulation of ErbB2 ligand Muc4 expression 

correlates with the overexpression of transcription 

factor PEA3 and the receptor tyrosine 

kinase ErbB2 (A. Perez). 

• Observation of the attachment of centrosomes 

to intermediate filaments (P. Salas). 

• Nerve growth factor (NGF) mediates the invasiveness 

of melanoma cells in vitro by inducing 

the coupling of the intracellular domain of the 

p75 neurotrophin receptor with the actin cytoskeleton 

(O. Shonukan). 

• Neurotrophin-induced melanoma invasiveness 

is mediated by signals generated through PI-3 

kinase (O. Shonukan). 

• NGF induces the disruption of cadherin-mediated 

cell-cell adhesion, thereby permitting melanoma 

cells to dissociate from the keratinocytes 

in the epidermis, and invade the dermis, from 

whence they metastasize to distant sites (O. 

Shonukan). 

• Aberrant p27 in breast cancer cells causes them 

to be unable to respond to antiestrogen therapies 

such as Tamoxifen (J. Slingerland). 

• Activation of the Src pathway is linked with 

both the lack of detectable estrogen receptor 

(ER) and clinically aggressive behavior of breast 

cancers (J. Slingerland). 



• Discovery of estrogen regulation of the gap 

junction protein connexin 43 via an internal 

ribosome entry site for translation (R. Werner). 

• Discovery of the requirement for Rho family 

GTPases for key adhesion-dependent G1 

events, including cyclin D1 expression, Rb 

phosphorylation, and cyclin A expression (C. 

Welsh). 

KERRY L. BURNSTEIN, PH.D. 

Professor of Molecular and Cellular 

Pharmacology 


Dr. Burnstein’s research focuses on signaling 

mechanisms that govern prostate cancer cell 

cycle and androgen responsiveness. Vitamin D is 

of particular interest, stemming from epidemiological 

data showing a relationship between vitamin 

D deficiency and increased risk of prostate 

cancer mortality. It has been shown that vitamin 

D inhibits the growth of prostate cancer cell lines 

and primary cell cultures derived from human 

prostate tumors. Researchers in Dr. Burnstein’s 

laboratory found that the mechanism underlying 

such growth arrest is a vitamin D-induced cellular 

accumulation in the initial phase of the cell 

cycle, G1. They demonstrated that vitamin D- 

mediated antiproliferative effects are not dependent 

on androgen/AR. This finding is of clinical 

relevance, as a requirement for androgen would 

severely limit use of vitamin D in advanced prostate 

cancer, which is customarily treated by androgen 

ablation. Furthermore, Dr. Burnstein’s 

laboratory showed that vitamin D causes upregulation 

of specific and potent cell cycle inhibitors, 

p21 and p27, a finding that has potentially 

important therapeutic implications. Her laboratory 

recently made the novel discovery that vitamin 

D mediates the nuclear exclusion of cyclin 

dependent kinase (cdk)-2, thereby decreasing its 

activity and promoting p27 stability. Current efforts 

are directed at understanding vitamin D 

regulation of cdk-2 nucleocytoplasmic trafficking. 

A finding that emerged from the studies on 

vitamin D was that the most highly malignant 

prostate cancer cell lines expressed very low levels 

of cdk inhibitors. Subsequent studies on human 

prostate cancer biopsies confirmed this observation. 

Because of these findings and the fact that 

the genes encoding these inhibitors are rarely mutated, 

Dr. Burnstein decided to investigate possible 

intracellular signaling alterations that might 

suppress levels of these inhibitory proteins and 

contribute to uncontrolled cell proliferation. In 

collaboration with Catherine F. Welsh, M.D., she 

made the novel observation that Rac1, a Ras-related 

Rho GTPase (small G protein), exhibits 

high activity in the more malignant prostate 

cancer cells. Specific inhibition of Rac1 in these 

cells results in increased levels of the cdk inhibitor 

p21 and decreased proliferation. These findings 

are unique in describing a role for Rac1 in the 

regulation of p21 and implicate the Rac1 signaling 

pathway as a therapeutic target. Recently, researchers 

found that a protein that activates Rac1 

also enhances the transcriptional activity 

of the androgen receptor (AR). This observation 

provides a tantalizing link between two critical 

signaling pathways in prostate cancer and suggests 

a plausible mechanism for AR activity 

during progression to androgen independence. 


2002 


and Burnstein, KL . Vitamin D-mediated growth 



and Cellular Endocrinology 186:69-79, 2002. 


Flanagan, JN, Burnstein, KL , Lokeshwar, BL, 





and Molecular Biology 81:135-40, 2002. 

68 



2003 

Kizu, R, Okamura, K, Toriba, A, Kakishima, H, 

Mizokami, A, Burnstein, KL , and Hayakawa, K. 

A role of aryl hydrocarbon receptor in the 

antiandrogenic effects of polycyclic aromatic hydrocarbons 

in LNCaP human prostate carcinoma 

cells. Archives of Toxicology 77:335-43, 2003. 

Yang, E and Burnstein, KL . Vitamin D inhibits 

G1 to S progression in LNCaP prostate cancer 

cells through p27Kip1 stabilization and Cdk2 

mislocalization to the cytoplasm. Journal of Biological 

Chemistry 278:46862-68, 2003. 

Chen, TC, Holick, MF, Lokeshwar, BL, 

Burnstein, KL , and Schwartz, GG. Evaluation of 



164:273-88, 2003. 

Kizu, R, Okamura, K, Toriba, A, Mizokami, A, 

Burnstein, KL , Klinge, CM, and Hayakawa, K. 

Antiandrogenic activities of diesel exhaust particle 

extracts in PC3/AR human prostate carcinoma 

cells. Toxicology Sciences 76:299-309, 2003. 


• Vitamin D inhibits the cell cycle by promoting 

nuclear exclusion of cdk-2, which opens up new 

avenues for prostate cancer therapy. Further, 

regulation of cdk-2 localization represents a 

new regulatory paradigm in G1 to S phase 

progression. 

KERMIT L. CARRAWAY, PH.D. 



For much of the past decade, Dr. Carraway’s 

primary research effort has been to examine 

the role of cell surface glycoproteins in mammary 

cancer, focusing on a particular glycoprotein 

complex (sialomucin complex, MUC4, rat 

Muc4) that his laboratory discovered about 20 

years ago. This complex has both mucin- and 

growth factor-containing subunits. This putative 

bi-functionality can potentially contribute to two 

of the major attributes of cancer cells, loss of adhesiveness, 

and autonomous growth. Consistent 

with both of those activities, MUC4 has been 

implicated in tumor metastasis. The anti-adhesive 

function of MUC4 allows it to block tumor cell 

killing by lymphokine-activated killer (LAK) 

cells, a mechanism that permits the MUC4-overexpressing 

tumor cells to escape immune surveillance. 

One of the two growth factor domains of 

the transmembrane subunit of MUC4 has been 

shown to act as an intramembrane ligand for the 

class I tyrosine kinase growth factor receptor 

ErbB2/HER2/Neu. Binding of MUC4 as a 

ligand to ErbB2 potentiates tyrosine phosphorylation 

of the receptor and its co-receptor ErbB3, 

when the latter is stimulated with its soluble 

ligand Neuregulin. 

Researchers in Dr. Carraway’s laboratory are 

currently investigating the effects of this receptor 

modulation on downstream signaling pathways 

and cellular functions. Recently, they have found 

that induction of MUC4 overexpression in a 

melanoma tumor cell model potentiates both primary 

tumor growth and metastasis when the tumors 

are injected into nude mice. The former is 

correlated with a reduction in apoptosis in the 

MUC4-overexpressing animals. One important 

question is whether the anti-apoptotic effects of 

MUC4 result from its growth factor domains or 

other features of its structure. Recent results have 

shown that MUC4 can regulate both the phosphorylation 

and location of ErbB2 in polarized 



epithelial cells, providing two mechanisms by 

which it can regulate signaling. Since MUC4 has 

been implicated in breast cancer progression, it is 

of interest to know how it is regulated in the 

mammary gland. Investigations of primary mammary 

epithelial cells indicate a major role for 

post-transcriptional regulation. Interactions with 

the extracellular matrix regulate MUC4 expression 

at the translational level, while transforming 

growth factor-beta (TGF-β) regulates it at the 

post-translational level. Both of these types of 

regulation are lost in rat mammary tumor cells, 

and both are known to change during human 

breast cancer progression. These and other results 

suggest that MUC4 acts as a “tumor progressor” 

gene rather than a primary oncogene. Thus, 

MUC4 might serve as a future target for prognosis 

and therapies in breast cancer. 


2002 

Carraway, KL , Perez, A, Idris, N, Jepson, S, 

Arango, M, Komatsu, M, Haq, B, Price-Schiavi, 

SA, Zhang, J, and Carraway, CA. Muc4/ 

sialomucin complex, the intramembrane ErbB2 

ligand, in cancer and epithelia: to protect and to 

survive. Progress in Nucleic Acid Research in Molecular 

Biology 71:149-85, 2002. 

Swan, JS, Arango, ME, Carothers Carraway, CA, 

and Carraway, KL . An ErbB2-Muc4 complex in 

rat ocular surface epithelia. Current Eye Research 

24:397-402, 2002. 

Jepson, S, Komatsu, M, Haq, B, Arango, ME, 

Huang, D, Carraway, CA, and Carraway, KL . 

Muc4/sialomucin complex, the intramembrane 

ErbB2 ligand, induces specific phosphorylation 

of ErbB2 and enhances expression of p27 (kip), 

but does not activate mitogen-activated kinase or 

protein kinase B/Akt pathways. Oncogene 

21:7524-32, 2002. 

Komatsu, M, Arango, ME, and Carraway, KL . 

Synthesis and secretion of Muc4/sialomucin 

complex: implication of intracellular proteolysis. 

Biochemical Journal 368:41-48, 2002. 

2003 

Ramsauer, VP, Carothers Carraway, CA, Salas, PJ, 

and Carraway, KL . Muc4/Sialomucin complex, 

the intramembrane ErbB2 ligand, translocates 

ErbB2 to the apical surface in polarized Epithelial 

cells. Journal of Biological Chemistry 278:30142- 

47, 2003. 

Carraway, KL , Ramsauer, VP, Haq, B, and 

Carothers Carraway, CA. Cell signaling through 

membrane mucins. BioEssays 25:66-71, 2003. 

Fischer, BM, Cuellar, JG, Diehl, ML, deFreytas, 

AM, Zhang, J, Carraway, KL , and Voynow, JA. 

Neutrophil elastase increases MUC4 expression 

in normal human bronchial epithelial cells. 

American Journal of Physiology. Lung Cellular 

and Molecular Physiology 284:L671-79, 2003. 

Hu, YP, Haq, B, Carraway, KL , Savaraj, N, and 






Soto, P, Price-Schiavi, SA, and Carraway, KL . 

SMAD2 and SMAD7 involvement in the posttranslational 

regulation of Muc4 via the transforming 

growth factor-beta and interferon-gamma 

pathways in rat mammary epithelial cells. Journal 

of Biological Chemistry 278:20338-44, 2003. 

Perez, A, Barco, R, Fernandez, I, Price-Schiavi, 

SA, and Carraway, KL . PEA3 transactivates the 

Muc4/sialomucin complex promoter in mammary 

epithelial and tumor cells. Journal of Biological 

Chemistry 278(38):36942-52, 2003. 


• MUC4 expression potentiates the phosphorylation/activation 

of the ErbB2 and ErbB3 tyrosine 

kinase receptors induced by neuregulin, 

providing a mechanism by which MUC4 may 

contribute to tumor progression through 

changes in cell signaling pathways. 

70 



• MUC4 in the mammary gland is regulated at 

the post-transcriptional level by extracellular 

matrix (basement membrane) and by TGF-β. 

Responses to both of these are known to change 

during breast cancer progression. 

• MUC4 regulation in the uterus during pregnancy 

is at the transcript level, indicating the 

complexity of the control of its gene. 

• MUC4 overexpression increases primary tumor 

growth in nude mice, acting as an antiapoptotic 

agent in the growing tumors and in 

cell culture. 

• MUC4 regulates the localization of the receptor 

tyrosine kinase ErbB2 in polarized epithelial 

cells. 

MURRAY P. DEUTSCHER, PH.D. 

Professor and Chairman of Biochemistry 

and Molecular Biology 


Researchers in Dr. Deutscher’s laboratory 

focus on two major areas of research. One 

deals with the identification, characterization, 

and determination of the physiological role of 

RNA processing and degradative enzymes. To 

date, eight exoribonucleases and seven endo-ribonucleases 

have been identified in Escheichia coli. 

Many of the enzymes have been purified and 

studied for their catalytic properties. Mutations 

have been constructed in the genes for each of 

these enzymes, and the genes have been cloned 

and their sequences identified. Several of these 

enzymes have now been shown to participate in 

transfer RNA and ribosomal RNA maturation, 

and in messenger RNA degradation. The availability 

of the purified enzymes and of mutants 

lacking these RNases is being used to elucidate 

complete RNA maturation pathways and to 

study the regulation of these processes. In addition, 

his studies have shown that cells contain 

RNA quality control mechanisms for eliminating 

defective RNA molecules. 

The second area of investigation deals with 

the translation system of mammalian cells. Protein 

synthesis in mammalian cells proceeds as 

much as 100-fold faster than synthesis in isolated 

cell-free systems. What is lost in these in vitro 

systems is the organization that normally exists in 

vivo. They have shown that many of the components 

of the translation apparatus are associated 

with each other, and that protein synthesis is a 

“channeled” pathway, i.e., the aminoacyl-tRNA 

and peptidyl-tRNA intermediates are directly 

transferred from one component of the translation 

apparatus to the next without dissociation 

into the cellular fluid. A permeabilized mammalian 

cell system has been developed that allows 

study of these events in close to an in vivo situation. 

Studies are in progress to determine the role 

of the actin cytoskeleton in maintaining the organization 

of the translation system and to identify 

other factors associated with the translation apparatus 

that affect its function. Dr. Deutscher’s 

laboratory has taken this work further to show 

that the whole mammalian cell is highly organized 

and that macromolecules don’t diffuse, but move 

in motor-driven processes on the cytoskeleton. 


2002 

Li, Z and Deutscher, MP . RNase E plays an essential 

role in the maturation of Escherichia coli 

tRNA precursors. RNA 8:97-109, 2002. 

Li, Z, Reimers, S, Pandit, S, and Deutscher, MP . 

RNA quality control: degradation of defective 

transfer RNA. EMBO Journal 21:1132-38, 2002. 

Cheng, ZF and Deutscher, MP . Purification and 

characterization of the Escherichia coli 

exoribonuclease RNase R. Comparison with 

RNase II. Journal of Biological Chemistry 

277:21624-29, 2002. 

Zuo, Y and Deutscher, MP . The physiological 

role of RNase T can be explained by its unusual 

substrate specificity. Journal of Biological Chemistry 

277:29654-61, 2002. 



Zuo, Y and Deutscher, MP . Mechanism of action 

of RNase T. I. Identification of residues required 

for catalysis, substrate binding, and dimerization. 


2002. 


of RNase T. II. A structural and functional model 

of the enzyme. Journal of Biological Chemistry 

277:50160-64, 2002. 

2003 

Nathanson, L, Xia, T, and Deutscher, MP . 

Nuclear protein synthesis: a re-evaluation. RNA 

9:9-13, 2003. 

Cheng, ZF and Deutscher, MP . Quality control of 

ribosomal RNA mediated by polynucleotide phosphorylase 

and RNase R. Proceedings of the National 

Academy of Sciences of the United States of 

America 100:6388-93, 2003. 

Deutscher, MP . Degradation of stable RNA in 

bacteria. Journal of Biological Chemistry 

278:45041-44, 2003. 

Hudder, A, Nathanson, L, and Deutscher, MP . 

Organization of mammalian cytoplasm. Molecular 

and Cellular Biology 23:9318-26, 2003. 


• Discovery of a new endoribonuclease, which 

has been called RNase G. This enzyme was 

shown to be essential for the maturation of the 

5’ terminus of E. coli 16S ribosomal RNA as 

part of a two-step process that also requires a 

second endoribonuclease, RNase E. Researchers 

have also identified RNase T as the enzyme that 

matures the 3’ terminus of 23S ribosomal 

RNA. Degradation of messenger RNA also was 

studied. They found that the enzyme 

oligoribonuclease is an essential component of 

this process, and that in its absence, small 

oligoribonucleotides derived from mRNA accumulate. 

They also have introduced the concept 

of quality control of stable RNA molecules. 

72 

• Development of an efficient, cell-free translation 

system that synthesizes protein at about 30 

percent of the in vivo rate. This compares with 

the one to two percent generally obtained in 

other systems. Development of this system depended 

on stabilization of the actin cytoskeleton 

during cell disruption. In a second study, 

they found that aminoacyl-tRNA synthetases 

are present in an active form in mammalian cell 

nuclei, and that these enzymes exist as part of a 

multi-enzyme complex that is analogous to, but 

more stable than, the cytoplasmic complex. 

Moreover, Dr. Deutscher’s laboratory has made 

the important discovery that mammalian cells 

are highly organized and behave like macromolecular 

assemblies. 

GENNARO D’URSO, PH.D. 

Assistant Professor of Molecular and 

Cellular Pharmacology 


Understanding the molecular mechanisms that 

control the initiation of DNA replication in 

eukaryotic cells is Dr. D’Urso’s main research interest. 

Researchers in his laboratory also are 

studying the checkpoint controls that prevent 

mitosis in the absence of a complete round of 

DNA synthesis or in response to DNA damage. 

Using the fission yeast Schizosaccharomyces pombe 

as a model system, they have identified genes that 

are required for DNA replication initiation. Most 

of the laboratory’s work has focused on the characterization 

of the genes encoding the catalytic 

subunit of DNA polymerase epsilon (Pol ε) and 

its associated subunits. Cells defective for Pol ε 

arrest at the G1/S boundary, indicating that this 

enzyme plays a critical role in the initiation step. 

Interestingly, the polymerization activity of this 

enzyme is not essential for cell viability, suggesting 

that Pol ε may have other roles, perhaps in 

the assembly of the replicative complex, that are 

not necessarily dependent on its ability to synthesize 

DNA. Studies in this laboratory on Pol ε 

have led to the discovery of a checkpoint control 



that is activated in response to defects in DNA 

replication initiation. The laboratory currently is 

continuing efforts to identify proteins that are 

involved in the early steps of DNA synthesis and 

how these proteins may be involved in the activation 

of a checkpoint pathway that prevents premature 

entry into mitosis. 


2003 

Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F. 

Control of cell polarity in fission yeast by association 

of Orb6p kinase with the highly conserved 

protein methyltransferase Skb1p. Journal of Biological 

Chemistry 278:25256-63, 2003. 

Feng, W, Rodriguez-Menocal, L, Tolun, G, and 

D’Urso, G. Schizosacchromyces pombe Dpb2 

binds to origin DNA early in S phase and is 

required for chromosomal DNA replication. 

Molecular Biology of the Cell 14:3427-36, 2003. 

Burhans, WC, Weinberger, J, Marchetti, MA, 

Ramachandran, L, D’Urso, G, and Huberman, J. 

Apoptosis-like yeast cell death in response to 

DNA damage and replication defects. Mutation 

Research 532:227-43, 2003. 


• Pol ε is required for initiation of DNA replication. 

These results were particularly important 

because Pol ε had earlier been shown to be nonessential 

for SV40 viral DNA replication, an 

extensively used model system of eukaryotic 

DNA replication. 

• Loss of the catalytic domains of this enzyme 

had no effect on cell viability in yeast. 

• These findings and observations led to an understanding 

of the role of Pol ε in DNA replication, 

and suggested that Pol ε provides multiple 

functions in promoting DNA replication. Recent 

data from this laboratory suggest that at 

least one of these functions is to facilitate assembly 

of the DNA replication initiation complex. 

TERACE M. FLETCHER, PH.D. 

Assistant Professor of Biochemistry 



Dr. Fletcher’s research interests focus on chromatin 

structure and steroid hormone regulation of 

transcription, telomere chromatin structure and 

genomic stability, telomerase biochemistry, and 

mechanisms of inhibition. 

The eukaryotic genome is organized into 

complex DNA-protein macromolecular assemblies 

known as chromatin. Chromatin has both 

an architectural and regulatory function in the 

nucleus. Dr. Fletcher’s laboratory efforts are concentrated 

in two processes influenced by chromatin 

structure: telomere maintenance and 

transcription. 

Telomere Chromatin Structure 

Telomeres, specialized nucleoprotein complexes 

at the end of chromosomes, have a crucial role in 

genomic stability. Disruption of telomere structure 

induces cell growth arrest or death. Cancer 

cells, unlike most normal somatic cells, maintain 

stable telomeres through the activation of the telomere-specific 

DNA polymerase, telomerase. 

Dr. Fletcher is particularly interested in the 

structural features of telomere higher-order assemblies 

and the mechanisms by which different 

telomere configurations are formed. Possible influences 

on telomere structure are telomerase activity, 

telomere length, association of telomere 

binding and DNA repair proteins, and DNA 

structure. 

To structurally and biochemically characterize 

telomere chromatin, Dr. Fletcher’s laboratory 

is reconstituting model telomeres in vitro. They 

use these model telomeres to determine recruitment 

of telomere binding and DNA repair proteins 

under certain conditions. They also are 

interested in the effects of telomere structure on 

functions such as telomerase activity and chromosome 

end protection. 



Finally, researchers in her laboratory are investigating 

the biochemical and hydrodynamic 

properties of telomere higher-order structures. 

One hydrodynamic method they will focus on is 

a unique agarose gel electrophoresis technique. 

This technique allows the investigator to analyze 

surface electrical charge density and solution 

structure of large macromolecular DNA/protein 

assemblies from either purified components or in 

complex mixtures. Dr. Fletcher and her colleagues 

are applying this technique to study the 

structure of native telomeres isolated from nuclei. 

Chromatin Structure and Transcription 

It is well established that the same promoter 

sequence in different chromatin contexts has 

diverse responses to cellular signals. The biochemical 

mechanisms by which nucleosomes, the 

fundamental units of chromatin, exert their influence 

are under intense investigation. The role of 

chromatin higher-order structures in transcriptional 

activation, however, is still largely unexplored. 

A goal of Dr. Fletcher’s research is to 

simultaneously analyze the structural characteristics 

of chromatin and transcriptional activation 

under various reaction conditions. 

Specifically, her laboratory is interested in 

the reciprocal relationship between transcription 

factors and their chromatin targets. Research efforts 

include reconstituting promoters and coding 

regions into chromatin in vitro and analyzing 

protein binding, chromatin remodeling, and 

transcriptional activation. Dr. Fletcher and her 

colleagues also are characterizing the solution 

structure of these chromatin fibers, both reconstituted 

in vitro and isolated from cells. 


2002 

Fletcher, TM, Xiao, N, Mautino, G, Baumann, 

CT, Wolford, R, Warren, BS, and Hager, GL. 

ATP-dependent mobilization of the glucocorticoid 

receptor during chromatin remodeling. Molecular 


Lu, H, Pise-Masison, CA, Fletcher, TM, Schiltz, 

RL, Nagaich, AK, Radonovich, M, Hager, G, 

Cole, PA, and Brady, JN. Acetylation of nucleosomal 

histones by p300 facilitates transcription 

from tax-responsive human T-cell leukemia virus 

type 1 chromatin template. Molecular and Cellular 

Biology 22:4450-62, 2002. 

Keeton, EK, Fletcher, TM, Baumann, CT, 

Hager, GL, and Smith, CL. Glucocorticoid receptor 

domain requirements for chromatin remodeling 

and transcriptional activation of the 

mouse mammary tumor virus promoter in different 

nucleoprotein contexts. Journal of Biological 

Chemistry 277:28247-55, 2002. 

2003 

Georgel, PT, Fletcher, TM, Hager, GL, and 

Hansen, JC. Formation of higher-order secondary 

and tertiary chromatin structures by genomic 

mouse mammary tumor virus promoters. Genes 

& Development 17:1617-29, 2003. 

Fletcher, TM. Telomere higher-order structure 

and genomic instability. IUBMB Life 55:443-49, 

2003. 


• Obtained patent for methods and compositions 

for modulation and inhibition of telomerase. 

74 



ELIZABETH J. FRANZMANN, M.D. 

Assistant Professor of Otolaryngology 


Dr. Franzmann is interested in the molecular 

mechanisms of head and neck squamous cell 

cancer (HNSCC) progression. Despite rigorous 

therapy using various combinations of surgery, 

radiation, and chemotherapy, successful treatment 

of head and neck cancer only occurs 50 

percent of the time. Because of the complexity of 

the head and neck, current therapy often results 

in facial disfigurement, speech and swallowing 

problems, and substantial health care costs. 

Screening and staging methods for HNSCC also 

are deficient. 

To better understand the molecular mechanisms 

that lead to HNSCC, Dr. Franzmann’s 

laboratory is investigating the CD44 family of 

alternatively spliced isoforms. Some CD44 

isoforms are found normally in cells. Other 

isoforms termed CD44 variant (CD44v) isoforms 

are found in tumor tissues and are associated with 

poor prognosis. There is particular interest in the 

CD44v3-containing isoforms since these 

isoforms contain a growth factor binding site. 

Preliminary work suggests that CD44v3-containing 

isoforms are differentially expressed in 

HNSCC tumors and normal tissue and may be 

involved in tumor cell growth. Using reverse 

transcriptase-polymerase chain reaction (RT- 

PCR), southern blot, cloning, and sequencing, 

the laboratory is defining CD44v3-containing 

isoform expression in head and neck tumor and 

normal tissues. The laboratory will perform immunohistochemical 

staining to characterize 

CD44v3 expression at the protein level. Transfection 

studies will be used to investigate the mechanisms 

by which these isoforms alter HNSCC cell 

behavior. In addition to identifying HNSCC in 

the early stage when treatment is much more effective, 

Dr. Franzmann’s laboratory is evaluating 

whether a salivary CD44 ELISA test is a useful 

screening tool for HNSCC. 


2003 





International Journal of Cancer 106:438-45, 2003. 


• CD44v3-containing isoforms are found in 

HNSCC tumor tissues and cell lines using RT- 

PCR. CD44v3 and CD44v3-10 have been 

cloned and sequenced from HNSCC cell lines. 

• In a preliminary study including 26 patients 

with HNSCC and ten normal controls, CD44 

levels were significantly higher in HNSCC patient 

saliva compared to normal volunteer saliva. 

ZHIYONG HAN, PH.D. 

Assistant Professor of Biology 


Dr. Han’s research seeks to understand how 

anti-cancer drugs induce apoptosis of cancer 

cells. His recent work focuses on how the natural 

product camptothecin (CPT) and its semi-synthetic 

derivatives such as CPT-11, 9-amino-CPT 

(9AC), and 9-nitro-CPT (9NC) induce apoptosis 

of human colon cancer cells. 

CPT and its derivatives are considered important 

anti-cancer drugs. Many aspects of the 

mechanism by which these drugs exert their 

death effect on cancer cells, however, remain 

largely unknown. In recent years, Dr. Han and 

his colleagues have used a cell model of human 

colon cancer to demonstrate that treatment with 

low doses of CPT induces senescence in the presence 

of a protein called p21, but apoptosis in the 

absence of p21. Therefore, p21 is a key determinant 

of the outcome of colon cancer cells treated 

with CPT drugs at doses that are relevant to 

clinical application. CPT treatment of colon cancer 

cells with p21 should result in disease stabili- 



zation, whereas CPT treatment of p21-deficient 

colon cancer cells should result in rapid apoptosis 

and disease regression. 

It is well established that p21 inhibits cyclindependent 

kinases (cdks) and several other factors 

including proliferating cell nuclear antigen. Dr. 

Han and his colleagues hypothesize that inhibition 

of cdks by p21 is essential to inhibit 

apoptosis and induce senescence. In this context, 

they propose that the protein, named E2F1, is 

essential for apoptosis of colon cancer cells 

treated with CPT. According to this hypothesis, 

inhibition of cdks should result in activation of 

another protein, named retinoblastoma (Rb), 

which in turn, inhibits E2F1 and consequentially 

E2F1-dependent apoptosis. They also hypothesize 

that the ability of p21 to induce senescence 

requires a protein called STAT1. To test their hypothesis, 

they are currently using techniques to 

selectively alter the status of a cdk, E2F1, Rb, and 

STAT1 in human colon cancer cells. Subsequently, 

Dr. Han’s laboratory will investigate the 

role of each protein in the process of apoptosis 

and senescence in the colon cancer cells after 

CPT treatment. 

The information obtained from these investigations 

will provide better insight into the molecular 

pathways activated in colon cancer cells 

after CPT treatment and eventually lead to specific 

experimental designs to completely understand 

how CPTs affect colon cancer. 


2002 

Han, Z, Wei, W, Dunaway, S, Darnowski, JW, 

Calabresi, P, Sedivy, J, Hendrickson, EA, Balan, 

KV, Pantazis, P, and Wyche, JH. Role of p21 in 

apoptosis and senescence of human colon cancer 

cells treated with camptothecin. Journal of Biological 

Chemistry 277(19):17154-60, 2002. 

2003 

Hu, X, Han, Z, Wyche, JH, and Hendrickson, 

EA. Helix 6 of tBid is necessary but not sufficient 

for mitochondrial binding activity. Apoptosis 

8:277-89, 2003. 

Pantazis, P, Han, Z, Balan, K, Wang, Y, 

and Wyche, JH. Camptothecin and 9- 

nitrocamptothecin (9NC) and anti-cancer, 

anti-HIV, and cell-differentiation agents. 

Development of resistance, enhancement of 

9NC-induced activities and combination treatments 

in cell and animal models. Anticancer 

Research 23:3623-38, 2003. 

Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche, 

JH, Han, Z, and Pantazis, P. Differential susceptibility 

to 9-nitrocamptothecin (9-NC)-induced 

apoptosis in clones derived from a human ovarian 

cancer cell line: possible implications in the treatment 

of ovarian cancer patients with 9-NC. Anticancer 

Drugs 14:427-36, 2003. 

THOMAS K. HARRIS, PH.D. 




Dr. Harris’ research seeks to understand the 

structure and mechanism of both 

phosphoinositide-dependent protein kinase 

(PDK1) and protein kinase B (PKB/Akt), which 

are important in maintaining the growth, survival, 

and proliferation of numerous types of cancer 

cells. PDK1 and PKB/Akt are pivotal 

signaling enzymes and are activated by growthfactor 

binding events to receptor tyrosine kinases, 

which activate phosphatidylinositol 3-kinase (PI3K) 

and result in generation of the membrane-bound 

second messenger phosphatidylinositol 3,4,5- 

triphosphate. Activation of PDK1 and PKB/Akt 

is facilitated by recruitment of each of these 

proto-oncogenic enzymes to the membranebound 

second messenger, which binds the 

pleckstrin homology (PH) domain present in 

each of these kinases. The specific goals are to 

1) determine the structural bases of specificity 

for membrane targeting mediated by the PH 

domains of human PDK1 and PKB/Akt, and 

2) determine how binding of the PH domains to 

76 



the membrane-bound second messenger leads to 

the catalytic activation of their respective kinase 

domains. 

A combination of high-resolution heteronuclear 

multidimensional nuclear magnetic resonance 

(NMR) methods, nuclear Overhauser 

effects, and nuclear relaxation rates will be used 

to determine the effects that Ins(1,3,4,5)P 4 

binding 

has on the solution structures and dynamics 

of the bacterially expressed recombinant 15 N- and 

13 

C-isotopically labeled PH domain constructs of 

both human PDK1 and PKB/Akt. In addition, 

the recombinant 15 N-isotopically labeled PH domain 

constructs of both PDK1 and PKB/Akt will 

be spliced with their corresponding bacterially 

expressed recombinant unlabeled kinase domains 

to determine the effects that Ins(1,3,4,5)P 4 

binding 

to the PH domain has on the conformations, 

dynamics, and position of the PH domain with 

respect to the corresponding kinase domain. 

Finally, the modes of activation of PDK1 

and PKB/Akt will be elucidated by measuring the 

effects of Ins(1,3,4,5)P 4 

binding to the PH domains 

on the equilibrium and activation free energies 

associated with binding of nucleotide, 

metal, or protein substrates, conformational 

changes, and covalent catalysis. Such structural 

and mechanistic understanding will be useful in 

the rational design of potent and selective inhibitors 

by “linking” the free energies of binding of 

substrate analogs with analogs of the inositol polar 

head group of the phospholipid second messenger. 


2002 

Harris, TK and Turner, GJ. Structural basis of 

perturbed pKa values of catalytic groups in enzyme 

active sites. IUBMB Life 53:85-98, 2002. 

2003 

Harris, TK . PDK1 and PKB/Akt: ideal targets 

for development of new strategies to structurebased 

drug design. IUBMB Life 55:117-26, 

2003. 

Gao, X, Yo, P, Keith, A, Ragan, TJ, and Harris, 

TK. Thermodynamically balanced inside-out 

(TBIO) PCR-based gene synthesis: a novel 

method of primer design for high-fidelity assembly 

of longer gene sequences. Nucleic Acids Research 

31:e143, 2003. 


• Designed and synthesized codon-optimized 

genes and gene constructs for PDK1 and PKB/ 

Akt in order to optimize production of 15 N- 

and 13 C-isotopically labeled human PDK1 and 

PKB/Akt necessary for NMR structural and 

dynamical studies, which facilitate high-level 

protein production in bacteria. Researchers developed 

a novel thermodynamically balanced 

inside-out (TBIO) method of polymerase chain 

reaction (PCR)-based synthesis to generate the 

codon-optimized human kinase genes. 

• Filed a U.S. Patent and Trademark Office provisional 

patent application for the TBIO method 

on August 28, 2003. 

MARY LOU KING, PH.D. 



Dr. King is trying to understand how spatial 

patterning and cell fate is determined in the 

early Xenopus embryo. Researchers in her laboratory 

and others in the field have shown that the 

first step in patterning the embryo appears to be 

the localization of specific mRNAs to the vegetal 

cortex during oogenesis. These maternal mRNAs 

are subsequently inherited by a subset of cells in 

the embryo. Evidence indicates that the proteins 

encoded by localized mRNAs influence gene expression 

in a region-specific manner, leading to 

cellular diversification. They are actively pursuing 

the mechanism through which the spatial distribution 

of mRNAs is established and maintained. 

Dr. King’s laboratory has isolated seven localized 

mRNAs from Xenopus oocytes. Remarkably, 

three RNAs, Xcat-2 (related to nanos), Xdazl (in 



DAZ family), and DeadSouth (in vasa family), are 

localized to germ plasm and are related to germ 

cell components in Drosophila and humans. All 

three of these RNAs encode RNA-binding proteins. 

The laboratory is interested in identifying 

the downstream targets of these germ cell components 

and their function in development. Most 

recently they have shown that interfering with 

Xdazl function eliminates or depletes primordial 

germ cells (PGCs) because these fail to migrate 

out of the endoderm. Another mRNA, VegT, encodes 

a T-box transcription factor. Dr. King and 

her colleagues have shown that maternal VegT is 

required for germ layer (endoderm, mesoderm, 

ectoderm) formation during gastrulation and specifically 

for endoderm identity. Experimental approaches 

used in these studies include the creation 

of dominant negatives, antisense oligos, over-expression, 

ectopic expression, frog transgenics, 

transgenics, reverse transcription-polymerase 

chain reaction (RT-PCR), immunocytochemistry, 

and in situ hybridization. A new gene, Xcat4, appears 

to control the cell cycle in early development, as 

over-expression of part of this protein completely 

blocks G1/S transition. 

Dr. King and her colleagues also have found 

that VegT and the germ plasm mRNAs localize by 

at least two different mechanisms and at different 

times during oogenesis. They have determined 

the RNA signal required for proper localization 

of Xcat-2 and VegT and are currently working on 

isolating the proteins that bind these localization 

signals. Their long-term goal is to characterize all 

seven genes as to their role in development as well 

as to characterize the transport systems involved 

in their localization. 


2002 

Kloc, M, Dougherty, MT, Bilinski, S, Chan, AP, 

Brey, E, King, ML, Patrick, CW Jr., and Etkin, 

LD. Three-dimensional ultrastructural analysis of 

RNA distribution within germinal granules of 

Xenopus. Developmental Biology 241:79-93, 

2002. 

Bubunenko, M, Kress, TL, Vempati, UD, 

Mowry, KL, and King, ML. A consensus RNA 

signal that directs germ layer determinants to the 

vegetal cortex of Xenopus oocytes. Developmental 

Biology 248:82-92, 2002. 

2003 

Zhou, Y, Zhang, J, and King, ML. Xenopus 

ARH couples lipoprotein receptors with the AP-2 

complex in oocytes and embryos and is required 

for vitellogenesis. Journal of Biological Chemistry 

278:44584-92, 2003. 

Bruce, AE, Howley, C, Zhou, Y, Vickers, SL, Silver, 

LM, King, ML, and Ho, RK. The maternally 

expressed zebrafish T-box gene eomesodermin 

regulates organizer formation. Development 

130:5503-17, 2003. 


• Demonstrated for the first time that a germ 

plasm component is required for PGC specification 

in a vertebrate. PGC migration out of 

the endoderm is a critical step in PGC differentiation 

and Xdazl is clearly involved. Dr. King 

and her colleagues want to learn more about 

this pathway and its requirements. They have 

shown that in Xenopus, germ plasm RNAs are 

under translational control and that most of 

them encode RNA binding proteins. 

• Observed that a single maternally expressed 

gene, VegT, appears to control the patterning of 

the Xenopus blastula. The laboratory’s studies on 

maternal VegT, a T-box transcription factor, 

have shown that it is essential for three important 

steps in development. VegT is required for 

endoderm specification, the production, activation, 

or delivery of the mesoderm inducer, and 

for maintaining the boundary between endoderm 

and mesoderm. Their results strongly suggest 

that the major mesoderm-inducing signal is 

a post-transcriptional event in Xenopus. 

78 



THEODORE J. LAMPIDIS, PH.D. 



Dr. Lampidis’ research has evolved from his 

preliminary work on the physiology and 

pharmacology of cultured cardiac cells. A video/ 

electronic-computerized system was developed to 

monitor cardiac cell function in vitro. Using pulsating 

myocardial cells as a model, he focused on 

why the widely used anti-tumor agent, Adriamycin, 

affected the hearts of patients treated with 

this drug. This initial idea led Dr. Lampidis to 

study drug selectivity between certain types of 

tumor and normal cells and the chemical requirements 

of anti-cancer drugs for reduced cardiotoxicity 

and increased tumoricidal potency. 

Dr. Lampidis’ efforts then turned toward 

understanding the mechanisms of drug resistance 

to mitochondrial agents such as rhodamine 123 

and the structure/function requirements of various 

chemotherapeutic agents for recognition by 

p-glycoprotein-mediated multiple drug resistance 

(MDR). Molecular and immunochemical probes 

of MDR and other cellular resistance mechanisms 

(i.e., multi-drug resistance-related protein 

(MRP)), were developed in his laboratory to 

detect and study these phenomena. He and his 

colleagues found that chemical charge and 

lipophilicity play critical roles in determining 

whether anti-cancer drugs are recognized by tumor 

cells expressing these MDR mechanisms. 

As an outcome of their studies on mitochondrial 

agents, the researchers realized that tumor 

cells treated with the uncoupling agent, rhodamine 

123, were strikingly similar to the poorly oxygenated 

cancer cells located at the inner core of solid 

tumors. In both conditions, the cells rely exclusively 

on anaerobic metabolism for survival. 

Moreover, cells in the center of a tumor divide 

more slowly than outer-growing aerobic cells and 

consequently are more resistant to standard chemotherapeutic 

agents, which target the more rapidly 

dividing cells. Thus, by the nature of their 

slow growth, these tumor cells exhibit a form of 

MDR, which contributes significantly to chemotherapy 

failures in the treatment of solid tumors. 

Anaerobiosis, however, also provides a natural 

window of selectivity for agents that interfere 

with glycolysis. This concept forms the basis for 

Dr. Lampidis’ current initiative to exploit the 

natural selectivity that inhibitors of glycolysis 

should have for hypoxic cells that are slowly 

growing at the inner core of solid tumors. His 

background and work on mitochondrial localizing 

drugs and MDR uniquely position him to 

stimulate new initiatives in his laboratory in this 

promising area of research. 

A long-term goal for Dr. Lampidis is the addition 

of the appropriate glycolytic inhibitors 

(which are presently being designed and synthesized) 

to current clinical protocols, which may 

significantly improve the success rate of cancer 

chemotherapy. Moreover, studying how tumor 

cells react to combinations of oxidative phosphorylation 

and glycolytic inhibitors could lead to 

the design of future novel approaches to more 

successfully treat cancer. 


2002 





51, 2002. 

2003 






of Oncology 23:173-9, 2003. 










• In osteosarcoma wild type (wt) cells treated 

with agents that inhibit mitochondrial oxidative 

phosphorylation (OXPHOS) by interacting 

with complexes I, III, and V of the electron 

transport chain in different ways—rhodamine 

123 (Rho-123), rotenone, oligomycin, and antimycin 

A—all of the agents were found to hypersensitize 

wt cells to the glycolytic inhibitors 

2-deoxyglucose (2-DG) and oxamate. 

• In ρ 0 cells that have lost their mitochondrial 

DNA and therefore cannot undergo OXPHOS, 

cells were found to be ten and 4.9 times more 

sensitive to 2-DG and oxamate, respectively, 

than wt cells. 

• Lactic acid levels, which are a measure of 

anaerobic metabolism, were found to be greater 

than 3 times higher in ρ 0 than in wt cells. 

Moreover, when wt cells were treated with Rho- 

123, lactic acid amounts increased as a function 

of increasing Rho-123 doses. Under similar 

Rho-123 treatment, ρ 0 cells did not increase 

their lactic aid levels. These data confirm these 

different cell models are similarly sensitive to 

glycolytic inhibitors due to their dependence on 

anaerobic metabolism. 

• These results suggest that inner core tumor cells 

are more dependent on glycolysis than outer 

growing aerobic cells, which provides a window 

of selectivity that can be exploited for therapeutic 

gain. Thus, glycolytic inhibitors could be 

used to specifically target the hypoxic slowgrowing 

cells of solid tumors and thereby increase 

the efficacy of current chemotherapeutic 

and irradiation protocols designed to kill rapidly 

dividing cells. Moreover, glycolytic inhibitors 

could be particularly useful in combination 

with anti-angiogenic and anti-hypoxic inducible 

factor (HIF) agents, which a priori, should 

make tumors more anaerobic. 

• Recently, Dr. Lampidis has provided proof of 

principle in two animal models of human cancer 

(non-small cell lung and osteosarcoma ) that 

the addition of the glycolytic inhibitor 2-DG 

(which targets the slowly growing hypoxic cells 

of a tumor), increases the efficacy of standard 

chemotherapeutic agents (which target the rapidly 

growing aerobic cells) in reducing tumor 

size and prolonging survival. In collaboration 

with Threshold Pharmaceuticals, the NCI, and 

UM/Sylvester, they have received FDA approval 

and are now nearing the first human trials testing 

his strategy. 

JIE LI, M.D., PH.D. 

Assistant Professor of Dermatology 

and Cutaneous Surgery 


Among the unanswered critical questions in 

cancer research is the mechanism for new 

blood vessel formation during tumor development, 

a process called tumor angiogenesis, which 

is important for both tumor growth and metastasis. 

Angiogenesis is dependent on the production 

and organization of the basement membrane 

zone, a structure underlying endothelial cells in 

blood vessels. Dr. Li’s current research focuses on 

the role of extracellular matrix laminins of major 

basement membrane components in tumor angiogenesis, 

invasion, and metastasis. The longterm 

goal of the study is to determine their 

potential in tumor diagnosis/prognosis and 

therapy. 

Dr. Li’s laboratory uses cellular and molecular 

biological approaches to study the function of 

laminins in the two most common and malignant 

human skin cancers: melanomas and squamous 

cell carcinomas (SCC). She and her 

colleagues have found that microvascular endothelial 

cells produce two laminins, laminin-8 and 

laminin-10. The laboratory has shown that 

laminin-8 has strong effects on human endothelial 

cell attachment, migration, and capillary tubule 

formation. Importantly, they have identified 

a high expression of laminin-10 in human melanomas 

while there is no expression of laminin-10 

in benign nevi. Significantly higher expression of 

laminin-10 also was detected in the basement 

80 



membranes of invasive SCC-masses and newly 

formed tumor vasculature. Strikingly, the studies 

demonstrated an incremental expression pattern 

as tumors progress from pre-malignant skin lesions 

of actinic keratosis to malignant SCC. The 

studies revealed a clear correlation between the 

expression level of laminin-10 and tumor invasiveness, 

which indicates that laminin-10 plays 

important roles in tumor angiogenesis and 

invasion. 

Dr. Li anticipates that her laboratory’s research 

will provide evidence that these two 

laminins play important roles in one or more key 

steps of tumor angiogenesis, including endothelial 

cell attachment, migration, basement membrane 

assembly, and microvascular blood vessel 

formation. She and her colleagues expect to establish 

the roles of laminins in cancer cell migration, 

invasion, and metastasis. These studies are 

expected to have profound implications for the 

development of novel therapies designed to target 

these extracellular matrix components and alter 

the angiogenesis and progression of cancers. 


2002 

Calautti, E, Grossi, M, Mammucari, C, Aoyama, 

Y, Pirro, M, Ono, Y, Li, J, and Dotto, GP. Fyn 

tyrosine kinase is a downstream mediator of Rho/ 

PRK2 function in keratinocyte cell-cell adhesion. 

Journal of Cell Biology 156:137-48, 2002. 

2003 

Li, J, Zhang, YP and Kirsner, RS. Angiogenesis in 

wound repair: angiogenic growth factors and the 

extracellular matrix. Microscopy Research and 

Technique 60:107-14, 2003. 

Vincek, V, Knowles, J, Li, J, and Nassiri, M. Expression 

of p63 mRNA isoforms in normal human 

tissue. Anticancer Research, 23:3945-48, 

2003. 


• Demonstrated that microvascular endothelial 

cells produce two extracellular matrix laminin 

proteins of laminin-8 and laminin-10, and that 

these two laminins play important roles in tumor 

angiogenesis. Angiogenesis is critical to 

tumor growth and metastasis and the aggressive 

behavior of malignant tumors is regulated by 

signals from their extracellular matrix environment. 

• Demonstrated that laminin-8 has strong effects 

on endothelial cell attachment, migration, and 

capillary tubule formation. 

• Identified the high expression of laminin-10 

in human malignant melanomas. Significantly 

higher expression of laminin-10 also was 

detected in the basement membranes of invasive 

SCC mass and newly formed tumor blood 

vessels. 

• Demonstrated an incremental expression pattern 

as tumors progress from pre-malignant 

skin lesions of actinic keratosis to malignant 

SCC. These studies revealed a clear correlation 

between the expression level of laminin-10 and 

SCC invasiveness and indicate that laminin-10 

plays important roles in tumor angiogenesis and 

invasion. 

Li, J, Tzu, J, Chen, Y, Zhang, YP, Nguyen, NT, 

Gao, J, Bradley, M, Keene, DR, Oro, AE, Miner, 

JH, and Marinkovich, MP. Laminin-10 is crucial 

for hair morphogenesis. EMBO Journal 

22(10):2400-10, 2003. 



CHIA-YANG LIU, PH.D. 

Assistant Professor of Ophthalmology 


Dr. Liu’s research focuses on the roles of a 

membrane/soluble glycoprotein complex 

(Muc4/sialomucin complex, SMC), which is a 

major contributing mucin at the ocular surface 

and in the ocular tear film. Two specific aims 

were designed to examine the biological function 

of Muc4/SMC in vivo. The first aim is to generate 

Muc4/SMC knockout (KO) mice to examine 

its loss-of-function. Dr. Liu’s rationale is that 

Muc4/SMC is composed of two subunits derived 

from a single gene: an O-glycosylated mucin subunit 

ASGP-1, which has been implicated in antiadhesion 

phenomena at epithelial cell surfaces, 

and a transmembrane subunit ASGP-2, which is 

N-glycosylated, has two epidermal growth factorlike 

(EGF-like) domains, and has been implicated 

in ErbB2cellular signaling. Immunohistochemical 

analyses have shown that Muc4/SMC is expressed 

only in the cell layers of the superficial half of the 

corneal and conjunctival epithelia. These results 

have led the group to hypothesize that Muc4/ 

SMC acts as an intrinsic differentiation and survival 

factor regulating the behavior of the cells in 

those epithelia through its effects on ErbB2. 

Muc4/SMC KO mice will be created via gene 

targeting. This KO mouse strain can be used to 

examine the biological function of Muc4/SMC 

and can be used as an animal model to investigate 

the pathogenesis of ocular surface disease such as 

dry eye. 

Dr. Liu’s second aim is to generate K14- 

Muc4 transgenic mice to investigate Muc4/SMC 

gain-of-function. His rationale is that a matured 

corneal epithelium contains three types of cells 

organized in five to six layers, which include basal 

cells (one layer), supra-basal cells (two layers), 

and superficial cells (two to three layers). These 

three types of cells are phenotypically distinct in 

terms of their proliferative activity and differentiative 

status. The basal cells are relatively 

proliferative, whereas the superficial cells are 

post-mitotic and become terminally differentiated. 

Since Muc4/SMC is expressed only in the 

cell layers of the superficial half of the corneal 

and conjunctival epithelia and Muc4/SMC can 

induce cellular signaling through ErbB2 receptor, 

it is hypothesized that Muc4/SMC-ErbB2 signaling 

may play an important role in regulating 

corneal epithelial differentiation, apoptosis, and 

desquamation. To test this hypothesis, an epithelial 

basal cell-specific promoter (K14 keratin 

promoter) will be used to drive Muc4/SMC expression 

in the K14-Muc4 transgenic (Tg) mice. 

It is anticipated that in the K14-Muc4 Tg, Muc4/ 

SMC will be aberrantly over-expressed in basal 

corneal epithelium, which in turn will affect the 

corneal epithelium homeostasis. The K14-Muc4 

Tg will allow Dr. Liu and his colleagues to investigate 

the corneal epithelial cell biology. These 

combined studies should help to provide them 

with a more complete picture of the functions 

of Muc4/SMC at the ocular surface as well as 

insights into the roles of this mucin in ocular 

surface diseases and aberrations. 


2002 

Saika, S, Ohnishi, Y, Ooshima, A, Liu, CY, and 

Kao, WW. Epithelial repair roles of extracellular 

matrix. Cornea (2 Suppl 1): S23-S29, 2002. 

Wang, IJ, Carlson, EC, Liu, CY, Kao, CW, Hu, 

FR, and Kao, WW. Cis-regulatory elements of 

the mouse Krt1.12 gene. Molecular Vision 8: 94- 

101, 2002. 

Austin, BA, Coulon, C, Liu, CY, Kao, WW, and 

Rada, JA. Altered collagen fibril formation in the 

sclera of lumican-deficient mice. Investigative 

Ophthalmology & Visual Science 43:1695-1701, 

2002. 

82 



Paradis, H, Liu, CY, Saika, S, Muhamad, A, 

Doetschman, T, Good, W, Nayak, R, Laver, N, 

Kao, C, Kao, WW, and Gendron, R. Tubedown- 

1 in remodeling of the developing vitreal vasculature 

in vivo and regulation of capillary outgrowth 

in vitro. Developmental Biology 249:140-55, 

2002. 

Nikitin, AY, Liu, CY, Flesken-Nikitin, A, Chen, 

CF, Chen, PL, and Lee, WH. Cell lineagespecific 

effects associated with multiple deficiencies 

of tumor susceptibility genes in Msh2 -/- Rb +/- 

mice. Cancer Research 62: 5134-38, 2002. 

2003 

Carlson, EC, Mamiya K, Liu, CY, Gendron, RL, 

Birk, DE, Funderburgh, JL, and Kao, WW. Role 

of 41 Cys in the N-terminal domain of lumican in 

ex vivo collagen fibrillogenesis by cultured corneal 

stromal cells. Biochemical Journal 369:461-68, 

2003. 

Kao, WW and Liu, CY. The use of transgenic 

and knockout mice in the investigation of ocular 

surface cell biology. The Ocular Surface 1:5-19, 

2003. 

Saika, S, Miyamoto, T, Tanaka, S, Tanaka, T, 

Ishida, I, Ohnishi, Y, Ooshima, A, Ishiwata, T, 

Asano, G, Chikama, T, Shiraishi, A, Liu, CY, 

Kao, CW, and Kao, WW. Response of lens epithelial 

cells to injury: role of lumican in epithelial-mesenchymal 

transition. Investigative 


2003. 

Liu, CY, Birk, DE, Hassell, JR, Kane, B, and 

Kao, WW. Keratocan-deficient mice display alterations 

in corneal structure. Journal of Biological 

Chemistry 278:21672-677, 2003. 

Espana, EM, Kawakita, T, Romano, A, 

DiPascuale, M, Smiddy, R, Liu, CY, and 

Tseng, SC. Stromal niche controls the plasticity 

of limbal and corneal epithelial differentiation in 

a rabbit model of recombined tissue. Investigative 

Ophthalmology & Visual Science 44: 5130-35, 

2003. 

Espana, EM, He, H, Kawakita, T, Di Pascuale, 

MA, Raju, VK, Liu, CY, and Tseng, SC. Human 

keratocytes cultured on amniotic membrane 

stroma preserve morphology and express 

keratocan. Investigative Ophthalmology & 

Visual Science 44: 5136-41, 2003. 

Carlson, EC, Wang, IJ, Liu, CY, Brannan, P, 

Kao, CW, and Kao, WW. Altered KSPG 

expression by keratocytes following corneal 

injury. Molecular Vision 9:615-23, 2003. 

Meek, KM, Quantock, AJ, Boote, C, Liu, CY, 

and Kao, WW. An X-ray diffraction investigation 

of corneal structure in keratocan-deficient mice. 

Matrix Biology 22:467-75, 2003. 


• Identified one targeted clone (#194) that was 

microinjected into the foster female mice by the 

gene targeting core facility at the University of 

Miami. Six chimeric founders have been obtained. 

The laboratory is in the process of 

breeding these chimeric mice with wt mouse to 

generate heterozygote mutant mice. 

• Plan to generate a Tg mouse model to study a 

mucin gene function on maintenance of epithelial 

tissues including mammary gland, ocular 

surface, and reproductive tract among others. 

Zhang, L, Wang, W, Hayashi, Y, Jester, JV, Birk, 

DE, Gao, M, Liu, CY, Kao, WW, Karin, M, and 

Xia, Y. A role for MEK kinase 1 in TGF-beta/ 

activin-induced epithelium movement and embryonic 

eyelid closure. EMBO Journal 22: 4443- 

54, 2003. 



BALAKRISHNA L. LOKESHWAR, PH.D. 



Dr. Lokeshwar’s research focuses on the 

mechanism of prostate cancer metastasis 

and its control by novel chemotherapeutic drugs. 

For the last several years, Dr. Lokeshwar’s laboratory 

has focused on the extracellular matrix degradation 

and tumor metastasis. His laboratory 

has studied the regulation of a class of basement 

membrane matrix degrading enzymes called the 

matrix metalloproteinases (MMPs) in prostate 

cancer. Using cancer cell cultures established 

from human prostate tumor tissues obtained after 

prostatectomy, they showed that an imbalance 

exists between the levels of MMPs (overproduction) 


in invasive prostate cancer cells. Based on 

this finding, they developed a hypothesis that a 

novel approach to control metastatic cancer is 

to correct the imbalance either by inhibition 

of secretion of MMPs or by increasing the extracellular 

levels of their endogenous inhibitor. 

Since several small synthetic inhibitors of 

MMPs exist, they tested the usefulness of the inhibitors 

using the criteria of oral bioavailability, 

systemic toxicity, and the ability to target bone 

metastasis. In their search for a suitable inhibitor, 

Dr. Lokeshwar’s laboratory tested a series of synthetic 

tetracycline analogues, which were shown 

to possess a strong anti-collagenase activity with 

little or no antibiotic activity. Researchers tested 

eight different chemically modified tetracyclines 

(CMTs) and found one of them, 6-deoxy, 6- 

demethyl, 4-dedimethylamino tetracycline 

(CMT-3, COL-3, now termed Metastat R by 

CollaGenix Pharmaceuticals, Newtown, Pennsylvania), 

to be the most promising. Oral dosing 

with this analogue to rats and mice-bearing metastatic 

prostate tumors reduced tumor growth and 

metastasis, with no measurable systemic toxicity. 

Furthermore, prophylactic dosing of the animals 

with the drug significantly reduced the incidence 

of tumor at the site of tumor cell injection. Their 

84 

demonstration of highly antimetastatic and antitumor 

activity of CMT-3 in a rat prostate tumor 

model led to its phase I clinical trial by the Developmental 

Therapeutics Division of the National 

Cancer Institute (NCI-DTP). In a recently 

concluded first human clinical phase I trial of 

COL-3, the NCI-DTP recommended COL-3 for 

phase II and phase III in patients with soft tissue 

sarcoma and advanced metastatic tumors. The 

University of Miami and the State University of 

New York at Stony Brook have jointly obtained a 

use patent on this drug. This finding also has 

generated wide interest in the use of COL-3 

among many investigators within and outside the 

University of Miami; a new patent was issued to 

the University for the treatment of corneal ulceration 

in patients with meibomian gland disease, 

also called ocular rosacea. Dr. Lokeshwar’s current 

research focuses on identifying novel plant products 

that have been used as folk medicine and on 

identifying novel combination therapies for advanced 

hormone-refractive prostate cancer. 

Dr. Lokeshwar’s research for this study also 

was funded by two consecutive grants from the 

Department of Defense Congressionally Directed 

Medical Program on Prostate Cancer. In its summary 

report to the U.S. Congress, his research was 

highlighted as one of the most significant outcomes 

of the CDMRP Prostate Cancer Program. 


2002 






506(Pt A):647-55, 2002. 


Lokeshwar, BL , Stern, ME, and Pflugfelder, SC. 



43:632-38, 2002. 









2002. 







and Molecular Biology 81:135-40, 

2002. 

2003 





164:273-88, 2003. 

Li, de Q, Shang, TY, Kim, HS, Solomon, A, 





& Visual Science 44:2928-36, 2003. 





Cancer Chemotherapy and Pharmacology 

52(1):59-66, 2003. 


• Demonstrated that an imbalance exists between 

the levels of MMPs (overproduction) and their 

natural inhibitors (underproduction) in invasive 

prostate cancer cells. 

• Identified a novel, chemically modified nonantimicrobial 

tetracycline (COL-3) as an effective 

anti-metastatic drug with the potential to 

treat prostate cancer metastatic to bone. The 

NCI has completed the phase I trial of this 

drug and is awaiting further trials. Other novel 

agents are being tested in Dr. Lokeshwar’s laboratory, 

not only for controlling cancer, but also 

other chronic diseases such as chronic ocular 

surface inflammation. Dr. Lokeshwar’s research 

has brought in one patent to the University of 

Miami jointly with the State University of New 

York at Stony Brook. Meanwhile, two patents 

are pending on the new application of his 

research findings. 

• Identified a potential application of CMTs to 

treat the meibomian gland dysfunction that 

leads to the ocular rosacea. This was done in 

collaboration with Stephen C. Pfulgfelder, 

M.D., Baylor College of Medicine, Houston, 

Texas. 

VINATA B. LOKESHWAR, PH.D. 



Dr. Lokeshwar’s research focuses on understanding 

the mechanism of cancer progression 

and tumor angiogenesis. Recent advances 

in cancer research have elucidated that the components 

of extracellular matrix (ECM) and 

ECM-degrading enzymes play a crucial role in 

regulating both the metastatic progression of 

localized tumors and tumor angiogenesis. Using 

bladder and prostate cancer model systems, her 

laboratory is trying to understand how ECM 

affects tumor metastasis and angiogenesis. 

Work in Dr. Lokeshwar’s laboratory demonstrates 

that an ECM component, hyaluronic acid 

(HA, which is a glycosaminoglycan), and its degrading 

enzyme, hyaluronidase (HAase), are 

closely associated with the biology of cancers of 

the bladder and prostate. They observed that elevated 

urinary HA and HAase levels are diagnostic 

indicators of bladder cancer and its grade, 

respectively. This finding has led to the development 

of a simple, noninvasive, highly sensitive, 



and specific urine test (HA-HAase test; 90 percent 

accuracy) for detecting bladder cancer and 

monitoring its recurrence. 

Dr. Lokeshwar’s research on prostate cancer 

showed that immunohistochemical localization of 

both HA and HAase in prostate cancer tissues is 

greater than 85 percent accurate in predicting 

prognoses for prostate cancer patients and are 

better than CD44v6 and microvessel density. 

Furthermore, both HAase and the HA-HAase 

combination are independent predictors of prognosis. 

Thus, use of these markers in biopsy specimens 

may help clinicians make individualized 

treatment decisions and improve patients’ 

prognoses. 

In their efforts to understand the function of 

tumor-derived HAase, Dr. Lokeshwar and her 

colleagues purified and cloned the first tumorderived 

HAase. They have demonstrated that this 

tumor-derived HAase degrades tumor-associated 

HA into small angiogenic fragments, which then 

interact with a HA receptor, RHAMM, on endothelial 

cells. The HA fragments and RHAMM 

interaction on the cell surface induces signaling 

events, resulting in the stimulation of endothelial 

cell functions, such as proliferation through the 

mitogen-activated protein kinase (MAPK) pathway. 

Endothelial cell proliferation is of key importance 

in tumor angiogenesis. Their recent 

work using anti-sense cDNA transfection strategy 

demonstrates that tumor-derived HAase is necessary 

for tumor growth and muscle invasion of 

bladder tumors. This is an important finding 

since 60 percent of bladder cancer patients with 

muscle invasive disease die within five years. 

Currently, Dr. Lokeshwar’s research focuses 

on three areas. First, the laboratory is comparing 

the efficacy of the HA-HAase test with other 

FDA-approved bladder tumor markers for monitoring 

bladder cancer recurrence. Secondly, they 

are testing the potential of HAase and HA-HAase 

to predict prognostic potential using prostate 

biopsy specimens. Thirdly, they are investigating 

the functions of HAase and HA-synthase enzymes 

in bladder and prostate cancer growth 

and progression. 


2002 



of Urology 167:1406-07, 2002. 







95:61-72, 2002. 


belirleyicileri ve HA-Haase testi. Uroloji Bulteni 

13:133-40, 2002. 





2002. 

2003 






66, 2003. 




47:91-107, 2003. 






2003. 


Civantos, F, Duncan, RC, and Lokeshwar, VB . 




86 




• Developed the HA-HAase urine test, a noninvasive 

test that is about 90 percent accurate in 

detecting bladder cancer and monitoring its 

recurrence. 

• Established that HA and HAase are greater than 

85 percent accurate prognostic indicators for 


• Demonstrated the function of tumor-derived 

HAase in bladder tumor growth and muscle 

invasion. 

ARUN MALHOTRA, PH.D. 

Assistant Professor of Biochemistry and 

Molecular Biology 


Dr. Malhotra’s research interests lie in structural 

biology of macromolecules involved in 

a variety of basic cellular functions. Three major 

areas of research include bacterial nucleases 

involved in RNA maturation and degradation, 

enzymes involved in RNA modification, and 

molecules involved in axonal guidance and 

neuronal development. These macromolecules 

are being studied using the tools of X-ray crystallography 

and molecular biology. 

Bacterial Exoribonucleases 

Ribonucleases play a central role in vital cellular 

RNA processes such as mRNA degradation and 

maturation and turnover of stable RNAs. Eight 

distinct exoribonucleases have been identified in 

E. coli. Of these, three (RNase T, RNase D, and 

oligoribonuclease) are members of a larger exonuclease 

superfamily (named the DEDD exonuclease 

family, after the four invariant acidic 

residues in these proteins) that includes the 

proofreading domains of DNA polymerases. 

While these proteins share similar sequence 

motifs, they are functionally quite different. 

RNase T is involved in tRNA turnover and maturation 

of tRNAs, 23S, and 5S rRNAs. RNase D 

also is involved in the maturation of tRNAs and 

small RNAs, but mainly as a backup enzyme. 

RNase D functions as a monomer, while RNase 

T and oligoribonuclease exist as dimers. 

Oligoribonuclease catalyzes the degradation of 

very short RNAs and is the only exoribonuclease 

essential for cell viability in E. coli. 

This project aims to obtain structures of 

these three exoribonucleases and to compare 

them to better understand differences in substrate 

specificities. The long-term goal of this research is 

to understand the structures and mechanisms of 

action of all exoribonucleases in a single organism; 

this study complements a parallel study under 

way in the laboratory of Murray P. Deutscher, 

Ph.D., (University of Miami), to completely 

characterize the physiological role of all the 

exoribonucleases in E. coli. 

Pseudouridine Synthases 

One of the most abundant post-transcriptional 

modifications seen in RNA is the isomerization 

of uridine to pseudouridine (5-ribosyluracil). 

While the physiological role of this modification 

in cells is not yet well understood, pseudouridines 

are often seen in functionally important regions 

of structural RNAs such as ribosomal RNAs, 

transfer RNAs, and splicing RNAs. 

The isomerization of uridines to pseudouridines 

is carried out by specialized enzymes called 

pseudouridine synthases. These enzymes fall into 

five different families; crystallographic studies in 

a number of laboratories have shown that three of 

these families have very similar structures in spite 

of limited sequence homologies. This project 

focuses on the structural studies of pseudouridine 

synthases from the other two families (RluD from 

the RluA family, and the newly discovered TruD 

family), in collaboration with the laboratory of E. 

James Ofengand, Ph.D., (University of Miami). 

Structural Studies of Axonal Guidance 

Molecules 

Research in this area aims to structurally characterize 

the interactions between ephrins and their 

receptors, a class of molecules involved in axonal 

guidance in the developing nervous system. Apart 

from axonal guidance, these receptors/ligands 



also are involved in cell migration, patterning of 

the nervous system, and angiogenesis. Given their 

critical roles in neuronal regeneration and angiogenesis, 

ephrins and their receptors are excellent 

targets for therapeutic intervention in a variety of 

cancers, injuries, and diseases. 

Eph receptors are the largest-known family 

of receptor tyrosine kinases, with at least 16 

members identified until now. Eph receptors have 

an extracellular region that consists of two 

fibronectin motifs, a cysteine-rich region, and a 

conserved 180 amino acids N-terminal globular 

domain. The ligands for Eph receptors are the 

ephrins, which have eight members identified so 

far. These ligands share conserved core sequences 

of approximately 125 amino acids, including four 

invariant cysteine residues. Ephrin A1–A5 are 

anchored by glycosil-phosphatidil-inositol (GPI) 

to cellular membranes, while ephrin B1–B3 receptors 

have a transmembrane domain and an 

intracellular domain, which interacts with a variety 

of adapter and signaling molecules such as 

PDZ-RGS3, GRB4, JNK, and others. 

The two classes of ephrins and their receptors, 

A and B, are defined by sequence homologies, 

mechanism of membrane anchorage, and by preferential 

binding of the ligands to their receptors. 

While within the same class, the ligand-receptor 

binding tends to be nonspecific; there is no cross 

interaction between the two classes, except Eph 

A4, which binds some of the B class ephrins. 

Ephrins-Eph interactions also are intriguing because 

these molecules often display bidirectional 

signaling: a forward signal (binding of ephrins to 

Eph receptor determines a response in a cell or 

axon) and a reverse/downstream signal (binding 

of Eph receptor to ephrin causes a change in the 

cell or axon to which ephrin molecule is bound). 

This research aims to better understand the 

structural basis of ephrin/Eph ligand-receptor binding 

and specificity by crystallographic studies of 

the extracellular domains of several of these molecules. 

Residues identified as being critical for ephrin/ 

Eph specificity also will be tested functionally using 

mutational approaches, in collaboration with the 

laboratory of Daniel J. Leibl, Ph.D., at The Miami 

Project to Cure Paralysis, University of Miami. 

88 


2003 

Everhart, D, Reiller, E, Mirzoian, A, McIntosh, 

JM, Malhotra, A, and Luetje, CW. Identification 

of residues that confer a-conotoxin-PnIA sensitivity 

on the α3 subunit of neuronal nicotinic acetylcholine 

receptors. Journal of Pharmacology 

and Experimental Therapeutics 306: 664-70, 

2003. 

Del Campo, M, Ofengand, J, and Malhotra, A. 

Purification and crystallization of Escherichia coli 

pseudouridine synthase RluD. Acta 

Crystallographica D, 59:1871-73, 2003. 


Crystal structure of the catalytic domain of 

RluD, the only rRNA pseudouridine synthase 

required for normal growth of Escherichia coli. 

RNA 10:231-39, 2003. 

AKILA MAYEDA, PH.D. 




The human genome project has underscored 

the critical importance of alternative premRNA 

splicing for expressing a full proteome 

with its complexity from an unexpectedly small 

set of genes, i.e., less than 30,000 by most recent 

estimation. 

Researchers in Dr. Mayeda’s laboratory are 

working to understand the basic mechanisms of 

splicing regulation in human genes. Three main 

projects are ongoing: 1) to study the function of 

the human splicing activator RNPS1, which is 

also an important factor to link splicing and the 

post-splicing process, e.g., nonsense-mediated 

mRNA decay (NMD); 2) to study the function 

of human HMGA1a, which is the hypoxia-inducible 

factor causing aberrant splicing of 

Presenilin-2 (PS2) pre-mRNA. PS2 is one of the 

genes linked to Alzheimer’s disease (AD); and 

3) to study the splicing mechanisms of extremely 



long introns using the dystrophin (DMD) gene. 

Many cases of Duchenne muscular dystrophy 

are caused by splicing defects of the DMD gene 

transcript. 

The high prevalence of clinically relevant 

mutations that affect splicing in genetic diseases 

and cancer has become increasingly apparent. 

The aberrant splicing patterns of many genes are 

involved in the establishment or maintenance of 

the transformed phenotype or in the progression 

to malignancy of cancer cells. Thus, Dr. Mayeda’s 

research will advance the basic understanding of 

the regulation of pre-mRNA splicing, which will 

undoubtedly have a long-term impact on public 

human health. 


2002 

Hou, VC, Lersch, R, Gee, SL, Ponthier, JL, Lo, 

AJ, Wu, M, Turck, CW, Koury, M, Krainer, AR, 

Mayeda, A, and Conboy, JG. Decrease in 

hnRNP A/B expression during erythropoiesis 

mediates a pre-mRNA splicing switch. EMBO 

Journal 21:6195-204, 2002. 

2003 

Liu, X, Mayeda, A, Tao, M, and Zheng, Z-M. 

Exonic splicing enhancer-dependent selection of 

bovine papillomavirus type 1 nucleotide 3225 3’ 

splice site can be rescued in a cell lacking splicing 

factor ASF/SF2 through activation of the 

phosphatidylinositol 3-kinase/Akt pathway. Journal 

of Virology 77:2105–15, 2003. 

Domsic, JK, Wang, Y, Mayeda, A, Krainer, AR, 

and Stoltzfus, CM. HIV-1 hnRNP A/B-dependent 

exonic splicing silencer ESSV antagonizes 

binding of U2AF65 to viral polypyrimidine 

tracts. Molecular and Cellular Biology 23:8762- 

72, 2003. 

Hu, D, Mayeda, A, Trembley, JH, Lahti, JM, and 

Kidd, VJ. CDK11 complexes promote premRNA 

splicing. Journal of Biological Chemistry 

278:8623–29, 2003. 

Manabe, T, Katayama, T, Sato, N, Gomi, F, 

Hitomi, J, Yanagida, T, Kudo, T, Honda, A, 

Mori, Y, Matsuzaki, S, Imaizumi, K, Mayeda, A, 

and Tohyama, M. Induced HMGAIa expression 

causes aberrant splicing of presenilin-2 premRNA 

in sporadic Alzheimer’s disease. Cell 

Death and Differentiation 10:698–708, 2003. 

Amada, N, Tezuka, T, Mayeda, A, Araki, K, 

Takei, N, Todokoro, K, and Nawa, H. A novel 

rat orthologue and homologue for the Drosophila 

crooked neck gene in neural stem cells and their 

immediate descendants. Journal of Biochemistry 

135:615–623, 2003. 


• Demonstrated that splicing activator RNPS1 is 

incorporated in the early splicing complex, 

stimulates formation of the ATP-dependent 

splicing complex, and subsequently increases 

generation of both intermediate and final 

spliced products. 

• Discovered experimental evidence supporting a 

novel mechanism, termed ‘nested intron splicing’, 

i.e., multiple splicing of internal nested 

introns preceding the eventual splicing at the 

authentic 5’ and 3’ splice sites by using the human 

DMD gene. 

CARLOS T. MORAES, PH.D. 

Associate Professor of Neurology 


Although mitochondrial genetics of yeast and 

trypanosomes has been explored extensively 

in the last 20 years, the study of human mitochondrial 

DNA (mtDNA) gained momentum in 

1988 with the discovery of diseases associated 

with mtDNA mutations. The human mtDNA is 

a compact circular genome (16.6 kb) coding for 

components of the ATP-producing oxidative 

phosphorylation system. Because mtDNA-coded 

polypeptides are synthesized in mitochondrialspecific 

ribosomes, the mtDNA also codes for a 



set of rRNAs and tRNAs necessary for intraorganelle 

translation. The contribution of the 

mitochondrial genome to cellular respiration, 

though vital, is not sufficient. Dozens of nuclearcoded 

proteins synthesized in the cytoplasm are 

imported into mitochondria and assembled with 

mitochondrially synthesized proteins to form a 

functional oxidative phosphorylation system. 

Recently, defects in mitochondrial function 

also have been associated with some forms of 

tumors. Mutations in the mtDNA also have 

been described in a large number of tumors. 

Dr. Moraes currently is studying the potential 

role of these mutations in cell signaling and invasion. 

Mitochondria also are major players in programmed 

cell death, an important determinant 

of tumorigenesis. A number of anti- and proapoptotic 

factors seem to mediate their functions 

in association with mitochondrial membranes. 

Dr. Moraes and his colleagues also are exploring 

the role of cytochrome c in stimulating apoposis. 


2002 

Moraes, CT, Srivastava, S, Kirkinezos, I, Oca- 

Cossio, J, van Waveren, C, Woischnick, M, and 

Diaz, F. Mitochondrial DNA structure and function. 

International Review of Neurobiology 53:3- 

23, 2002. 

Moraes, CT. Studying mitochondria of animal 

cells. Methods 26:291, 2002. 

Woischnik, M and Moraes, CT. Pattern of organization 

of human mitochondrial pseudogenes in 

the nuclear genome. Genome Research 12:885- 

93, 2002. 

Lanza, RP, Chung, HY, Yoo, JJ, Wettstein, PJ, 

Blackwell, C, Borson, N, Hofmeister, E, Schuch, 

G, Soker, S, Moraes, CT, West, MD, and Atala, 

A. Generation of histocompatible tissues using 

nuclear transplantation. Nature Biotechnology 

20:689-96, 2002. 

Diaz, F, Bayona-Bafaluy, MP, Rana, M, Mora, M, 

Hao, H, and Moraes, CT. Human mitochondrial 

DNA with large deletions repopulates organelles 

faster than full-length genomes under relaxed 

copy number control. Nucleic Acids Research 

30:4626-33, 2002. 

2003 

Manfredi, G, Kwong, JQ, Oca-Cossio, JA, 

Woischnik, M, Gajewski, CD, Martushova, K, 

D’Aurelio, M, Friedlich, AL, and Moraes, CT. 

BCL-2 improves oxidative phosphorylation and 

modulates adenine nucleotide translocation in 

mitochondria of cells harboring mutant mtDNA. 


2003. 

Bacman, SR, Atencio, DP, and Moraes, CT. Decreased 

mitochondrial tRNALys steady-state levels 

and aminoacylation are associated with the 

pathogenic G8313A mitochondrial DNA mutation. 


Bayona-Bafaluy, MP, Manfredi, G, and Moraes, 

CT. A chemical enucleation method for the 

transfer of mitochondrial DNA to rho(o) cells. 

Nucleic Acids Research 31:e98, 2003. 


• Discovered that cells with defective mitochondrial 

respiration can be more resistant to cell 

death. This is a counterintuitive concept since it 

was previously thought that the less energy a 

cell has, the easier it is to kill it. Programmed 

cell death, however, does require a considerable 

amount of ATP (energy) to occur. These findings 

may explain the presence of mtDNA mutations 

in some cancers. 

• Demonstrated that mitochondrial defects 

stimulate the production of metalloproteases, 

which in turn, promote tissue invasion. 

90 



AYMEE PEREZ, PH.D. 

Assistant Professor of 



Sialomucin complex (SMC/Muc4) is a 

heterodimeric glycoprotein complex consisting 

of a mucin subunit ascites sialoglycoprotein-1 

(ASGP-1) and a transmembrane subunit (ASGP- 

2), which is aberrantly expressed on the surface of 

a variety of tumor cells. Muc4 is transcribed from 

a single gene, translated into a large polypeptide 

precursor, and further processed to yield the mature 

ASGP-1/ASGP-2 complex. Muc4 has complex 

spatial and temporal expression patterns in 

the normal rat, suggesting that it has complex 

regulatory mechanisms. 

Muc4 is expressed in most vulnerable epithelia 

and is presumed to serve as a protective agent 

whose mucin subunit provides a steric block to 

the access of noxious agents such as bacteria or 

viruses. In many of these epithelia, such as the 

airway and cervix/vagina, Muc4 is constitutively 

expressed. Two notable exceptions are the mammary 

gland and uterus. In the uterus, Muc4 is 

expressed in the virgin animal, but down-regulated 

hormonally at the transcript level to repress 

Muc4 expression at the time of blastocyst implantation. 

Regulation in the mammary gland is 

even more complex and includes transcriptional 

and post-transcriptional levels of regulation. 

Dr. Perez has two ongoing projects in her 

laboratory. The first project investigates the 

mechanisms involved in the transcriptional regulation 

of Muc4 by prolactin and the transcription 

factor PEA3. The second project focuses on the 

post-transcriptional regulatory mechanisms involved 

in repressing Muc4 in the virgin animal, 

which are overridden during mid-pregnancy and 

tumor progression. Dr. Perez and her colleagues 

believe that these regulatory mechanisms provide 

a key to understanding the function of Muc4 in 

both the normal gland and its tumors. 


2002 

Carraway, KL, Perez, A, Idris, N, Jepson, S, 





survive. Progress in Nucleic Acid Research and 

Molecular Biology 71:149-85, 2002. 

2003 


SA, and Carraway, KL. PEA3 transactivates the 

Muc4/Sialomucin Complex promoter in mammary 


Chemistry 278:36942-52, 2003. 


• Demonstrated that up-regulation of the Muc4 

gene in the 13762 sublines of the rat mammary 

adenocarcinoma correlates with the overexpression 

of transcription factor PEA3 and the receptor 

tyrosine kinase ErbB2. PEA3 is capable of 

transactivating the Muc4 promoter in a dosedependent 

manner via direct attachment to a 

PEA3 binding site. Ras and MEKK1 kinases 

potentiate transcriptional activation of Muc4 by 

PEA3. These data suggest that expression of 

PEA3 in mammary tumors leads to up-regulation 

of MUC4 transcription, the gene product 

of which may contribute to the metastatic 

potential of mammary tumors. 



PEDRO J. I. SALAS, M.D., PH.D. 

Associate Professor of Cell Biology 

and Anatomy 


Centrosomes are an essential piece of the mitotic 

machinery. In polarized epithelial cells, 

centrosomes and other non-centrosomal microtubule 

organizing centers (MTOC) are distributed 

in a subapical localization. During mitosis, centrosomes 

migrate to the lateral domain, from 

where they organize the spindle. This orientation 

of the spindle is crucial for the maintenance of 

epithelial polarity since it determines that the cytokinesis 

will proceed in a plane perpendicular to 

the plane of the epithelial layer. Likewise, the polarization 

of MTOCs during interphase is essential 

to the polarization because it ensures that the 

minus ends of microtubules will be aligned under 

the apical domain. 

Dr. Salas’ research has demonstrated that 

centrosomes and non-centrosomal MTOCs colocalize 

with the apical intermediate filament (IF) 

cytoskeleton by using high-resolution confocal 

microscopy, near-neighbor deconvolution, and 

3D image reconstruction. At the electron microscopy 

level, co-localization indicated that 

pericentriolar material containing g-tubulin and 

the cytokeratin (CK) 19 intermediate filaments 

approach up to 10 nm. Using sonication, homogenization, 

and immunoprecipitation coupled 

with immunoblot, his laboratory also demonstrated 

that CKs 18 and 19 co-immunoprecipitate 

with g-tubulin in fragments that cannot 

sustain physical trapping. The down-regulation of 

CK19 IF using anti-sense oligonucelotides resulted 

in changes in localization of the centrosomes. 

The analysis of the sonication 

fragments indicated that only a few proteins 

other than CKs and g-tubulin are present, so that 

two potential candidates identified by yeast twohybrid 

and MS-MS microsequencing to fulfill 

the role of the “glue” attaching centrosomes, are 

now under consideration. Interestingly, one of 

those proteins is phosphorylated by p34cdc2. Because 

the IF do not depolymerize during mitosis 

92 

in epithelial cells, the attachment of centrosomes 

to IF must be necessarily broken at the onset of 

mitosis. Current laboratory projects include the 

isolation and identification of the protein(s) involved 

in the apical attachment of centrosomes to 

IF and their function during mitosis. Theoretically, 

a manipulation of this mechanism may halt 

the cell cycle in actively dividing epithelial cells. 

In addition, the relevance of this mechanism during 

ischemia or ATP depletion also is under 

investigation. 


2002 

Yang, X, Salas, PJ , Pham, TV, Wasserlauf, BJ, 

Smets, MJ, Myerburg, RJ, Gelband, H, 

Hoffman, BF, and Bassett, AL. Cytoskeletal actin 

microfilaments and the transient outward potassium 

current in hypertrophied rat ventriculocytes. 

Journal of Physiology 541:411-21, 2002. 

Figueroa, Y, Wald, FA, and Salas, PJ . p34cdc2- 

mediated phosphorylation mobilizes microtubule-organizing 

centers from the apical 

intermediate filament scaffold in CACO-2 epithelial 

cells. Journal of Biological Chemistry 

277:37848-54, 2002. 

2003 

Ramsauer, VP, Carothers Carraway, CA, Salas, 

PJ, and Carraway, KL. MUC4/Sialomucin complex, 


ErbB2 to the apical surface in polarized 

epithelial cells. Journal of Biological Chemistry 

278:30142-47, 2003. 

Ameen, NA, Marino, C, and Salas, PJ . cAMPdependent 

exocytosis and vesicle traffic regulate 

CFTR and fluid transport in rat jejunum in vivo. 

American Journal of Physiology Cell Physiology 

284:C429-38, 2003. 

Wald, FA, Figueroa, Y, Oriolo, AS, and Salas, PJ . 

Membrane repolarization is delayed in proximal 

tubules after ischemia-reperfusion: possible role 

of microtubule-organizing centers. American 

Journal of Physiology Renal Physiology 

285:F230-40, 2003. 




• Observed the attachment of centrosomes to IF. 

Although the implications of the mechanism of 

detachment during mitosis are still to be assessed, 

this may be relevant for cancer therapy. 

OLUWATOYIN SHONUKAN, M.D. 



Malignant melanoma arises from the melanocytes, 

cells that originate in the neural 

crest. Normal melanocyte development in the 

neural crest and subsequent migration of the 

melanocyte precursors into the skin require 

trophic signals from the neurotrophin family 

of growth factors. With terminal differentiation, 

melanocytes lose expression of neurotrophin 

receptors. Following transformation, however, 

melanoma cells aberrantly express the receptors 

for the neurotrophins, with more advanced stages 

of the disease being more likely to express the 

neurotrophin receptors than the earlier stages. 

Dr. Shonukan’s research discovered that the 

melanoma cells also express several members of 

the neurotrophin growth factor family, thus 

suggesting that the neurotrophin/neurotrophin 

receptor system may be involved in the mediation 

of melanoma progression. The focus of her 

laboratory’s research is to understand the role 

of the neurotrophins and their receptors in the 

mediation of tumor progression in malignant 

melanoma. 


2003 

Shonukan, O, Bagayogo, I, McCrea, P, Chao, M, 

and Hempstead, B. Neurotrophin-induced melanoma 

cell migration is mediated through the actin-bundling 

protein fascin. Oncogene 

22:3616-23, 2003. 


• Nerve growth factor (NGF), the prototypic 

member of this family of growth factors, mediates 

the invasiveness of melanoma cells in vitro 

by inducing the coupling of the intracellular 

domain of the p75 neurotrophin receptor with 

the actin cytoskeleton. 

• Neurotrophin-induced melanoma invasiveness 

is mediated by signals generated through PI-3 

kinase. 

• NGF induces the disruption of cadherin-mediated 

cell-cell adhesion, thereby permitting melanoma 

cells to dissociate from the keratinocytes 

in the epidermis and invade the dermis, from 

whence they metastasize to distant sites. Dr. 

Shonukan’s ongoing research efforts include 

identifying the components of this pathway in 

order to identify therapeutic targets. 

RAKESH SINGAL, M.D. 



Dr. Singal’s research focuses on the mechanisms 

that inactivate certain tumor-suppressor 

genes in prostate cancer. A common mode of 

such inactivation involves a modification (methylation) 

in DNA. By understanding how genes are 

silenced, treatments can be developed to activate 

them and thereby prevent the development and/ 

or progression of prostate cancer. Researchers in 

Dr. Singal’s laboratory also are studying methylation 

of selected genes as a diagnostic and prognostic 

marker in prostate cancer. 

The present screening techniques for prostate 

cancer are very inefficient, and two out of three 

patients undergo prostate biopsy unnecessarily 

to detect cancer. Cancer patients often have a 

small amount of DNA circulating in their serum, 

thought to be released from the cancer cells. Dr. 

Singal’s laboratory has shown that certain methylated 

genes are present at a substantially higher 

percentage in prostate cancer tissue but not in 

benign prostatic conditions. Researchers are 



investigating if these methylated genes can be 

detected in serum DNA in patients with prostate 

cancer. If so, this test can be used as a part of 

prostate cancer screening, saving unnecessary 

prostate biopsies. 

DNA methylation plays a role during development 

by regulating gene expression. Another 

project in Dr. Singal’s laboratory focuses on understanding 

the role of methylation in regulating 

the expression of genes responsible for hemoglobin 

synthesis. Understanding the contribution of 

methylation to globin gene expression and the 

mechanisms involved will lead to the development 

of safe and effective therapies for globin gene disorders 

like thalassemia and sickle cell anemia. 


2002 

Singal, R, vanWert, JM, and Ferdinand, L Jr. 



cells. Blood 100:4217-22, 2002. 












2003 




carcinoma of lung. Endocrine Practice 9:233-35, 

2003. 

JOYCE M. SLINGERLAND, M.D., PH.D., 

F.P.R.C. (C) 



Dr. Slingerland’s research investigates how 

cancers escape negative growth controls. Following 

her discovery of a key inhibitor of cell 

cycle progression, p27, Dr. Slingerland and her 

colleagues went on to demonstrate that p27 levels 

are reduced in up to 60 percent of common human 

cancers (breast, prostate, lung, ovarian, and 

others), in association with poor patient prognosis. 

Dr. Slingerland showed that the therapeutic 

effect of antiestrogens in breast cancer requires 

the cyclin-dependent kinase (cdk) inhibitors p21 

and p27 to mediate growth arrest. Oncogenic 

activation of mitogenic signaling via the mitogenactivated 

protein kinase (MAPK) pathway deregulates 

p27 function, causing tamoxifen resistance 

in breast cancer. She provided key insights demonstrating 

the role of cell cycle inhibitors p15 and 

p27 as mediators of G1 arrest by transforming 

growth factor-beta (TGF-β) and demonstrated 

that cancer cells lose responsiveness to this 

growth inhibitory cytokine through loss or deregulation 

of p27. In a recent publication, her 

laboratory demonstrated that checkpoint loss 

during cancer progression makes p27 an essential 

mediator of arrest. They also showed that functional 

inactivation of p27 in human cancers can 

either occur through accelerated p27 degradation 

or through altered p27 phosphorylation leading to 

p27 mislocalization. The laboratory recently 

showed that activation of mitogenic signaling 

via the receptor tyrosine kinases and the 

phosphoinositol 3’ kinase pathway alters p27 

phosphorylation and function and the protein 

accumulates in the cytoplasm away from its targets 

in the nucleus. This work links oncogene 

activation with loss or inactivation of the cell 

cycle inhibitor, p27, elucidating a major mechanism 

of loss of growth control in cancer progression. 

Dr. Slingerland’s laboratory also is investigating 

the cause of aggressive estrogen receptor 

94 



negative (ER-) breast cancers. Her laboratory has 

found that oncogenic receptor tyrosine kinase 

and cSrc activation may not only activate mitogenic 

signaling leading to aggressive proliferation, it 

may also lead to loss of detectable ER protein in 

ER- breast cancers. One-third of newly diagnosed 

breast cancers are ER- and have a poor prognosis. 

Investigation of mechanisms underlying loss of 

ER expression showed that all of 70 primary ERbreast 

cancers expressed ER mRNA. Src or 

proteasome inhibition increased ER levels and 

Src transfection stimulated both ligand-activated 

ER transcriptional activity and ER proteolysis. 

Cotransfection of Her2 and Src reduced ER levels 

further. ER- primary breast cancers and cell lines 

showed increased Src activity compared to ER+ 

cancers and cell lines, and the ER protein half-life 

was reduced in ER- breast cancer lines. These 

data support a model in which Her2 and cSrc 

cooperate with liganded ER to promote both ER 

dependent transcription and transcription linked 

ER proteolysis. 


2002 






2002. 

Liang, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R, 


Catzavelos, C, Beniston, R, Franssen, E, and 




2002. 








2003 







14:201-13, 2003. 

Liang, J and Slingerland, JM . Multiple roles of 

the PI3K/PKB (Akt) pathway in cell cycle progression. 

Cell Cycle 2:339-45, 2003. 

FULVIA VERDE, PH.D. 




Control of Cell Morphogenesis 

Dr. Verde’s research seeks to understand the 

molecular basis of cell morphogenesis in eukaryotic 

cells and its coordination to cell proliferation. 

To this end, Dr. Verde and her colleagues 

have investigated the function of Orb6, a conserved 

protein kinase that is required for maintenance 

of cell polarity and regulation of the cell 

cycle. They have identified six proteins that 

physically interact with Orb6 and established 

their role in the control of Orb6 function. Five of 

these proteins are conserved in human cells. 

These factors are involved in Orb6 activity regulation, 

are implicated in the control of Orb6 intracellular 

localization, or function as substrate 

effectors of Orb6 kinase in the control of cell 

morphology and the cell cycle. 

Furthermore, Dr. Verde’s laboratory has been 

working with Tea1, a microtubule-associated protein, 

that functions as a marker for cell polarity 

and shows similarity to human ERM (ezrin, 

radixin, and moesin) proteins. They have identified 

several proteins that interact with Tea1 by 2- 

hybrid screening. One of these proteins has been 

recently shown to be essential for spatial organi- 



zation of microtubule dynamics. These findings 

are important because little is known about the 

mechanism of microtubule-dependent cell morphogenesis. 


2003 





Chemistry 278:25256-63, 2003. 

Hou, MC, Wiley, DJ, Verde, F, and McCollum, 

D. Mob2p interacts with the protein kinase 

Orb6p to promote coordination of cell polarity 

with cell cycle progression. Journal of Cellular 

Science 116:125-35, 2003. 

Kim, H, Yang, P, Catanuto, P, Verde, F, Lai, H, 

Du, H, Chang, F, and Marcus, S. The kelch repeat 

protein, Tea1, is a potential substrate target 

of the p21-activated kinase, Shk1, in the fission 

yeast, Schizosaccharomyces pombe. Journal of Biological 

Chemistry 278:30074-82, 2003. 


• Demonstrated that Bot1 may function as a molecular 

bridge between Tea1, a microtubuleassociated 

protein required to establish cell 

polarity and Orb6, a conserved protein kinase 

related to mammalian Rho kinase and myotonic 

dystrophy kinase. These findings suggest 

that one of the effectors of Orb6 kinase is the 

formin For3p that functions in the control of 

actin cable polymerization. They also offer insight 

into the hierarchy of events that lead to 

polarized cell growth and in the mechanisms of 

microtubule-dependent cell polarity control. 

DONALD T. WEED, M.D., F.A.C.S. 



MUC4 (Sialomucin Complex) Expression in 

Head and Neck Cancer 

Sialomucin complex (SMC) is a novel membrane/soluble 

glycoprotein complex originally 

identified and isolated from membranes of 

ascites sublines of the highly metastatic 13762 rat 

mammary adenocarcinoma. Peptide sequence 

homology between the gene product of the human 

mucin MUC4 and rat SMC has recently 

been reported. SMC is composed of a mucin subunit 

ASGP-1 (ascites sialoglycoprotein-1) linked 

to the plasma membrane via an N-glycosylated 

transmembrane subunit ASGP-2. The transmembrane 

subunit has two epidermal growth factor 

(EGF)-like domains and can act selectively as a 

ligand for the receptor tyrosine kinase ErbB2. 

The mucin subunit ASGP-1 also has anti-adhesive 

activity. The human MUC4 has corresponding 

transmembrane (MUC4-β) and mucin 

(MUC4-α) subunits, with similar growth factor 

domains and anti-adhesive potential. These characteristics 

suggest SMC/MUC4 plays a functional 

role in normal cells by providing a direct protective 

barrier at the cell surface to limit absorption 

of microbes and other noxious agents to the epithelial 

surface, while also participating in repair 

and cell replacement processes in the epithelia as 

a ligand and modulator of signaling via ErbB2. 

SMC/MUC4 can participate in cell signaling 

pathways via its complex with ErbB2 to mediate 

pathways characterized by cell proliferation, or 

pathways characterized by cell cycle inhibition 

and growth arrest. Disregulation of proliferative 

pathways may lead to transformation of the normal 

epithelia to a neoplastic phenotype by means 

of autocrine stimulation of cell growth and proliferation 

via activation of ErbB2. The antiadhesive 

properties of the ASGP-1/MUC4-α component 

of the molecules result in reversible disruption of 

integrin-mediated cell adhesion to the extracellular 

matrix, and may be important in the develop- 

96 



ment of metastatic potential of the transformed 

cell. Alternatively, SMC/MUC4 may be an important 

mediator of differentiation by its cell 

cycle inhibitory functions. MUC4 expression has 

been associated with several human malignancies, 

including some where MUC4 expression correlates 

with poor prognosis and others where the 

opposite association is seen. 

Immunocytochemical analyses have shown 

that the oral cavity is one of the earliest sites of 

expression of SMC during development of the 

rat, and that the molecule is expressed throughout 

the upper aerodigestive tract and in the salivary 

glands of the adult animal. This study 

postulates that human MUC4 is similarly expressed 

in the epithelia of the human upper aerodigestive 

tract and salivary glands, and that the 

molecule participates in the normal processes of 

cellular protection, repair, and replacement of 

these vulnerable tissues. It is further postulated 

that alterations in MUC4 expression are relevant 

to the cell biology of neoplastic transformation 

and subsequent invasion and metastasis of these 

cancers. The hypotheses of this study are threefold: 

1) MUC4 expression is altered in head and 

neck malignancies compared with normal epithelial 

expression; 2) cellular expression of MUC4 

modulates as lesions progress from dysplastic noninvasive 

lesions to invasive lesions with regional 

and distant metastases; 3) characterization of 

MUC4 expression in neoplasia will correlate with 

tumor behavior such as invasion and metastasis, 

and clinical outcomes such as likelihood of recurrence 

and prognosis. 

Preliminary data from immunoblotting studies 

using fresh frozen operative tissue samples and 

immunohistochemical localization studies using 

paraffin embedded tissue blocks have identified 

MUC4 throughout the normal human upper 

aerodigestive tract mucosa, and in major and minor 

salivary glands. MUC4 is identified in squamous 

cell carcinomas (SCCA) of the upper 

aerodigestive tract, as well as in metastatic cervical 

lymph nodes. SMC/MUC4 also is identified 

in a variety of salivary neoplasms. Alterations in 

the normal mucosal MUC4 expression are seen 

in otherwise histologically normal mucosa adjacent 

to invasive tumors. MUC4 expression in the 

salivary gland tumor mucoepidermoid carcinoma 

has been associated with improved prognosis independent 

of pathologic grade, the strongest 

known predictor of clinical behavior in this malignancy. 

No clear correlation between MUC4 

expression and ErbB2 expression was seen by immunohistochemical 

analysis. On the other hand, 

MUC4 expression was noted to be expressed in 

the minority (14 percent) of head and neck 

SCCA, but a significant association between 

MUC4 expression and ErbB2 expression has 

been identified. Furthermore, MUC4 expression 

is associated with improved survival and decreased 

risk of recurrence in these tumors as established 

by immunohistochemical analysis. 

These studies suggest that in mucoepidermoid 

carcinoma and in head and neck SCCA MUC4 

may be functioning as a marker or mediator of 

differentiation, with tumors that lose this expression 

associated with a more aggressive clinical course. 

These studies have established MUC4 as a 

novel molecular prognostic marker for these 

tumors. Mechanistic studies to better define the 

functional relationship between MUC4 and 

ErbB2 in these tumors are planned. 


2003 






2003. 





Head & Neck 25:1-9, 2003. 

Foster, PK and Weed, DT. Tongue viability after 

bilateral lingual artery ligation and surgery for 

recurrent tongue-base cancer. Ear, Nose, & 

Throat Journal 82:720-724, 2003. 



CATHERINE F. WELSH, M.D. 



Dr. Welsh studies the cell cycle progression 

through the G1 phase and its regulation by 

growth factor receptors and adhesion to the extracellular 

matrix. Her laboratory is particularly interested 

in how these signaling pathways 

contribute to breast cancer tumorigenesis and 

progression. Signals from the plasma membrane 

emanating from receptor tyrosine kinases as well 

as integrins are each required for G1 progression. 

Cell spreading and cytoskeletal integrity as a consequence 

of integrin engagement also are necessary. 

Their laboratory studies involve the role of 

Rho family GTPases, a subset of the Ras superfamily, 

in the regulation of adhesion-dependent 

cell cycle progression. These proteins have been 

shown to play a role in integrin- and growth factor-mediated 

signaling, and they are potent mediators 

of cytoskeletal architecture during cell 

spreading. They are therefore situated to play a 

key role in the regulation of adhesion-dependent 

cell cycle progression. Recent research has revealed 

that Rho GTPases become deregulated in 

breast cancer and may contribute to tumorigenesis. 

Dr. Welsh’s laboratory is currently investigating 

the contribution of Rho GTPases to 

abnormalities in cell cycle proteins that typify 

poor prognosis breast cancer. 


• Rho family GTPases are in fact required for key 

adhesion-dependent G1 events, including 

cyclin D1 expression, Rb phosphorylation, and 

cyclin A expression. In addition, they participate 

in the activation of the mitogen-activated 

kinase, ERK1/2, a key upstream regulator of 

cyclin D1 expression. Furthermore, Rho proteins 

appear to be involved in determining the 

timing of cyclin D1 expression within G1 

phase. 

• Hyperactivation of Rho proteins in a subset of 

breast cancers underlies abnormalities in cell 

cycle regulators that typify poor prognosis 

breast cancer. In addition, inactivation of Rho 

GTPases normalizes these regulatory molecules 

and restores a more orderly progression through 

the cell cycle, even in aggressively growing 

breast cancer cells. Pathways mediating these 

actions include the MEK-ERK pathway. These 

findings may have implications for more targeted 

therapeutic approaches that specifically 

inhibit the autonomous proliferation of breast 

cancer cells. 

RUDOLF K. WERNER, PH.D. 

Professor of Biochemistry and 



Dr. Werner’s research focuses on the regulation 

of connexin43 expression. He and his colleagues 

had discovered that the 5’-UTR of 

connexin43 mRNA contains a very active internal 

ribosome entry site (IRES) element that appears 

to be regulated by estrogen. His laboratory 

continues to investigate this regulation in the 

myometrium where connexin43 is produced at 

parturition in response to estrogen. Dr. Werner’s 

research also has demonstrated that in several 

other tissues, such as heart and smooth muscle, 

connexin43 pre-mRNA is alternatively spliced 

producing mRNA with different 5’-UTRs but 

identical coding regions. This finding suggests 

that the expression of connexin43 is regulated at 

the translational level in different tissues. 

Dr. Werner and his colleagues discovered 

alternatively spliced 5’-UTR-coding exons in five 

other connexins. Again, the splicing seems to be 

tissue-specific. They currently are investigating 

whether some of these novel exons contain IRES 

elements. 

98 



Dr. Werner’s laboratory also is pursuing the 

investigation of Ini, a novel transcription factor 

that is involved in connexin43 gene regulation at 

the transcriptional level. Knockout experiments 

in Saccharomyces pombe indicated that the yeast 

homolog of Ini is an essential protein. It appears 

to be involved in the mRNA splicing process. 


2003 

Oltra, E, Pfeifer, I, and Werner, R. Ini, a small 

nuclear protein that enhances the response of the 

connexin43 gene to estrogen. Endocrinology 

144:3148-58, 2003. 


• Demonstrated that, in humans, connexin43 is 

expressed in the heart and the uterus, as well as 

in many other tissues. Because it is an essential 

protein (as determined in mice) that affects 

early development, it is important to understand 

the mechanisms of its regulation of expression. 

In the uterus, connexin43 expression 

is inducible by estrogen. This regulation is clinically 

important because women who suffer 

from premature labor also express connexins 

prematurely. 

JAMES WYCHE, PH.D. 

Professor of Biology 


One of Dr. Wyche’s interests has been to understand 

how anti-cancer drugs induce 

apoptosis (cell deaths) of cancer cells. Recently, 

he and his colleagues studied how the natural 

product camptothecin (CPT) and its semi-synthetic 

derivatives such as CPT-11, 9-amino-CPT 

(9AC), and 9-nitro-CPT (9NC) induce apoptosis 

of human colon cancer cells. Many aspects of the 

mechanism by which these drugs exert their 

death effect on cancer cells, however, remain 

largely unknown. In recent years, Dr. Wyche and 

his colleagues have used a cell model of human 

colon cancer to demonstrate that treatment with 

low doses of CPT induces senescence in the presence 

of a protein call p21. Apoptosis, however, 

occurs in the absence of p21. Therefore, p21 is a 

key determinant of the outcome of colon cancer 

cells treated with CPT drugs at doses that are relevant 

to clinical application. Thus, CPT treatment 

of colon cancer cells with p21 should result 

in disease stabilization, whereas CPT treatment 

of p21-deficient colon cancer cells should result 

in rapid apoptosis and disease regression. 

It is well established that p21 inhibits cyclindependent 

kinases (Cdks) and several other factors, 

including proliferating cell nuclear antigens. 

They hypothesize that inhibition of Cdks by p21 

is essential to inhibit apoptosis and induce senescence. 

In this context, Dr. Wyche and his colleagues 

propose that a protein named E2F1 is 

essential for apoptosis of colon cancer cells 

treated with CPT. According to this hypothesis, 

inhibition of Cdks should result in activation of 

another protein, named retinoblastoma (Rb), 

which in turn, inhibits E2F1 and consequentially 

E2F1-dependant apoptosis. They also hypothesize 

that the ability of p21 to induce senescence 

requires a protein called STAT1. To test their 

hypothesis, Dr. Wyche’s laboratory currently is 

using techniques to selectively alter the status of 

Cdk, E2F1, Rb, and STAT1 genes in human 

colon cancer cells. They will then investigate the 

role of each protein in the process of apoptosis 

and senescence in the colon cancer cells after 

CPT treatment. 

The information obtained from these investigations 

will provide a better insight into the 

molecular pathways activated in colon cancer 

cells after CPT treatment and eventually will lead 

to specific experimental designs to completely 

understand how CPTs affect colon cancer. 




2002 






Chemistry 277:17154-60, 2002. 

Han, Z, Ribbizi, I, Pantazis, P, Wyche, J, 

Darnowski, J, and Calabresi, P. The antibacterial 

drug taurolidine induces apoptosis by a mitochondrial 

cytochrome c-dependent mechanism. 

Anticancer Research 22:1959-64, 2002. 

2003 




8:277-89, 2003. 

Pantazis, P, Han, Z, Balan, K, Wang, Y, and 

Wyche, JH. Camptothecin and 9- 

nitrocamptothecin (9NC) and anti-cancer, anti- 

HIV, and cell-differentiation agents: 


9NC-induced activities, and combination treatments 

in cell and animal models. Anticancer Research 

23:3623-38, 2003. 


J, Han, Z, and Pantazis, P. Differential susceptibility 





Drugs 14:427-36, 2003. 


• The research activities in Dr. Wyche’s laboratory 

focus on the use of natural products that induce 

the death of cancer cells. They use several human 

tumor types, but predominantly colon 

cancer cells, and exploit substances that damage 

the cells’ genetic material with a specific effect 

on killing or controlling the proliferation of 

theses cells. Current research has led the team 

to focus on key cellular proteins and manipulation 

of their genes that may eliminate protein 

production. They then observe the concomitant 

impact on cellular functions such as growth or 

death of the target cancer cell. 

TERESA A. ZIMMERS, PH.D. 

Assistant Professor of Surgery 


Dr. Zimmers’ research aims to understand the 

mechanisms regulating tissue homeostasis in 

order to apply such knowledge to the prevention 

and treatment of human disease. Recently, she 

has focused on the roles of the transforming 

growth factor-beta (TGF-ß) superfamily member—myostatin—in 

the regulation of skeletal 

muscle and fat mass. Myostatin is a highly conserved 

gene expressed at high levels in skeletal 

muscle and at low levels in white fat. Mice and 

cattle lacking myostatin function develop skeletal 

muscle hypertrophy and hyperplasia. Research 

in Dr. Zimmers’ laboratory has shown that 

overexpression of myostatin in mice produces 

hypoglycemia along with a wasting syndrome 

similar to the cachexia that complicates many 

chronic diseases such as cancer, AIDS, and organ 

failure. Concomitant over-expression of the 

myostatin binding proteins, follistatin and 

myostatin propeptide, inhibits this wasting, suggesting 

a means of interfering with endogenous 

myostatin signaling in animals and patients. 

100 



Dr. Zimmers’ current research focuses on the 

following questions: 

1) Is dysregulation of the myostatin signaling 

pathway involved in the etiology of muscle 

wasting due to cancer, AIDS, congestive heart 

failure, burn, or sepsis in mouse models and in 

humans? 

2) How does myostatin regulate muscle and fat 

mass in vivo? 

3) What are the target genes induced by 

myostatin signaling? 

4) How does myostatin influence glucose homeostasis? 

5) How does myostatin-induced wasting differ 

from that induced by cytokines such as 

interleukin-6 (IL-6) or tumor necrosis factor 

(TNF)? 

Dr. Zimmers’ latest data derived from 

microarray analysis of RNA from muscle cells 

treated in vitro and in vivo with myostatin suggest 

that myostatin may regulate skeletal muscle mass 

on several levels, including by altering proteolysis, 

cell proliferation and apoptosis, and cell energetics/metabolism. 

Using this approach, she has 

identified a number of candidate genes that 

might control skeletal muscle regulation in normal 

development and disease. 

A second, long-standing focus of Dr. 

Zimmers’ research is the remarkable phenomenon 

of liver regeneration, a striking manifestation 

of tissue growth regulation. The laboratory 

has examined the roles of several members of the 

TGF-ß superfamily in liver regeneration using 

gene targeting, transgenesis and overexpression 

studies. Using such strategies, they demonstrated 

that the TGF-ß family members inhibin-ßC and 

–ßE, alone and in combination, and bone morphogenetic 

protein (BMP)-9 are not essential for 

liver regeneration after hepatectomy. 

Dr. Zimmers’ current work, done in collaboration 

with Leonidas G. Koniaris, M.D., focuses 

upon the role of the IL-6 signaling pathway in 

hepatocyte proliferation. They have shown that 

administering high levels of IL-6 to mice results 

in profound liver growth (with concomitant peripheral 

cachexia) without activating known 

growth factor signaling pathways. These results 

suggest that IL-6 may be a hepatocyte mitogen. 

Because elevated IL-6 levels also are associated 

with human liver disease, however, their current 

effort focuses upon identifying the mechanisms 

by which IL-6 induces liver growth and facilitate 

regeneration when administered acutely, but suppresses 

the regenerative response and potentially 

contributes to progressive liver injury and failure 

when present chronically. 

Finally, a chance observation that mice 

treated with high-dose IL-6 develop increased 

intestinal growth (increased gut length, diameter, 

and mass) has led to a third project examining 

the role of IL-6 in epithelial cell proliferation in 

the gut. 

Dr. Zimmers’ ultimate goal is to apply what 

is learned in the basic science laboratory to solving 

clinical problems, including the treatment of 

patients with muscle wasting disorders, obesity, 

diabetes, and liver disease. 


2002 

Zimmers, TA , Davies, MV, Koniaris, LG, 


Wolfman, NM, and Lee, S-J. Cachexia induced 


Science 296:1486-1488, 2002. 

2003 

Sean, JJ, Klover, PJ, Nowak, IA, Zimmers, TA , 


Suppressor of cytokine signaling-3, a potential 

mediator of interleukin-6 dependent insulin resistance 

in hepatocytes. Journal of Biological Chemistry 

278:13740-13746, 2003. 




Zimmers, TA . Liver regeneration. Journal of the 


Zimmers, TA , McKillop, IH, Pierce, RH, Yoo, 



Hepatology 38:326-34, 2003. 

Klover, PJ, Zimmers, TA , Koniaris, LG, and 



52:2784-89, 2003. 


• Demonstrated that overexpression of the TGFß 

family member, myostatin, leads to hypoglycemia 

and muscle and fat wasting despite 

adequate food intake, suggesting a role for the 

myostatin pathway in the etiology or treatment 

of human wasting diseases such as cancer 

cachexia. 

• Observed that overexpression of the inflammatory 

cytokine IL-6 leads to hypoglycemia and 

peripheral cachexia, along with increased liver 

and bowel growth, suggesting a role for IL-6 in 

human wasting syndromes and in treatment or 

progression of liver disease, hepatocellular carcinomas, 

or short gut syndrome. 

102 


T U M O R I M M U N O L O G Y P R O G R A M 






The Tumor Immunology Program presently 

consists of 15 faculty members from four different 

departments at the University of Miami 

School of Medicine. The program comprises 

multiple aspects of basic immunology and a substantial 

number of studies involving tumor systems 

and samples obtained from patients. The 

program investigates numerous characteristics of 

the immune system in relation to the development 

and treatment of cancer. 


1) Elucidate the mechanisms underlying the activities 

of innate and adaptive immune cells. 

2) Study various aspects of stem cell biology and 

bone marrow transplantation. 

3) Analyze the role of T cells and B cells in the 

host defenses against tumors. 

4) Study the mechanisms of tumor evasion of the 

immune system. 

5) Devise novel immunotherapeutic protocols. 

PARTICIPANTS 

Adkins, Rebecca D., Ph.D. 


Blomberg, Bonnie B., Ph.D. 


Jurecic, Roland, Ph.D. 


Lee, Kelvin P., M.D. 


Levy, Robert B., Ph.D. 


Lichtenheld, Mathias G., M.D. 


Lopez, Diana M., Ph.D. 


Malek, Thomas R., Ph.D. 


Podack, Eckhard R., M.D., Ph.D. 


Riley, Richard L., Ph.D. 


Rosenblatt, Joseph D., M.D. 

Medicine 

Thomas, Giovanna R., M.D. 


Tolba, Khaled, M.D. 

Medicine 

Torroella-Kouri, Marta, Ph.D. 


Vincek, Vladimir, M.D., Ph.D. 

Pathology 

HIGHLIGHTS 

• Recent findings reveal that the primary function 

of interleukin 2 (IL-2) is the generation of 

T regulatory cells and not T-cell proliferation 

and sensitization to cell death as previously 

thought. (T. Malek) 

• During in vitro priming, IL-2 promotes subsequent 

engraftment and successful adoptive tumor 

immunotherapy by persistent memory 

phenotypic CD8 + T cells. (T. Malek) 

• Heatshock fusion vaccines generate CD8 

cytotoxic T lymphocytes (CTL) without CD4 

help; progress towards novel and efficient tumor-specific 

vaccines is underway. (E. Podack) 



• CD30 is identified as a major negative regulator 

of cytotoxic lymphocytes; blocking CD30 signals 

in vivo may enhance anti-tumor immune 

responses. (E. Podack) 

• A phase I study testing a vaccine therapy protocol 

in advanced non-small cell lung carcinoma 

showed that the vaccine was safe and stimulated 

an immune response. Clinical benefit was seen 

in six patients. (E. Podack) 

• A role for perforin in lymphocyte homeostasis 

revealed that cytotoxicity by perforin is necessary 

to remove antigen-presenting cells and turn 

off T-cell activation. (E. Podack) 

• A unique peptide with immunoenhancing 

properties has been identified in a secreted form 

of human MUC1 and used in vaccination experiments. 

This peptide inhibits tumor development 

in the mammary cells transfected with the 

secreted MUC1 and also protects against a variety 

of other tumor types. (D. Lopez) 

• Thymuses of mammary tumor bearers are profoundly 

involuted, and this is not due to a decrease 

of the thymocytes proliferation. A minor 

increase of apoptosis was noted; however, the 

major cause of this phenomenon appears to be 

an arrest at an early stage of differentiation, possibly 

brought about by the direct or indirect 

effects of tumor derived factors. (D. Lopez and 

R. Adkins) 

• After allogeneic bone marrow transplant, the 

recipient can resist the engraftment of transplanted 

donor stem cells by using immune responses, 

which do not involve the two major 

pathways of T lymphocyte-mediated killing. 

This is a surprising finding and demonstrates 

that it is likely that for some transplants, different 

pathways in the recipient must be blocked 

to help the transplanted bone marrow engraft. 

(R. Levy) 

• Lymphocytes, which were added to donor stem 

cells before transplant to help or facilitate the 

engraftment by these stem cells after transplant, 

use different functions for the purposes of: 1) 

helping to “seed” the stem cells in the recipient, 

and 2) helping to maintain their permanent 

presence. (R. Levy) 

• Direct activation of protein kinase C (PKC) 

causes normal human hematopoietic CD34 + 

stem cells to differentiate into dendritic cells 

(DC). (K. Lee) 




as “cellular” anti-leukemia vaccines. (K. Lee) 

• Researchers identified two essential enhancers 

of the perforin gene and demonstrated that they 

are under the control of Stat5 molecules. This 

work sheds molecular light on fundamental 

principles of effector gene activation in cytotoxic 

lymphocytes. (M. Lichtenheld) 






(B. Blomberg) 

• Breast cancer patients show improved immune 

response after psychosocial intervention. (B. 

Blomberg) 

• The molecular deficits, which underlie dysfunctions 

in lymphocyte activity during old age, 

have yet to be well characterized. The finding 

that expression of a transcription factor (E47) 

and surrogate light chains, both of which are 

critical to B-lineage cell development, are decreased 

in aged B-cell precursors provides a molecular 

basis for understanding deficient 

lymphopoiesis in senescence. (R. Riley) 

104 



REBECCA D. ADKINS, PH.D. 

Associate Professor of Microbiology and 

Immunology 


Cancer in infants and children differs markedly 

from that in adults. For example, there 

are some solid tumors that occur in children but 

never or rarely develop in adults, including neuroblastoma, 

Wilms tumor, rhabdomyosarcoma, 

osteosarcoma, hepatoblastoma, Ewing’s sarcoma, 

and retinoblastoma. Moreover, solid tumors as 

well as hematologic malignancies, such as acute 

lymphoblastic leukemia (ALL) or acute myeloid 

leukemia (AML), demonstrate distinct biological 

features and responses to treatment in children 

and adults. During the last half of the 20 th century, 

great strides were made in improving survival 

rates of many pediatric cancers. This was 

achieved largely by increasing the aggression of 

chemotherapy treatments. Because of the high 

intensity of current therapy, however, future improvements 

are unlikely to come from further 

increases in chemotherapy intensity. Moreover, 

chemotherapy is not ideal for use in children because 

of adverse side effects that can manifest in 

later life. In this light, it appears that the improved 

survival of pediatric cancer patients is 

awaiting the application of new therapeutic regimens. 

One relatively new and especially promising 

approach for treating cancers in adults is the 

application of immunotherapy. A good deal of 

attention is being paid to the possibility of 

enhancing endogenous anti-tumor responses. 

Because of the limitations with current therapies, 

the idea of enhancing the anti-tumor responses of 

children with cancer is very appealing. At the 

present time, however, all hands are tied because 

there simply is not enough known about the 

neonatal/juvenile immune system to devise the 

appropriate immunotherapeutic approaches. 

Using a mouse model system, Dr. Adkins has 

focused on studying the development of immune 

system function in neonatal life. Her laboratory 

has made many interesting and important 

observations that have significantly broadened 

the knowledge base of neonatal immunity. First, 

Dr. Adkins and her colleagues have shown that, 

unlike in adults, responses mediated by T lymphocytes 

differ in the newborn lymph nodes and 

spleen. Second, they have found that neonates 

show an abnormal persistence of anti-inflammatory 

T-cell responses following exposure to model 

vaccine antigens. Third, they have demonstrated 

definitively that the immature responses of neonatal 

T lymphocytes are due to inherent properties 

of this population of cells rather than 

immature signals in the neonatal environment. 

Lastly, they most recently discovered that the 

properties of neonatal T lymphocytes are at least 

partly due to an “imprinting” that occurs during 

embryonic life. Currently, Dr. Adkins and her 

colleagues are beginning to uncover the molecular 

regulation of the neonatal phenomenon. 

These studies will aim at identifying new tools that 

can be applied to enhancing neonatal immune 

responses. It is becoming increasingly apparent 

that murine newborns are immunologically quite 

similar to human fetuses and infants. On this 

basis, it reasonably can be argued that they stand 

to learn a great deal about what is potentially 

happening in humans by studying murine models. 

Thus, the long-term goal of these studies will 

be to utilize the information gained here to devise 

new strategies for the prevention and treatment 

of pediatric cancer. 


2002 

Muller-Sieburg, CE, Cho, RH, Thoman, M, 

Adkins, B, and Sieburg, HB. Deterministic regulation 

of hematopoietic stem cell self-renewal and 

differentiation. Blood 100:1302-9, 2002. 

Adkins, B, Bu, Y, and Guevara, P. Murine neonatal 

CD4+ lymph node cells are highly deficient in 

the development of antigen-specific Th1 function 

in adoptive adult hosts. Journal of Immunology 

169:4998-5004, 2002. 



Lopez, DM, Charyulu, V, and Adkins, B. Influence 

of breast cancer on thymic function in mice. 

Journal of Mammary Gland Biology and Neoplasia 

7:191-9, 2002. 

2003 

Petito, CK, Adkins, B, McCarthy, M, Roberts, B, 

and Khamis, I. CD4+ and CD8+ cells accumulate 

in the brains of acquired immunodeficiency 

syndrome patients with human immunodeficiency 

virus encephalitis. Journal of 

Neurovirology 9:36-44, 2003. 

Adkins, B, Williamson, T, Guevara, P, and Bu, Y. 

Murine neonatal lymphocytes show rapid early 

cell cycle entry and cell division. Journal of Immunology 

170:4548-56, 2003. 

Auais, A, Adkins, B, Napchan, G, and 

Piedimonte, G. Immunomodulatory effects of 

sensory nerves during respiratory syncytial virus 

infection in rats. American Journal of Physiology—Lung 

Cellular and Molecular Physiology 

285:L105-13, 2003. 

Adkins B, Bu Y, Vincek V, and Guevara P. The 

primary responses of murine neonatal lymph 



Clinical and Developmental Immunology 10:43- 

51, 2003. 

Adkins, B. Peripheral CD4 + lymphocytes derived 

from fetal versus adult thymic precursors differ 

phenotypically and functionally. Journal of Immunology 

171:5157, 2003. 

BONNIE B. BLOMBERG, PH.D. 



Research in Dr. Blomberg’s laboratory focuses 

on two projects. One of those projects involves 

basic research on the molecular regulation 

of B lymphopoiesis in mice. Generation of B 

lymphocytes is important in cancer patients receiving 

bone marrow as well as in the normal 

production of the humoral (antibody) response. 

Aged humans and other mammals have a poorer 

immune response to pathogens. 

In collaboration with Richard L. Riley, 

Ph.D., in the department of Microbiology and 

Immunology, Dr. Blomberg has shown that aged 

mice, those greater than or equal to about 80 

percent of their full life span, have a substantial 

decrease in the number of precursor B lymphocytes 

as well as the amount of the precursor B-cell 

receptor (preBCR) including the surrogate light 

chain (SLC)y5 and VpreB. Their data indicate 

that this affects the antibody V H 

repertoire at the 

pre-B cell level, i.e., before antigen selection. 

More recent data indicate that the transcription 

factor, E2A, is reduced in not only precursor B 

cells but also in mature B cells in peripheral lymphoid 

organs in aging, leading to defects in Ig 

class switch and humoral immunity. Current 

studies will reveal the molecular and cellular 

causes of these defects in the aged humoral immune 

response and attempt to reverse these defects. 

These studies are important for cancer for 

two reasons: 1) the depressed immune response 

seen in aged humans likely contributes to increased 

susceptibility to cancer, and 2) bone marrow 

transplantation given to many types of 

cancer patients requires generation of mature B 

lymphocytes from the precursors in the bone 

marrow. Knowledge about the cellular and molecular 

requirements for B lymphopoiesis in 

young and aged individuals should lead to improvements 

in the humoral immune system of 

cancer patients. 

106 



Another project in Dr. Blomberg’s laboratory 

involves clinical research with breast cancer patients. 

In collaboration with Michael H. Antoni, 

Ph.D., in the department of Psychiatry and Behavioral 

Sciences, Charles S. Carver, Ph.D., in the 

department of Psychology, Sharlene Weiss, R.N., 

Ph.D., in the department of Medicine, and members 

of the Cancer Prevention and Control Program 

at the University of Miami Sylvester 

Comprehensive Cancer Center, researchers are 

measuring the status of various immune parameters 

in patients in response to psychosocial intervention 

(e.g., group therapy, stress reduction). 

Preliminary experiments have shown that intervention 

patients have an improved immune response 

as seen by the ability of their T cells to 

proliferate in response to an antigen-specific receptor 

stimulus (anti-CD3). Current studies are 

measuring T, NK, and lymphokine-activated 

killer cells (LAK) cytotoxic function as well as 

potential TH1/TH2 differences by cytokine production 

resulting from T-cell stimulation. These 

studies are important to allow optimal immune 

response in cancer patients, which will better 

detect and destroy residual cancer and allow for 

better patient survival. 


2002 


Blomberg, BB , Wei, YT, Ciancio, G, Burke, GW 

3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional 




75, 2002. 






34:1610-11, 2002. 

Ricordi, C, Tzakis, A, and Miller, J. Human bone 

marrow cells retrovirally transduced with the allogeneic 

class II gene, HLA-DR3beta, down regulate 

anti-allogeneic responses of autologous 

lymphoid cells. Human Immunology 63:S19, 

2002. 

2003 

Mathew, JM, Blomberg, BB, Fuller, L, Burke, 






272:67-80, 2003. 





Retroviral transduction of an allogeneic class II 

gene into human bone marrow down regulates 


64:S128, 2003. 





of allogeneic T-cell proliferation through blocking 

of NF-κB in the differentiation process of human 

dendritic cells. Human Immunology 64:S128, 

2003. 










38:1137-47, 2003. 


S, Carreno, M, Hnatyszyn, H, Garcia-Morales, 

R, Fuller, L, Vallone, T, Rosen, A, Esquenazi, V, 




RL, and Blomberg, BB. The age-related decrease 


Id Inhibitory proteins in bone marrowderived 


8:A110-16, 2003. 

Frasca D, Nguyen D, Riley RL, and Blomberg, 









170:719-26, 2003. 





172:2155-62, 2003. 







• Decreased transcription factor E2A is important 

for decreased Ig class switch and optimal humoral 

immunity. 

• Demonstrated improved immune response is 

shown by breast cancer patients after psychosocial 

intervention. 

ROLAND JURECIC, PH.D. 

Assistant Professor of Microbiology 



The lifelong maintenance and regenerative capacity 

of the blood cell-forming (hematopoietic) 

system depend on self-renewal, lineage commitment, 

and differentiation of hematopoietic 

stem cells (HSC) and progenitors. HSC hold tremendous 

promise for the development of stem 

cell transplantation and cell and gene therapy 

protocols for treatment of various diseases. Research 

in Dr. Jurecic’s laboratory focuses on: 1) 

elucidation of genetic mechanisms that regulate 

self-renewal, lineage commitment, and differentiation 

of HSC, 2) identification and functional 

genetic analysis of novel genes that are involved 

in the leukemogenesis, and 3) developmental 

plasticity of HSC. 

Molecular Genetics of Stem Cell Self-Renewal 

and Maintenance 

Self-renewal of stem cells in diverse species and 

tissues suggests that evolutionarily conserved 

mechanisms regulate this common feature. Dr. 

Jurecic’s laboratory is studying the role of the evolutionarily 

conserved Pumilio family of RNAbinding 

proteins in self-renewal and maintenance 

of mammalian hematopoietic and neural stem 

cells. Gain of function experiments have shown 

that: 1) overexpression of mouse Pum genes leads 

to increased maintenance and suppression of 

multilineage differentiation of HSC and 

multipotent progenitors, and 2) Pum genes support 

maintenance and self-renewal of multipotent 

hematopoietic cells through regulation of the 

SCF/c-kit signaling pathway. 

Molecular Genetics of Hematopoietic Stem Cell 

Differentiation 

The developmental cascade from HSC to mature 

blood cells, defined by a series of commitment 

steps that gradually restrict the developmental 

potential of intermediate progenitor cells, is regu- 

108 



lated by an intricate network of genes. Through a 

comprehensive gene expression analysis during 

stem cell differentiation, Dr. Jurecic and his colleagues 

have identified a novel evolutionarily conserved 

RING finger protein FLRF (Rnf41). 

During blood cell development, FLRF (fetal liver 

ring finger) acts as an E3 ubiquitin ligase and affects 

proliferation and differentiation of HSC and 

multipotent progenitors by regulating cytokine 

receptor levels through ligand independent degradation. 

By regulating steady-state levels of 

cytokine receptors, FLRF could be maintaining 

optimal signaling for a proper cellular response 

(proliferation, lineage commitment, differentiation) 

of HSC and progenitors, while preventing 

oversignaling that could lead to leukemogenesis. 

Developmental Biology and Plasticity of 

Hematopoietic Stem Cells 

HSC may have the capacity to develop into cells 

of unrelated tissue(s). This discovery could have 

important implications for designing new stem 

cell transplantation and cell therapy protocols for 

treatment of various diseases. The aim of this 

project is to analyze whether HSC possess the 

potential for differentiation into cell types other 

than that of blood lineages. To study the full developmental 

potential of HSC, Dr. Jurecic’s laboratory 

has developed a new in utero stem cell 

transplantation assay, named blastocyst engraftment 

assay (BEA). BEA is based on microinjection 

of purified HSC into mouse preimplantation 

embryos (blastocysts), similar to embryonic stem 

(ES) cell technology. Using BEA, they have demonstrated 

that microinjected transgenic HSC successfully 

engraft fetal hematopoietic tissues (yolk 

sac, fetal liver). They also obtained preliminary 

evidence that mouse adult HSC have the capacity 

to develop into fetal central nervous system 

(CNS) and heart muscle cells. If adult HSC can 

indeed develop into functional cells from unrelated 

tissues, this would permit the possibility of 

using autologous HSC to treat disorders affecting 

various tissues. 


2002 

Chen, AJ, Zhou, G, Juan, T, Colicos, SM, Cannon, 

JP, Cabriera-Hansen, M, Meyer, CF, Jurecic, 

R, Copeland, NG, Gilbert, DJ, Jenkins, NA, 

Fletcher, F, Tan, TH, and Belmont, JW. The dual 

specificity JKAP specifically activates the c-Jun 

N-terminal kinase pathway. Journal of Biological 

Chemistry 277:36592-601, 2002. 

Spassov, DS and Jurecic, R. Cloning and comparative 

sequence analysis of PUM1 and PUM2 

genes, human members of the Pumilio family of 

RNA-binding proteins. Gene 299:195-204, 

2002. 

2003 

Spassov, DS and Jurecic, R. Mouse Pum1 and 

Pum2 genes, members of the Pumilio family of 

RNA-binding proteins, show differential expression 

in fetal and adult hematopoietic stem cells 

and progenitors small star, filled. Blood Cells, 

Molecules and Diseases 30:55-69, 2003. 

Komatsu, M, Mammolenti, M, Jones, M, 

Jurecic, R, Sayers, TJ, and Levy, RB. Antigenprimed 

CD8+ T cells can mediate resistance, preventing 

allogeneic marrow engraftment in the 

simultaneous absence of perforin-, CD95L-, 

TNFR1-, and TRAIL-dependent killing. Blood 

101:3991-99, 2003. 

Spassov, DS and Jurecic, R. The PUF family of 

RNA-binding proteins: does evolutionarily 

conserved structure equal conserved function? 

IUBMB Life 55: 359-66, 2003. 

Liang, H, Chen, Q, Coles, AH, Anderson, SJ, 

Pihan, G, Bradley, A, Gerstein, R, Jurecic, R, and 

Jones, SN. Wnt5a inhibits B cell proliferation 

and functions as a tumor suppressor in hematopoietic 

tissue. Cancer Cell 4:349-60, 2003. 




• Discovered Pum genes as an evolutionarily conserved 

intrinsic mechanism that supports the 

self-renewal of HSC and multipotent progenitors 

by regulating the SCF/c-kit signaling pathway. 

• Discovered a new E3 ubiquitin ligase that affects 

proliferation and differentiation of HSC 

and multipotent progenitors by regulating 

steady-state cytokine receptor levels through 

ligand independent degradation, and that may 

be involved in etiology of hematological malignancies. 

• Found that the Wnt5a gene negatively regulates 

B-cell proliferation, and that inactivation of 

Wnt5a leads to development of myeloid leukemias 

and B-cell lymphomas. Discovery of the 

deletion of the WNT5a gene and/or loss of 

WNT5a expression in human primary leukemias, 

demonstrating for the first time that the 

WNT5a gene functions as a tumor suppressor 

(in collaboration with Stephen Jones, Ph.D., 

University of Massachusetts Medical School). 

KELVIN P. LEE, M.D. 




Research in Dr. Lee’s laboratory focuses on 

the cells and the molecules that play central 

roles in initiating the adaptive immune response. 

Understanding these interactions is essential for 

developing effective immune-based therapies 

against cancer. At the cellular level, they are specifically 

studying the dendritic cells (DC), which 

are thought to be the most important professional 

antigen presenting cell (APC). Because 

DC monitor the local environment for immunologic 

“danger” signals and control what antigens 

are presented to T cells to activate them, they are 

positioned to regulate the initiation of immune 

responses. Their work has examined how DC 

arise from hematopoietic progenitors and their 

intracellular/genetic characteristics. They previously 

have reported that activation of the protein 

kinase C (PKC) intracellular signal transduction 

pathway in human hematopoietic CD34 + stem 

cells causes direct differentiation to a pure population 

of DC. Thus, PKC signaling specifically 

triggers the DC differentiation “program” in 

these cells. Additionally, specific isoforms of PKC 

appear to regulate specific aspects of DC differentiation. 

Ongoing studies are seeking to completely 

characterize the components of the PKC 

signaling pathway and what genetic events are 

triggered by this signal. 

From a translational standpoint, researchers 

in Dr. Lee’s laboratory have found that in 

addition to normal cells, PKC activation can 

drive DC differentiation in acute and chronic 

myeloid leukemic blasts. Because these “leukemic” 

DC retain the ability to activate T cells and 

are endogenously loaded with leukemia antigens, 

they can potentially be used as “cellular” antileukemia 

vaccines by re-infusion back into patients. 

This work aims to bring this approach to 

clinical trials. 

In addition to the DC studies, a clinical trial 

(headed by Dr. Lee) and basic laboratory research 

currently are looking at novel agents against multiple 

myeloma (MM). The NCI-sponsored phase 

I/II clinical trial is examining arsenic trioxide + 

ascorbic acid in the treatment of refractory/relapsed 

MM. Initial results demonstrate that this 

combination is effective against myeloma that is 

resistant to standard chemotherapy (including 

thalidomide) with acceptable toxicity. The laboratory 

component of these studies seeks to understand 

how arsenic kills myeloma, how ascorbic 

acid potentiates that killing, how myeloma cells 

become resistant to arsenic, and which host (i.e., 

patient) factors may actually help the myeloma 

survive in the bone marrow. 

110 




2002 

Strbo, N, Yamazaki, K, Lee, KP, Rukavina, D, 


gp96-Ig mediates strong CD8 CTL expansion in 

vivo. American Journal of Reproductive Immunology 

48:220-25, 2002. 





arsenic trioxide combined with ascorbic acid-mediated 

depletion of intracellular glutathione for 

the treatment of relapsed/refractory multiple myeloma. 


2002. 

Gray, Parkin K, Stephan, RP, Apilado, RG, Lill- 







Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence 

for the requirement of T cell costimulation 

in the pathogenesis of natural Pneumocystis 

carinii pulmonary infection. Microbial Pathogenesis 

33:193-201, 2002. 

2003 




T-cell activation. Xenotransplantation 10:252-58, 

2003. 

McCafferty-Grad, J, Bahlis, NJ, Krett, N, 

Aguilar, TM, Reis, I, Lee, KP, and Boise, LH. 

Arsenic trioxide utilizes caspase-dependent and 

caspase-independent death pathways in myeloma 

cells. Molecular Cancer Therapeutics 2:1155-64, 

2003. 






of NF-KB in the differentiation process of 


64:S128, 2003. 


• Direct activation of PKC causes normal human 

hematopoietic CD34 + stem cells to differentiate 

into DC. 




as “cellular” anti-leukemia vaccines. 

• Specific intracellular signaling pathways downstream 

of PKC activation control specific aspects 

of DC differentiation. 

• Arsenic trioxide + ascorbic acid is an effective 

combination in the treatment of refractory/relapsed 

myeloma. 

Lindner, I, Kharfan-Dabaja, MA, Ayala, E, 

Kolonias, D, Carlson, LM, Beazer-Barclay, Y, 

Scherf, U, Hnatyszyn, JH, and Lee, KP. Induced 

dendritic cell differentiation of chronic myeloid 

leukemia blasts is associated with down-regulation 

of BCR-ABL. Journal of Immunology 

171:1780-91, 2003. 



ROBERT B. LEVY, PH.D. 



Researchers in Dr. Levy’s laboratory study the 

immunological responses following allogeneic 

bone marrow transplantation (BMT), which 

determine the success or failure of the hematopoietic 

graft. The primary objective of these studies 

is to define how different effector molecules 

produced by transplanted donor T cells and by 

barrier cells in the recipient regulate the development 

of graft versus host disease (GVHD) and 

control hematopoietic engraftment, respectively. 

The work concerning GVHD has focused 

on elucidating the role of donor-mediated cytotoxicity 

against recipient cells following the transplant. 

Their findings have demonstrated that 

differing pathways of cytotoxicity play different 

roles in the GVHD process. Granule dependent 

cytotoxicity dependent on perforin function is 

important in the development and onset of the 

disease. Cytotoxicity mediated by CD95L (FasL) 

is an important pathway in the pathogenesis 

occurring in the liver during GVHD and also can 

contribute to cutaneous GVHD. Most interestingly, 

even when both of these molecular pathways 

are absent in donor T cells (i.e., when they 

are “doubly cytotoxic deficient”), they remain 

capable of inducing many GVHD symptoms and 

death in recipients. Dr. Levy and his colleagues 

have recently found that highly purified populations 

of CD8 + or CD4 + T cells lacking these killing 

functions also induce lethal GVHD posttransplant. 

Researchers in this laboratory also investigate 

the process of engraftment following BMT. These 

studies examine the presence of defined donor 

progenitor cell populations (lineage committed 

and more primitive multi-lineage stem cells) and 

peripheral chimerism in recipients post-transplant. 

They are interested in understanding the 

mechanisms used by: 1) donor lymphoid cells for 

their facilitation and support of progenitor cells 

and engraftment after transplant, and 2) barrier 

cells in the host, which inhibit progenitor cells 

112 

and engraftment. Their recent findings have surprisingly 

demonstrated that total body irradiated 

BMT recipients lacking both perforin- and 

CD95L-dependent mechanisms maintain strong 

barrier function. Thus, efforts directed at diminishing 

the host’s ability to affect cytotoxicity 

through these pathways are unlikely to facilitate 

the engraftment process. Transplant of progenitor 

cells with defined cytokine receptor deficiencies 

will be used to further investigate the molecules 

involved. Recent studies also have documented 

that during the first month following BMT, there 

are two defined stages of engraftment, i.e., an 

early period when progenitor cells from the donor 

are present in the recipient followed by a later 

period during which time such cells may be 

eliminated. These findings show that cytotoxic 

function via perforin and FasL is not necessary to 

establish early progenitor presence but is required 

for the establishment of long-term chimerism in 

the recipient. 


2002 

Jiang, Z, Adams, GB, Hanash, AM, Scadden, 

DT, and Levy, RB. The contribution of cytotoxic 

and noncytotoxic function by donor T-cells that 

support engraftment after allogeneic bone marrow 

transplantation. Biology of Blood and Marrow 

Transplantation 8:588-96, 2002. 

Chill, JH, Nivasch, R, Levy, RB, Albeck, S, 

Schreiber, G, and Anglister, J. The human interferon 

receptor: NMR-based modeling, mapping 

of the IFN-alpha 2 binding site, and observed 

ligand-induced tightening. Biochemistry 

41:3575-85, 2002. 

Levy, RB and Aoki, C. Alpha7 nicotinic acetylcholine 

receptors occur at postsynaptic densities 

of AMPA receptor-positive and -negative excitatory 

synapses in rat sensory cortex. The Journal of 

Neuroscience 22:5001-15, 2002. 



2003 

Yu, A, Zhou, J, Marten, N, Bergmann, CC, 

Mammolenti, M, Levy, RB, and Malek, TR. Efficient 

induction of primary and secondary T celldependent 

immune responses in vivo in the 

absence of functional IL-2 and IL-15 receptors. 



• After allogeneic BMT, the recipient can resist 

the engraftment of transplanted donor stem 

cells by using immune responses, which do not 

involve the two major pathways of T lymphocyte-mediated 

killing. This is a surprising finding 

and demonstrates that it is likely that for 

some transplants, different pathways in the recipient 

must be blocked to help the transplanted 

bone marrow engraft. 

• Lymphocytes that are added to donor stem cells 

before transplant to help or facilitate the engraftment 

by these stem cells after transplant, 

use different functions for the purposes of: 1) 

helping to “seed” the stem cells in the recipient, 

and 2) helping to maintain their permanent 

presence. 

MATHIAS G. LICHTENHELD, M.D. 




Cytotoxic lymphocytes defeat tumors and virus 

infections. Their prevailing mechanism 

to kill the diseased targets requires a unique organelle—the 

cytotoxic granule. Perforin, 

granzyme A, and granzyme B constitute the 

prototypic killer molecules of the granule, which 

collaborate to induce the target to commit suicide. 

Researchers in Dr. Lichtenheld’s laboratory 

investigate which genes and transcriptional 

mechanisms promote the identity and function 

of cytotoxic lymphocytes through their endowment 

with cytotoxic granules. Recently, his laboratory 

has shown that the activation and differentiation 

of cytotoxic lymphocytes involves the Stat 

signaling pathway and epigenetic controls of the 

perforin gene. Interestingly, distal regulatory elements 

rather than proximal promoter elements 

are involved, suggesting long-range changes of 

the chromatin structure, which are under investigation 

along with the further characterization of 

the far-distal enhanceosomes that may comprise a 

locus control-like region. To study the hierarchy 

of nuclear events induced during the differentiation 

process, these researchers are characterizing 

transcription factors differentially expressed in 

cDNA subtractions and nuclear proteins differentially 

present in proteomic analyses of 2D gels. 

The functional analysis of the respective genes is 

undertaken in transgenic mice and a unique 

model cell line for the maturation process of cytotoxic 

lymphocytes in which cytokine receptor 

signals determine the maturation process of cytotoxic 

lymphocytes but not their growth and survival. 

Frequently, dysregulation of signaling pathways 

is an essential component of hematopoietic 

malignancies. A particular example is multiple 

myeloma (MM), an incurable B-cell malignancy. 

The goal of a new project is to develop preclinical 

therapies defined at the molecular level. To that 

end, Dr. Lichtenheld’s laboratory has shown that 

the farnesyl transferase inhibitor R115777, 

known to inhibit Ras signaling, kills MM cell 

lines despite Ras prenylation, implying participation 

of Ras-independent mechanism(s). This 

mechanism requires activation of caspase-9. The 

molecular components of this pathway and their 

characterization are under investigation. 


2002 

Zhou, J, Zhang, J, Lichtenheld, MG, and Meadows, 

GG. A role for NF-kappa B activation in 

perforin expression of NK cells upon IL-2 receptor 

signaling. Journal of Immunology 169:1319- 

25, 2002. 



2003 

Lu, Q, Wu, A, Ray, D, Deng, C, Attwood, J, 

Hanash, S, Pipkin, M, Lichtenheld, MG, and 

Richardson, B. DNA methylation and chromatin 

structure regulate T-cell perforin gene expression. 


Beaupre, D, Grad, J, Bahlis, N, Boise, L, and 

Lichtenheld, MG. Farnesyl transferase inhibitors 

sensitize to death receptor signals and induce 

apoptosis of multiple myeloma cells. Leukemia & 

Lymphoma 44:2123-34, 2003. 


• Successfully cloned mouse and human perforin 

genes, including the functional identification of 

the complete transcriptional territory. 

• Identified Stat5 as a central player in lymphocyte-mediated 

cytotoxicity. 

• Developed a novel method to detect regulatory 

domains in up to 100,000 bp restriction fragments. 

• Demonstrated Ras-independent, caspases 9- 

dependent cell death of MM by farnesylation 

inhibitors. 

DIANA M. LOPEZ, PH.D. 



Matrix metalloproteinase-9 (MMP-9), a matrixdegrading 

enzyme, is crucial in tumor 

invasion and metastasis and is implicated in 

leukocyte extravasation. Dr. Lopez and her colleagues 

have demonstrated that during growth of 

the D1-7, 12-dimethylbenzanthracene-3 mammary 

tumor in BALB/c mice, there is progressive 

up-regulation of MMP-9 in splenic T cells at 

both the transcriptional and translational levels. 

Their previous work has identified several factors 

produced by this tumor, including PGE2, granulocyte 

macrophage-colony stimulating factor 

(GM-CSF), and phosphatidyl serine; however, 

none of these agents induces increased production 

of MMP-9 by normal splenic T cells. 

Although not produced by the tumor, tumor necrosis 

factor-alpha (TNF-α), and interleukin-6 

(IL-6) are up-regulated in both macrophages and 

B cells in tumor-bearing mice. Exposure of normal 

T cells to these two cytokines, however, also 

fails to up-regulate MMP-9 production. Vascular 

endothelial growth factor (VEGF) is produced by 

many tumors, and it was determined that the 

mammary tumors used in studies express high 

levels of this angiogenic growth factor. Importantly, 

splenic T cells from tumor bearers constitutively 

produce increased amounts of VEGF, 

and treatment of normal T cells with VEGF results 

in up-regulated MMP-9 production. Of 

crucial importance is their finding that tumorinfiltrating 

T cells also produce high levels of 

VEGF and MMP-9. Studies indicate that VEGF 

can act directly on T lymphocytes and that elevated 

VEGF levels may contribute to the aberrant 

MMP-9 secretion by mammary tumor 

bearers’ T cells. 

Development of mammary tumors results in 

profound down-regulation of macrophage 

functions. Dr. Lopez and her colleagues have 

previously described that peritoneal elicited macrophages 

(PEMs) from mice-bearing large mammary 

tumors have profoundly depressed 

production of IL-12 and nitric oxide (NO). 

Analysis of the molecular events occurring during 

these down-regulations has revealed that the 

mRNA expression of both IL-12p40 and the inducible 

nitric oxide synthase (iNOS) appears to 

be diminished. An analysis of transcription factors 

that might be involved in such phenomena 

was undertaken, using electromobility shift assay 

(EMSA). The major transcription factors reported 

to be involved in the synthesis of IL- 

12p40 are NFκB, C/EBP, ets (PU.1), and AP-1. 

In the case of iNOS, NFκB is the major transcription 

factor reported to be involved. Recent 

evidence using transfection experiments with 

dominant negative mutants suggest that C/EBP 

and ATF-2 also may be involved in the regulation 

of the iNOS promoter. Comparative studies by 

114 



EMSA, using probes specific for the IL-12p40 

and iNOS murine promoters, revealed that in 

macrophages from tumor-bearing mice, the binding 

activities of NFκB and C/EBP are downregulated 

in both promoters. Their results suggest 

that in macrophages from tumor hosts, the 

NFκB and C/EBP might be functionally impaired. 

These two transcription factors are crucial 

for appropriate innate immunity functions. Pertinent 

studies are ongoing in Dr. Lopez’s laboratory 

to determine if these deficiencies in the presence 

of the tumor environment could be due to insufficient 

amounts, inadequate levels of phosphorylation, 

or impaired translocation of these 

transcription factors. 

Implantation of DA-3 mammary tumor 

cells into BALB/c mice results in tumor growth, 

metastatic lesions, and death. These cells were 

transfected with genes encoding for either 

the transmembrane (DA-3/TM) or secreted 

(DA-3/sec) form of human mucin 1 (MUC1). 

Although the gene for the secreted form lacks the 

transmembrane and cytoplasmic domains, the 5’ 

sequences of these mucins are identical. However, 

the gene for the secreted mucin isoform ends 

with a sequence encoding for a unique 11 amino 

acid peptide. The DA-3/TM cells or DA-3 cells 

transfected with the neomycin vector only (DA- 

3/neo) have the same in vivo growth characteristics 

as the parent cell line. In contrast, DA-3/sec 

cells implanted in nude mice resulted in tumor 

development verifying the tumorigenic potential 

of these cells. Pre-exposure of BALB/c mice to 

DA-3/sec cells afforded protection against challenge 

with DA-3/TM or DA-3/neo mammary 

tumors and the unrelated tumors K7, an osteosarcoma, 

and RENCA, a renal cell carcinoma. 

Partial protection against subsequent tumor 

challenges was also achieved by substituting 

the 11 amino acid peptide found only in the 

secreted mucin-1 isoform, as it also retarded the 

growth of Lewis lung carcinoma cells in C57 

BL/6 mice. These findings reveal that a unique 

peptide present in the secreted MUC1 has 

immunoenhancing properties and may be a 

potential agent for use in immunotherapy. 


2002 

Sun, QL, Charyulu, V, Lobo, D, and Lopez, 

DM. Role of thymic stromal cell dysfunction in 

the thymic involution of mammary tumor-bearing 

mice. Anticancer Research 22:91-6, 2002. 




7:191-99, 2002. 

2003 

Torroella-Kouri, M, Keith, JC, Ivanova, M, and 

Lopez, DM. IL-11-induced reduction of C/EBP 

transcription factor binding may contribute to 

the IL-12 downregulation in tumor-bearing mice. 

International Journal of Oncology 22:439-48, 

2003. 

Owen, JL, Iragavarapu-Charyulu, V, Gunja- 

Smith, Z, Herbert, LM, Grosso, JF, and Lopez, 

DM. Up-regulation of matrix metalloproteinase- 

9 in T lymphocytes of mammary tumor bearers: 

role of vascular endothelial growth factor. Journal 

of Immunology 171(8):4340-51, 2003. 

Torroella-Kouri, M and Lopez, D. Mammary 

tumor derived TGF-β impairs crucial innate immune 

responses in tumor hosts. Journal of Immunology 

and Immunopathology 5:31-38, 2003. 


• The thymus is crucial for the development of 

T lymphocytes involved in cell-mediated immunity 

to tumors. The thymuses of mammary 

tumor bearers are profoundly involuted and 

their studies have shown that this is not due to 

a decrease of the thymocytes proliferation. A 

minor increase of apoptosis was noted; however, 

the major cause of this phenomenon appears to 

be an arrest at an early stage of differentiation 

possibly brought about by the direct or indirect 

effects of tumor derived factors. 

• A unique peptide with immunoenhancing 

properties has been identified in a secreted form 

of human MUC1 and used in vaccination ex- 



periments. This peptide inhibits tumor development 

not only in the mammary cells transfected 

with the secreted MUC1, but also provides protection 

against a variety of other tumor types. 

• The very important molecule MMP-9 has been 

shown to be overproduced by T lymphocytes from 

tumor bearing mice due in part to the overexpression 

of vascular endothelial growth factor. 

The intriguing possibility that this molecule 

may be helping tumor spread is being evaluated. 

THOMAS R. MALEK, PH.D. 



The development of lymphocytes and the 

regulation of the immune response are critically 

controlled by cytokines that mediate their 

function by binding to specific multi-subunit cell 

surface receptors. Recent evidence by others has 

established that the genetically inherited X-linked 

severe combined immunodeficiency disease 

(SCID) is the result of mutations in the γc cytokine 

receptor subunit that is a shared component of 

the receptors for interleukin-2 (IL-2), IL-4, IL-7, 

IL-9, and IL-15. This genetic defect prevents the 

function of these five cytokines, resulting in a 

severe blockade in T-lymphocyte development 

and a greatly impaired immune system. These 

cytokines and receptors are also important regulators 

of the peripheral immune compartment. 

A long-term goal of Dr. Malek’s laboratory 

is to understand the role of cytokine receptors, 

especially the IL-2 receptor, in the regulation of 

the immune system. A current research emphasis 

is to establish the molecular basis by which the γc 

subunit contributes to binding multiple cytokines 

as a component of five cytokine receptors and to 

determine the mechanism by which γc utilizing 

cytokines control T-cell development and function. 

Another major aim of his laboratory is to 

study the interaction of tumor-specific T cells 

with its cognate tumor to define the mechanisms 

responsible for failed anti-tumor immunity and 

to develop new strategies to more effectively engage 

the immune system to reject tumors. 

Related to these goals, progress has been 

made in the following areas: 1) distinct functional 

regions of the extracytoplasmic domain of 

γc have been defined and demonstrate that IL-2 

and IL-7 utilize largely overlapping sites within 

γc; 2) a cytoplasmic subdomain of γc was identified 

that is critical for rapid IL-2-induced receptor-mediated 

endocytosis, which occurs by a 

novel proteasome dependent pathway; 3) IL-7 

and IL-15 were found to be the essential gc-dependent 

cytokines important for thymic-dependent 

T-cell development, while IL-2, IL-7, and 

IL-15 are required for the full production of 

intraepithelial T lymphocytes, a second anatomical 

site of T-cell development; 4) separate cytoplasmic 

domains of the IL-7Rα chain controlled 

distinct activities during T-cell development, 

while normal IL-7R-dependent thymic development 

requires the integrated activity of all these 

domains; 5) a novel and unexpected role for IL-2 

in thymic development was uncovered that is essential 

to prevent autoimmunity and is related to 

the production of T regulatory cells; and 6) one 

important reason for failed anti-tumor immunity 

is that tumor-specific T cells are ignorant of the 

growing tumor. Memory T cells, however, were 

shown not to be ignorant and induced effective 

anti-tumor immune responses. Importantly, a 

dendritic cell (DC)-based vaccine potently functioned 

to induce tumor immunity, which sometimes 

may lead to the rejection of the tumor. 


2002 

Olosz, F and Malek, TR. Structural basis for 

binding multiple ligands by the common 

cytokine receptor gamma-chain. Journal of Biological 

Chemistry 277:12047-52, 2002. 

Demirci, G, Gao, W, Zheng, XX, Malek, TR, 

Strom, TB, and Li, XC. On CD28/CD40 ligand 

costimulation, common gamma-chain signals, 

and the alloimmune response. Journal of Immunology 

168:4382-90, 2002. 

116 







Immunity 17:167-78, 2002. 

Malek, TR. T helper cells, IL-2 and the generation 

of cytotoxic T-cell responses. Trends in Immunology 

23:465-67, 2002. 

2003 

Molano, RD, Pileggi, A, Berney, T, Poggioli, R, 

Zahr, E, Oliver, R, Malek, TR, Ricordi, C, and 

Inverardi, L. Long-term islet allograft survival in 

nonobese diabetic mice treated with tacrolimus, 

rapamycin, and anti-interleukin-2 antibody. 


Bathe, OF, Dalyot-Herman, N, and Malek, TR. 

Therapeutic limitations in tumor-specific CD8+ 

memory T cell engraftment. BMC Cancer 3:21, 

2003. 


• Established that the essential non-redundant 

function of IL-2 is the development of 

CD4 + CD25 + T regulatory cells. 

ECKHARD R. PODACK, M.D., PH.D. 

Professor and Chairman of Microbiology 



Induction of Immunity by Heat Shock 

Protein gp96-Ig 

Heat shock protein gp96 is a natural adjuvant 

and a peptide chaperone binding to antigen 

presenting cells (APC) inducing APC activation, 

maturation, and channeling gp96-associated 

peptides into the class I major histocompatibility 

complex (MHC) presentation pathway for 

priming CD8 cytotoxic T lymphocyte (CTL) 

responses. Gp96 is unique in that it provides 

antigenicity and peptide-specificity through its 

peptide chaperone function and adjuvanticity 

through its ability to bind to scavenging receptors 

and toll-like receptors (TLRs) and to activate 

APC. Realizing the potential of gp96 as a vaccine, 

Dr. Podack’s laboratory had previously created a 

gp96-Ig fusion protein that is secreted from tumor 

cells upon transfection. In murine studies, 

tumor secreted gp96-Ig induced specific CD8 

cytotoxic T lymphocyte (CTL) expansion and, 

when used as vaccine, mediated tumor rejection 

and long lasting tumor immunity by CD8 cells 

with the help of natural killer (NK) cells. Murine 

preclinical data suggest that human tumor cells 

secreting gp96-Ig will be a powerful, therapeutic 

CD8 CTL vaccine, because gp96-Ig provides 

both the adjuvant effect and the specific peptides 

for dendritic cell (DC) activation and presentation. 

Tumor secreted gp96-Ig recruits and activates 

DC and NK cells, and causes CD8 CTL 

expansion. The molecular determinants of the 

three-way cell interaction are studied by Dr. 

Podack and his colleagues. The potential of gp96- 

Ig to break immune tolerance to tumors is also 

under investigation. 

Death Receptor and its Ligand TL1a Mediate 

TH2 Switch and Contribute to Asthma 

The biological function of death receptor 3 

(DR3, TNFR-SF12) is not known. DR3- 

transgenes expressed on T cells were used to determine 

the physiological function of DR3, a 

member of the tumor necrosis factor (TNF)- 

receptor family expressing an intracellular death 

domain. The full-length form of DR3, a dominant 

negative form of DR3 (DR3-DN) lacking 

the intracellular death domain and an alternatively 

spliced form of DR3 (DR3-∆5, 6) lacking 

exon 5 and 6 encoding the fourth extracellular 

cysteine rich domain, was analyzed by Dr. 

Podack’s laboratory. Transgenic expression of 

DR3 on T cells mediated TH2 polarization of 

cytokine and antibody production upon T-cell 

activation and antigen exposure. In addition, 

DR3 partially inhibited T-cell receptor (TCR) 

driven proliferation of CD4 and CD8 cells and 

reduced total T cell numbers in lymphoid organs 

without inducing apoptosis. CD8 cells were more 



affected by DR3 than CD4 cells. They concluded 

that DR3 signals may be important in effector 

responses to pathogens by shaping the ensuing 

polarization toward TH2 or toward a mixed 

TH1/TH2 response. 

DR3 transgenic mice were highly susceptible 

to antigen-induced airway hyper-reactivity in an 

asthma model in mice and produced increased 

quantities of interleukin-13 (IL-13) and eosinophils 

in the lung upon antigen exposure by inhalation. 

Transgenic mice expressing a dominant 

negative form of DR3 showed increased resistance 

to airway hyper reactivity when compared 

to wild type mice. Similarly, a blocking anti- 

TL1a antibody was able to ameliorate asthma in 

wild type mice, indicating that DR3 and TL1a 

are involved in the pathogenesis of asthma. 

CD30—Governor of T Cells? 

CD30-L knock-out mice, when challenged with 

tumor secreted gp9-Ig, exhibit severely diminished 

CD8 CTL expansion. When used as allogeneic 

bone marrow graft recipients, collaboration 

with the laboratory of Robert B. Levy, Ph.D., 

showed that CD30-L knock-out exhibit diminished 

graft versus host disease in a MHC II mismatch. 

CD30 is highly expressed on CD45-RO 

memory cells and serves as a T-cell costimulator 

and as a regulator of trafficking molecules and of 

pro- and anti-apoptotic molecules. CD30 signals 

lead to IL-13 and Ifn-g production. Researchers 

in Dr. Podack’s laboratory are studying the function 

of CD30 and its ligand in tumor rejection 

following vaccination. 

Immunotherapy for Advanced Non-Small Cell 

Lung Carcinoma 

To determine whether CD8-mediated immune 

responses could be elicited in stage IIIB/IV nonsmall 

cell lung carcinoma (NSCLC) patients, 19 

subjects were immunized several times with allogeneic 

NSCLC cells transfected with CD80 

(B7.1) and HLA-A1 or A2. Patients enrolled 

were matched or unmatched at the HLA A1 or 

A2 locus and their immune response compared. 

Immunization significantly increased the frequencies 

of interferon-γ secreting CD8 T cells in 

all but one patient in response to ex vivo challenge 

with NSCLC cells. The CD8 response of 

matched and unmatched patients was not statistically 

different. NSCLC reactive CD8 cells did 

not react to K562. Clinically, 6 of 19 patients 

responded to immunization with stable disease or 

partial tumor regression. The study demonstrates 

that CD8 Ifn-γ responses against non-immunogenic 

or immunosuppressive tumors can be 

evoked by cellular vaccines even at advanced 

stages of disease. The positive clinical outcome 

suggests that non-immunogenic tumors may be 

highly susceptible to immune effector cells generated 

by immunization. Further trials with curative 

intent are warranted. 

Macrophage-Perforin, a New Member of the 

Perforin/C9 Family of Proteins 

Searching the genomic database with perforin as 

query sequence, Dr. Podack and colleagues found 

two novel members of the perforin family. Structure 

analysis suggests that the novel members 

have a typical pore-forming domain but that the 

proteins themselves are membrane anchored. Expressed 

sequence tags (EST) analysis suggests that 

one new perforin member is expressed in trophoblast 

cells, while the second member is expressed 

in macrophages. The laboratory has cloned the 

macrophage-perforin (MΦ-Pf) and fused a gfp 

tag to it for ease of detection. Expression of MΦ- 

Pf-gfp in NIH 3T3 cells and in 293T cells results 

in fluorescence in the nucleus and in the cytoplasm. 

Fluorescent cells, however, subsequently 

round up and die, and after several days no fluorescence 

is detected. The data suggest that expression 

of MΦ-Pf leads to cell death, putatively by 

ectopic expression of a pore former. The data further 

suggest that MΦ-perforin and trophoblastperforin 

have essential lytic functions that need to 

be carefully regulated for expression. Dr. Podack’s 

laboratory team is in the process of deleting MΦ- 

Pf and trophoblast-Pf in order to discover their 

physiological function. 

118 




2002 

Metkar, SS, Wang, B, Aguilar-Santelises, M, Raja, 

SM, Uhlin-Hansen, L, Podack, ER, Trapani, JA, 

and Froelich, CJ. Cytotoxic cell granule-mediated 

apoptosis: perforin delivers granzyme B-serglycin 

complexes into target cells without plasma membrane 

pore formation. Immunity 16:417-28, 

2002. 

Kawasaki, C, Ohshima, K, Muta, H, Muta, K, 

Deyev, V, Podack, ER, and Kikuchi, M. Prognostic 

value of Bcl 10 rearrangement in diffuse large 

B-cell lymphoma. Leukemia & Lymphoma 

43:823-26, 2002. 

Merger, M, Viney, JL, Borojevic, R, Steele- 

Norwood, D, Zhou, P, Clark, DA, Riddell, R, 

Maric, R, Podack, ER, and Croitoru, K. Defining 

the roles of perforin, Fas/FasL, and tumour 

necrosis factor alpha in T cell induced mucosal 

damage in the mouse intestine. Gut 51:155-63, 

2002. 

Harlin, H, Podack, ER, Boothby, M, and Alegre, 

ML. TCR-independent CD30 signaling selectively 

induces IL-13 production via a TNF receptor-associated 

factor/p38 mitogen-activated 

protein kinase-dependent mechanism. Journal of 

Immunology 169:2451-59, 2002. 

Nam, SY, Cho, KS, Heo, YM, Ha, JC, Kim, YH, 

Keun Yi, H, Han Hwang, P, Kim, HM, and 

Podack, ER. Regulation of lymphocyte clustering 

by CD30-mediated ICAM-1 up-regulation. Cellular 

Immunology 219:38-47, 2002. 

Laskarin, G, Tokmadzic, VS, Strbo, N, Bogovic, 

T, Szekeres-Bartho, J, Randic, L, Podack, ER, 

and Rukavina, D. Progesterone induced blocking 

factor (PIBF) mediates progesterone induced suppression 

of decidual lymphocyte cytotoxicity. 

American Journal of Reproductive Immunology 

48:201-9, 2002. 

Par, G, Rukavina, D, Podack, ER, Horanyi, M, 

Szekeres-Bartho, J, Hegedus, G, Paal, M, 

Szereday, L, Mozsik, G, and Par, A. Decrease in 

CD3-negative-CD8dim(+) and Vdelta2/ 

Vgamma9 TcR+ peripheral blood lymphocyte 

counts, low perforin expression and the impairment 

of natural killer cell activity is associated 

with chronic hepatitis C virus infection. Journal 

of Hepatology 37:514, 2002. 

Strbo, N, Yamazaki, K, Lee, K, Rukavina, D, and 

Podack, ER. Heat shock fusion protein gp96-Ig 

mediates strong CD8 CTL expansion in vivo. 


48:220-25, 2002. 

Tokmadzic, VS, Tsuji, Y, Bogovic, T, Laskarin, G, 

Cupurdija, K, Strbo, N, Koyama, K, Okamura, 

H, Podack, ER, and Rukavina, D. IL-18 is 

present at the maternal-fetal interface and enhances 

cytotoxic activity of decidual lymphocytes. 


48:191-200, 2002. 

Podack, ER, Strbo, N, Sotosec, V, and Muta, H. 

CD30-governor of memory T cells? Annals of the 

New York Academy of Sciences 975:101-13, 

2002. 

2003 

Dai, J, Liu, B, Caudill, MM, Zheng, H, Qiao, Y, 

Podack, ER, and Li, Z. Cell surface expression of 

heat shock protein gp96 enhances cross-presentation 

of cellular antigens and the generation of 

tumor-specific T cell memory. Cancer Immunity 

3:1, 2003. 

Dix, RD, Podack, ER, and Cousins, SW. Loss of 

the perforin cytotoxic pathway predisposes mice 

to experimental cytomegalovirus retinitis. Journal 

of Virology 77:3402-8, 2003. 

Strbo, N, Oizumi, S, Sotosek-Tokmadzic, V, and 

Podack, ER. Perforin is required for innate and 

adaptive immunity induced by heat shock protein 

gp96. Immunity 18:381-90, 2003. 

Gulan, G, Ravlic-Gulan, J, Strbo, N, Sotosek, V, 

Nemec, B, Matovinovic, D, Rubinic, D, Podack, 

ER, and Rukavina, D. Systemic and local expression 

of perforin in lymphocyte subsets in acute 

and chronic rheumatoid arthritis. Journal of 

Rheumatology 30:660-70, 2003. 



Dix, RD, Podack, ER, and Cousins, SW. Murine 

cytomegalovirus retinitis during retrovirus-induced 

immunodeficiency (MAIDS) in mice: 

interleukin-2 immunotherapy correlates with increased 

intraocular levels of perforin mRNA. Antiviral 

Research 59:111-19, 2003. 

Raez, L, Cassileth, PA, Schlesselman, JJ, 

Padmanabhan, S, Fisher, EZ, Baldie, PA, 

Sridhar, K, and Podack, ER. Induction of CD8 

T-cell-Ifn-γ response and positive clinical outcome 

after immunization with gene-modified 

allogeneic tumor cells in advanced non-small-cell 

lung carcinoma. Cancer Gene Therapy 10:850- 

58, 2003. 


• Completed successful lung tumor vaccine trial. 

• Discovered that MΦ-perforin, a new member 

of the perforin family, promises interesting discoveries. 

• Discovered that death receptor 3 does not kill, 

but produces, IL-13, which is immunosuppressive 

and mediates asthma. 

• Realized potential of heat shock proteins to 

enter the clinical field of immunotherapy. 

RICHARD L. RILEY, PH.D. 



Altered B Cell Development in Senescence 

Senescent mice show diminished B lymphopoiesis 

when compared to young mice and typically 

exhibit decreased numbers of pre-B cells and 

newly formed B cells within the bone marrow. 

Researchers in Dr. Riley’s laboratory have focused 

upon elucidating the mechanisms responsible for 

the altered B lymphopoiesis in old age and the 

ramifications for antibody repertoire and humoral 

immunity. In particular, he and his colleagues 

have found that B lymphopoiesis in old 

age is partially interrupted at the pro-B to pre-B 

cell transition, a developmental step that requires 

both function of the pre-B cell receptor complex 

and responses to the growth and survival cytokine 

interleukin-7 (IL-7). Expression of a critical component 

of the pre-B cell receptor, the surrogate 

light chain, is reduced in aged mice, and IL-7 

responsiveness is diminished. This predisposes the 

B-cell precursors in aged mice to apoptotic cell 

death. These functions, and others important to 

B-cell development, are governed, in part, via the 

transcriptional regulator E2A. E2A expression 

also is compromised in old age; this appears to 

involve enhanced degradation of E2A proteins. 

As a consequence of the B-cell developmental 

deficits in old age, the repertoire of antibody 

specificities is skewed and the capacity to develop 

effective immune responses is hindered. 


2002 

Riley, RL, Knowles, J, and King, AM. Levels of 

E2A protein expression in B cell precursors are 

stage-dependent and inhibited by stem cell factor 

(c-kit ligand). Experimental Hematology 

30:1412-18, 2002. 

2003 



precursor phenotypes differing in activation, proliferation 


38:1137-47, 2003. 





170:719-26, 2003. 

Sherwood, EM, Xu, W, and Riley, RL. B cell precursors 

in senescent mice exhibit decreased recruitment 

into proliferative compartments and 

altered expression of Bcl-2 family members. 

Mechanisms of Ageing and Development 

124:147-53, 2003. 

120 











Id Inhibitory proteins in bone marrowderived 


8:A110-6, 2003. 





170:719-26, 2003. 

Wilson, EL, Sherwood, EM, King, AM, and 

Riley, RL. A phenotypically distinct subset of 

bone marrow immature B cells exhibits partial 

activation, increased survival, and preferential 

expression of VhS107. European Journal of Immunology 

33:3398, 2003. 


• Molecular deficits, which underlie dysfunctions 

in lymphocyte activity during old age, have yet 

to be well characterized. These findings, that 

expression of a transcription factor (E2A) and 

surrogate light chains, both of which are critical 

to B-lineage cell development, are decreased in 

aged B-cell precursors, provide a molecular basis 

for understanding deficient lymphopoiesis in 

senescence. 

JOSEPH D. ROSENBLATT, M.D. 

Professor of Medicine and 

Division Chief of Hematology-Oncology 


Dr. Rosenblatt’s research focuses on the development 

of novel immune therapy and gene 

therapy strategies for cancer. Current research has 

focused on the potential role of recruitment of 

immune effector cells, using the local elaboration 

of both constitutive and inflammatory chemokines, 

such as secondary lymphoid chemokine 

(SLC), DC-CK1, and/or RANTES respectively, 

on the development of an anti-tumor response. 

Chemokine delivery has been investigated alone, 

or in combination with, expression of the costimulatory 

ligands CD80 (B7.1) or CD40L. 

Several delivery strategies have been investigated 

including the use of retroviral vectors, and/or the 

use of herpes simplex virus (HSV) amplicon vectors 

in several murine tumor models. Preliminary 

results suggest that the recruitment of naïve T 

cells using SLC is a particularly effective means of 

enhancing the anti-tumor immune response, particularly 

when combined with CD40L-induced 

co-stimulation. This strategy is being formally 

investigated using the OT-1 transgenic mouse 

model, which has a constitutively expressed T-cell 

receptor with defined anti-ovalbumin specificity 

and the murine tumors expressing the target ovalbumin 

antigen, for effects on tumor-induced tolerance 

and the development of systemic 

immunity. 

In a separate effort, the utility of HSV-derived 

helper virus-free amplicons is being tested 

for efficacy in augmenting the immunogenicity 

and antigen-presenting capability of fresh chronic 

lymphocytic leukemia cells (CLL). Both CD40L, 

CD80, and/or the tumor necrosis factor (TNF) 

ligand family member LIGHT, have been targeted 

to fresh CLL cells using the helper free 

HSV amplicons. Results suggest the augmented 

ability of such CLL cells to present antigen in an 

allogeneic mixed-lymphocyte-tumor cell reaction 

and/or to serve as stimulatory cells for the deriva- 



tion of autologous cytolytic T cells in vitro without 

deleterious effects on major histocompatibility 

complex (MHC)-I expression seen with HSV 

helper virus-containing preparations. 

A novel means of immune effector molecule 

delivery, which combines the antigen binding 

capabilities and localization characteristics of antibodies 

with the local delivery of a co-stimulatory 

molecule, anti-angiogenic peptide, or a 

chemokine, also is under investigation. Antibody 

fusion proteins targeting the human breast and 

ovarian cancer her2/neu antigen, linked to the 

extracellular domains of the B7.1 and/or 41BB-L 

costimulatory ligands, have been synthesized and 

the in vitro ability to bind to cognate antigenic 

targets and to deliver a local costimulatory signal 

documented. Additional fusions currently being 

developed in the laboratory include fusion of the 

anti-angiogenic peptide endostatin to anti-her2/ 

neu antibody sequences, as well as fusion of the 

inflammatory chemokine RANTES. Selective 

targeting of immune effector cells using both local 

chemokine vector administration or antibodyfusion 

protein administration is being evaluated 

further. 

A novel antibody-fusion that targets delivery 

of endostatin to the site of her2/neu expressing 

tumors also has been synthesized in collaboration 

with Seung-Uon Shin, M.D., and shows excellent 

efficacy in preclinical models. This fusion appears 

to substantially improve the results obtained with 

either antibody or endostatin alone. 

Currently, Dr. Rosenblatt’s laboratory is 

studying efficacy using a novel B-cell deficient 

mouse model, which allows testing of antibody 

fusion protein targeting to xenogeneic (e.g., CEA, 

her2/neu) antigens, while preserving T-cell immune 

effector functions. The B cell-deficient model 

also has demonstrated that T-cell responses to 

tumor may be better than those seen in the immunocompetent 

mouse. The laboratory currently 

is investigating the reasons for altered responses 

in the absence of B cells and the possibility of 

applying this approach to the human setting using 

antibody depletion of B cells with rituximab. 

Dr. Rosenblatt and his colleagues also have 

collaborated with the laboratory of Vicente 

122 

Planelles, Ph.D., at the University of Utah, on 

the development of several new approaches to 

HIV-1 gene therapy. These include the use of 

mutated tRNA LYS3 primers, which can anneal to 

the sequences other than primer–binding sequences 

on the HIV-1 genome, or tRNA LYS3 mutated 

in adenosine residue A58, which prevents 

normal methylation of the adenosine residue and 

disrupts proper termination of the nascent reverse 

transcript, thereby inhibiting completion of HIV- 

1 reverse transcription in model systems. Other 

investigations have centered on the effects of defective 

HIV-1 derived vectors on HIV-1 spread in 

culture. Recent experiments have demonstrated 

that efficient trafficking of defective HIV-1 vectors 

is observed in vitro and the following superinfection 

with wild type HIV-1 and that such 

trafficking results in a marked inhibition of wild 

type viral spread. 


2002 





39:31-35, 2002. 







2002. 



in immune therapy of cancer. Israel Medical Association 

Journal 4:1054-59, 2002. 



HSV amplicon mediated-delivery of LIGHT enhances 



63, 2002. 



Andela, VB, Rosenblatt, JD , Schwarz, EM, Puzas, 

EJ, O’Keefe, RJ, and Rosier, RN. Synergism of 

aminobisphosphonates and farnesyl transferase 

inhibitors on tumor metastasis. Clinical Orthopaedics 

and Related Research 397:228-39, 2002. 

2003 








10:251-9, 2003. 





415 (Supplement): S59-66, 2003. 


Lu, C, McNair, C, Abboud, CN, and Rosenblatt 



Leukemia 17:1806-12, 2003. 




21:323-24, 2003. 


• Developed novel antibody-chemokine and antibody 

co-stimulatory ligand fusion proteins with 

dual function and preserved targeting capabilities. 

• Developed a novel strategy for gene therapy of 

HIV-1 using mutations introduced into 

tRNA LYS3 primers. 

• Demonstrated the potential role for HSV 

amplicon vectors in gene therapy of malignancy, 

particularly CLL. 

• Demonstrated trafficking and inhibition by 

defective HIV-1 as a novel approach to HIV-1 

gene therapy. 

• Demonstrated the utility of combining 

chemokine delivery with costimulating ligands 

in augmenting mouse response to tumors. 

GIOVANNA R. THOMAS, M.D. 



Head and neck squamous cell carcinoma 

(HNSCC) of the upper aerodigestive tract is 

a devastating disease that impacts human communication 

and survival. Lack of effective immune 

responses is important in the progression 

of HNSCC and is a prognostic marker for poor 

clinical response and decreased survival. The 

long-range goal of Dr. Thomas’ research is to develop 

novel therapeutic modalities to improve 

anti-tumor immunity in patients with HNSCC 

who continue to have disappointingly low survival 

rates despite aggressive treatments. The 

CD80/CD28 co-stimulation pathway is critical 

for T-cell activation and proliferation. It has been 

well documented in the literature that engagement 

of CD80 on antigen-presenting cells by its 

receptor CD28 on T cells leads to multiple effects 

on immune responses in addition to increasing 

the synthesis of autocrine growth factors such as 

interleukin-2 (IL-2). To date, however, not much is 

known regarding the role of CD80 co-stimulatory 

molecules in generating anti-tumor immune responses 

against tumors formed from epithelial cells. 

Dr. Thomas’ objective is to determine the 

role and regulation of the CD80 co-stimulatory 

molecule during tumor progression of HNSCC. 

Her laboratory has previously characterized the 

expression of CD80 in different murine HNSCC 

clones derived naturally following tumor progression 

in the absence of T cell-mediated immunity 

in severe combined immune deficient (SCID) 

mice. Exciting features observed during their 

study were that HNSCC that did not express 

CD80 grew as progressors, while those that expressed 

CD80 were regressors when grown in immune 

competent animals. Preliminary data show 



CD80-mediated T-cell dependent anti-tumor 

immunity and the generation of protective immunity 

in animals are resistant to rechallenge. In 

addition, they found that constitutive expression 

of one or more of the cytokines IL-1α, IL-6, and 

GM-CSF is associated with down-modulation of 

CD80 co-stimulatory molecule expression in oral 

HNSCC cells. The HNSCC cell lines that exhibit 

a combination of constitutive cytokine expression 

and low CD80 expression also exhibit 

increased tumorigenic potential in immune-competent 

mice, as previously reported. Reduction of 

CD80 co-stimulatory molecule expression by 

pro-inflammatory cytokines IL-1α, IL-6, and 

GM-CSF has not been previously described. This 

decrease in CD80 expression during malignant 

progression of HNSCC may result in dysfunctional 

anti-tumor immunity, thereby promoting 

malignant growth. 

Studies are under way to determine the regulatory 

mechanisms of cytokine-induced downregulation 

of CD80 expression and to determine 

the prognostic significance of its expression on 

tumor specimens from patients with HNSCC. 

Once the role and regulation of CD80 in 

HNSCC are understood, CD80 expression can 

be up-regulated pharmacologically in new and 

innovative approaches to increase anti-tumor immune 

responses for the prevention and treatment 

of HNSCC. 


2002 

Thomas, GR, Regalado, JJ, and McClinton, M. 

A rare case of mucoepidermoid carcinoma of the 

nasal cavity. Ear, Nose, and Throat Journal 

81:519-22, 2002. 

2003 

Pandey, M, Chandramohan, K, Thomas, G, 

Mathew, A, Sebastian, P, Somanathan, T, 

Abraham, EK, Rajan, B, and Krishnan Nair, M. 

Soft tissue sarcoma of the head and neck region 

in adults. International Journal of Oral and Maxillofacial 

Surgery 32:43-48, 2003. 

124 

KHALED TOLBA, M.D. 



During the past five years, Dr. Tolba has been 

developing immunotherapeutic strategies for 

B-cell hematologic malignancies, with particular 

interest in chronic lymphocytic leukemia (CLL). 

CLL is the most common leukemia in the Western 

hemisphere. As a relatively slow-progressing 

tumor with readily accessible tumor cells, it offers 

an opportunity to develop and test immunotherapeutic 

interventions. A number of profound 

immunologic deficiencies affecting both the B- 

and T-cell responses, however, have posed a challenge 

to immune therapy of CLL. 

The laboratory has co-developed and 

adapted the use of herpes simplex virus (HSV) 

amplicons for gene transduction of CLL cells. 

Using CD40L as an effector molecule, they have 

shown robust induction of co-stimulatory molecules 

on transduced and bystander cells 

and in roughly one-third of tested patients 

demonstrated the capacity to generate cytotoxic 

T lymphocyte (CTL) activity. This capacity to 

elicit autologous CTL response, however, was not 

universal as more than half the patients tested 

failed to mount such a response in spite of adequate 

up-regulation of co-stimulatory signal on 

both transduced and bystander CLL cells. In addition 

to being a highly efficient gene transfer vector, 

herpes simplex virus (HSV)-based amplicons 

possess the capacity to engage and activate different 

elements of the innate immune system. Currently, 

the laboratory is studying various aspects of HSV 

amplicon/innate immune interaction and their 

influence on the outcome of an adaptive antitumor 

immune response. 

Immune therapeutic strategies targeting the 

innate immune system might offer an alternative 

pathway to bypass inherent CD8 + T-cell defects 

and effectively mount a systemic anti-tumor immune 

response. Dr. Tolba and his colleagues are 

exploring how HSV amplicon interacts with the 

family of toll-like (TL) receptors and up-regulates 

NKG2D ligands on target cells. 




2002 



Herpes simplex virus (HSV)-amplicon-mediated 

delivery of LIGHT enhances the antigen-presenting 

capacity of chronic lymphocytic leukemia. 

Molecular Therapy 6:455-63, 2002. 







2002. 



in immune therapy of cancer. Israel Medical 

Association Journal 4:1054-59, 2002. 

MARTA TORROELLA-KOURI, PH.D. 

Assistant Professor of Microbiology 



When tumor cells initially emerge in a 

healthy organism, they are recognized by 

the immune system. This recognition leads to an 

incipient defense reaction and elimination of the 

initial tumor cell population. For unknown reasons, 

however, some tumors progress, infiltrate, 

and eventually metastasize and kill the host. Before 

this occurs, a progressive decline in the immune 

response of the host is observed. Today, 

researchers know that the tumor is directly responsible 

for this immunodepression observed in 

tumor-bearing organisms. 

The study of the interplay between a tumor 

and its host, in terms of the mechanisms displayed 

by the tumor that eventually control and 

diminish the otherwise healthy immune response 

of the host organism, is the center of Dr. 

Torroella-Kouri’s research. She is particularly interested 

in the role of the innate immune response 

in cancer. Researchers in her laboratory 

work with a mouse mammary tumor model in 

which they observe a profound decrease in the 

immune response of tumor-bearing animals. Specifically, 

and among many other events, a deregulation 

in the production of cytokines, important 

mediators in cell-to-cell communication, is observed. 

One of them, the critical cytokine 

interleukin-12 (IL-12), produced by macrophages 

and dendritic cells (DC), is seriously decreased in 

the diseased animals. IL-12 has not only been 

shown to play a central role in the communication 

between the innate and induced immune 

responses, but also recently has been the center of 

much clinical interest due to its recognized antitumor 

properties. 

The laboratory has shown that several mammary 

tumor-derived factors appear to be responsible 

for the decreased production of IL-12 in the 

tumor host. Their present research focuses particularly 

in elucidating the mechanisms through 

which the tumor-derived phospholipid phosphatidylserine, 

as well as the cytokine IL-6, overproduced 

in tumor-bearing animals, are able to 

impair IL-12 expression in tumor animals. The 

understanding of the molecular mechanisms governing 

the expression of the critical cytokine IL- 

12 in the context of the interaction between a 

tumor and the immune system is essential in efforts 

aimed at designing therapeutic strategies to 

treat malignant disorders. Given its many roles, 

direct applications of IL-12 or modulation of IL- 

12 levels will remain an important aspect of research 

for the treatment of cancer. The 

laboratory’s tumor system, which like in the human 

situation presents a severe impairment of IL- 

12 production, is an excellent model in which to 

design future translational research. 




2003 

Torroella-Kouri, M and Lopez, D. Mammary 

tumor derived TGF-β impairs crucial innate immune 

responses in tumor hosts. Journal of Immunology 

and Immunopathology 5:31-38, 2003. 

Torroella-Kouri, M , Keith, JC, Ivanova, M, and 



the IL-12 down-regulation in tumor-bearing 

mice. International Journal of Oncology 22:439- 

48, 2003. 


• Focused on the tumor-induced mechanisms 

that explain the impaired expression of IL-12 in 

the macrophages of the mice bearing the D1- 

DMBA-3 mammary tumor. 

• Demonstrated that indeed there is a decreased 

IL-12 production in elicited peritoneal macrophages 

from tumor-bearing mice, both at the 

level of the protein (ELISA) as well as at the 

level of the gene (RT-PCR and Northern blot). 

They have shown that the expression of gene 

p40 is profoundly decreased, although gene p35 

has a slightly diminished expression as well in 

macrophages of tumor bearers (IL-12 is a 

heterodimer comprised of two independently 

regulated genes, p40 and p35). 

• Demonstrated that in message stability experiments 

there is no difference in the mRNA stability 

of the p40 message between normal and 

tumor-bearing animals, meaning that the regulation 

of the deficiency seems not to be posttranscriptional. 

• Electromobility shift assays (EMSAs) with 

nuclear extracts of macrophages from normal 

and tumor animals have shown that of several 

transcription factors that appear to be relevant 

in the transcription of the p40 gene, there is a 

diminished binding activity of NFκB and 

C/EBP transcription factors to their sites in the 

p40 promoter of tumor-bearing animals. It is 

known that there are several factors produced 

by the D1-DMBA-3 tumor that are able to 

down-regulate IL-12. Among these, 

phopsphatidylserine and prostaglandin E2, 

which are produced by this tumor, have been 

shown to down-regulate IL-12 in macrophages 

of normal mice pretreated with these factors. 

• Demonstrated that this mammary tumor produces 

the anti-inflammatory and metastasispromoting 

cytokine IL-11, and that IL-11 

decreases IL-12 production as well, by diminishing 

the expression of p40 gene (RT-PCR). 

Researchers in her laboratory also have demonstrated 

that IL-11 decreases the binding activity 

of the C/EBP transcription factor, but not that 

of NFκB to the p40 promoter in tumor bearing 

animals. 

• Demonstrated that the immunosuppressor 

cytokine transforming growth factor-beta 

(TGF-β) also is produced by the D1-DMBA-3 

tumor, as well as by macrophages and T cells 

from these tumor-bearing animals. TGF-β also 

is known to down-regulate IL-12. On the other 

hand, macrophages and B cells from tumorbearing 

animals overproduce the cytokines IL-6 

and tumor necrosis factor-alpha (TNF-α). 

TNF-α is known to down-regulate IL-12, and 

her laboratory has been able to demonstrate 

that IL-6 decreases the production of this 

cytokine as well. Therefore, there are different 

tumor-associated factors that could be playing a 

role in the impairment of IL-12 production in 

the laboratory’s tumor model. Some of their 

mechanisms have been worked out. 

• Observed that two of these molecules, the phospholipid 

PS and the cytokine IL-6 are novel 

modulators of this important cytokine. Dr. 

Torroella-Kouri plans to focus her laboratory’s 

immediate research efforts on the elucidation 

of the molecular mechanisms by which these 

molecules down-regulate the expression of the 

IL-12 genes. 

126 



• Currently studying the expression of IL-12 

receptor in the T cells from tumor bearers, in 

order to determine if the decreased levels of 

IFN-gamma observed in T cells from tumor 

bearers might also be explained in part because 

of a low level of expression of this receptor, in 

addition to low levels of IL-12. IL-12 is known 

to stimulate the production of interferongamma 

(IFN-γ) in naïve T cells. 

VLADIMIR VINCEK, M.D., PH.D. 



Progress in the understanding of molecular 

events involved in the development and progression 

of human disease is revolutionizing the 

way diseases are diagnosed and treated. Physicians 

and scientists now are harnessing the power of 

molecular techniques to diagnose and prognosticate 

pathologic disorders. Furthermore, it is now 

possible to direct therapeutic agents to specific 

products expressed by diseased cells without affecting 

normal tissues. On the other hand, while 

standard histopathologic methods maintain tissue 

architecture for morphologic assessment, they do 

not preserve macromolecules. The extraction of 

nucleic acids from formaldehyde-fixed, paraffinembedded 

tissue, the most widely available material 

for clinical studies, is a notoriously unreliable 

and irreproducible process. Therefore, macromolecules 

usually are extracted from fresh or snapfrozen 

tissue specimens. Fresh or frozen tissue 

specimens, however, have limited value for the 

assessment of histomorphology and cannot be 

utilized for long-term retrospective studies. Similarly, 

currently available tissue preservatives that 

protect nucleic acids cause considerable damage 

to the cell and tissue architecture and render 

them unsuitable for histomorphologic evaluation. 

Current studies in this laboratory show that 

it is feasible to simultaneously protect histomorphology 

and the integrity of macromolecules 

in fixed and processed tissue. The UMFIX 

reagent, developed in collaboration with other 

members of the Department of Pathology, seems 

to provide enormous advantage over the conventional 

fixation methods in allowing diagnosis, 

prognostication, and identification of treatment 

targets in patient samples. 


2002 





Immunity 17:167-78, 2002. 


and Nadji, M. Continuous-specimen flow, highthroughput, 



2002. 

2003 



Research 23:3945-48, 2003. 





Adkins, B, Bu, Y, Vincek, V, and Guevara, P. The 

primary responses of murine neonatal lymph 




51, 2003. 

Vincek, V, Nassiri, M, Nadji, M, and Morales, 

AR. A novel tissue preservative that protects macromolecules 

(DNA, RNA, protein) and histomorphology 

in clinical samples. Laboratory 







apoptosis. The British Journal of Dermatology 

149:1-4, 2003. 


• Applied for a patent for an alcohol-based 

UMfix preservative that preserves histomorphology 

and macromolecules; the patent 

currently is pending. 

128 


V I R A L O N C O L O G Y P R O G R A M 


PROGRAM LEADERS 






The Viral Oncology Program currently consists 

of faculty members from five different departments 

at the University of Miami School of 

Medicine. The principal objective of this program 

is to promote clinical and basic investigation of 

oncogenic viruses. The investigators were recruited 

on the basis of productive track records in 

their respective disciplines and a commitment to 

innovative and complementary research. 

Each investigator studies a particular aspect 

of cancer biology and therapy such as apoptosis, 

DNA replication and repair, mechanisms of 

cytokines, interferons and oncolytic viruses, 

membrane transport, and experimental therapeutics. 

This has resulted in the formation of an integrated, 

collaborative effort where each member 

provides an important, yet distinct, contribution. 

The program also is committed to the development 

of physician-scientists and basic researchers 

in the field of viral oncology. 

Bench research conducted by members of 

this program has translated into novel clinical 

trials. A forum for such experimental trials exists 

through the NIH-sponsored AIDS Malignancy 

Consortium (AMC), and the University of 

Miami Sylvester Comprehensive Cancer Center is 

a fully funded independent member. National 

trials for AIDS-related central nervous system 

lymphoma, AMC 019, originated at the University 

of Miami School of Medicine. The program is 

developing pre-clinical models for cancer therapy 

by utilizing oncolytic viruses as targeted anti-cancer 

and immuno-therapeutic agents. Program members 

also are investigating the basic mechanisms 

of lympho-magenesis by focusing on cytokine 

dependence (IL-6), pro- and anti-apoptotic gene 

expression, viral interactions with transcription 

factors, and the effect of viruses on nuclear membrane 

transport. 

There is a concerted effort to extend pathogenesis-based 

studies and therapeutic trials of viral 

malignancies to developing nations such as Zambia 

and Brazil. These efforts are funded through 

Fogarty grants and the NCI. A principal goal is to 

establish the University of Miami as a preeminent 

center for international studies of viral oncology. 

UM/Sylvester, with its diverse patient base 

and large numbers of cases of HIV gamma 

herpesvirus and human T-lymphotropic virus 

type I (HTLV-I) associated tumors, is the ideal 

site for the study of viral oncology. 




1) Investigate the regulation of programmed cell 

death, membrane transport, interferons, 

cytokines, and viral and cellular gene expression 

in cancers that arise in immunocompromised 

patients. 

2) Devise novel therapeutic strategies for therapy 

of viral malignancies. 

3) Train investigators in the field of viral oncology 

and extend our basic and clinical studies 

to developing nations with a high incidence of 

viral-induced malignancies. 

PARTICIPANTS 

Barber, Glen N., Ph.D. 


Boehmer, Paul E., Ph.D. 


Boise, Lawrence H., Ph.D. 


Byrne, Jr., Gerald E., M.D 

Pathology 

Fontoura, Beatriz M.A., Ph.D. 


Harhaj, Edward W., Ph.D. 


Harrington, Jr., William J., M.D. 

Medicine 

Mian, Abdul M., Ph.D. 

Medicine 

So, Antero G., M.D., Ph.D. 

Medicine 

HIGHLIGHTS 

Basic/Translational Research 

• Glen N. Barber, Ph.D., and his colleagues study 

the mechanisms of host defense against viral 

and malignant disease. Their research focuses 

on elucidating the mechanisms of interferons 

including their role in regulating apoptosis. 

These researchers recently have demonstrated 

that vesicular stomatitis virus (VSV), an essentially 

nonpathogenic negative-stranded RNA 

virus, can selectively induce the cytolysis of numerous 

transformed human cell lines in vitro. 

The ability of these viruses to selectively kill 

tumor cells and not normal cells was dependent 

on the protein kinase R/interferon (PKR/IFN) 

pathway being defective in susceptible cells. 

They have now demonstrated in vivo that tumors 

defective in p53 function or transformed 

with myc or activated ras also are susceptible to 

viral cytolysis, and that the mechanism of viral 

oncolytic activity involves the induction of multiple 

caspase-dependent apoptotic pathways. 

Furthermore, VSV caused significant inhibition 

of tumor growth when administered intravenously 

in immunocompetent hosts. Their findings 

suggest that VSV could be used as a 

potential oncolytic agent against a wide variety 

of malignant diseases associated with a diversity 

of genetic defects. Extensions of this work now 

include engineering VSV to express proteins 

from viruses associated with cancer such as 

hepatitis C (HCV) and human papilloma virus 

(HPV) for vaccine and therapeutic purposes. 

For example, chimeric VSV containing HCV 

structural proteins is being examined as a therapeutic 

or preventative vaccine. 

• William J. Harrington, Jr., M.D., investigates 

the use of antiviral agents in viral-induced malignancies. 

He has found that antiviral thymidine 

analogues such as azidothymidine (AZT) 

and IFN α induce marked apoptosis in Epstein- 

Barr virus (EBV) and human herpes virus type 

8 (HHV-8)-associated primary effusion lymphomas 

(PELs). This therapy was very effective 

in eradicating AIDS-related brain lymphoma 

and formed the basis for a nationwide clinical 

130 



trial. His data demonstrate that IFN α potently 

induces the death receptor ligand TRAIL. AZT 

is phosphorylated by the herpes virus thymidine 

kinase and acts by blocking NF-κB (p50, p65) 

translocation into the nucleus allowing for an 

unopposed death signal. AZT also down-regulates 

the expression of anti-viral, anti-apoptotic 

proteins such as vFLIP. A similar mechanism 

has been shown to occur in other viral-induced 

tumors such as post-transplant lymphoma 

(EBV). Dr. Harrington and his colleagues have 

initiated a new clinical trial for HHV-8-associated 

lymphomas that utilizes parenteral AZT 

and IFN α (these tumors virtually are always 

fatal). The first patient enrolled has remained in 

complete remission for more than two years. 

AZT-mediated blockade of NF-κB is a potentially 

exciting novel strategy that combines both 

anti-HIV and EBV activity. The target malignancy 

(and one of the most common worldwide) 

for this type of approach is endemic 

Burkitt’s lymphoma. Current studies focus on 

understanding the specificity of this therapy for 

herpes virus-associated lymphomas, the development 

of more potent antiviral antilymphoma 

thymidine analogues, and the extension of this 

approach to other gamma herpes and lymphomas 

that occur in the immunocompromised 

patients (post-transplant, hereditary immunodeficiencies). 

This work is done in collaboration 

with Abdul M. Mian, Ph.D., and Ram Agarwal, 

Ph.D. Dr. Harrington also recently received a 

NCI-funded career award (K24), which will 

enable him to focus on the above described 

laboratory and clinical studies. 

• Antero G. So, M.D., Ph.D., and Kathleen M. 

Downey, Ph.D., recently have identified a novel 

protein, polymerase delta interacting protein 

(PDIP1). This protein interacts with the small 

subunit (p50) of DNA polymerase delta (the 

primary polymerase responsible for cell growth 

and differentiation) and the proliferating cell 

nuclear antigen (PCNA). PDIP1 colocalizes 

with pol delta and PCNA at replication foci in 

the nuclei of S-phase cells and stimulates its 

activity (in the presence of PCNA). The expression 

of PDIP1 can be induced by the cytokines 

tumor necrosis factor alpha (TNF-α) and IL-6. 

PDIP1 is a distal target of IL-6. There is increasing 

evidence suggesting that the cytokine 

IL-6 plays an important role in the pathogenesis 

of certain types of AIDS-related lymphomas. 

Recent studies strongly have implicated a critical 

role for IL-6 in EBV-dependent lymphoproliferative 

disease. It also has been reported 

that the development of AIDS-associated 

Burkitt’s/small non-cleaved cell lymphoma is 

preceded by elevated serum levels of IL-6. In 

addition, cell lines derived from HHV-8-associated 

AIDS primary effusion lymphomas constitutively 

secrete high levels of both IL-6 and the 

HHV-8 IL-6 homologue (vIL-6). Consistent 

with these findings is the observation that the 

inhibition of NF-κB (by AZT or other inhibitors) 

down-regulates cytokine IL-6 and induces 

apoptosis in Karposi’s sarcoma-associated herpes 

virus (KSHV) infected cells. 

• Researchers in Lawrence H. Boise, Ph.D.’s laboratory 

investigate factors that regulate the pathways 

associated with death receptor-induced 

apoptosis. Previous studies have indicated that 

cells can utilize one of two pathways to propagate 

death signals resulting from the ligation of 

the TNF receptor as well as from CD95 (Fas/ 

Apo-1). Cells referred to as type I cells can activate 

a caspase cascade that does not require release 

of factors from the mitochondria. 

Expression of anti-apoptotic proteins Bcl-2 or 

Bcl-x L 

is incapable of inhibiting death receptor 

signaling in type I cells. In contrast, death receptor 

signaling in type II cells requires release 

of mitochondrial factors and is inhibited by 

Bcl-2/x L 

expression. Dr. Boise has demonstrated 

that cells can utilize both type I and type II signals 

and that Bcl-2/x L 

can affect type I death 

receptor signaling when used in concert with 

inhibitors of signaling caspases. Interestingly, γ- 

herpes viruses associated with Karposi’s sarcoma 

and PELs encode both a Bcl-2 homologue as 

well as an inhibitor of CD95 signaling (vFlip). 

While it has been previously suggested that viruses 

express these molecules to block distinct 



death pathways, based on his results it is hypothesized 

that vBcl-2 and vFlip may work in 

concert to block complex death receptor signaling. 

Researchers currently are testing this hypothesis 

through the introduction of these 

genes into TNF-α-sensitive cell lines as well as 

inhibiting expression of virally expressed genes 

in PEL cell lines. This work is being carried out 

primarily by M.D./Ph.D. student Esther 

Obeng. Ms. Obeng has received a Howard 

Hughes Medical Institute Fellowship to support 

her research. This work is the basis of collaboration 

with William J. Harrington, Jr., M.D., on 

his studies to determine the mechanisms of 

anti-viral induced apoptosis in AIDS-related 

lymphomas that appear to be death receptor 

mediated. 

• Beatriz M.A. Fontoura, Ph.D.’s laboratory 

works on the signal-mediated nuclear import 

and export of molecules that occurs through 

nuclear pore complexes (NPC). These are 

highly regulated pathways that control nuclear 

entry and exit of molecules such as transcription 

factors, RNAs, kinases, and viral particles. 

NPCs are composed of proteins termed 

nucleoporins or Nups, which have a role in the 

structure of the NPC and also in regulating 

translocation of molecules through the NPC. 

Nups are targets of viral proteins and disruption 

of Nup function is involved in cancer. Dr. 

Fontoura has identified and characterized two 

major Nups—Nup98 and Nup96—which are 

key controllers of nuclear entry and exit of proteins 

and RNAs. The Nup98-Nup96 pathway 

is highly regulated by specific signaling pathways, 

is a target of viral proteins, and is involved 

in tumorigenesis. The goal of the 

investigators working in this laboratory is to 

understand the molecular mechanisms of the 

nuclear transport machinery and how they are 

regulated by different signaling pathways and 

viruses. The discovery of novel mechanisms or 

factors of this pathway are important for controlling 

cell growth and also may serve as therapeutic 

targets. 

• Edward W. Harhaj, Ph.D.’s laboratory studies 

viral-induced malignancy by the human T-cell 

leukemia virus type I (HTLV-I). HTLV-I is associated 

with several diseases including adult T- 

cell leukemia (ATL) and a neurological disorder 

known as HTLV-I-associated myelopathy/tropical 

spastic paraparesis (HAM/TSP). HTLC-I 

encodes a trans-activating protein, Tax, which 

has pleiotropic functions and is highly oncogenic. 

Tax activates cellular signaling pathways 

and transcription factors, such as NF-κB, resulting 

in global changes in gene expression. 

NF-κB is a family of dimeric DNA-binding 

proteins that regulates the expression of genes 

that control a variety of cellular functions such 

as activation, differentiation, survival, and effector 

function. A major effort of Dr. Harhaj’s 

laboratory is to elucidate the mechanisms utilized 

by Tax to activate the NF-κB signaling 

pathway. Toward this end, researchers are identifying 

cellular proteins that interact with Tax 

and are examining the role of these proteins in 

Tax-medicated NF-κB activation and cellular 

transformation. 

An example of how the laboratories interact is 

demonstrated in the illustration on page 133. 

Each group addresses a distinct area relevant to 

viral lymphomagenesis. 

Training and International Effort 

The laboratories of Dr. Harrington and Charles 

Wood, Ph.D., (University of Nebraska) have a 

long-standing relationship in AIDS-associated 

malignancies and currently collaborate on two 

R01-funded research projects and two Fogarty 

International Training Programs. These research 

projects center around the molecular epidemiology 

of the transmission of HHV-8 and EBV and 

the role these viruses play in the induction of malignancies. 

The objectives of these projects are: 1) 

determine the factors associated with transmission 

of HHV-8 in Zambia and its relationship on 

progression to AIDS, 2) develop an NCI-sponsored 

research repository in Brazil and Africa, 

132 



V I R A L L Y M P H O M A 

3) initiate clinical trials for AIDS-related malignancies 

in Brazil, and 4) study the molecular 

tumor pathogenesis of viral lymphomas in Africa 

and Brazil. 

Researchers in the Viral Oncology Program 

recently collaborated with Dr. Carlos Brites (Brazil) 

and successfully obtained funding through 

Fogarty to establish a viral oncology training program 

in Salvador, Brazil. Such studies are critical 

to understanding and developing rational therapy 

for malignancies in immunocompromised patients. 

The program recently was funded through 

the NCI for a study of inhibition of NF-κB and 

disruption of latency in high-grade primary lymphomas 

derived from Brazilian patients. Juan 

Carlos Ramos, M.D., (University of Miami) received 

a supplemental NCI grant linked to the 

AMC parent grant for a molecular study of PELs. 

In collaboration with the Federal University of 

Bahia in Brazil, a five-year training grant for 

AIDS/oncology was submitted. Bahia is a unique 

area that principally is populated by descendants 

of West Africa and is endemic for HTLV-I. The 

majority of non-Hodgkin’s lymphomas are associated 

with EBV or HTLV-I. Therefore, this presents 

an outstanding opportunity for clinical and 

basic investigation of these illnesses. 

Zambia is a central African nation located in 

the “AIDS and tumor belt.” In order to support 

their research activities in Zambia, the University 

of Nebraska at Lincoln, under Dr. Wood, and the 

University of Miami under Dr. Harrington and 

Charles D. Mitchell, M.D., have developed a successful 

training and research collaboration with 

the University of Zambia School of Medicine and 

the University Teaching Hospital, under the auspices 

of the Zambian Ministry of Health. This 

program, funded through the Fogarty International 

Post-Doctoral Training Program in HIV/ 

AIDS, has provided instruction to Zambian 

health care personnel in clinical, epidemiological, 

and basic science research methodology at both 

the Universities of Miami and Nebraska. 



GLEN N. BARBER, PH.D. 



Dr. Barber’s research focuses on understanding 

the mechanisms of innate immunity to viral 

infection and malignant disease. Specifically, one 

area of research in his laboratory aims to understand 

the mechanisms by which the interferons 

(IFNs) mediate their anti-viral and anti-proliferative 

effects. One key IFN-inducible gene is the 

dsRNA-dependent protein kinase PKR, which is 

activated upon virus infection and limits viral 

replication by inhibiting host cell protein translation. 

Researchers recently have shown that mice 

lacking PKR are very sensitive to lethal infection 

by vesicular stomatitis virus (VSV) and influenza 

virus, underscoring the importance of this 

molecule in host defense. They additionally have 

shown that PKR and IFN can contribute towards 

the induction of apoptosis in a virally infected 

cell. The laboratory currently is identifying new 

IFN-induced genes and examining their importance 

in cellular growth control and immunity. 

In addition to examining the mechanisms of 

innate immunity to viral infection, researchers in 

Dr. Barber’s laboratory are interested in studying 

how viruses such as hepatitis C (HCV) and 

human herpes virus type-8 (HHV-8) contribute 

towards oncogenesis. Such viruses are known to 

subvert key checkpoints of host-cell growth control. 

Understanding the mechanisms involved in 

these processes could lead to an improvement of 

current therapies as well as the identification of 

new therapeutic targets and of malignant disease 

involving these viruses. 


2002 

Fernandez, M, Porosnicu, M, Markovic, D, and 

Barber, GN. Genetically engineered vesicular stomatitis 

virus in gene therapy: application for 

treatment of malignant disease. Journal of Virology 

76:895-904, 2002. 

Pataer, A, Vorburger, SA, Barber, GN, Chada, S, 

Mhashilkar, AM, Zou-Yang, H, Stewart, AL, 

Balachandran, S, Roth, JA, Hunt, KK, and 

Swisher, SG. Adenoviral transfer of the melanoma 

differentiation-associated gene 7 (mda7) 

induces apoptosis of lung cancer cells via upregulation 

of the double-stranded RNA-dependent 

protein kinase (PKR). Cancer Research 

62:2239-43, 2002. 

Grandvaux, N, Servant, MJ, tenOever, B, Sen, 

GC, Balachandran, S, Barber, GN, Lin, R, and 

Hiscott, J. Transcriptional profiling of interferon 

regulatory factor 3 target genes: direct involvement 

in the regulation of interferon-stimulated 

genes. Journal of Virology 76:5532-9, 2002. 

Vorburger, SA, Pataer, A, Yoshida, K, Barber, 

GN, Xia, W, Chiao, P, Ellis, LM, Hung, MC, 

Swisher, SG, and Hunt, KK. Role for the doublestranded 

RNA activated protein kinase PKR in 

E2F-1-induced apoptosis. Oncogene 21:6278- 

88, 2002. 

Ezelle, HJ, Markovic D, and Barber, GN. Generation 

of hepatitis C virus-like particles by use of 

a recombinant vesicular stomatitis virus vector. 

Journal of Virology 76:12325-34, 2002. 

2003 

Ogilvie, VC, Wilson, BJ, Nicol, SM, Morrice, 

NA, Saunders, LR, Barber, GN, and Fuller-Pace, 

FV. The highly related DEAD box RNA helicases 

p68 and p72 exist as heterodimers in cells. 

Nucleic Acids Research 31:1470-80, 2003. 

Saunders, LR and Barber, GN. The dsRNA 

binding protein family: critical roles, diverse cellular 

functions. The FASEB Journal 17:961-83, 

2003. 

134 



Obuchi, M, Fernandez, M, and Barber, GN. Development 

of recombinant vesicular stomatitis 

viruses that exploit defects in host defense to augment 

specific oncolytic activity. Journal of Virology 

77:8843-56, 2003. 

Ghosh, SK, Wood, C, Boise, LH, Mian, AM, 

Deyev, VV, Feuer, G, Toomey, NL, Shank, NC, 

Cabral, L, Barber, GN, and Harrington, WJ Jr. 

Potentiation of TRAIL-induced apoptosis in primary 

effusion lymphoma through 

azidothymidine-mediated inhibition of NFkappa 

B. Blood 101:2321-7, 2003. 

Balachandran, S and Barber, GN. Defective 

translational control facilitates vesicular stomatitis 

virus oncolysis. Cancer Cell 5:51-65, 2003. 

Poroniscu, M, Mian, A, and Barber, GN. The 

oncolytic effect of recombinant vesicular stomatitis 

virus is enhanced by expression of the fusion 

cytosine deaminase/uracil phosphoribosyltransferease 

suicide gene. Cancer Research 63:8366-76, 2003. 


• Discovered that IFN-inducible protein kinase 

PKR is a critical mediator of innate immunity 

to a number of viruses, since mice lacking this 

kinase are very susceptible to lethal infection by 

several viruses at doses that are innocuous to 

wild type mice. 

• Discovered that VSV has potent oncolytic (antitumor) 

properties. Dr. Barber’s laboratory has 

shown that VSV replicates to high levels in tumorigenic, 

but not normal cells, and has identified 

defects in IFN signaling and translational 

control in tumorigenic cells as possible reasons 

for this uncontrolled replication. 

• Developed recombinant VSV that expresses 

other virus proteins, such as from HCV and 

HPV (implicated in tumorigenesis), as possible 

vaccines for these viruses. 

• Constructed VSV variants expressing suicide 

cassettes and immunomodulatory genes in an 

effort to increase the potency and specificity of 

VSV oncolysis. 

PAUL E. BOEHMER, PH. D. 

Associate Professor of Biochemistry and 



Researchers in Dr. Boehmer’s laboratory are 

studying molecular mechanisms of replication 

and recombination in herpes simplex virus 

type-1 (HSV-1). HSV-1 serves as an excellent 

system in which to study DNA transactions. 

Hence, like eukaryotic chromosomes, the HSV-1 

genome contains multiple origins of replication. 

Replication of the HSV-1 genome is mediated by 

the concerted action of several virus-encoded proteins 

that are thought to assemble into a 

multiprotein complex. Several host-encoded factors 

have also been implicated in viral DNA replication. 

Furthermore, replication of the HSV-1 

genome is known to be closely associated with 

homologous recombination, which may function 

in the initiation of DNA replication and in maintaining 

genome stability. Moreover, the virusencoded 

enzymes also provide a system in which 

to investigate the interaction of DNA replication 

enzymes with DNA damage. 

HSV-1 also is the prototypic herpes virus 

and therefore serves as a model to understand the 

mechanism of replication of this class of virus. In 

this regard, HSV-1 is one of eight human herpes 

viruses that are known to cause diverse diseases 

ranging from cold sores and chicken pox to mononucleosis 

and even cancer. The high incidence of 

herpes viruses in the human population and the 

increased susceptibility of immunocompromised 

individuals to these viruses make them a very important 

public health problem. HSV-1 in particular 

is the cause of oro-labial lesions as well as 

more serious encephalitis and corneal blindness. 

Most recently, Dr. Boehmer’s laboratory has 

proposed to examine how the virus initiates replication 

at an origin, the role recombination plays 

during initiation and at later times during the 

replicative cycle, how leading and lagging strand 

DNA synthesis are coordinated at the viral replication 

fork, and finally, the mechanism whereby 



the viral DNA polymerase can promote translesion 

DNA synthesis. Collectively, the proposed studies 

will provide novel insight into the replication of 

this medically important and biologically fascinating 

virus. They also will serve to increase the 

overall knowledge of fundamental mechanisms in 

DNA replication and recombination. 


2002 

Tanguy Le Gac, N and Boehmer, PE. Activation 

of the herpes simplex virus type-1 origin-binding 

protein (UL9) by heat shock proteins. Journal of 


Nimonkar, AV and Boehmer, PE. In vitro strand 

exchange promoted by the herpes simplex virus 

type-1 single strand DNA-binding protein 

(ICP8) and DNA helicase-primase. Journal of 


Villani, G, Tanguy Le Gac, N, Wasungu, L, 

Burnouf, D, Fuchs, RP, and Boehmer, PE. Effect 

of manganese on in vitro replication of damaged 

DNA catalyzed by the herpes simplex virus type- 

1 DNA polymerase. Nucleic Acids Research 

30:3323-32, 2002. 

2003 

Boehmer, PE and Nimonkar, AV. Herpes virus 

replication. IUBMB Life 55:13-22, 2003. 

Nimonkar, AV and Boehmer, PE. The herpes 

simplex virus type-1 single-strand DNA-binding 

protein (ICP8) promotes strand invasion. Journal 


Nimonkar, AV and Boehmer, PE. On the mechanism 

of strand assimilation by the herpes simplex 

virus type-1 single-strand DNA-binding protein 

(ICP8). Nucleic Acids Research 31:5275-81, 

2003. 

Nimonkar, AV and Boehmer, PE. Reconstitution 

of recombination-dependent DNA synthesis in 

herpes simplex virus 1. Proceedings of the National 

Academy of Sciences USA 100:10201-6, 

2003. 

Boehmer, PE and Villani, G. Herpes simplex virus 

type-1: a model for genome transactions. 

Progress in Nucleic Acid Research and Molecular 

Biology 75:139-171, 2003. 


• Discovered that recombination reactions were 

promoted by the HSV single-strand DNA 

binding protein. 

• Reconstituted recombination-dependent DNA 

synthesis in a eukaryotic viral system. 

• Discovered that cellular heat shock proteins 

participate in the initiation of viral origin-specific 

replication. 

• Discovered translesion synthesis by a model 

eukaryotic replicative DNA polymerase. 

LAWRENCE H. BOISE, PH.D. 


Immunology 


Regulation of Programmed Cell Death 

Programmed cell death, or apoptosis, is a process 

utilized by multicellular organisms to 

eliminate unnecessary or damaged cells without 

inducing an inflammatory response. The ability 

of inducing a cellular suicide is required for normal 

development and maintenance of cell number 

in multicellular organisms since loss of 

control of this process can lead to cancer, autoimmune 

disease, or neurodegenerative disorders in 

mice and humans. While the genetic studies in 

the nematode suggest that members of the Bcl-2 

family should function upstream of caspases, this 

result could be the consequence of two biochemical 

explanations—either Bcl-2 blocks caspase activation 

or Bcl-2 blocks the consequence of 

protease activation. 

In studies performed on a pro-B cell line, 

Dr. Boise and his colleagues have found 

cooperativity between overexpression of Bcl-2 

family members and inhibition of caspases in the 

136 



prevention of tumor necrosis factor (TNF)- 

induced cell death. Together these data suggest 

that the cell death pathway in mammalian cells is 

not likely to be a simple linear pathway as has 

been suggested by C. elegans genetics. They are 

currently using biochemical and genetic tools to 

dissect this pathway and to determine the interplay 

between the Bcl-2 family and the caspase 

family. Additionally, from these studies researchers 

have determined that many of the changes 

that occur to mitochondria during apoptosis are 

caspase dependent. These include loss of the mitochondrial 

membrane potential. His laboratory 

has determined that mitochondria must be inactivated 

during apoptosis to prevent excessive production 

of reactive oxygen species. They are 

currently examining the mechanisms by which 

caspases regulate mitochondrial function. 

As a product of the laboratory’s studies of 

bcl-x expression in drug resistant tumors, they 

became interested in the study of arsenic trioxide 

as a potential therapeutic agent in the treatment 

of multiple myeloma. Dr. Boise and his colleagues 

are studying the mechanism by which this agent 

can kill chemo refractory myeloma cells as well 

as determine the mechanisms of acquired arsenic 

resistance in myeloma cell lines. These studies 

have led to a new clinical trial initiated at 

UM/Sylvester. They also will gather corollary 

scientific information from patients on this trial. 


2002 

Anderson, KC, Boise, LH, Louie, R, and 

Waxman, S. Arsenic trioxide in multiple myeloma: 

rationale and future directions. Cancer 

Journal 8:12-25, 2002. 




LH, and Lee, KP. Feasibility and correlates of arsenic 

trioxide combined with ascorbic acid-mediated 

depletion of intracellular glutathione for the 

treatment of relapsed/refractory multiple myeloma. 


2002. 

2003 



Cabral, L, Barber, GN, and Harrington, WJ Jr. 




B. Blood 101:2321-7, 2003. 

McCafferty Grad, J, Bahlis, N, Aguilar, T, Kratt, 

N, Lee, KP, and Boise, LH. Arsenic trioxide utilizes 


death pathways in multiple myeloma cells. Molecular 

Cancer Therapeutics 2:1155-64, 2003. 

Beaupre, DM, McCafferty Grad, J, Bahlis, NJ, 

Boise, LH, and Lichtenheld, MG. Farnesyl transferase 

inhibitors sensitize to death receptor signals 

and induce apoptosis in multiple myeloma cells. 

Leukemia & Lymphoma 44:2123-34, 2003. 

BEATRIZ M.A. FONTOURA, PH.D. 




Signal-mediated nuclear import and export of 

molecules occurs through nuclear pore complexes 

(NPC). These are highly regulated pathways 

that control nuclear entry and exit of 

molecules such as transcription factors, RNAs, 

kinases, and viral particles. In general, to be imported 

or exported from the nucleus, molecules: 

1) bind to transport receptors, 2) are transported 

through NPC present in the nuclear envelope, 

and 3) translocate from NPC to intranuclear or 

cytoplasmic target sites. Although progress has 

been made regarding the composition and 

mechanisms of the nuclear transport machinery, 

less is known about the function and regulation 

of major constituents of NPC. NPC are composed 

of proteins termed nucleoporins or Nups, 

which have a role in the structure of NPC and 

also in regulating translocation of molecules 

through NPC. Nups also are target of viral 



proteins and disruption of Nup function is involved 

in cancer. 

Researchers in Dr. Fontoura’s laboratory have 

identified and characterized two major Nups, 

Nup98 and Nup96, which are key controllers of 

nuclear entry and exit of proteins and RNAs. The 

Nup98 and Nup96-mediated pathway(s) is 

highly regulated by specific signaling pathways 

such as interferon (IFN) pathways, is a target of 

viral proteins, and is involved in tumorigenesis. 

Her laboratory currently is characterizing novel 

constituents of this pathway and studying their 

regulation by signaling pathways, viruses, and 

during mitosis. The researchers’ goal is to understand 

the molecular mechanisms of the nuclear 

transport machinery and how they are regulated 

by different signaling pathways and viruses. Thus, 

Dr. Fontoura’s research proposes innovative findings 

on Nup function and regulation, which are 

important to advance the nuclear transport field 

and essential for understanding the role of Nups 

in cancer and in IFN-mediated processes, such as 

anti-viral response, innate immunity, and cell 

proliferation. 


2002 

Enninga, J, Levy, DE, Blobel, G, and Fontoura, 

BM. Role of nucleoporin induction in releasing 

an mRNA nuclear export block. Science 

295:1523-5, 2002. 

Comment on the Science publication by 


BM. Nature Cell Biology 4:E55, 2002. 

2003 

Yin, X, Fontoura, BM, Morimoto, T, and 

Carroll, RB. Cytoplasmic complex of p53 and 

eEF2. Journal of Cellular Physiology 196:474-82, 

2003. 

Enninga, J, Levay, A, and Fontoura, BM. Sec13 

shuttles between the nucleus and the cytoplasm 

and stably interacts with Nup96 at the nuclear 

pore complex. Molecular and Cellular Biology 

23:7271-7284, 2003. 


• Discovered in 2002 that two major NPC proteins 

that Dr. Fontoura’s laboratory had previously 

identified, Nup98 and Nup96, can 

regulate antiviral response by controlling 

nuclear export of mRNA. These findings were 

published in Science and a comment was published 

in Nature Cell Biology. This pathway is 

involved in tumorigenesis. 

• Discovered in 2003 another constituent of the 

Nup98-Nup96 pathway(s), Sec13, which also is 

a component of the endoplasmic reticulum. 

The findings were recently published in Molecular 

and Cellular Biology. Sec13 may be involved 

in a crosstalk between the NPC and the endoplasmic 

reticulum. 

EDWARD W. HARHAJ, PH. D. 

Assistant Professor of Microbiology and 

Immunology 


Dr. Harhaj’s research interests focus on the 

mechanisms of viral-induced malignancy by 

the human T-cell leukemia virus type I (HTLV- 

I). HTLV-I is linked to the genesis of both adult 

T-cell leukemia (ATL) and a neurological disorder 

known as HTLV-I-associated myelopathy/ 

tropical spastic paraparesis (HAM/TSP). Although 

it is unclear why HTLV-I infection proceeds 

to either ATL, HAM/TSP, or an 

asymptomatic state, there are likely cellular, viral, 

and environmental determinants that influence 

disease progression. The host immune response 

to HTLV-I appears to be an important cellular 

determinant of HTLV-I-associated disease. 

Whereas ATL patients are commonly immunosuppressed, 

asymptomatics and particularly 

HAM/TSP patients mount vigorous immune 

responses to HTLV-I. One of the goals of the 

laboratory is to define the molecular mechanisms 

that account for dysregulated host immune responses 

to HTLV-I. Understanding how HTLV-I 

influences the host immune response may pro- 

138 



vide targets for therapeutic intervention to control 

infection and decrease proviral load. 

HTLV-I encodes a trans-activating protein, 

Tax, which is responsible for the oncogenic properties 

of HTLV-I. Tax activates numerous cellular 

signaling cascades, including NF-κB and CREB/ 

ATF, resulting in global changes in gene expression. 

Tax regulates the expression of a multitude 

of cellular genes that control T-cell activation, 

proliferation and apoptosis. Another goal of Dr. 

Harhaj’s laboratory is to delineate the mechanisms 

utilized by Tax to activate cellular signaling 

pathways, such as NF-κB, which are essential for 

Tax-mediated immortalization of T cells. Toward 

this end, identification of cellular proteins that 

interact with Tax may shed light on strategies 

used by Tax to constitutively activate NF-κB and 

mediate T-cell oncogenesis. 


2003 

Barmak, K, Harhaj, EW, and Wigdahl, B. Mediators 

of central nervous system damage during 

the progression of HTLV-I-associated myelopathy/tropical 

spastic paraparesis. Journal of 

NeuroVirology 9:522-9, 2003. 

Barmak, K, Harhaj, EW Grant, C, Alefantis, T, 

and Wigdahl, B. Human T cell leukemia virus 

type I-induced disease: pathways to cancer and 

neurodegeneration. Virology 308:1-12, 2003. 

Alefantis, T, Barmak, K, Harhaj, EW, Grant, C, 

and Wigdahl, B. Characterization of a nuclear 

export signal within the human T cell leukemia 

virus type I transactivator protein Tax. Journal of 


WILLIAM J. HARRINGTON, JR., M.D. 



Dr. Harrington's laboratory efforts center on 

understanding the mechanisms of antiviralmediated 

apoptosis of viral-mediated malignancies. 

His team found that interferon (IFN) potently 

induces death receptor ligands in certain unique 

viral-mediated lymphomas. This had led to a 

novel therapeutic approach for these deadly tumors. 

Epstein-Barr virus (EBV)-related Burkitts 

(BL) and primary central nervous system (CNS) 

lymphoma, human herpes virus-type 8 (HHV-8)- 

associated primary effusion lymphoma (PEL), 

and human T lymphotropic virus-type I (HTLV- 

I)-associated adult T-cell leukemia (ATL) are all 

refractory to conventional chemotherapy yet remarkably 

sensitive to antiviral therapy. Clinical 

trials have been designed and implemented that 

exploit this phenomenon. Their AIDS-related 

brain lymphoma study is now a national trial and 

is run through the NCI cooperative group, the 

Aids Malignancy Consortium (AMC). 

The three principal projects currently underway 

include: 

• Mapping the apoptotic pathways induced in 

viral-associated lymphomas. Their work has 

demonstrated that IFNα induced the soluble 

death receptor ligand TRAIL, which when 

combined with AZT, indicates a FADD-dependent 

suicide program in gamma herpes virus 

lymphomas. Signal transduction deficits in 

IFNα and pathways in resistant tumors also are 

being studied. 

• Studying the signaling components involved in 

constitutive activation of NF-κB in all forms of 

viral-mediated non-Hodgkin's lymphoma 

(NHL). Their data demonstrate specific activation 

pathways that may serve as targets for future 

therapeutic agents. 

• Elucidating the mechanism whereby AZT 

inhibits NF-κB in EBV+ endemic BL. New 

data demonstrate that this mechanism is highly 

specific and occurs through interruption of 



lymphotoxin beta-mediated activation of 

NF-kB. AZT appears to be a targeted form of 

therapy particularly active in type 1 latency BL 

cells. Dr. Harrington recently has received NCI 

funding to study this mechanism in primary 

endemic BL cells from patients seen at the National 

Cancer Institute of Brazil (INCA). This 

also will be translated to a clinical trial for refractory 

EBV+ B1. They have received a major 

commitment from GlaxoSmithKline to provide 

parenteral AZT. This will be used as part of a 

protocol to treat patients at the INCA. 


2002 

Tulpule, A, Groopman, J, Saville, MW, 

Harrington, WJ Jr , Friedman-Kien, A, Espina, 

BM, Garces, C, Mantelle, L, Mettinger, K, 

Scadden, DT, and Gill, PS. Multicenter trial of 

low-dose paclitaxel in patients with advanced 

AIDS-related Kaposi sarcoma. Cancer 95:147- 

54, 2002. 

2003 



Cabral, L, Barber, GN, and Harrington, WJ Jr . 

Potentiation of TRAIL-induced apoptosis in 

primary effusion lymphoma through 


B. Blood 101:2321-7, 2003. 

Rosenblatt, J and Harrington, WJ Jr . Leukemia 



21:323-4, 2003. 

Schultz, DR and Harrington, WJ Jr . Apoptosis: 

programmed cell death at a molecular level. 

Seminars in Arthritis and Rheumatism 32:345- 

69, 2003. 

ANTERO G. SO, M.D., PH.D. 



Dr. So and Kathleen M. Downey, Ph.D., are 

studying the molecular mechanism by which 

normal cells regulate proliferation during the cell 

cycle and how this is altered in cancer cells. The 

major focus of these studies is DNA polymerase 

delta, the principal mammalian DNA polymerase 

required for replication of chromosomal DNA 

and involved in several major DNA repair pathways. 

DNA polymerase delta was the first eukaryotic 

DNA polymerase found to have an intrinsic 

proofreading 3’ to 5’ exonuclease activity and 

therefore capable of editing errors made during 

DNA synthesis. The importance of this proofreading 

activity in DNA replication was recently 

shown by a report that inactivation of the exonuclease 

activity of DNA polymerase delta in mice 

resulted in a recessive mutator phenotype characterized 

by a high incidence of epithelial (carcinoma) 

and mesenchymal (lymphomas and 

sarcomas) cancers. Current research emphasizes 

the elucidation of the molecular mechanism of 

regulation of DNA polymerase delta activity by 

its processivity factor, the proliferating cell 

nuclear antigen (PCNA), and the identification 

of new proteins that regulate DNA polymerase 

delta activity. 

140 




2002 

Carastro, LM, Tan, CK, Selg, M, Jack, HM, So, 

AG, and Downey, KM. Identification of delta 

helicase as the bovine homolog of HUPF1: demonstration 

of an interaction with the third subunit 

of DNA polymerase delta. Nucleic Acids 

Research 30:2232-43, 2002. 

Meyer, PR, Matsuura, SE, Tolun, AA, Pfeifer, I, 

So, AG, Mellors, JW, and Scott, WA. Effects of 

specific zidovudine resistance mutations and substrate 

structure on nucleotide-dependent primer 

unblocking by human immunodeficiency virus 

type 1 reverse transcriptase. Antimicrobial Agents 

and Chemotherapy 46:1540-5, 2002. 

Lu, X, Tan, CK, Zhou, JQ, You, M, Carastro, 

LM, Downey, KM, and So, AG. Direct interaction 

of proliferating cell nuclear antigen with the 

small subunit of DNA polymerase delta. Journal 



• Demonstrated a direct interaction between the 

small subunit of human DNA polymerase delta 

(p50) and PCNA, a marker for cell proliferation, 

by reciprocal co-immunoprecipitation of 

the two proteins using antibodies against either 

p50 or PCNA, suggesting that this interaction 

is primarily responsible for processive DNA 

synthesis by DNA polymerase delta. Researchers 

in Dr. So’s laboratory have now confirmed 

that this interaction readily occurs in cells. This 

is important because the interaction of DNA 

polymerase delta with PCNA is at the core of 

replication machinery (replisome) function and 

crucial to our understanding of how DNA replication 

is coordinated with DNA repair and 

cell cycle progression. 

• Identified a novel 36-kDa protein, designated 

polymerase delta interacting protein 1 (PDIP1) 

that physically and functionally interacts with 

both PCNA and the 50-kDa subunit of DNA 

polymerase delta, both in vitro and in vivo. 

Researchers further have shown the expression 

of this protein is induced by tumor necrosis factor 

α (TNF-α) and interleukin-6 (IL-6). These 

cytokines are essential for growth and proliferation 

of many cell types and implicated in the 

tumorigenesis of a number of cancers, including 

AIDS-related non-Hodgkin’s lymphoma and 

multiple myeloma. Thus, PDIP1 is a potential 

target for the development of novel therapeutic 

agents for the treatment of these tumors. 



142 


S H A R E D R E S O U R C E S 


A N A L Y T I C A L I M A G I N G C O R E 

MANAGER 

Alberto Pugliese, M.D. 


CO-MANAGER 

Beata R. Frydel, Ph.D. 

Associate Scientist of Neurosurgery 

PURPOSE 

Many research endeavors rely on state-of-theart 

imaging and molecular histology techniques 

requiring the use of complex and costly 

equipment not practical for the individual investigator 

to acquire and maintain. The Analytical 

Imaging Core is a campus-wide resource spearheaded 

by the Diabetes Research Institute and 

UM/Sylvester, with seed support from the dean 

of the University of Miami School of Medicine. 

The Juvenile Diabetes Research Foundation 

awarded additional support for a five-year period 

in December 2003. The core’s main goals are to: 

• Provide access to sophisticated, modern instrumentation 

for imaging and molecular analysis 

of tissue and cellular specimens to investigators. 

• Provide expertise, guidance, and training to 

core users and help them optimize protocols for 

their applications that can be shared with other 

investigators. 

SERVICES 

This core provides the following services: 

1) Confocal Microscopy: Confocal microscopy offers 

many advantages over standard fluorescent 

microscopy including increased sensitivity, 

resolution, and the ability to image relatively 

thick, fluorescently labeled biological specimens 

in two or three dimensions. Confocal 

microscopy creates an “optical section” of the 

cells or tissues being imaged and an increase in 

effective resolution due to a large increase in 

signal-to-noise ratio. As a result, outstanding 

images can be collected from cells and tissue 

sections that would otherwise yield little or no 

information. 

The workhorse instrument for confocal microscopy 

is the Zeiss LSM-510, which can detect 

up to five channels and four fluorescent 

channels simultaneously—from UV to far red, 

plus a separate detector for transmitted light. 

The outstanding beam control afforded by the 

Zeiss LSM-510 makes it an ideal instrument 

for other advanced fluorescent applications 

such as fluorescence resonance energy transfer 

(FRET), fluorescence recovery after photo 

bleaching (FRAP), or ratio-imaging for 

fluorescence quantitation. The core also is 

equipped with an Atto Instruments spinning 

disk confocal microscope (CARV), a confocal 

instrument particularly suited for live cell 

analysis, and video-rate (30 frames per second) 

imaging. 

2) Standard Epifluorescence Microscopy: The core 

also is equipped with a Leica DMIRB inverted 

microscope capable of performing triple fluorescence, 

phase contrast, and light microscopy, etc. 



3) Laser Scanning Cytometer (LSC): The LSC allows 

“flow cytometer-like” fluorescent imaging 

and quantitation of tissue sections on a microscope 

slide. The LSC records the position and 

time of measurement for each cell analyzed so 

that multiple biochemical, immunological, 

and morphological measurements can be made 

on each cell. Possible applications for the LSC 

include: detection and quantitation of 

apoptosis (TUNEL, annexin); in situ hybridization 

(FISH); and the study of cell adhesion, 

cell cycle, and DNA content, etc. 

4) MetaMorph Imaging System (MIS): This imaging 

system consists of hardware and software 

that enables the capture and analysis of microscopy 

and digital images obtained using the 

instruments described above. 

5) Laser Capture Dissection Microscope (LCM): 

The LCM can dissect portions of tissues (or 

even single cells) from cell smears and fixed 

and frozen tissue sections, obtaining essentially 

pure samples of a desired cell population (500- 

1,000 cells per hour). The dissected cells can 

then be used to extract RNA, DNA, or proteins 

for further studies. LCM offers unprecedented 

access to specific cells for defining 

their pattern of gene expression, in combination 

with powerful techniques such as gene 

array and real-time PCR. This technology is 

particularly powerful in the study of human 

diseases and several cancer applications, where 

only small amounts of tissue may be available 

for study. 

144 



B I O S T A T I S T I C S 

MANAGER 


Professor of Epidemiology and Public Health 

PURPOSE 

The division of Biostatistics provides statistical 

expertise in the study, design, and analysis 

of data for UM/Sylvester members. Statisticians 

collaborate on developing protocols for clinical 

trials, work together on research proposals for 

laboratory-based investigations, and conduct epidemiological 

studies. They also perform statistical 

analyses, interpret results, and author or coauthor 

papers for publication. Biostatistics is 

committed to applying statistical and computational 

methods to improve the way in which 

clinical trials and translational research are conducted 

within UM/Sylvester and to developing 

statistical methodology that aids cancer research. 

SERVICES 

Biostatistics provides cancer center members with 

the following services: 

1) Collaboration: Biostatistics seeks to establish 

enduring collaborations with UM/Sylvester 

investigators to advance the cancer center’s 

programmatic research. Such collaborations 

develop statisticians’ knowledge of specific areas 

of cancer-related investigation and ensure 

that statistical considerations are adequately 

incorporated throughout the course of ongoing 

research programs. Priority is given to collaborative 

work, not consulting. 

2) Consulting: In contrast to collaborations, 

which involve long-term collegial relationships 

in planning studies or analyzing data, statistical 

consulting generally entails statistical advice 

or analysis with little involvement in the 

studies themselves and no co-authorship of 

publications. Consulting, however, is sometimes 

a preliminary step to collaborative research 

where Biostatistics plays a significant 

role. 

3) Study Design: Biostatistics formulates study 

objectives and endpoints in terms that are appropriate 

for statistical analysis, recommends 

alternative study designs, determines the 

sample size needed to address study objectives 

at an appropriate level of significance and 

power, and develops and writes plans for statistical 

analyses. 

4) Data Analysis: After study data have been collected, 

biostatisticians provide graphical and 

tabular reports of the results as well as substantive 

interpretation of the findings. 

5) Clinical Trial Applications: Biostatisticians contribute 

to the design and statistical analysis of 

investigator-initiated phase I and phase II cancer 

clinical trials; clinical epidemiology studies; 

novel diagnostic tests; clinical investigations of 

cancer therapies; basic science studies of cancer 

mechanisms; and translational studies of immunologic 

therapies, chemotherapy-modifying 

agents, and radio-sensitizing drugs. 



C E L L P U R I F I C A T I O N A N D B A N K I N G F A C I L I T Y 

MANAGER 



Immunology 

PURPOSE 

For many UM/Sylvester researchers, the transition 

from small animal to human studies is 

prevented by their inability to obtain primary 

human cells, whether normal or malignant. The 

overall goal of this facility is to generate purified 

primary human cells for the cancer research community 

at the University of Miami. 

SERVICES 

Specifically, the services of this facility are to: 

1) Provide purified normal primary human hematopoietic 

cells (T cells, B cells, monocytes, 

and CD34+ stem cells) for cancer-related 

research. 

2) Bank and provide primary leukemia, lymphoma, 

and myeloma cell isolates to investigators 

working with these malignancies. 

3) Provide centralized hematopoietic cell isolation, 

banking, inventory, and database capability 

for cancer-related clinical trials that are 

collecting cell samples for research. 

146 



C L I N I C A L R E S E A R C H S E R V I C E S R E S O U R C E 

CLINICAL DIRECTOR 

Joseph A. Lucci, III., M.D. 

Associate Professor of Obstetrics and 

Gynecology 

ASSISTANT DIRECTOR 


Manager 

PURPOSE 

The Clinical Research Services Resource 

provides UM/Sylvester investigators with 

broad-based support for their clinical research 

activities to: 

• Evaluate clinical trial protocol design, scientific 

merit, and patient care-related issues through 

the UM/Sylvester Protocol Review Committee. 

• Provide support services for screening, evaluating, 

recruiting, tracking, protecting, and maintaining 

patients on clinical protocols. 

• Assist investigators with protocol development 

by providing consultation in protocol design, 

access to other needed resources, and assistance 

with reporting requirements and other federal 

regulations. 

• Assure compliance with guidelines for investigational 

drug use and toxicity reporting and 

maintain quality data management. 

• Develop a data safety and monitoring board to 

monitor institutional clinical trials. 

• Support national cooperative group activities 

and interact with UM/Sylvester affiliates. 

• Develop, operate, and maintain a computerized 

protocol data management system. 

• Budget clinical trial expenditures and negotiate 

contracts with clinical trial sponsors. 

SERVICES 

1) Regulatory Office: This office handles all activities 

involving activation of clinical trials, which 

include preparing and presenting documents 

to both the Protocol Review Committee 

and the University of Miami Internal Review 

Board, writing informed consents, and distributing 

active protocols throughout the clinical 

areas on the medical campus. 

2) Informatics Office: This office maintains the 

database for institutional trials, monitors the 

charge-back system, provides lists of active 

clinical trials, and assists with quality control 

procedures. 

3) Budget Office: This office controls the budget 

for the Clinical Research Services Resource’s 

personal and office expenditures and negotiates 

contracts with clinical trial sponsors. 

4) Quality Assurance: This office monitors the 

quality of data management and conducts case 

auditing to ensure compliance with FDA requirements. 

It also interacts with the Data 

Safety and Monitoring Board. 

5) Research Pharmacy: The research pharmacy is 

responsible for investigational drug accountability 

and inventory, as well as providing drug 

information for medical, nursing, and pharmacy 

staff. 



D N A C O R E F A C I L I T Y 

MANAGER 

Rudolf K. Werner, Ph.D. 

Professor of Biochemistry and Molecular 

Biology 

PURPOSE 

The purpose of the DNA Core Facility is to 

make DNA sequencing services available to 

UM/Sylvester members in support of their peerreviewed 

funded research. 

SERVICES 

This facility provides cancer center investigators 

with the following services: 

1) DNA Sequencing: The investigator provides 

purified DNA for analysis and receives a sequence 

within three to five days. The sequence 

data are about 98 percent accurate. Some investigators 

perform their own sequencing reactions 

and provide the completed reaction 

mixture for analysis on the instrument. 

To achieve more uniform DNA quality, the 

facility also offers, for a small surcharge, DNA 

purification from a single bacterial colony 

containing the plasmid to be sequenced. 

In addition to the sequence analysis of doublestranded 

DNA, the facility also provides 

sequencing of polymerase chain reaction 

(PCR) products. These results are usually 

superior to those obtained from cloning DNA. 

2) Order Coordination: The facility coordinates 

orders for the synthesis of oligonucleotides 

from commercial sources. 

148 



F L O W C Y T O M E T R Y R E S O U R C E 

MANAGER 

Richard L. Riley, Ph.D. 


PURPOSE 

The Flow Cytometry Resource provides 

UM/Sylvester investigators, in support of 

their peer-reviewed funded research, with sophisticated 

methods for analysis and preparative 

sorting of normal and tumor cells, and trains 

investigators in the use of flow cytometry for 

their research. 

SERVICES 

This resource provides the following services to 

cancer center members: 

1) Laser-excited flow cytometry for analysis of 

cell surface antigens expressed in complex cell 

mixtures; up to four different fluorescent 

parameters and two light-scatter parameters 

(forward and side scatter) can be analyzed 

simultaneously. 

2) Laser-excited cell sorting (six parameters) for 

isolation of selected cell populations from 

heterogeneous mixtures. 

3) DNA content/cell cycle analysis via both 

visibly excited dyes (propidium iodide) and 

UV-excited dyes (Hoescht dyes) with pulse 

processing or doublet discrimination. 

4) High-efficiency sorting and sorting of large 

particles via the MacroSort system. 

5) Intracellular calcium ratio measurements. 

6) Applications for limiting dilution or cloning 

experiments via the automatic cell deposition 

unit (ACDU). 

7) Training in the use of the FACScan and LSR 

analytical flow cytometers, computer programs 

for data analysis, and data storage; consultation 

in the procedures for cell preparation, 

staining, fixation, data analysis, and preparative 

sorting also are provided. 



G E N E K N O C K O U T A N D T R A N S G E N E F A C I L I T Y 

MANAGER 

Thomas R. Malek, Ph.D. 

Professor and Vice Chair of Microbiology 


PURPOSE 

The Gene Knockout and Transgene Facility 

produces transgenic and knockout mice and 

trains investigators to apply this technology to 

their research. The major goal of the facility is to 

provide this technological capability to peer-reviewed 

funded cancer researchers at UM/ 

Sylvester. 

SERVICES 

This facility provides the following services to 

cancer center members: 

1) Set up breeding of donor and recipient mice 

and subsequently check plugs to confirm 

mating. 

2) Perform vasectomies of male mice for the 

recipient colony. 

3) Collect fertilized eggs or blastocysts. 

4) Sort and culture eggs. 

5) Prepare microinjection needles. 

6) Microinject eggs with DNA or blastocysts 

with cells. 

7) Inject donor and recipient mice with 

hormones. 

8) Perform microsurgery to re-implant eggs or 

blastocysts. 

9) Culture and transfer embryonic stem cells for 

microinjection into blastocysts. 

10) Generate gene-targeting constructs rapidly 

by using an arrayed library. 

11) Provide investigators with tissue biopsies to 

screen for transmission of transgene. 

12) Advise investigators in the production of 

transgenic and gene knockout constructs. 

13) Advise investigators in culturing and gene 

targeting in embryonic stem cells. 

150 



H I S T O L O G Y R E S E A R C H L A B C O R E 

MANAGER 

Carol K. Petito, M.D. 

Professor of Pathology 

PURPOSE 

The UM/Sylvester Histology Research Lab 

Core provides histology services to cancer 

center members in support of their peer-reviewed 

funded research and of their preliminary studies 

completed to prepare for grant submission. 

SERVICES 

The facility currently provides the following services: 

1) Processing of fixed material into paraffin 

blocks. 

2) Tissue sectioning for routine hematoxylineosin 

stains and other stains. 

3) Tissue sectioning for immunohistochemistry. 

4) Professional consulting for methodology and 

for histological interpretation. 



I N F O R M A T I C S 

ASSOCIATE DIRECTOR 


Associate Professor of Surgery 

PURPOSE 

The Division of Informatics at UM/Sylvester 

facilitates the integration of information to 

support patient care, research, education, and 

administration. The division is composed of 

two subdivisions: Systems Development and 

Support and Network Management and Personal 

Computing. 

SERVICES 

Systems Development and Support 

The Systems Development team conducts 

technical research and development to meet 

UM/Sylvester’s short- and long-term requirements. 

It also delivers software solutions in 

the areas of research, administration, and web 

development. The team’s primary objective is 

to increase productivity and efficiency in various 

areas of the cancer center by providing: 

1) Systems analysis and design services. 

2) Database development, administration, and 

support. 

3) Programming of quality computer applications. 

4) Development of Intranet web sites that provide 

employees with organized, readily accessible 

information in a central repository and 

secured web-based applications. 

5) Project management and implementation, 

which includes technical and user documentation 

and user training. 

6) Expedited document processing via electronic 

forms that are accessible through the web. 

The group provides infrastructure support with 

web-enabled database systems as follows: 

Research: The essential support needed by 

UM/Sylvester investigators is provided by the 

Systems Development team for the management 

of clinical trials and the protocol approval process; 

tracking of patient accrual data; collection of research 

personnel time and generation of invoices 

for protocol billing; management of investigatorinitiated 

clinical trial patient data; administration 

of web accessible protocols and related documents; 

secure dissemination of reports to investigators; 

and management of patient tissue banks 

including a web interface that allows investigators 

to search the tissue bank and request specimens 

according to their investigational interests. 

Administration: A centralized database system has 

been developed that unifies information from the 

various administrative divisions and facilitates the 

management and sharing of information. The 

database and related applications provide functionality 

for the management of UM/Sylvester’s 

members as well as profiles of their research interests 

and involvement, investigator’s published 

materials, grants, and research funded projects, 

shared resource facilities, and human resources. 

Network Management and Personal 

Computing 

The Network Management team provides infrastructure 

support for cancer center connectivity, 

central computing hardware, and firewall security. 

The network group has four major functions: 

1) Integrate information systems and communications 

for the research, administrative, and 

clinical areas of the cancer center. 

2) Support the operation of a center-wide 

Intranet with defined security. 

3) Support connectivity to campus networks 

including access to wide-area networks. 

4) Assist with hardware and software installation 

and support. 

5) Provide system backup, disaster recovery, and 

high availability. 

152 



M O L E C U L A R A N A L Y S I S C O R E 

MANAGER 

Roland Jurecic, Ph.D. 

Assistant Professor of Microbiology and 

Immunology 

PURPOSE 

The Molecular Analysis Core provides UM/Sylvester 

members with: 1) capillary-based DNA 

sequencing of plasmids and polymerase chain 

reaction (PCR) fragments, 2) shotgun sequencing 

of large cDNA and genomic DNA inserts 

(transgenic and knockout/targeting vectors), 3) 

basic DNA fragment analysis, and 4) real time 

quantitative PCR and reverse transcriptase-PCR 

(RT-PCR) using LightCycler technology. 

3) Basic DNA fragment analysis. Detection of 

isoforms, alternative transcripts, and DNA rearrangements, 

etc. 

4) Automated heterozygote detection. 

Quantitative Real Time PCR Techniques Using 

the Roche LightCycler 

1) Real time quantitative PCR and RT-PCR. 

2) Full melt curve analysis of amplified products. 

3) Design and testing of fluorogenic probes for 

rapid and sensitive detection of gene targets. 

4) Genotyping of transgenic and knockout 

mouse models. 

SERVICES 

This facility provides UM/Sylvester investigators, 

in support of their peer-reviewed research, with 

the following services: 

Genetic Analysis using the Beckman CEQ 2000 

Genetic Analyzer 

1) Capillary-based DNA sequencing of plasmids 

and PCR fragments (800 base pairs in 90 minutes), 

using standard (T3, T7, Sp6, M13, etc.) 

or custom-designed primers. 

2) Shotgun sequencing of large cDNA and genomic 

DNA inserts (transgenic and knockout/targeting 

vectors) using transposon technology for 

fast and easy insertion of sequencing primer 

binding sites and kanamycin resistance markers 

into target DNA in vitro. Selection of different 

clones with transposon integrated only 

into the genomic insert (not the plasmid 

backbone) by digest restriction and size difference. 

Based on the insert size, 20 to 40 different 

clones are subjected to automated sequencing 

and assembled into contigs using sequence utility 

software. 



P O P U L A T I O N R E S E A R C H C O R E 

(Developing Shared Resource) 

DIRECTOR 



MANAGER 

Dorothy F. Parker, M.H.S. 

PURPOSE 

The purpose of the Population Research Core 

will be to provide services to support population-based 

cancer prevention and control research 

at UM/Sylvester and to help increase the diversity 

of study participants to represent the racial, ethnic, 

and socioeconomic composition of South 

Florida’s diverse and unique community. 

The Population Research Core evolved from 

the Florida Comprehensive Cancer Control Initiative 

(FCCCI), a project funded by the Centers 

for Disease Control that established regional cancer 

control collaboratives throughout Florida. 

UM/Sylvester continues to support the Southeast 

Florida Regional Cancer Control Collaborative, a 

group of more than 40 organizations that are a 

potential source of recruitment for populationbased 

studies. FCCCI’s staff of three also supports 

the Population Research Core. They have 

experience in cancer control research, data analysis, 

and community outreach. 

SERVICES 

The Population Research Core will offer services 

in three areas: recruitment, data and measurement, 

and education. Additionally, in an effort to 

better meet the needs of UM/Sylvester investigators, 

the core is conducting a faculty survey to 

determine what is needed to facilitate research 

and recruitment. 

Recruitment 

1) Help UM/Sylvester investigators develop and 

assess recruitment and retention plans for 

funded projects. 

2) Increase awareness of population research 

studies open for accrual. 

3) Serve as liaison with local health care providers 

and community organizations. 

4) Develop agreements and procedures for recruitment 

of participants in cancer control 

studies. 

5) Pretest and/or conduct focus groups with target 

populations to develop appropriate recruitment 

tools and strategies (e.g., brochures, 

flyers, and advertisements). 

Data and Measurement 

1) Provide aggregate local, regional, and national 

cancer and demographic data. 

2) Help develop or identify appropriate questionnaires 

and survey tools. 

3) Arrange for translation of materials (e.g., into 

Spanish and Haitian Creole). 

4) Provide assistance with data collection tools 

and database design. 

Education 

1) Assess needs of investigators for understanding 

issues related to population science. 

2) Provide workshops and training on issues such 

as: community outreach and campus-community 

research concerns, cultural and socioeconomic 

factors that affect recruitment 

strategies, study design, the informed consent 

process, and participation in studies. 

154 


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169:4998-5004, 2002. 




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Petito, CK, Adkins, B, McCarthy, M, Roberts, B, 

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virus encephalitis. Journal of 


Adkins, B, Williamson, T, Guevara, P, and Bu, Y. 

Murine neonatal lymphocytes show rapid early 

cell cycle entry and cell division. Journal of Immunology 

170:4548-56, 2003. 

Auais, A, Adkins, B, Napchan, G, and 

Piedimonte, G. Immunomodulatory effects of 

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190 


G L O S S A R Y 


2-DG—2 deoxyglucose 

ACDU—Automatic Cell Deposition Unit 

ACS—American Cancer Society 

ALL—acute lymphocytic leukemia 

AMC—AIDS Malignancy Consortium 

AML—acute myeloid leukemia 

APC—antigen presenting cell 

ATL—adult T-cell leukemia 

AZT—azidothymidine 

BEA—blastocyst engraftment assay 

BF—benefit-finding 

BMT—bone marrow transplantation 

CBSM—cognitive-behavioral stress management 

CBCTR—Cooperative Breast Cancer 

Tissue Resource 

CDC—Centers for Disease Control 

Cdk—cyclin-dependent kinase 

CK—cytokeratin 

CLL—chronic lymphocytic leukemia 

CMT—chemically-modified tetracycline 

CNS—central nervous system 

COL-3—chemically modified non-antimicrobial 

tetracycline 

CPOR—Center for Psycho-Oncology Research 

CPT—natural product camptothecin 

CTL—cytotoxic T lymphocytes 

DC—dendritic cells 

DLBCL—diffuse large B-cell lymphoma 

DR3—death receptor 3 

DSMB—Data and Safety Monitoring Plan 

EBV—Epstein-Barr virus 

ECM—extracellular matrix 

EGF—epidermal growth factor 

EMSA—electromobility shift assay 

ER—estrogen receptor 

ERM—ezrin, radixin, and moesin 

ER/PR—estrogen receptor/progesterone receptor 

ES—embryonic stem 

EST—expressed sequence tag 

FAMRI—Flight Attendant Medical Research 

Institute 

FDA—Food and Drug Administration 

FCCCI—Florida Comprehensive Cancer 

Control Initiative 

FCDS—Florida Cancer Data System 

FDOH—Florida Department of Health 

FLRF—fetal liver ring finger 

FRAP—fluorescence recovery after photo 

bleaching 

FRET—fluorescence resonance energy transfer 

GC—germinal center 

GCRC—General Clinical Research Center 

GI—gastrointestinal 

GIS—geographic information system 

GM-CSF—granulocyte macrophage-colony 

stimulating factor 

GPI—glycosil-phosphatidil-inositil 

GVHD—graft versus host disease 

HA—hyaluronic acid 

HAASE—hyaluronidase 

HAM/TSP—HTLB-associated myelomathy/ 

tropical spastic paraparesis 

HCC—hepatocellular carcinoma 

HCV—hepatitis C virus 

HGAL—human germinal center-associated 

lymphoma 

HHV—human herpes virus 

HIF—hypoxic inducible factor 

HIV—human immunodeficiency virus 

HNSCC—head and neck squamous cell carcinoma 

HPV—human papilloma virus 

HSC—hematopoietic stem cells 

HSV—herpes simplex virus 

HTLV-I—human T-lymphotropic virus type I 

HYAL1—hyaluronidase 

IF—intermediate filament 


191


IFN—interferon 

IL—interleukin 

INCA—National Cancer Institute of Brazil 

IND—Investigational New Drug 

INOS—inducible nitric oxide synthase 

IRB—Institutional Review Board 

KO—knock-out 

LAK—lymphokine-activated killer cells 

LCM—laser capture dissection microscope 

LSC—laser scanning cytometer 

MAPK—mitogen-activated protein kinase 

MDR—multiple drug resistance 

MHC—major histocompatability complex 

MIC-1—macrophage inflammatory cytokine-1 

MIS—MetaMorph Imaging System 

MM—multiple myeloma 

MMPs—matrix metalloproteinases 

mRNA—messenger RNA 

mtDNA—human mitochondrial DNA 

MTOC—microtubule organizing centers 

MUC1—human mucin 1 

NASA—National Aeronautics and 

Space Administration 

NCI—National Cancer Institute 

NCI-DTP—National Cancer Institute- 

Developmental Therapeutics Program 

NGF—nerve growth factor 

NHL—non-Hodgkin lymphoma 

NHLBL—National Heart, Lung, and 

Blood Institute 

NIEHS—National Institute of Environmental 

Health Sciences 

NIH—National Institutes of Health 

NIOSH—National Institute of Occupational 

Safety and Health 

NK—natural killer 

NKB—Dutch Cancer Foundation 

NKCC—natural killer cell cytotoxicity 

NMR—nuclear magnetic resonance 

NO—nitric oxide 

NPC—nuclear pore complexes 

Nups—nucleoporins 

ORF—open reading frame 

OXPHOS—oxidative phosphorylation 

PCMR—Pediatric Cardiomyopathy Registry 

PCNA—proliferating cell nuclear antigen 

PCR—polymerase chain reaction 

PDIP1—polymerase delta interacting protein-1 

PDK1—phosphoinositide-dependent protein 

kinase-1 

PEL—primary effusion lymphomas 

PEMs—peritoneal elicited macrophages 

PGCs—primordial germ cells 

PH—pleckstrin homology 

PKB—protein kinase B 

PKC—protein kinase C 

Polε—polymerase epsilon 

QLACS—quality of life in adult cancer survivors 

Rb—retinoblastoma 

RENCA—renal cell carcinoma 

RT—reverse transcriptase 

RTOG—Radiation Therapy Oncology Group 

SCCA—squamous cell carcinoma 

SCID—severe combined immunodeficiency 

disease 

SIL—squamous intraepithelial lesions 

SIR—standardized incidence ratios 

SMC—sialomucin complex 

TBIO—thermodynamically balanced inside-out 

TGF-α—transforming growth factor-alpha 

TGF-β—transforming growth factor-beta 

TNF—tumor necrosis factor 

UM/Sylvester—University of Miami Sylvester 

Comprehensive Cancer Center 

VEGF—vascular endothelial growth factor 

VSV—vesicular stomatitis virus 

wt—wild type 

192 


University of Miami Sylvester Comprehensive Cancer Center 

1475 N.W. 12th Avenue 

Miami, Florida 33136 

UM/Sylvester at Deerfield Beach 

1192 East Newport Center Drive, Suite 100 

Deerfield Beach, Florida 33442 

www.sylvester.org 

305-243-1000 / 1-800-545-2292

SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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