tumor cell biology program - Sylvester Comprehensive Cancer Center

TABLE OF CONTENTS 

SCIENTIFIC REPORT 2002 

Research Activities 1999-2001 

INTRODUCTION ................................................... i 

PROGRESS REPORT .............................................. ii 

LEADERSHIP ....................................................... vi 

SCIENTIFIC PROGRAMS 

Tumor Cell Biology Program ....................................... 1 

Tumor Immunology Program .................................... 21 

Viral Oncology Program ............................................ 37 

Cancer Prevention and Control Program ................... 45 

Clinical Oncology Research Program ......................... 55 

SHARED RESOURCES 

EDITOR 

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

Director 

University of Miami 

Sylvester Comprehensive Cancer Center 

Gene KnockOut and Transgene Facility ..................... 73 

DNA Core Facility..................................................... 73 

Flow Cytometry Resource .......................................... 73 

Media Facility ............................................................ 74 

Protein Analysis Facility ............................................. 74 

Cell Purification and Banking Facility ........................ 74 

Analytical Imaging Care ............................................. 74 

Clinical Research Services Resource ........................... 75 

Core Research Histology Laboratory............................76 

PRODUCTION COORDINATION 

DIVISION OF BIOSTATISTICS ............................. 77 

Office of Research Administration 

Office of Education and Training 

Office of Marketing and Communications 

Sabia Communications 

DIVISION OF INFORMATICS .............................. 79 

SCIENTIFIC REPORT PUBLICATIONS ................. 81 

UM/Sylvester Comprehensive Cancer Center Scientific Report 2002


INTRODUCTION 


Director 

Bi-directional translational research, with ideas flowing from 

the laboratory bench to the patient’s bedside and back 

again, is the essence of a comprehensive cancer center. The 

University of Miami Sylvester Comprehensive Cancer Center 

supports a large group of basic laboratory scientists and a growing 

cadre of physician scientists who work together to help 

establish better treatment regimens for cancer patients everywhere. 

The State of Florida, the citizens of South Florida, and 

the University of Miami are investing in this important work. 

This report demonstrates the wisdom of that investment. I 

am proud of our scientists, and of their research product, as 

reported on the pages that follow. 

The content of this report follows our operational structure. 

Our scientists are grouped into multidisciplinary research 

programs, which address important aspects of the cancer problem. 

The scientific programs that we have established (Tumor 

Cell Biology, Tumor Immunology, Viral Oncology, Cancer Prevention 

and Control, and Clinical Oncology Research) reflect 

our strengths and our priorities. This selection of programs is 

what makes us unique among the many fine cancer centers in 

our great country. We are focusing our attention on facilitating 

translational research in each of these programs. 

The clinical testing of targeted therapies, using molecules 

identified as promising by our scientists, is among our most 

exciting and significant activities. Our scientists work within 

the established research programs, and with physicians in UM/ 

Sylvester’s 13 multidisciplinary, site-based oncology groups, 

to design and conduct the clinical trials necessary to test the 

value of these new treatments. Current examples include: 

• A Phase III trial of antiviral drugs along with interferon 

for patients with HIV-related lymphomas 

• A Phase I trial of arsenic plus ascorbic acid in patients 

with refractory multiple myeloma 

• A Phase I trial of a vaccine in refractory, non-small cell 

lung cancer 

• A Phase II trial of vitamin D, along with radiation therapy, 

in hormone refractory prostate cancer 

Conducting clinical trials, with patients as research subjects, 

is a weighty responsibility. The Clinical Research Services 

resource is especially important to UM/Sylvester in that 

it is charged with assisting the principal investigator with the 

safe and effective conduct of each trial. I am grateful to the 

research nurses and data managers who work on the front lines 

of this effort. All who do this work recognize that our patients 

are the real heroes. 

The addition of Dr. Joseph D. Rosenblatt to UM/ 

Sylvester’s leadership team in 2001 was especially significant. 

Dr. Rosenblatt serves as division chief of Hematology-Oncology 

in the Department of Medicine and scientific director of 

UM/Sylvester. As a world-class physician scientist and an experienced 

leader, he is the ideal individual to provide direction 

for the translational research program outlined above. His 

recruitment confirms our commitment to this effort. Dr. 

Rosenblatt has quickly proved himself to be a terrific colleague, 

and it is truly a personal pleasure for me to formally recognize 

his many contributions to UM/Sylvester here. 

I would like to dedicate this report to two inspiring individuals 

and a remarkable volunteer group. We lost Dr. Kasi 

Sridhar to lymphoma this past year. He combined all the best 

qualities seen in each of us, and served as the president of our 

medical staff for six years. We miss him dearly. Mr. Stuart 

Danoff was a UM/Sylvester founder, a member of our Board 

of Governors, and chaired our Research Committee. His courage 

remains a constant inspiration to me. And in an era when 

most volunteer groups struggle to maintain their momentum, 

the Papanicolaou Corps for Cancer Research celebrated their 

50 th anniversary this year, with a gift of nearly $2 million. The 

Corps has grown to 37 units and 12,000 members, and has 

donated more than $7 million to support cancer research during 

the past six years. Their tireless efforts continue to impress 

and amaze me. 

We are slowly winning the war against cancer. Age-adjusted 

death rates for most cancer sites and for cancer overall 

began to decline in the early 1990s, and that decline has accelerated. 

Nearly as important, the quality of life experienced by 

those waging a personal battle with cancer also has improved. 

But that is not good enough. We must do more, and the pages 

of this report demonstrate our passion to make a difference. 

I hope that you find this report to be useful, and I welcome 

your comments. 

UM/Sylvester Comprehensive Cancer Center Scientific Report 2002 

i

PROGRESS REPORT 1999-2001 

Joseph D. Rosenblatt, M.D. 

Scientific Director 

Since joining the University of Miami 

Sylvester Comprehensive Cancer 

Center last year as division chief in Hematology-Oncology 

and scientific director, 

I have participated in a number of 

exciting activities. UM/Sylvester’s goals 

are simple: to provide state-of-the-art 

cancer care to patients in South Florida 

and the region, including the many patients 

from Latin America and the Caribbean 

seeking tertiary care, clinical trials, 

and novel therapeutic options; and second, 

to facilitate the rapid translation of 

research into new and better means of 

cancer prevention, diagnosis, and treatment. 

There is no question we must meet 

these challenges head on. Almost 

550,000 Americans will die of cancer this 

year, and Florida ranks second only to 

California in the number of new cancer 

cases, projected to exceed more than 

88,000 this year. Our tumor registry at 

Jackson Memorial Hospital, UM/ 

Sylvester, and Bascom Palmer Eye Institute 

records over 5,000 newly referred 

cases per year, exclusive of skin cancer. 

Our unique and diverse populations provide 

us with unparalleled opportunities, 

as well as profound logistical challenges 

as we expand clinical research activities. 

During the past year, we have conducted 

a systematic review of where we 

are as a cancer center, where we want to 

be, and have outlined a series of steps 

already in progress to assume our rightful 

place in the ranks of America’s premiere 

cancer centers. Our distinguished 

External Advisory Board visited us in November 

of 2001, carefully reviewed our 

programs, and left impressed with UM/ 

Sylvester’s progress and enthusiastic 

about our future. To further fulfill our 

potential, we need to build upon the excellent 

programs already in place, expand 

our portfolio of clinical trials, and develop 

new multidisciplinary initiatives 

across departmental lines. 

During the past year we have been 

meeting and planning at all levels of the 

organization. Our success will be determined 

by our ability to stimulate innovative 

clinical and translational trials and 

augment existing scientific programs 

through the careful application of available 

philanthropic and human resources 

and the acquisition of important new 

shared resources for our investigators. To 

meet these challenges, Dr. W. Jarrard 

Goodwin, UM/Sylvester director; our 

associate directors for Basic and Clinical 

Research, Drs. Eckhard R. Podack and 

Shou-Ching Tang, respectively; and I 

have embarked on an ambitious overhaul 

of our clinical and research infrastructure, 

and on an equally ambitious recruitment 

program. 

The years 1999-2001 saw a steady 

increase in National Cancer Institute 

funding from $7.7 million in 1999 to 

$8.3 million in 2001. New research space 

is being prepared in the Batchelor Building, 

administrative space in the Fox 

Building, and future space renovation 

and construction are in the advanced 

planning phase to allow us to pursue our 

very ambitious recruitment goals. 

Over the past year, UM/Sylvester has 

organized site-specific multidisciplinary 

oncology groups, which now meet 

regularly to coordinate both patient care, 

protocol development, and translational 

research efforts and function across UM/ 

Sylvester, JMH, and the Miami Veteran’s 

Administration Hospital. Site-specific 

clinics in head and neck oncology, lung 

cancer, hematologic malignancies, breast 

cancer, and others have been introduced 

at the JMH outpatient clinic and are 

abetting clinical trial accrual, fellow education, 

and translational research. Of necessity, 

these groups function in a 

complex environment and across departmental 

lines to provide state-of-the-art 

care and conduct innovative clinical research. 

We are working to assure that the 

primary site-specific groups, e.g., breast, 

lung, and genitourinary, assemble a critical 

mass so as to position the groups and 

UM/Sylvester for future National Institute 

of Health SPORE submissions. 

We’ve taken a major step forward with 

the recent recruitment of Dr. Joyce M. 

Slingerland from the University of 

Toronto to head our efforts in breast cancer, 

and Dr. Rakesh Singal from Louisiana 

State University to join the genitourinary 

program. 

Although utilization of clinical space 

at UM/Sylvester and JMH is being maximized 

and optimized, the steady growth 

of patients is presenting severe logistical 

challenges to already strained resources. 

A major expansion of the Clinical Treatment 

Unit at UM/Sylvester and relocation 

and expansion of outpatient facilities 

at JMH are planned to allow provision 

of multidisciplinary care at both sites by 

teams organized and coordinated 

through UM/Sylvester. 

BASIC SCIENCE RESEARCH 

We have continued to emphasize 

three longstanding scientific programs 

with excellent track records: Tumor Cell 

Biology led by Dr. Kermit L. Carraway, 

Tumor Immunology led by Dr. Diana 

M. Lopez, and Viral Oncology led by Dr. 

William J. Harrington, Jr. 

ii 


The Tumor Cell Biology Program continues 

to develop a strong translational 

focus, involving faculty from seven departments 

under the leadership of Dr. 

Carraway. The program has maintained 

its emphasis on cell signaling and cell 

cycle regulation, and has recently increased 

emphasis on the regulation of 

transcription and RNA trafficking. The 

program has been especially effective at 

mentoring junior faculty—such as Drs. 

Balakrishna L. and Vinata B. Lokeshwar 

and Catherine Welsh—who have been 

able to develop their own independent 

efforts at the University of Miami. Many 

of their translational research efforts 

within the Tumor Cell Biology Program 

are now yielding substantial dividends. 

Research into the biology of MUC4, a 

heterodimeric glycoprotein expressed in 

epithelial tissue and often aberrantly expressed 

in tumors, has highlighted an 

important role for this molecule in the 

regulation of signaling through growth 

factor receptors such as her2/neu, an important 

therapeutic target in breast and 

other cancers. MUC4 expression may 

also be of prognostic significance in several 

cancers, and Dr. Carraway and a 

cadre of investigators are working to 

better understand MUC4 regulation 

and biology. 

Drs. Kelvin P. Lee and Lawrence H. 

Boise have studied mechanisms of 

apoptosis in multiple myeloma and have 

shown that arsenic in concert with ascorbic 

acid may have substantial therapeutic 

potential. A newly inaugurated Phase 

I/II study has accrued well and early results 

using the combination suggest considerable 

efficacy with an acceptable 

toxicity profile. Dr. Welsh has studied the 

biology of p27 kip , an important cell cycle 

regulatory protein in breast cancer, and 

has made critical new insights into p27 kip 

regulation. The anticipated arrival of Dr. 

Slingerland in the early fall should further 

strengthen our strong efforts in cell 

cycle biology, especially as these relate to 

breast cancer. Drs. Balakrishna and 

Vinata Lokeshwar, working with Dr. 

Bernard A. Roos in the area of prostate 

cancer, have demonstrated a critical role 

for hyalouronic acid and hyalouronidase 

as markers of metastatic potential and 

progression. Dr. Rakesh Singal is an important 

new recruit to our prostate cancer 

effort. Dr. Singal, soon to arrive at 

UM/Sylvester, has developed new assays 

for DNA methylation and demonstrated 

the important effects of methylation on 

gene expression in prostate and other cancers. 

Finally, Dr. Theodore J. Lampidis 

has developed several tumor models for 

hypoxia and demonstrated the potential 

utility of glycolytic inhibitors in sensitizing 

solid tumors to the effects of radiation 

and chemotherapy. Several of these 

strategies could be readily tested in patients 

in Phase I trials. Hence in recent 

years, the program has spawned a large 

number of new and potentially useful 

clinical approaches. 

The Tumor Immunology Program has 

seen several of its basic concepts translate 

into the clinical arena. The program 

continues to emphasize T-cell and cytolytic 

effector cell biology as it relates to 

cancer, with emphasis on novel immunotherapeutic 

applications. Drs. Robert 

B. Levy and Thomas R. Malek have extensively 

investigated the special role of 

T-regulatory cells in the induction of 

immune tolerance and hematopoietic 

graft acceptance. Unique mouse models 

may shed important light on resistance 

to marrow engraftment as well as provide 

new avenues for regulation of Graft 

versus Host disease and transplantation 

across histocompatibility barriers. The 

Rosenblatt laboratory has developed new 

approaches to gene therapy using Herpes 

Amplicon vectors in hematological 

malignancies such as chronic lymphocytic 

leukemia. In addition, the laboratory 

has explored the important role of 

chemokines in recruiting effector cells to 

the site of tumors in an effort to enhance 

local and systemic responses. Together 

with Dr. Seung-uon Shin, the laboratory 

has also investigated the potential for localized 

delivery of chemokines, costimulatory 

molecules, and/or anti-angiogenic 

peptides, such as endostatin, through the 

use of antibody fusion proteins. Preliminary 

results suggest that the efficacy of 

endostatin can be markedly improved 

using this approach. 

Dr. Eckhard R. Podack, together 

with Dr. Luis E. Raez, in the Thoracic 

Clinic, have explored the use of lung cancer 

cells genetically engineered to express 

the B7.1 T-cell costimulatory ligand as a 

means of evoking an immune response 

in lung cancer patients. Preliminary testing 

has been carried out in a Phase I trial, 

and partial responses, as well as disease 

stabilization, have been noted in several 

patients. An exceedingly novel approach 

involving the localized secretion of the 

heat shock protein gp96 has been developed 

in the laboratory and should shortly 

enter clinical testing in lung cancer as 

well. Finally a new monoclonal antibody 

developed by Dr. Podack targeting the 

CD30 receptor, present on Reed 

Sternberg cells in Hodgkin’s disease, and 

on many non-Hodgkin’s lymphomas as 

well, has entered clinical testing at UM/ 

Sylvester and several outside cancer centers. 

Dr. Lopez and colleagues have investigated 

the ability of a short peptide 

derived from the MUC-1 tumor associated 

antigen to stimulate an enhanced 

innate immune response, and have secured 

important industrial support for 

the testing of the reagent in the clinic. 

The Tumor Immunology Program has 

demonstrated the ability to ask clinically 

relevant translational questions, define 

new clinical approaches, and reduce basic 

science concepts to the clinic at an 

impressive rate. Critical recruitment of 

physician scientists, as well as basic scientists 

with an interest in dendritic cell 

biology and innate immunity, should 

augment what is already a stellar effort. 

The Viral Oncology Program has from 

its inception capitalized on the unique 

South Florida patient base, which includes 

a large migratory population from 

the Caribbean and South America. A 

large number of cases of adult T-cell leukemia 

linked to HTLV-1, as well as 

HTLV-1 induced myelopathy, are followed 

here as well as a large cohort of 

patients with HIV-1 linked lymphomas. 


iii

A seminal observation by Dr. Harrington 

and coworkers regarding the activity of 

antivirals in ATL, as well as in HHV-8 

linked primary effusion related lymphoma, 

has spawned a highly successful 

correlative and basic research effort. The 

unexpected clinical activity of AZT in 

these malignancies has led to a concerted 

search for underlying mechanisms leading 

to the fundamental observation that 

constitutive activation of the NFkB pathway 

may play a central role in resistance 

to therapy as well as susceptibility to antivirals. 

In addition, working with Drs. 

Lawrence H. Boise and Glen Barber, a 

central role for upregulation of the death 

receptor TRAIL has been demonstrated, 

leading to new therapeutic approaches 

to these refractory lymphomas. 

In a new and promising gene 

therapy approach, Dr. Barber’s laboratory 

has also developed new oncolytic viruses 

derived from Vesicular Stomatitis Virus 

(VSV), a common cause of “cold sores” 

that have the selective ability to kill cancer 

cells, and has used these to eradicate 

a variety of tumors either directly or 

through the local delivery of cytokines 

and/or costimulatory molecules. A 

unique aspect of the Viral Oncology Program 

has been its ability to rapidly translate 

clinical observations into meaningful 

basic questions in the lab. Ongoing efforts 

to further develop the program are 

directed at recruitment of additional scientists 

with interests in Gamma Herpes 

virus biology and other oncogenic viruses, 

which will broaden what has been 

a highly focused and original effort. 

CLINICAL RESEARCH 

INFRASTRUCTURE 

As a tertiary referral center, many 

patients arrive at UM/Sylvester seeking 

options and therapies not yet available 

in the community. UM/Sylvester is especially 

invested in the development of 

home grown intramural trials based on 

science and technology developed at the 

University of Miami. Furthermore, special 

emphasis continues to be placed on 

the investigation of patient related 

samples for purposes of correlative research. 

To facilitate the improvement and 

expansion of our translational research 

efforts as well as our clinical trials portfolio, 

the Clinical Research Services office 

has been reorganized under the 

leadership of Dr. Shou-Ching Tang, a 

newly arrived recruit from the University 

of Newfoundland. In Canada, Dr. 

Tang acquired an international reputation 

in the conduct of breast and lung 

cancer trials as a leading investigator in 

both the Canadian cooperative group, 

AECOG, and the international breast 

cancer research group, BCIRG. In addition, 

Dr. Tang is an accomplished laboratory 

researcher who has made seminal 

observations regarding the role of BAG- 

1 in apoptosis and has identified BAG-1 

as an important prognostic factor in both 

breast and lung cancer. Since his arrival 

earlier this year, Dr. Tang has presided 

over the rapid reorganization of the 

Clinical Research Services regulatory 

arm, site-specific protocol management, 

and centralized research nursing and data 

and safety monitoring functions, in order 

to assure rapid throughput of studies, 

monitoring of accrual and data 

acquisition, and compliance with the 

highest federal and scientific standards. 

Clinical Research Services, along with 

our able Biostatistics Division under the 

seasoned leadership of Dr. James J. 

Schlesselman, has become an important 

resource to UM/Sylvester investigators 

seeking to develop new trials and/or correlative 

research protocols. 

As we work to integrate JMH patients 

into ongoing trials, Clinical Research 

Services has worked to facilitate 

screening and successful shepherding of 

patients through complex protocols, and 

to assure that the many options available 

to patients at UM/Sylvester are also available 

to our JMH population. As scientific 

director, I accord the integration of 

JMH special priority as we expand our 

clinical research activity. 

CANCER PREVENTION AND 

CONTROL PROGRAM 

We are both jubilant and saddened 

by the recent departure of Dr. Edward 

Trapido to a senior leadership position 

at the National Cancer Institute in Cancer 

Control. Dr. Trapido has worked very 

hard over the years to establish our Cancer 

Prevention and Control Program as 

one of the foremost in the nation. This 

program has done an excellent job of 

capitalizing on the unusually diverse patient 

base in South Florida and on the 

unique epidemiology of cancer in our 

population. The program has made exciting 

discoveries of new and different 

BRCA1 mutations in African-American 

familial breast cancer patients that have 

allowed the development of specialized 

screening assays. The impact of emotional 

distress and chemotherapy on the 

immune system continues to be investigated 

by Dr. Michael H. Antoni, our new 

Cancer Prevention and Control Program 

leader, and Dr. Bonnie Blomberg, as we 

expand investigations in the emerging 

discipline of psychoneuroimmunology. 

Important new advances have been made 

in our ability to monitor the cumulative 

effects of stress on immune function. 

New surrogate markers for the effects of 

stress are being tested and the effectiveness 

of psychological intervention in reversing 

changes engendered in response 

to stress can now be more definitively 

measured. Dr. Antoni and his group are 

pioneering important new means of 

group intervention to reduce anxiety and 

stress among cancer patients. Dr. Trapido 

has also continued his leadership of the 

Florida Youth Tobacco Prevention Program, 

the most successful program of its 

type in the United States. This program 

has dramatically reduced the rates of tobacco 

use in the state’s high schools and 

middle schools. 

It is impossible to fully enumerate 

the progress of UM/Sylvester in recent 

years, and these comments serve to highlight 

but a few of our outstanding 

achievements. Under the dynamic leadiv 


ership of Dr. Goodwin, and with the full 

support of our trustees and dedicated 

philanthropists in the community, we 

have embarked on an ambitious program 

of scientific and clinical expansion that 

will transform UM/Sylvester into one of 

the premiere cancer centers in the nation 

and the hemisphere. Outstanding scientists 

and clinicians such as Drs. Isidore 

Lossos, Singal, and Slingerland will join 

us shortly, and many more are being recruited. 

This program of expansion and 

refinement will positively impact the care 

delivered to our patients, and the cancer 

community in Miami as a whole. 

These are interesting times at the 

University of Miami, and it is a privilege 

to be part of this exhilarating effort. Together 

with the enthusiastic support of 

our Dean John G. Clarkson and University 

of Miami President Donna E. 

Shalala, we aim to place UM/Sylvester 

at the forefront of cancer care and research 

in the new millennium. We are 

well positioned to succeed, and it is a joy 

to be part of the team effort. 

I thank my colleagues for their insight, 

help, and support, and our patients 

for their enduring trust, as I look back 

on an extraordinary first year in Miami 

and negotiate the challenges that lie 

ahead. To paraphrase a famous Talmudic 

saying, “The time is short, the task 

abundant, and the Master of the House 

insistent.” 


v

UM/SYLVESTER COMPREHENSIVE CANCER CENTER 

Leadership 

MEDICAL SCHOOL LEADERSHIP 

John G. Clarkson, M.D. 

Senior Vice President and Dean 

SENIOR LEADERSHIP 


Director 



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

Associate Director, Basic Science 

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

Associate Director, Clinical and Translational Research 

Edward Trapido, Sc.D. 

Associate Director, Cancer Prevention and Control 

Robert S. Powell, M.Ed. 

Associate Director, Administration 

David L. Stansberry, M.S. 

Hospital Administrator 

Marilyn Stern Emas, M.Ed. 

Acting Executive Director, Development 

Judith B. Hayden, M.B.A. 

Director, Marketing and Communications 

RESEARCH PROGRAM LEADERS 

Michael H. Antoni, Ph.D. 

Cancer Prevention and Control 

Kermit L. Carraway, Ph.D. 

Tumor Cell Biology 

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

Antero G. So, M.D., Ph.D. 

Viral Oncology 

Kelvin P. Lee, M.D. (Acting) 

Clinical Oncology Research (Developing Program) 

Diana M. Lopez, Ph.D. 

Tumor Immunology 


Arba Ager, Ph.D. 

Media Facility 

Kelvin P. Lee, M.D. 

Cell Purification and Banking Facility 

Thomas R. Malek, Ph.D. 

Gene KnockOut and Transgene Facility 

Vladimir A. Malinovskii, M.D., Ph.D. 

Protein Analysis Facility 

Carol K. Petito, M.D. 

Core Research Histology Laboratory (Developing Resource) 

Alberto Pugliese, M.D. 

Analytical Imaging Care 

Richard L. Riley, Ph.D. 

Flow Cytometry Resource 


Clinical Research Services Resource 

Rudolf K. Werner, Ph.D. 

DNA Core Facility 

DIVISIONS 

Dido Franceschi, M.D. 

Division of Informatics 

James J. Schlesselman, Ph.D. 

Division of Biostatistics 


Division of Cancer Prevention and Control 

Cancer Information Service 

Florida Cancer Data System 

Florida Comprehensive Cancer Control Initiative 

Florida Tobacco Research and Evaluation Coordinating Center 

vi 


SYLVESTER COMPREHENSIVE CANCER CENTER 

EXECUTIVE COMMITTEE 


Director 

Glen H. Barber, Ph.D. 

Associate Professor, Microbiology and Immunology 

Awtar Ganju Krishan, Ph.D. 

Professor, Radiation Oncology 




Associate Professor, Microbiology and Immunology 


Associate Director, Basic Science 



Stephen P. Richman, M.D. 

Professor, Medicine 



Antonieta Sauerteig, M.S. 

Director, Research Administration 


Professor, Epidemiology and Public Health 

David L. Stansberry, M.S. 

Hospital Administrator 




Associate Director, Clinical and Translational Research 


Associate Director, Cancer Prevention and Control 

SYLVESTER COMPREHENSIVE CANCER CENTER 

SCIENTIFIC STEERING COMMITTEE 

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

Microbiology and Immunology 


Cell Biology and Anatomy 

Charles S. Carver, Ph.D. 

Psychology 

Murray Deutscher, Ph.D. 

Biochemistry and Molecular Biology 

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

Epidemiology and Public Health 


Otolaryngology 




Microbiology and Immunology, Medicine 

Robert B. Levy, Ph.D. 







Medicine 

Antonieta Sauerteig, M.S. 

Director, Research Administration 




Medicine 

Richard Spring 

UM/Sylvester Board of Governors 



Edward Trapido, Sc.D 


Sandra M. Walsh, Ph.D. 

School of Nursing 


vii

CLINICAL AND TRANSLATIONAL RESEARCH 

COMMITTEE 

Kelvin P. Lee, M.D., Chair 

Microbiology and Immunology, Medicine 

Glen H. Barber, Ph.D. 


Lawrence H. Boise, Ph.D. 


Kerry L. Burnstein, Ph.D. 

Molecular and Cellular Pharmacology 

Lynn G. Feun, M.D. 

Medicine 

Mark S. Goodman, M.D. 

Medicine 


Medicine 

Niramol Savaraj, M.D. 

Medicine 

Donald T. Weed, M.D. 


UM/SYLVESTER BOARD OF GOVERNORS 

Joaquin F. Blaya, Chair 

Diane Abrams 

William H. Allen, Jr. 

Minor Anderson 

Joe Arriola 

Jose Bared 

Gloria Berkowitz 

Minette Brown 

Robert Burlington 

Ira C. Clark 

John G. Clarkson, M.D. 

Diane M. Cook 

Michael Elliott 

Denny Feinsilver 

Thomas J. Fitzpatrick 

Bernard J. Fogel, M.D. 

Gail Gidney 

W. Jarrard Goodwin, M.D. 

Rose Ellen Greene, Vice Chair 

Mark Halpern 

Peggy Hollander 

Sherrill W. Hudson 

Thomas B. Levinson, Vice Chair 

Alan J. Livingstone, M.D. 

Jayne S. Malfitano 

Frederick L. Moffat, Jr., M.D. 

Eugene K. Montoya 

Sharon Pontious, Ph.D., M.S.N. 


John Schulte 

Anne Smith, R.N. 

Richard Spring 

David L. Stansberry 

Barbara Weintraub 

Jay Weiss 

viii 


TUMOR CELL BIOLOGY PROGRAM 

PROGRAM LEADER 


Professor of Cell Biology and Anatomy 

DESCRIPTION OF PROGRAM 

The Tumor Cell Biology Program 

currently comprises 26 faculty 

members in nine different departments 

at the University of Miami School of 

Medicine. These faculty members are 

engaged in fundamental research to expand 

the base of knowledge in the biomedical 

sciences. The faculty members 

were chosen as program faculty due to 

the potential of their research to contribute 

to important aspects of our understanding 

of cancer cell biology. The focus 

of the individual studies varies widely— 

from gene therapy to the ultrastructural 

analyses of protein—but all investigators 

are involved in cutting-edge research using 

the developing methods of molecular 

biology and cell structural analyses to 

ask questions of importance to tumor cell 

biology. A substantial amount of the 

work is oriented toward understanding 

how genetic information in cells is translated 

into functional cell proteins, a fundamental 

issue throughout the history of 

cancer research. 

A second important question is 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 so often determines mortality 

of cancer patients. 

A third problem is 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 program. 

GOALS OF THE PROGRAM 

1) Create fundamental knowledge in the 

areas of cell and molecular biology. 

2) Extend that knowledge into important 

areas of cancer research. 

3) Use such extensions to develop opportunities 

for clinical applications. 

PARTICIPANTS 

Bishopric, Nanette H., M.D., F.A.C.C. 


Bixby, John L., Ph.D. 


Burnstein, Kerry L., Ph.D. 


Carraway, Coralie C., Ph.D. 


Carraway, Kermit L., Ph.D. 


Deutscher, Murray P., Ph.D. 


Dickerson, Ian M., M.D., Ph.D. 

Physiology and Biophysics 

D’Urso, Gennaro, Ph.D. 


Fregien, Nevis, Ph.D. 


King, Mary Lou, Ph.D. 


Lampidis, Theodore J., Ph.D. 


Li, Jei, M.D., Ph.D. 

Dermatology 

Lokeshwar, Balakrishana L., Ph.D. 

Urology 

Lokeshwar, Vinata B., Ph.D. 

Urology 

Malhotra, Arun, Ph.D. 


Mayeda, Akila, Ph.D. 


Moraes, Carlos T., Ph.D. 

Neurology 

Myers, Richard S., Ph.D. 


Perez, Aymee, Ph.D. 


Rudd, Kenneth E., Ph.D. 


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


Verde, Fulvia, Ph.D. 


Webster, Keith A., Ph.D. 


Weed, Donald T., M.D. 


Welsh, Catherine F., M.D. 

Medicine 

Werner, Rudolf K., Ph.D. 


HIGHLIGHTS 

• Development of a hyaluronic acid and 

hyaluronidase urine test for bladder 

cancer and its recurrence, which is 

about 90 percent accurate (V. Lokeshwar). 

• Discovery that hyaluronic acid and 

hyaluronidase are >85 percent accurate 

prognostic indicators for prostate cancer 

(V. Lokeshwar). 

UM/Sylvester Comprehensive Cancer Center Scientific Report 2002 1

• Discovery of anti-tumor and anti-metastatic 

activity of specific tetracyclines 

toward prostate cancer models (V. 

Lokeshwar). 

• Discovery that the cell surface glycoprotein 

complex MUC4 can potentiate 

signaling through the breast cancer 

oncogene HER2/Neu and block tumor 

cell apoptosis (K. Carraway). 

• Discovery that MUC4 expression is 

regulated by basement membrane and 

TGF, two factors whose effects are lost 

during breast cancer progression (K. 

Carraway). 

• Discovery that cell cycle regulators p21 

and p27 are vitamin D targets and may 

serve as indicators of vitamin D sensitivity 

in prostate cancer (K. Burnstein). 

• Discovery that the proto-oncogene 

transcription factor Myc cooperates 

with the androgen receptor in the regulation 

of androgen receptor message, 

suggesting that Myc may play a role in 

determining androgen-sensitive cell 

proliferation (K. Burnstein). 

• Discovery that cells with defective 

mitochondrial respiration can be more 

resistant to cell death, a possible explanation 

for the presence of mitochondrial 

mutations in some cancers (C. 

Moraes). 

• Discovery that gene silencer or repressor 

elements can be used in gene 

therapy to conditionally regulate expression 

of a transgene (K. Webster). 

• Discovery of an essential internal ribosome 

entry site for initiating translation 

of connexin32 mRNA, the first 

demonstration of functional IRES elements 

in normal cellular mRNAs (R. 

Werner). 

• Discovery that centrosomes are attached 

to cellular intermediate filaments 

(P. Salas). 

John L. Bixby, Ph.D. 

Professor of Molecular and 

Cellular Pharmacology 

DESCRIPTION OF RESEARCH 

Dr. Bixby’s research focuses on nervous 

system development. Specifically, 

his laboratory research is trying to 

achieve a molecular understanding of the 

ways that specific neural connections are 

formed and maintained, using the neuromuscular 

junction as model. Two aspects 

of motor neuron differentiation are 

being studied: axon growth and synapse 

formation. In the former case, Dr. Bixby’s 

research has focused on the signal transduction 

mechanisms underlying the 

regulation of axon growth by cell adhesion 

molecules and extracellular matrix 

proteins. In the case of synapse formation, 

the focus is on the role of the synaptic 

protein agrin in specifying both preand 

postsynaptic differentiation. Major 

projects include: 

Function and Binding Properties 

of Receptor Protein Tyrosine 

Phosphatases (PTPs) 

This project has identified two receptorclass 

PTPs (RPTPs), PTP-delta and 

CRYPδ, that are likely to play key roles 

in axon growth. His team is concentrating 

on two related questions. First, what 

are the regulatory ligands (extracellular 

binding partners) for these two RPTPs? 

Second, can these RPTPs bind to neurons 

and thereby modulate axon growth, 

either alone or in combination with other 

regulatory signals? 

In vivo Functions of Tyrosine 

Phosphatases 

Two PTPs, CRYPδ and SHP-2, have 

been identified, which are believed to be 

developmental regulators of axon 

growth. Researchers are testing this idea 

with genetic manipulations in mice, using 

both transgenic and gene knockout 

approaches. 

Presynaptic Actions of Agrin 

The preliminary work suggests that agrin 

is a “bi-directional” differentiation signal 

at the neuromuscular junction. At 

present, the research is aimed at characterizing 

neuronal surface proteins that are 

potential receptors for agrin and using 

recombinant agrin fragments and agrin 

antibodies to define the strucutural regions 

of agrin that interact with neurons. 

Role of MAPK in Neurite Growth 

The mechanisms through which axon 

growth signals are transduced are incompletely 

understood. Their preliminary 

work suggests that one common signal 

may be the activation of MAPK. Researchers 

are using developing chick 

retinal neurons to examine the activation 

of MAPK by FGF, N-cadherin, and 

laminin, and to determine the role of this 

activation in the induction of neurite 

growth. 

PUBLICATIONS 

Perron, J and Bixby, JL. ERK activation 

by stimulators of retinal neurite 

outgrowth. Molecular and Cellular Neuroscience 

13:362, 1999. 

Ledig, M, Haj, F, Wang, J, Bixby, 

JL, Mueller, BK and Stoker, AW. Expression 

of receptor tyrosine phosphatases in 

the development of the retinotectal projection 

of the chick. Journal of Neurobiology 

39:81, 1999. 

Wang, J and Bixby, JL. Receptor tyrosine 

phosphatase delta is a homophilic, 

neurite promoting cell adhesion molecule 

for CNS neurons. Molecular and 

Cellular Neuroscience 14:370, 1999. 

Ledig, M, Haj, F, Bixby, JL, Stoker, 

AW, and Mueller, B. The receptor tyrosine 

phosphatase CRYPδ promotes 

intraretinal axon growth. Journal of Cell 

Biology 147:375, 1999. 

Perron, J and Bixby, JL. Tetraspanins 

expressed in the embryonic nervous 

system. FEBS Letters 461:86, 1999. 

2 


Dimitropoulou, A and Bixby, JL. 

Regulation of retinal neurite growth by 

alterations in MAPK/ERK kinase 

(MEK) activity. Brain Research 858:205, 

2000. 

Sun, QL, Wang, J, Bookman, RJ 

and Bixby, JL. Growth cone steering by 

receptor tyrosine phosphatase delta defines 

a distinct class of guidance cue. Molecular 

and Cellular Neurosciences 

16:686, 2000. 

Bixby, JL. Ligands and signaling 

through receptor-type tyrosine phosphatases. 

Iubmb Life 51:157, 2001. 

Stepanek, L., Sun, QL, Wang, J, 

Wang, C and Bixby, JL. CRYPδ/ 

cPTPRO is a neurite inhibitory repulsive 

guidance cue for retinal neurons in 

vitro. Journal of Cell Biology 154:867, 

2001. 

HIGHLIGHTS/DISCOVERIES 

• In 1999, Dr. Bixby’s laboratory discovered 

that a receptor tyrosine phosphatase 

called PTP-delta can steer 

growth cones when presented to axons 

in a gradient. This is the first evidence 

that a vertebrate receptor tyrosine phosphatase 

is involved in axon guidance 

during development. 

Kerry L. Burnstein, Ph.D. 

Associate Professor of Molecular 

and Cellular Pharmacology 


Dr. Burnstein’s laboratory is evaluating 

the effects of two steroid hormones—androgen 

and vitamin D—and 

their receptors on prostate cancer epithelial 

cell growth and gene expression. Her 

team has found that the sensitivity of 

prostate cancer cells to these steroid hormones 

is highly variable. This variability 

is due, in part, to differences in steroid 

receptor levels. Her team is beginning 

to understand the cellular mechanisms 

that regulate androgen receptor (AR) 

levels in prostate cancer and in bone cells 

(osteoblasts). The AR is a transcription 

factor that, in addition to controlling the 

expression of a variety of genes, regulates 

the gene encoding AR itself (autoregulation). 

Her laboratory has identified a 

unique internal enhancer of the AR gene 

encompassing exon D, intron 4 and exon 

E of the AR gene that mediates androgen 

induction of AR mRNA. This region 

contains DNA sequences termed 

androgen response elements (AREs) that 

are involved in androgen-specific transcriptional 

regulation of AR mRNA in 

aggressive prostate cancer and osteoblastic 

cell lines. The AREs are present within 

the AR coding region, which is unusual 

as DNA regulatory sequences are more 

typically found in the region 5' to the 

promoter of a target gene. Despite the 

presence of functional AR, these AREs 

are not regulated by androgen in less aggressive 

prostate cancer or in breast cancer 

cells lines. Her group is investigating 

the molecular basis for the cell- and androgen-specific 

activity of these AREs. 

A recently initiated project will utilize 

cDNA microarray gene profiling to identify 

the gene expression changes that accompany 

the transition of prostate cancer 

from androgen dependence to the more 

deadly androgen independent form. 

Prostate cancer cells exhibit variable 

growth inhibition by vitamin D. The 

actions of vitamin D are mediated by the 

vitamin D receptor (VDR), which is 

closely related in structure and function 

to the other steroid receptors. Lack of 

sensitivity to vitamin D is correlated with 

low levels of VDR in some cell lines. 

However, in other cell lines, levels of 

functional VDR do not correlate with 

the antiproliferative effects of vitamin D. 

Thus, VDR is necessary but not sufficient 

for vitamin D mediated growth 

inhibition. The research has shown that 

vitamin D inhibits prostate cancer cell 

proliferation via cell cycle mechanisms 

that result in cell accumulation in the G1 

phase of the cell cycle. Consistent with 

G1 accumulation, they found that vitamin 

D dramatically inhibits the activity 

of cyclin dependent kinase 2 and that 

vitamin D up-regulates the cyclin dependent 

kinase inhibitors p21 and p27. Certain 

prostate cancer cells are insensitive 

to the antiproliferative effects of vitamin 

D despite adequate levels of VDR. They 

found that this insensitivity is due to lack 

of p21 and p27 expression. They are currently 

examining the mechanisms of p21 

and p27 induction by vitamin D and 

investigating whether the cell signaling 

pathways mediated by Rho GTPases suppress 

p21 and p27 in aggressive prostate 

cancer cells. 

Together these studies may contribute 

to the development of more 

effective endocrine therapies and 

chemoprevention strategies for prostate 

cancer as well as lead to the identification 

of biological markers for aggressive 

tumors. 

PUBLICATIONS 

Grad, J, Dai, JL, Wu, S and 

Burnstein, KL. Multiple androgen response 

elements and a Myc consensus site 

in the androgen receptor (AR) coding 

region are involved in androgen mediated 

up-regulation of AR mRNA. Molecular 

Endocrinology 13:1896, 1999. 

Lokeshwar, BL, Schwartz ,GG, Seltzer, 

MG, Burnstein, KL, Zhuang, S-H, 

Block, NL and Binderup, L. Inhibition 

of prostate cancer metastasis in vivo: a 

comparison of 1a,25 dihydroxyvitamin 

D (calcitriol) and EB1089. Cancer Epidemiology 

Biomarkers and Prevention 

8:241, 1999. 

Gkonos, PJ, Guo, F and Burnstein, 

KL. Type 1 vasoactive intestinal peptide 

receptor expression in PC3/AR cells is 

evidence of prostate epithelial differentiation. 

Prostate 2:137, 2000. 

Chen, T, Schwartz, G, Burnstein, 

KL, Lokeshwar, BL and Holick MF. 

The in vitro evaluation of 25-hydroxy vitamin 

D3 and 19-nor-1, 25-hydroxyvitamin 

D2 as therapeutic agents for 

prostate cancer. Clinical Cancer Research 

6:901, 2000. 


Qadan, LR, Perez-Stable, C, 

Schwall, RH, Burnstein, KL, Ostenson, 

RC, Howard, GA and Roos, BA. Hepatocyte 

growth factor and vitamin D cooperatively 

inhibit androgen-unresponsive 

prostate cancer cell lines. Endocrinology 

141:2567, 2000. 

Grad, JM, Lyons, LS, Robins, D and 

Burnstein, KL. The androgen receptor 

(AR) amino-terminus imposes androgenspecific 

regulation of AR gene expression 

via an exonic enhancer. Endocrinology 

142:1107, 2001. 

Tekur, S, Lau, KM, Long, J, 

Burnstein, KL and Ho, SM. Expression 

of RFG/ELE1 alpha/ARA70 in normal 

and malignant prostatic epithelial cell 

cultures and lines: Regulation by methylation 

and sex steroids. Molecular Carcinogenesis 

30:1, 2001. 

Schwartz, GG, Lokeshwar, BL, 

Burnstein, KL. Correspondence re: S. 

E. Blutt, T. C. Polek, L. V. Stewart, M. 

W. Kattan, and N. L. Weigel, A Calcitriol 

Analogue, EB1089, inhibits the growth 

of LNCaP tumors in nude mice. Cancer 

Research 61:4294, 2001. 


• The identification of p21 and p27 as 

the vitamin D targets involved in halting 

the cell cycle predict that these cell 

cycle regulators may serve as indicators 

of vitamin D sensitivity in prostate cancer 

biopsies. They found that the transcription 

factor Myc cooperates with 

AR in the regulation of AR mRNA. 

This finding suggests that Myc may 

play a role in dictating androgen sensitivity 

and androgen-mediated cell proliferation. 

Since the Myc gene is often 

amplified in advanced prostate cancer, 

there may be a link between AR and 

Myc in tumor progression. 


Professor of Cell Biology 

and Anatomy 


For much of the past decade, Dr. 

Carraway’s primary research effort 

has been concerned with the role of cell 

surface glycoproteins in mammary cancer, 

focusing on a particular glycoprotein 

complex (sialomucin complex, SMC, rat 

Muc4) that his laboratory discovered 

about 20 years ago. This complex 

has both mucin- and growth factorcontaining 

subunits. This putative 

bifunctionality can potentially contribute 

to two of the major attributes of 

cancer cells, loss of adhesiveness, and autonomous 

growth. It has been implicated 

in metastasis. The anti-adhesive function 

of SMC allows it to block tumor cell killing 

by lymphokine-activated killer cells, 

a mechanism, which permits the SMCoverexpressing 

tumor cells to escape immune 

surveillance. One of the two 

growth factor domains of the transmembrane 

subunit of SMC has been shown 

to act as an intramembrane ligand for 

the class I tyrosine kinase growth factor 

receptor ErbB2/HER2/Neu. Binding of 

SMC 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. 

His team is currently investigating 

the effects of this receptor modulation 

on downstream signaling pathways and 

cellular functions. Recently, they have 

found that induction of SMC 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 SMC-overexpressing animals. One 

important question is whether the antiapoptotic 

effects of SMC result from its 

growth factor domains or other features 

of its structure. Since SMC has been 

implicated in breast cancer progression, 

it is of interest to know how it is regulated 

in mammary gland. Investigations 

of primary mammary epithelial cells indicate 

a major role for post-transcriptional 

regulation. Interactions with the 

extracellular matrix regulate SMC expression 

at the translational level, while transforming 

growth factor-beta 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, SMC might 

serve as a target for prognosis and therapies 

in breast cancer. 

PUBLICATIONS 

Komatsu, M, Yee, L and Carraway, 

KL. Overexpression of sialomucin complex, 

a rat homolog of MUC4, inhibits 

tumor killing by lymphokine-activated 

killer cells. Cancer Research 59:2229, 

1999. 

Carraway, KL III, Rossi, EA, 

Komatsu, M, Price-Schiavi, SA, Huang, 

D, Guy, PM, Carvajal, ME, Fregien, N, 

Carraway, CAC and Carraway, KL. An 

intramembrane modulator of the ErbB2 

receptor tyrosine kinase that potentiates 

neuregulin signaling. Journal of Biological 

Chemistry 274:5263, 1999. 

Huang, J, Zhang, B-T, Li, Y, Mayer, 

B, Carraway, KL and Carraway, CAC. 

c-Src association with and phosphorylation 

of p58 gag , a membrane- and 

microfilament-associated retroviral gaglike 

protein in a xenotransplantable rat 

mammary tumor. Oncogene 18:4099, 

1999. 

Carraway, CAC, Carvajal, ME and 

Carraway, KL. Association of the Ras/ 

MAP kinase signal transduction pathway 

with microfilaments. Evidence for a 

p185neu-containing cell surface signal 

transduction particle. Journal of Biological 

Chemistry 274:25659, 1999. 

Li, Y, Carraway, KL and Carraway, 

CAC. Molecular associations of the core 

glycoprotein complex from a microfilament-associated 

signal transduction par- 

4 


ticle from ascites tumor cell microvilli. 

Journal of Biological Chemistry 

274:25651, 1999. 

Carraway, CAC and Carraway, KL. 

p58 gag . Guidebook to the Cytoskeletal 

and Motor Proteins. T. Kreis and R.D. 

Vale, eds., Oxford University Press, 1999. 

Idris, N and Carraway, KL. 

Sialomucin complex (Muc4) expression 

in the rat female reproductive tract. Biological 

Reproduction 61:1431, 1999. 

Carraway, KL, Price-Schiavi, SA, 

Zhu, X and Komatsu, M. Regulation of 

expression of sialomucin complex (rat 

Muc4), the intramembrane ligand for 

ErbB2, at the transcriptional, translational 

and post-translational levels in rat 

mammary gland. Cancer Control 6:613, 

1999. 

Fregien, N, Carraway, CAC and 

Carraway, KL. An intramembrane 

modulator of the ErB2 receptor tyrosine 

kinase that potentiates neuregulin signaling. 


274:5263, 1999. 

Weed, DT, Carraway, KL, Carvajal, 

M, Lee, T, Pacheco, J, Gomez-Fernandez, 

C, Bello, A and Goodwin, WJ. MUC4 

(sialomucin complex) expression in salivary 

tumors and squamous cell carcinoma 

of the upper aerodigestive tract. 

Otolaryngology Head Neck Surgery 

121:87, 1999. 

Carraway, KL. Preparation of membrane 

mucin. Methods Molecular Biology 

125:15, 2000. 

Pflugfelder, SC, Liu, Z, Monroy, D, 

Li, DQ, Carvajal, ME, Price-Schiavi, SA, 

Idris, N, Solomon, A, Perez, A and 

Carraway, KL. Detection of sialomucin 

complex (MUC4) in human ocular surface 

epithelium and tear fluid. Investigative 

Ophthalmologic Visual Science 

41:1316, 2000. 

Price-Schiavi, SA, Zhu, X, Aquinin, 

R, and Carraway, KL. Sialomucin complex 

(rat muc4) is regulated by transforming 

growth factor beta in mammary 

gland by a novel post-translational 

mechanism. Journal of Biological Chemistry 

275:17800, 2000. 

Price-Schiavi, SA, Perez, A, Barco, 

R and Carraway, KL. Cloning and characterization 

of the 5’ flanking region of 

the sialomucin complex/rat Muc4 gene: 

promoter activity in cultured cells. Biochemistry 

Journal 349:641, 2000. 

Zhu, X, Price-Schiavi, SA and 

Carraway, KL. Extracellular regulated 

kinase (ERK)-dependent regulation of 

sialomucin complex/rat Muc4 in mammary 

epithelial cells. Oncogene 19:4354, 

2000. 

Hu, Y, Carvajal, ME and Carraway, 

KL. Sialomucin complex (rMuc4) expression 

during development of the rat 

cornea. Current Eye Research 21:820, 

2000. 

Komatsu, M, Jepson, S, Arango, 

ME, Carraway, CAC and Carraway, KL. 

Muc4/sialomucin complex, an intramembrane 

modulator of ErbB2/HER2/ 

Neu, potentiates primary tumor growth 

and suppresses apoptosis in a xenotransplanted 

tumor. Oncogene 20:461, 2001. 

Carraway, KL. Cell surface and extracellular 

components in the mammary 

gland and breast cancer - Preface. Journal 

of Mammary Gland Biology and 

Neoplasia 6:249, 2001. 

Carraway, KL. Idris, N. Regulation 

of sialomucin complex/Muc4 in the female 

rat reproductive tract. Biochemical 

Society Transactions 29:162, 2001. 

Carraway, KL. Price-Schiavi, SA. 

Komatsu, M. Jepson, S. Perez, A. 

Carraway, CAC. Muc4/sialomucin complex 

in the mammary gland and breast 

cancer. Journal of Mammary Gland Biology 

and Neoplasia 6:323, 2001. 

Li, P, Price-Schiavi, SA, Rudland, PS 

and Carraway, KL. Sialomucin complex 

(rat Muc4) transmembrane subunit 

binds the differentiation marker peanut 

lectin in the normal rat mammary gland. 

Journal of Cellular Physiology 186:397, 

2001. 


• SMC expression potentiates the phosphorylation/activation 

of the ErbB2 

and ErbB3 tyrosine kinase receptors induced 

by neuregulin, providing a 

mechanism by which SMC may contribute 

to tumor progression through 

changes in cell signaling pathways. 

• SMC 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. 

• SMC regulation in the uterus during 

pregnancy is at the transcript level, indicating 

the complexity of the control 

of its gene. 

• SMC overexpression increases primary 

tumor growth in nude mice, acting as 

an anti-apoptotic agent in the growing 

tumors and in cell culture. 

Murray P. Deutscher, Ph.D. 

Professor and Chairman of the 

Department of Biochemistry and 

Molecular Biology 


Two major areas of research are carried 

out in Dr. Deutscher’s laboratory. 

One area deals with the identification, 

characterization, and determination 

of the physiological role of RNA processing 

and degradative enzymes. To date, 

eight exoribonucleases and seven 

endoribonucleases 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 now being used to 


elucidate complete RNA maturation 

pathways and to study the regulation of 

these processes. 

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 is 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 aminoacyltRNA 

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. 

PUBLICATIONS 

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

Maturation of 23S ribosomal RNA requires 

the exoribonuclease RNase T. 

RNA 5:139, 1999. 

Ghosh, S and Deutscher, MP. Oligoribonuclease 

is an essential component 

of the messenger RNA decay pathway. 

Proceedings National Academy of Science 

USA 96:4372, 1999. 


RNase G (CafA Protein) and RNase E 

are both required for the 5’ maturation 

of 16S ribosomal RNA. Embolism Journal 

18:2878, 1999. 

Zuo, Y and Deutscher, MP. The 

DNase activity of RNase T and its application 

to DNA cloning. Nucleic Acid 

Research 27:4077, 1999. 

Callahan, C, Neri-Cortes, D and 

Deutscher, MP. Purification and characterization 

of the tRNA-processing enzyme 

RNase BN. Journal of Biological 

Chemistry 275:1030, 1999. 

Nathanson, L and Deutscher, MP. 

Accelerated publication - Active aminoacyltRNA 

synthetases are present in nuclei 

as a high molecular weight multienzyme 

complex. Journal of Biological Chemistry 

275:31559, 2000. 

Deutscher, MP and Li, ZW. Exoribonucleases 

and their multiple roles in 

RNA metabolism. Progress in Nucleic 

Acid Research and Molecular Biology 

66:67, 2001. 

Zuo, YH and Deutscher, MP. 

Exoribonuclease superfamilies: structural 

analysis and phylogenetic distribution. 

Nucleic Acids Research 29:1017, 2001. 


• Dr. Deutscher’s team discovered 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. This team 

has 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. 

• Dr. Deutscher’s laboratory has developed 

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 have 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. 

Nevis Fregien, Ph.D. 

Associate Professor of 



The research being conducted in Dr. 

Fregien’s laboratory focuses on understanding 

the molecular basis for the 

progression of noninvasive tumor cells 

into highly aggressive, metastatic cancer 

cells. This is an extremely important 

problem for developing anticancer therapies, 

because this metastatic ability to 

migrate throughout the body and generate 

multiple tumors is the most life 

threatening aspect of cancer. Since they 

believe that the cellular properties associated 

with metastasis involve molecules 

expressed on the cell surface, their approach 

is to identify changes in the cell 

surface molecules expressed by metastatic 

cells and determine how they are regulated 

and how they might affect metastatic 

cellular properties. One specific 

change in molecules expressed by metastatic 

cells is an increase in the amount 

and complexity of oligosaccharide structures 

post-translationally added to cell 

surface proteins. The synthesis of these 

oligosaccharides is accomplished by a 

number of enzymes known as glycosyltransferases. 

Dr. Fregien’s laboratory 

has shown that one of the glycosyltransferases, 

N-acetylglucosa-minyltransferase 

V, is over-expressed in tumor 

cells. Furthermore, this elevated expression 

is due to activation of the promoter 

for this gene by the action of some 

oncogenes such as src and neu. This 

shows that oncogenes do not only stimulate 

uncontrolled cellular proliferation, 

as previously believed, but they also cause 

changes, which can affect the cell surface. 

Dr. Fregien’s group is trying to understand 

the regulation of this promoter 

as well as the promoter of a similar gene, 

the Core 2 transferase, with the hope that 

this information will be useful to design 

therapies to turn off the expression of 

these genes and inhibit metastatic 

progession. 

6 


PUBLICATIONS 



D, Guy, PM, Carvajal, ME, Fregien, 

N, Carraway, CAC and Carraway, KL. 

An intramembrane modulator of the 

ErbB2 receptor tyrosine kinase that potentiates 

neuregulin signaling. Journal of 

Biological Chemistry 274:5263, 1999. 

Buchman, CA. Fregien, N. Influenza: 

A virus infection of human middle 

ear cells in vitro. Laryngoscope. 110: 

1739, 2000. 


• The regulation of the N-acetylglucosaminyltransferase 

gene is quite complex, 

possibly involving alternative splicing 

and multiple promoters. 

• The promoter of the Core 2 transferase 

gene is different than previously believed 

and might also be controlled by 

oncogenes. 

Mary Lou King, Ph.D. 


and Anatomy 


Dr. King is trying to understand how 

spatial patterning and cell fate is 

determined in the early Xenopus 

embryo. 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 team 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. They are 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 because the 

PGCs fail to migrate out of the endoderm. 

Another mRNA, VegT, encodes a 

T-box transcription factor. They 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, 

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. 

Her group has found that VegT, and 

the germ plasm mRNAs, localize by at 

least two different mechanisms and at 

different times during oogenesis. They 

also 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. Her team’s 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. 

PUBLICATIONS 

MacArthur, H, Bubunenko, M, 

Houston, D and King, ML. Xcat2 RNA 

is a translationally sequestered germ 

plasm component in Xenopus. Mechanisms 

of Development 84:75, 1999. 

King, ML, Zhou, Y and Bubunenko, 

M. Polarizing genetic information 

in the egg: RNA localization in the 

frog oocyte. BioEssay 21:546, 1999. 

Houston, DW and King, ML. A 

criticial role for Xdazl, a germ plasmlocalized 

RNA, in the differentiation of 

primordial germ cells in Xenopus. Development 

127:447, 2000. 

Houston, DW and King, ML. 

Germ plasm and molecular determinants 

of germ cell fate. Current Topics in Developmental 

Biology 50:155, 2000. 

Zhang, J and King, ML. PCR-based 

cloning of cortically localized RNAs from 

Xenopus oocytes. Methods in Molecular 

Biology 136:309, 2000. 

Bubunenko, M. King, ML. Biochemical 

characterization of a cellular 

structure retaining vegetally localized 

RNAs in Xenopus late stage oocytes. Journal 

of Cellular Biochemistry 80:560, 

2001. 


• Dr. King’s work on maternal Xdazl represents 

something of a breakthrough as 

it reveals 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’s 

team wants 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. How is the 

translation of these RNAs regulated? 

What are the functions of these germ 

plasm components in PGC migration 

and differentiation? 

• Remarkably, a single maternally expressed 

gene that her team discovered, 

VegT, appears to control the pattern- 


ing of the Xenopus blastula. These 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. Future studies should provide 

insights into the genetic pathways operating 

to establish some of these organ 

systems and may explain specific 

birth defects where meso-endodermal 

tissue is affected. In addition, the 

downstream targets of VegT must play 

a role in morphogenesis, as gastrulation 

is profoundly disrupted and epiboly inhibited. 

Very little is known about the 

genes that regulate the regional cellular 

movements of gastrulation. 

Theodore J. Lampidis, Ph.D. 


and Anatomy 


Dr. Lampidis’ research has evolved 

since his preliminary work on the 

physiology and pharmacology of cultured 

cardiac cells. A video/electroniccomputerized 

system was developed to 

monitor cardiac cell function in vitro. 

Using pulsating myocardial cells as a 

model, attention was then placed on why 

the widely used anti-tumor agent, 

Adriamycin, affected the hearts of patients 

treated with this drug. This initial 

idea led them to the study of drug selectivity 

between certain types of tumor and 

normal cells and the chemical requirements 

of anticancer drugs for reduced 

cardiotoxicity and increased tumoricidal 

potency. 

His research team’s 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. MRP, were developed 

in his laboratory to detect and study these 

phenomena. The researchers 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, they 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 similarly 

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 his 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. Dr. 

Lampidis believes their background and 

work on mitochondrial localizing drugs 

and MDR uniquely positions them to 

stimulate new initiatives in this promising 

area of research. 

A long-term research goal for Dr. 

Lampidis is the addition of the appropriate 

glycolytic inhibitors (which they 

are presently designing and synthesizing) 

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. 

PUBLICATIONS 

Kolonias, D, Podona, T, Savaraj, N, 

Gate, L, Cossum, P and Lampidis, TJ. 

Comparison of annamycin to adriamycin 

in cardiac and MDR tumor cell systems. 

Anticancer Research 19:1277, 1999. 

Zou, JY, Landy, H, Feun, L, Xu, R, 

Lampidis, TJ, Wu, CJ, Furst, AJ, and 

Savaraj, N. Correlation of a unique 220- 

kd protein with vitamin D sensitivity in 

glioma cells. Biochemistry Pharmacology 

60:1361, 2000. 

Hu, Y, Moraes, CT, Savaraj, N, 

Priebe, W and Lampidis, TJ. Rho(0) 

tumor cells: a model for studying 

whether mitochondria are targets for 

rhodamine 123, doxorubicin and other 

drugs. Biochemical Pharmacology 

60:1897, 2000. 

Hiu, H, Hu, YP, Savaraj, N, Priebe, 

W and Lampidis, TJ. Hypersensitization 

of tumor cells to glycolytic inhibitors. 

Biochemistry 40:5542, 2001. 


• In Model A, which represents 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, i.e. 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 and 

oxamate. 

• In Model B, which are ρ cells that have 

lost their mitochondrial DNA and 

therefore cannot undergo Oxphos, 

were found to be 10 and 4.9 times 

more sensitive to 2-deoxyglucose and 

oxamate, respectively, than wt cells. 

• Lactic acid levels, which are a measure 

of anaerobic metabolism, were found 

to be >3 times higher in ρ than in wt 

cells. Moreover, when wt cells were 

8 


treated with rho 123, lactic acid 

amounts increased as a function of increasing 

rho 123 doses. Under similar 

rho 123 treatment, ρ cells did not increase 

their lactic aid levels. These data 

confirm that cell models A and B are 

similarly sensitive to glycolytic inhibitors 

due to their dependence on anaerobic 

metabolism. 

• Overall, 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 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 

agents, which a priori, 

should make tumors more anaerobic. 

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 five 

years, Dr. Lokeshwar’s laboratory has 

focused on the extracellular matrix degradation 

and tumor metastasis. His 

group has been studying 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 there exist an imbalance 

between the levels of MMPs (overproduction) 

and their natural inhibitors (under 

production) in invasive prostate 

cancer cells. Based on this finding he forwarded 

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. 

As an approach to control tumor 

metastasis, they asked whether synthetic 

inhibitors of MMPs would decrease the 

rate of metastasis and prolong the survival 

of animals implanted with metastatic 

prostate tumor cells. In their search 

for a suitable inhibitor, his team tested a 

series of synthetic tetracycline analogues, 

which were shown to possess a strong 

anti-collagenase activity with little or no 

antibiotic activity. They tested eight different 

CMTS and found one of them, 

6-deoxy, 6-demethyl, 4-dedimethylamino 

tetracycline (CMT-3, COL-3, 

now termed Metastat R by Collageneix 

Pharmaceuticals, Newtown, PA) was the 

most promising. Oral dosing with this 

analogue to rats bearing metastatic prostate 

tumors reduced tumor growth and 

metastasis, with no measurable toxicity. 

Furthermore, prophylactic dosing of the 

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 impressed the Developmental 

Therapeutics Division of the National 

Cancer Institute (NCI-DTP). The 

NCI-DTP has conducted a clinical trial 

of this compound. Recently it concluded 

the first human clinical Phase-I trial of 

COL-3, next phase of the trial is underway. 

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 has also generated 

a wide interest in the use of COL- 

3 among many investigators within and 

outside the University of Miami. In a 

current collaboration with Dr. Stephen 

Pflugfelder, Department of Ophthalmology, 

University of Miami, we have identified 

a potential application of CMTs 

to treat the Meibomian gland dysfunction 

that leads to the Ocular rosacea. 

PUBLICATIONS 

Alfonso, AA, Sobrin, L, Monroy, 

DC, Seizer, MG, Lokeshwar, BL and 

Pflugfelder, SC. Tear fluid gelatinase B 

activity correlates with IL-1 concentration 

and fluorescein clearance. Investigative 

Ophthalmology and Visual 

Science 40:2506, 1999. 

Lokeshwar, BL, Schwartz, GG, 

Seizer, MG, Burnstein, K, Zhuang, S and 

Block, NL. Inhibition of metastasis by 

1α, 25-[OH] 2 

vitamin D and EB1089, 

a vitamin D analogue, in a prostate cancer 

model. Cancer Epidemiology 

Biomarkers and Prevention 8:241, 1999. 

Lokeshwar, BL, Escatel, E, Houston-Clark, 

HL and Zhu, BQ. Rapid induction 

of apoptosis signaling as a 

mechanism of cytotoxic activity by a 

chemically modified tetracycline, a novel 

antitumor drug. Signal Transduction and 

Therapeutic Strategies W. J. Whelan, et 

al: Advances in Gene Technol. Miami 

Nature Biotechnology Short Reports. Vol 

10:117a. Oxford U. Press, 1999. 

Lokeshwar, BL. MMP inhibition in 

prostate cancer. Annals NY Academy of 

Science 878:271, 1999. 

Zhu, B-q, Block, NL and Lokeshwar, 

BL. Organ-specific stromal cells and 

their extracellular matrix modify the response 

of tumor cells to antitumor drugs. 

Annals NY Academy of Science 878:642, 

1999. 

Selzer, MG, Zhu, B-q, Block, NL 

and Lokeshwar, BL. CMT-3, a chemically 

modified tetracycline, inhibits bony 

metastases and delays the development 

of paraplegia in a rat model of prostate 

cancer. Annals NY Academy of Science 

878:678, 1999. 

Lokeshwar, BL, Schwartz, GG, Seltzer, 




comparison of 1α, 25 dihydroxyvitamin 



8:241, 1999. 



KL, Lokeshwar, BL and Holick, MF. The 

in vitro evaluation of 25-hydroxy vitamin 




6:901, 2000. 

Krishan, A, Oppenheimer, A, You, 

W, Dubbin, R, Sharma, D and 

Lokeshwar, BL. Flow cytometric analysis 

of androgen receptor expression in 

human prostate tumors and benign tissues. 

Clinical Cancer Research 6:1922, 

2000. 

Lokeshwar, BL, Escatel, E and Zhu, 

B. Cytotoxic activity and inhibition of 

tumor cell invasion by derivatives of a 

chemically modified tetracycline CMT- 

3 (COL-3). Current Medical Chemistry 

8:271, 2001. 

Schwartz, GG, Lokeshwar, BL and 

Burnstein, KL. Correspondence re: S. E. 

Blutt, T. C. Polek, L. V. Stewart, M. W. 

Kattan, and N. L. Weigel, A Calcitriol 



Research 61:4294, 2001. 

Lokeshwar, VB, Rubinowicz, D, 

Schroeder, GL, Forgacs, E, Minna, JD, 

Block, NL, Nadji, M and Lokeshwar, 

BL. Stromal and epithelial expression of 

tumor markers hyaluronic acid and 

HYAL1 hyaluronidase in prostate cancer. 


276:11922, 2001. 

INVENTIONS AND PATENTS 

Title: “Method of inhibiting cancer 

growth.” Principal Inventor: B.L. 

Lokeshwar, Co-Inventors: Marie G. 

Seizer, Norman L Block, (University 

of Miami), and L.M. Golub, T.M. 

McNamara, N.S., Ramamurthy, H-M. 

Lee, S. Simon (State University of New 

York, Stony Brook, NY). U.S. Patent No. 

US 58,37696. 

Title: “Method for prevention and 

treatment of cancer.” Inventors: Gary G. 

Schwartz, B.L. Lokeshwar (University of 

Miami); Michael F. Holick, Tai C. Chen, 

Lyman W. Whitlash (Boston University) 

Temp. U.S. Patent No. 6474-2, March 

25, 1999. 

Title: “Method for treating meibomian 

gland disease.” Inventors: S.G. 

Pflugfelder, B.L. Lokeshwar, M.G. Seizer 

U.S. Patent Application S.N. 60/ 

084,873 (revised filing May 8, 1999). 


• An imbalance exists between the levels 

of MMPs (overproduction) and their 

natural inhibitors (under production) 

in invasive prostate cancer cells. 

• A novel chemically modified nonantimicrobial 

tetracycline (COL-3) has 

been identified as an effective antimetastatic 

drug with potential to treat 

prostate cancer metastatic to bone. The 

National Cancer Institute has completed 

the Phase I trial of this drug and 

awaiting further trials. Other novel 

agents are being tested in Dr. 

Lokeshwar’s laboratory not only for 

controlling cancer but 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 State 

University of New York at Stony 

Brook, and two patents are pending 

on the new application of his research 

findings. 

• In collaboration with Dr. Stephen 

Pflugfelder, Department of Ophthalmology, 

University of Miami, Dr. 

Lokeshwar has identified a potential 

application of CMTs to treat the Meibomian 

gland dysfunction that leads to 

the Ocular rosacea. 

Vinata B. Lokeshwar, Ph.D. 

Assistant Professor of Urology 


Dr. Lokeshwar’s research focuses on 

understanding the mechanism of 

cancer progression with a special emphasis 

on tumor angiogenesis, i.e., neovascularization. 

Angiogenesis is a process 

that is required to nurture tumor growth 

both at the primary and secondary metastatic 

sites. 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 team 

is trying to understand how ECM affects 

tumor metastasis and angiogenesis. 

Recent advances show that an ECM 

component, hyaluronic acid (HA; which 

is a glycosaminoglycan), and its degrading 

enzyme, hyaluronidase (HAase), are 

closely associated with the biology of 

bladder cancer. 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. 

Their studies on prostate cancer 

showed that immunohistochemical localization 

of both HA and HAase in prostate 

cancer tissues is > 85% accurate in 

predicting prognosis for prostate cancer 

patients. Thus, use of these markers in 

biopsy specimens may help clinicians to 

make individualized treatment decisions 

and improve patients’ prognosis. 

This finding led to the identification, 

purification, and cloning of the first 

tumor-derived HAase. Furthermore, the 

research has demonstrated that this tumor-derived 

HAase degrades tumorassociated 

HA into small angiogenic frag- 

10 


ments which then interact with a HA 

receptor, RHAMM, on endothelial cells. 

The HA fragments and RHAMM interaction 

on the cell surface induces signaling 

events, including protein tyrosine 

phosphorylation and MAP-kinase pathway, 

resulting in the stimulation of 

endothelial cell functions such as proliferation. 

Endothelial cell proliferation is 

of key importance in tumor angiogenesis. 

Currently, Dr. Lokeshwar’s research 

efforts focus on the following three areas: 

1) An extension of HA-HAase test’s 

application to include follow-up of bladder 

cancer patients for monitoring of 

bladder tumor recurrence; 2) Immunohistochemical 

localization of HA and 

HAase in bladder tumor tissues to evaluate 

their prognostic potential; 3) Generation 

of specific antibody and 

PCR-based probes to detect HAase and 

HA synthetase (an HA synthesizing 

enzyme) in clinical specimens to design 

second-generation diagnostic tools that 

accurately predict the malignant potential 

of primary tumors. 

PUBLICATIONS 

Lokeshwar, VB, Young, MJ, 

Goudarzi, G, Iida, N, Yudin, AI, Cherr, 

GN and Selzer, MG. Identification of 

bladder tumor-derived hyaluronidase: Its 

similarity to HYAL1. Cancer Research 

59:4464, 1999. 

Lokeshwar, VB, Obek, C, Pham, 

HT, Wei, DC, Young, MJ, Duncan, RC, 

Soloway, MS and Block, NL. Urinary 

hyaluronic acid and hyaluronidase: 

Markers for bladder cancer detection and 

evaluation of grade. Journal of Urology 

163:348, 2000. 

Wei, DC, Politano, VA and 

Lokeshwar, VB. Association of elevated 

urinary total to sulfated glycosaminoglycan 

ratio and high molecular mass hyaluronic 

acid with interstitial cystitis. 

Journal of Urology 163:1577, 2000. 

Lokeshwar, VB and Block, NL. HA- 

HAase urine test: A sensitive and specific 

method for detecting bladder cancer and 

evaluating its grade. Urology Clinics 

North America 27:53, 2000. 

Lokeshwar,VB, Rubinowicz, D, 


Block, NL, Nadji, M and Lokeshwar, BL. 

Stromal and epithelial expression of 




276:11922, 2001. 

Lokeshwar, VB and Soloway, M.S. 

Current bladder tumor tests: Does their 

projected utility fulfill clinical necessity? 


Hautmann, SH, Lokeshwar, VB, 

Schroeder, GL, Civantos, F, Duncan, 

RC, Gnann, R, Friedrich, MG and 

Soloway, M.S. Elevated tissue expression 

of hyaluronic acid and hyaluronidase 

validates the HA-HAase urine test 

for bladder cancer. Journal of Urology 

165:2068, 2001. 


• Established the HA-HAase urine test, 

a non-invasive test that is about 90 percent 

accurate in detecting bladder cancer 

and monitoring its recurrence. 

• Established that HA and HAase are > 

85 percent accurate prognostic indicators 

for prostate cancer. 

• Identification of the first tumor-derived 

HAase. 

Arun Malhotra, Ph.D. 

Assistant Professor of Biochemistry 

and Molecular Biology 


Dr. Malhotra’s research interests 

focuses on understanding the 

mechanisms of gene expression and regulation 

by looking at the three-dimensional 

structure of macromolecules that 

underlie these processes. In transcription, 

two areas of current focus in his laboratory 

are the bacterial sigma54 directed 

transcription initiation, and transcription 

in negative strand RNA viruses. In the 

area of translation, work is under way on 

ribosomal subunits and proteins. Another 

collaborative project is looking at 

the structure of bacterial exoribonucleases. 

These macromolecules are being 

studied using the tools of X-ray crystallography, 

electron microscopy, and molecular 

biology. 

Transcription Initiation and 

Regulation 

Transcription is the central step in the 

expression of genes. Regulation of this 

process is the major mechanism for control 

of gene expression, and defects in this 

regulation are the basis for many cancers 

and diseases. Dr. Malhotra’s team is looking 

at the process of transcription regulation 

using two simple model 

systems—bacterial sigma54 directed 

transcription initiation and transcription 

in negative strand RNA viruses. 

Bacterial RNA polymerase (RNAP) 

shares both sequence and structural homologies 

from bacteria to man, and is 

an attractive model system for structural 

studies of the transcription machinery. 

The core RNAP requires sigma factors 

for promoter specific initiation. While 

much of bacterial transcription is initiated 

by sigma70 type sigmas, some genes 

require sigma54 for expression. Sigma54 

shares almost no sequence homology 

with sigma70, and acts by a very different 

mechanism that requires additional 

enhancer binding proteins, ATP hydroly- 


sis, and proceeds in a manner that has 

many similarities to eukaryotic transcription 

initiation. 

Dr. Malhotra’s laboratory is studying 

the mechanism of sigma54-enhancer 

directed transcription initiation using X- 

ray crystallography. Crystallization work 

on sigma54 and an associated activator 

protein is in progress. His team is also 

looking at the overall architecture of the 

sigma54-core RNAP activated complexes 

by 3D electron microscopy, and biochemical 

approaches such as protein-protein 

footprinting and cross-linking. 

Negative strand RNA viruses (involved 

in diseases such as measles, rabies 

and ebola) encode a multifunctional 

RNA dependent RNA polymerase, 

which performs both transcriptive and 

replicative functions and also displays 

mRNA capping and polyadenylation 

activities. Crystallographic studies of this 

polymerase and associated proteins are 

in progress in his laboratory. 

Ribosomal Structure 

Ribosomes are complex ribonucleoprotein 

particles responsible for mRNA directed 

protein synthesis in all living cells. 

The large size of this macromolecular 

assembly (the E. coli ribosome has a MW 

of about 2.7 million daltons) makes it 

necessary to use both electron microscopy 

and X-ray crystallography to understand 

its structure. His laboratory is 

using 3-D electron-microscopy data 

from the laboratory of Dr. Joachim 

Frank, a Howard Hughes Research Investigator 

at the Wadsworth laboratories 

in Albany, New York, to understand the 

overall architecture of the ribosomal 

RNA in the ribosome. In addition, the 

structure of some ribosomal proteins and 

protein-RNA complexes by X-ray crystallography 

is also being investigated. 

Structural Studies of Bacterial 

Exoribonuclease 

Ribonucleases (RNases) play a central 

role in several aspects of cellular RNA 

metabolism, including mRNA decay 

and maturation and turnover of structural 

RNAs. In collaboration with the 

laboratory of Dr. Murray Deutscher in 

the Department of Biochemistry and 

Molecular Biology, crystallographic studies 

are underway to decipher the atomic 

structure of RNase T from Escherichia 

coli. 

PUBLICATIONS 

Malhotra, A and Frank, J. Predicting 

three-dimensional structure of ribosomal 

RNA using cryo-electron 

microscopy maps of the E. coli ribosome. 

Nucleic Acid Research Symposium Series 

41: 32, 1999. 

Akila Mayeda, Ph.D. 




Dr. Mayeda’s research focuses on the 

molecular mechanisms of constitutive 

and alternative pre-mRNA splicing. 

By taking advantage of biochemical, 

molecular-biological, and immunological 

approaches together with splicing 

assays in vitro and in vivo, Dr. Mayeda’s 

team is attempting to purify and clone 

novel splicing factors that are involved 

in the general splicing pathways and in 

the alternative splicing regulations (Figure). 

To study the structure, post-translational 

modifications, and function of 

splicing factors, recombinant proteins 

from E. coli or baculovirus are routinely 

prepared. Specific antibodies also are 

used to characterize the tissue-specific expression 

patterns and the subcellular localization 

of the factors. 

Dr. Mayeda’s team has advanced the 

understanding of pre-mRNA splicing 

through the isolation and characterization 

of two distinct classes of RNA-binding 

proteins, known as SR and hnRNP 

A/B family proteins. Interestingly, these 

two kinds of protein have antagonistic 

effects upon the selection of splice sites 

and the use of alternative exons (Figure). 

Recently his team has purified and characterized 

a novel human splicing factor 

RNPS1, which is a typical RNA-binding 

protein with a single canonical RNArecognition 

motif (RRM) and extensive 

serine-rich domain in upstream. 

Human RNPS1 was identified as a general 

splicing activator but it would be also 

a potential alternative splicing regulator. 

Further characterizations of 

RNPS1 together with its associated factors 

are ongoing research projects in his 

laboratory. 

Exon-Inclusion/Skipping 

Mutually Exclusive Exons 

Alternative 3’ Splice Sites 

Alternative 5’ Splice Sites 

Retained Intron 

Patterns of constitutive and alternative pre-mRNA splicing. 

White and black boxes indicate constitutively spliced exons and alternatively 

spliced exons, respectively. Possible splicing patterns are shown. 

12 


PUBLICATIONS 

Mayeda, A, Screaton, GR, Chandler, 

SD, Fu, X-D and Krainer, AR. Substrate 

specificities of SR proteins in 

constitutive splicing are determined by 

their RNA-Recognition Motifs and composite 

pre-mRNA exonic elements. Molecular 

Cellular Biology 19:1853, 1999. 

Koizumi, JY, Okamoto, H, Onogi, 

A, Mayeda, A, Krainer, AR and 

Hagiwara, M. The subcellular localization 

of SF2/ASF is regulated by direct 

interaction with SR protein kinases 

(SRPKs). Journal of Biological Chemistry 

274:11125, 1999. 

Mayeda, A and Krainer, AR. Preparation 

of HeLa cell nuclear and cytosolic 

S100 extracts for in vitro splicing. Methods 

Molecular Biology 118:309, 1999a. 

Mayeda, A and Krainer, AR. Mammalian 

in vitro splicing assays. Methods 

Molecular Biology 118:315, 1999b. 

Caputi, M, Mayeda, A, Krainer, AR 

and Zahler, AM. hnRNP A/B proteins 

are required for inhibition of HIV-1 premRNA 

splicing. Embolism Journal 

18:4060, 1999. 

Ismaïli, N, Pérez-Morga, D, Walsh, 

P, Mayeda, A, Pays, A, Tebabi, P, Krainer, 

AR and Pays, E. Characterization of a 

SR protein from Trypanosoma brucei 

with homology to RNA-binding cissplicing 

proteins. Molecular Parasitology 

Biology 102:103, 1999. 

Mayeda, A, Badolato, J, Kyobayashi, 

R, Zhang, MQ, Gardiner, EM, and 

Krainer, AR. Purification and characterization 

of human RNPS1: A general activator 

of pre-mRNA splicing. Embolism 

Journal 18:4560, 1999. 

Chew, SL, Liu, H-X, Mayeda, A and 

Krainer, AR. Evidence for the function 

of an exonic splicing enhancer after the 

first catalytic step of pre-mRNA splicing. 

Proceedings National Academy of 

Science USA 96:10655, 1999. 

Dirksen, WP, Li, X, Mayeda, A, 

Krainer, AR and Rottman, FM. Mapping 

the SF2/ASF binding site in the 

bovine growth hormone exonic splicing. 

Journal of Biological Chemistry 275: 

29170, 2000. 

Eperon, IC, Makarova, OV, 

Mayeda, A, Munroe, SH, Cáceres, JF, 

Hayward, DG and Krainer, AR. Selection 

of alternative 5’ splice sites: Role of 

U1 snRNP and models for the antagonistic 

effects of SF2/ASF and hnRNP A1. 

Molecular Cellular Biology 20:8303, 

2000. 

Adams, DJ, van der Weyden, L, 

Mayeda, A, Stamm, S, Morris, BJ and 

Rasko, JEJ. ZNF265 - a novel spliceosomal 

protein able to induce alternative 

splicing. Journal of Cell Biology 154:25, 

2001. 

Bilodeau, PS, Domsic, JK, Mayeda, 

A, Krainer, AR and Stoltzfus, CM. RNA 

splicing at human immunodeficiency 

virus type 1 3’ splice site A2 is regulated 

by binding of hnRNP A/B proteins to 

an exonic splicing silencer element. Journal 

of Virology 75:8487, 2001. 

Saunders, LR, Perkins, DJ, 

Balachandran, S, Michaels, R, Ford R, 

Mayeda, A and Barber, GN. Characterization 

of two evolutionarily conserved, 

alternatively spliced nuclear phosphoproteins, 

NFAR-1 and -2, that function 

in mRNA processing and interact with 

the double-stranded RNA-dependent 

protein kinase, PKR. Journal of Biological 

Chemistry 276:32300, 2001. 

Carlos T. Moraes, Ph.D. 

Associate Professor of Neurology 


Although mitochondrial genetics of 

yeast and trypanosomes has been 

extensively explored 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 mitochondrial-specific 

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 nuclear-coded proteins synthesized 

in the cytoplasm are imported 

into mitochondria and assembled with 

mitochondrially-synthesized proteins to 

form a functional oxidative phosphorylation 

system. 

Large-scale rearrangements and 

point mutations of mtDNA have been 

associated with devastating clinical syndromes. 

Organs with high-energy requirements 

such as brain and muscle are 

preferentially affected. Symptoms include: 

seizures, strokes, muscle weakness, 

blindness, diabetes, and hearing loss. 

More recently, defects in mitochondrial 

function have also been associated with 

some forms of tumors. Mitochondria 

have also become major players in programmed 

cell death. A number of antiand 

pro-apoptotic factors seem to 

mediate their functions in association 

with mitochondrial membranes. 

Dr. Moraes’ laboratory has been 

studying the role of mtDNA mutations 

in cancer and how defects in mitochondrial 

function could modulate cell 

growth and death. 

PUBLICATIONS 

Chen, CH, Segal, DM, Moraes, CT 

and Mash, DC. Dopamine transporter 

mRNA in autopsy studies of chronic 

cocaine users. Brain Research and Molecular 

Brain Research 73:181, 1999. 

Pugliese, A, Kawasaki, E, Zeller, M, 

Yu, L, Babu, S, Solimena, M, Moraes, 

CT, Pietropaolo, M, et al. Sequence 

analysis of the diabetes-protective human 

leukocyte antigen-DQBI 0602 allele in 

unaffected, islet cell antibody-positive 

first degree relatives and in rare patients 

with type 1 diabetes. Journal of Clinical 

Endocrinology Metabolism 84:1722, 

1999. 


Moraes, CT, Kenyon, L and Hao, 

H. Mechanisms of human mitochondrial 

DNA maintenance: the determining role 

of primary sequence and length over 

function. Molecular Biological Cell 

10:3345, 1999. 

Barrientos, A and Moraes, CT. Titrating 

the effects of mitochondrial complex 

I impairment in the cell physiology. 


274:16188, 1999. 

Hao, H, Morrison, LE and Moraes, 

CT. Suppression of a mitochondrial 

tRNA gene mutation phenotype associated 

with changes in the nuclear background. 

Human Molecular Genetics 

8:1117, 1999. 

Barrientos, A, Muller, S, Dey, R, 

Wienberg, J and Moraes, CT. Cytochrome 

c oxidase assembly in primates 

is sensitive to small evolutionary variations 

in amino acid sequence. Molecular 

Biology and Evolution 17:1508, 

2000. 

Dey, R, Barrientos, A and Moraes, 

CT. Functional constraints of nuclearmitochondrial 

DNA interactions in 

xenomitochondrial rodent cell lines. 


31520, 2000. 

Dey, R, Tengan, CH, Morita, MPA, 

Kiyomoto, BH and Moraes, CT. A novel 

myopathy-associated mitochondrial 

DNA mutation altering the conserved 

size of the tRNA(Gln) anticodon loop. 

Neuromuscular Disorders 10:488, 2000. 

Rana, M, de Coo, I, Diaz, F, Smeets, 

H and Moraes, CT. An out-of-frame 

cytochrome b gene deletion from a patient 

with parkinsonism is associated 

with impaired complex III assembly and 

an increase in free radical production. 

Annals of Neurology 48:774, 2000. 

Dey, R and Moraes, CT. Lack of 

oxidative phosphorylation and low mitochondrial 

membrane potential decrease 

susceptibility to apoptosis and do 

not modulate the protective effect of Bclx 

L 

in osteosarcoma cells. Journal of Biological 

Chemistry 275:7087, 2000. 

Hu, Y, Moraes, CT, Savaraj, N, 

Priebe, W and Lampidis, TJ. Rho(0) tumor 

cells: a model for studying whether 

mitochondria are targets for rhodamine 

123, doxorubicin and other drugs. Biochemical 

Pharmacology 60:1897, 2000. 

Moraes, CT. A helicase is born. 

Nature Genetics 28:200, 2001. 

Moraes, CT. What regulates mitochondrial 

DNA copy number in animal 

cells? Trends in Genetics 7:199, 2001. 

Moraes, CT, Dey, R and Barrientos, 

A. Transmitochondrial technology in 

animal cells. Methods In Cell Biology 

65:397, 2001. 

Xu, G, Dave, KR, Moraes, CT, 

Busto, R, Sick, TJ, Bradley, WG and 

Perez-Pinzon, MA. Dysfunctional mitochondrial 

respiration in the wobbler 

mouse brain. Neuroscience Letters 

300:141-144, 2001. 


• Dr. Moraes’ group has found that cells 

with defective mitochondrial respiration 

can be more resistant to cell death. 

This is a counterintuitive concept, as 

it was thought that the less energy a 

cell has, the easier it is to kill it. However, 

programmed cell death does require 

a considerable amount of ATP 

(energy) to occur. These findings may 

explain the presence of mtDNA mutations 

in some cancers. 

Kenneth E. Rudd, Ph.D. 


Biochemistry and 



Dr. Rudd’s research focuses on functional 

characterization of a selected 

set of genes and gene products of Escherichia 

coli. The 4.6 Mb genome of E. coli 

is now completely sequenced and contains 

over 4,100 protein-encoding genes. 

Less than half of these genes have been 

functionally characterized. Most protein 

sequences can be organized into families 

based upon homologous relationships. 

Some families are restricted to the bacterial 

domain of life whereas others contain 

Ancient Conserved Regions (ACRs) 

that are present in both bacterial and 

eucaryotic proteins, including human 

proteins. Their genome-scale homology 

analysis is used both to organize the genes 

of E. coli into functional predictionbased 

classes and to identify a set of genes 

to characterize experimentally. 

Their characterization of E. coli 

ORFs (Open Reading Frames) of unknown 

biological function is directed at 

selected proteins that fall into different 

functional classes based on homologous 

relationships. Some functional predictions 

are quite specific. However, sometimes 

the functional prediction is limited 

to a general type of protein activity, for 

example a membrane permease of unknown 

specificity. In other cases, no 

functions have been attributed to any 

member of the homologous family, even 

though the family might be quite widespread 

in nature. Their approach includes 

determining the phenotype associated 

with mutations in the genes of interest 

as well as cloning, overproducing, purifying, 

and characterizing the proteins of 

interest. They are particularly interested 

in proteins of less than 150 amino acids 

in length as they are among the most 

difficult to analyze using bioinformatic 

approaches alone. Some of the proteins 

they are characterizing have predicted 

functions that include protein phosphorylation, 

ligand binding, protein-protein 

interactions, transport functions and protease 

activity. They hope that this selective 

top-down approach to functional 

genomics will illuminate important new 

functions, not just in E. coli, but in organisms 

with related proteins as well. 

14 


PUBLICATIONS 

Rudd, KE. Novel intergenic repeats 

of Escherichia coli. Research Microbiology 

150:663, 1999. 

Conrad, J, Niu, L, Rudd, KE, Lane, 

BG and Ofengand, J. 16S ribosomal 

RNA pseudouridine synthase RsuA of 

Escherichia coli: deletion, mutation of 

the conserved Asp102 residue, and sequence 

comparison among all other 

RNA pseudouridine synthases. RNA 

5:751, 1999. 

Rudd, KE. EcoGene: A genome sequence 

database for Escherichia coli. 


Rudd, KE. New tools for an old 

workhorse. Nature Biotechnology 

18:1241, 2000. 

Sarker, S, Rudd, KE and Oliver, D. 

Revised translation start site for secM 

defines an atypical signal peptide that 

regulates Escherichia coli secA expression. 

Journal of Bacteriology 182:5592, 

2000. 

Sarker, S, Rudd, KE and Oliver, D. 

Revised translation start site for secM 

defines an atypical signal peptide that 

regulates Escherichia coli secA expression 

(vol 182, pg 5594, 2000). Journal of 

Bacteriology 183:804, 2001. 


• In 1999 the EcoGene website, Eco- 

Web, was created and funding for 

EcoWeb was obtained from the NIH. 

EcoWeb contains information about E. 

coli genes, including protein and DNA 

sequences derived from a revised E. coli 

genome sequence annotation. A literature 

survey was conducted to obtain a 

compilation of 740 genes whose starts 

are verified by N-terminal sequencing 

of their protein products. This set of 

experimentally verified gene starts has 

been used to derive a new computer 

model of the E. coli ribosome binding 

sites responsible for the initiation of 

protein synthesis. A search for new 

DNA repeat families in the intergenic 

regions of the E. coli genome identified 

several new families of intergenic 

repeat sequences. YedX, a bacterial homolog 

of human transthyretin, was 

purified and crystallized in collaboration 

with Arun Malhotra in preparation 

for 3-D structural determination. 

A small uncharacterized E. coli ORF, 

ynfA, was shown to confer ampicillin 

resistance when deleted and to cause 

cell death when overproduced. 

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




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 citokinesis 

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 co-localize with the apical intermediate 

filament (IF) cytoskeleton by 

using high-resolution confocal microscopy, 

near-neighbor deconvolution, and 

3-D 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, we 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 a relatively short list 

of potential candidates to fulfill the role 

of the “glue” attaching centrosomes is 

now under consideration. 

Interestingly, one of those proteins 

is phosphorylated by p34cdc2. Because 

the IF do not depolymerize during mitosis 

in epithelial cells, the attachment 

of centrosomes to IF must be necessarily 

broken at the onset of mitosis. The 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. In addition, the relevance of 

this mechanism during ischemia or ATP 

depletion is also under investigation. 

PUBLICATIONS 

Salas, PJI. Insoluble Tubulin-containing 

structures are anchored to the 

apical network of intermediate filaments 

in polarized CACO-2 epithelial cells. 

Journal of Cell Biology 146:645, 1999. 

Ameen, NA and Salas, PJI. Microvillus 

Inclusion Disease: a genetic defect 

affecting apical membrane protein 

traffic in intestinal epithelia. Traffic 1:76, 

2000. 

Ameen, NA, Alexis, J and Salas, PJI. 

Cellular localization of the cystic fibrosis 

trans-membrane conductance regulator 

in mouse intestinal tract. Histochemistry 

Cell Biology 114:69, 2000. 

Ameen, NA, Figueroa, Yand Salas, 

PJI. Anomalous apical plasma membrane 

phenotype in CK8-deficient mice indicates 

a novel role for intermediate filaments 

in the polarization of simple 

epithelia. Journal of Cell Science 

114:563, 2001. 



• The attachment of centrosomes to intermediate 

filaments is a novel observation. 

Although the implications of 

the mechanism of detachment during 

mitosis are still to be assessed, it may 

be relevant for cancer therapy. 

Fulvia Verde, Ph.D. 




Dr. Verde’s research goal is to understand 

the molecular basis of cell 

morphogenesis in eukaryotic cells and its 

coordination to cell proliferation. To this 

end, her laboratory has investigated the 

function of Orb6, a conserved protein 

kinase that is required for maintenance 

of cell polarity and regulation of the cell 

cycle. Her research team has identified 

two proteins that physically interact with 

Orb6 and established their role in the 

control of Orb6 function. One of these 

proteins, Skb1, is conserved in human 

cells and regulates Orb6 activity. The 

other, that we named Bot1, has an important 

role in localizing Orb6 to the cell 

surface through its interaction with components 

of the microtubule cytoskeleton. 

They also have identified a potential substrate 

of Orb6 kinase. 

Furthermore, Dr. Verde 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 organization of 

microtubule dynamics (Brunner and 

Nurse, Cell 102, Sept1, 2000). These 

findings are important because little is 

known about the mechanism of microtubule-dependent 

cell morphogenesis. 

PUBLICATIONS 

Verde, F. Cell polarity: A tale of two 

Ts. Current Biology 11:R600, 2001. 

Bao, S, Qyang, Y, Yang, P, Kim, H, 

Du, H, Bartholomeusz, G, Henkel, J, 

Pimental, R, Verde, F and Marcus, S. The 

highly conserved protein methyltransferase, 

Skb1, is a mediator of hyper-osmotic 

stress response in the fission yeast 

Schizosaccharomyces pombe. Journal of 



• Dr. Verde’s findings show that Bot1 

may function as a molecular bridge between 

Tea1, a microtubule-associated 

protein required for the establishment 

of cell polarity and Orb6, a conserved 

protein kinase related to mammalian 

Rho-kinase and Myotonic Dystrophy 

kinase. These findings offer insight into 

the hierarchy of events that lead to polarized 

cell growth. 

Keith A. Webster, Ph.D. 

Associate Professor of Molecular 

and Cellular Pharmacology 


Development of Gene Therapy for 

the Treatment of Peripheral Arterial 

Occlusive Disease, Myocardial 

Ischemia, and Solid Hypoxic Tumors 

Dr. Webster’s research examines the development 

of gene therapy for the treatment 

of peripheral arterial occlusive 

disease, myocardial ischemia, and solid 

hypoxic tumors. The goal of this work is 

to create gene therapy delivery systems 

that will allow treatment of patients suffering 

from ischemia-related diseases and 

solid tumors. Dr. Webster’s team has identified 

the essential components of this 

system and tested them in cultured cells 

and intact animals using plasmid and 

viral vectors. This technology is protected 

by two patents—one issued, one pending. 

Through examination of the pathways 

of myocardial cell damage in response 

to ischemia-reperfusion (I/R), Dr. 

Webster has identified some of the early 

signals that mediate the stress response 

in cardiac myocytes during ischemia and 

after reperfusion. These include release 

of free radicals from mitochondria, early 

activation of neutral sphingomyelinase 

and ceramide production, activation of 

c-Jun N-terminal kinase, p38 kinase, and 

finally cell death by apoptosis or survival. 

Recent work indicates that JNK activation 

protects against apoptosis. Ongoing 

work is deciphering the functions of the 

signals, how they relate to cell death and 

how they can prevent the cell death safely 

using gene therapy. (See InteGene link 

on the Molecular Cardiology website.) 

Analyses of Gene Regulation by 

Hypoxia and Ischemia in Muscle: 

Glycolytic Enzyme, Endothelin-1 

(ET-1), and Metallothionine Genes 

These experiments have shown that a 

major response of both skeletal and cardiac 

muscles to hypoxia involves the coordinate 

inductions of glycolytic enzyme 

mRNAs. Since there are 11 glycolytic 

enzyme genes and they have observed 

transcript inductions of up to ten-fold 

in some instances in cardiac cells over two 

to three days, this response constitutes a 

major switching of the muscle transcriptional 

apparatus and suggests a significant 

physiological adaptation. Dr. 

Webster’s current and proposed studies 

are focusing on the mechanism and coordination 

of this response. Similarly the 

ET-1 gene is over-expressed in hypoxic 

and ischemic myocardial tissue, and because 

ET-1 is a very powerful vasoconstrictor 

its over-expression can increase 

the damage caused by ischemia. They are 

interested in the molecular pathway for 

the regulation of ET-1 by hypoxia, which 

involves the factors HIF-1, Sp1, and Sp3 

and a series of accessory factors. 

16 


PUBLICATIONS 

Ing, D, Zang, J, Dzau, V, Webster, 

KA and Bishopric, NH. Nitric Oxide 

mediates ANP-activated apoptosis in 

cardiac myocytes. Circulation Research 

84:21, 1999. 

Webster, KA. One step, two step 

regulation of therapeutic genes. The Scientist 

13:13, 1999. 

Discher, DJ, Bishopric, NH and 

Webster, KA. High frequency rearrangement 

of a multiple copy enhancer in plasmid 

vectors: Practical considerations 

Biotechniques 26:1026, 1999. 

Webster, KA. Molecular switches for 

regulating therapeutic genes. Gene 

Therapy 6:951, 1999. 

Webster, KA, Discher, D, Kaiser, S, 

Hernandez, O, Sato, B and Bishopric, 

NB. Hypoxia-activated apoptosis of cardiac 

myocytes requires reoxygenation or 

a pH shift and is independent of p53. 

Journal of Clinical Investigation 

104:239, 1999. 

Alexander, Y, Webster, KA and 

Prentice, H. Gene Transfer and models 

of gene therapy for the myocardium. 

Clinical and Experimental Pharmacology 

and Physiology 29:661, 1999. 

Dougerty, C, Discher, D, Bishopric, 

NH and Webster, KA. C-Jun N-Terminal 

kinase protects cardiac myocytes from 

reoxygenation-mediated apoptosis. Circulation 

99:324, 1999. 

Hernandez, O, Discher, D, Bishopric, 

NH and Webster, KA. Activation of 

Neutral Sphingomyelinase ceramide, and 

JNK precede apoptosis in Hypoxiareoxygenated 

cardiac myocytes. Circulation 

99:2533, 1999. 

Leri, A, Fiordaliso, F, Manabu, S, 

Discher, D, Bishopric, NH, Webster, KA 

and Anversa, P. Inhibition of p53 function 

prevents stretch-mediated activation of the 

myocyte renin-angiotensin system and 

apoptosis. Circulation 99:4086, 1999. 

Yamashita, K, Discher, D, Bishopric, 

NH and Webster, KA. Induction of 

endothelin-1 by hypoxia is mediated by 

cooperative physical interactions between 

HIF-1, AP-1, GATA-2, and CAAT binding 

factors. Circulation 99:4475, 1999. 

Zang, J, Slepak, T, Webster, KA and 

Bishopric, NH. Role of mitogen activated 

protein kinases ERK1/2 and JNK 

1/2 in nitric oxide-induced cardiac myocyte 

apoptosis. Circulation 99:1853, 

1999. 

Murphy, BJ, Andrews, G, Bittle, D, 

Discher, DJ, McCue, J, Green, C, 

Yanovsky, M, Giaci, A, Sutherland, RM, 

Laderoute, KL and Webster, KA. Activation 

of metallothionine gene expression 

by hypoxia involves metal response 

elements and metal transcription factor- 

1. Cancer Research 59:1315, 1999. 

Hernandez, O, Discher, DJ, Bishopric, 

NB and Webster, KA. Rapid activation 

of neutral sphingomyelinase by 

hypoxia-reoxygenation of cardiac 

myocytes. Circulation Research 86:142, 

2000. 

Leri A, Fiordaliso F, Setoguchi M, 

Limana F, Bishopric NH, Kajstura J, 

Webster, KA and Anversa, P. Inhibition 

of p53 function prevents renin-angiotensin 

system activation and stretch-mediated 

myocyte apoptosis. American 

Journal of Pathology 157:843, 2000. 

Andreka, P, Zang, J, Dougherty, C, 

Slepak, T, Webster, KA and Bishopric, 

NH. Cytoprotection by Jun kinase during 

nitric oxide-induced cardiac myocyte 

apoptosis. Circulation Research 88:305, 

2001. 

Slepak, TI, Webster, KA, Zang, J, 

Prentice, H, O’Dowd, A, Hicks, MN, 

Bishopric, NH. Control of cardiac-specific 

transcription by p300 through myocyte 

enhancer factor-2D. Journal of 


Yamashita, K, Discher, DJ, Hu, J, 

Bishopric, NH and Webster, KA. Molecular 

regulation of the endothelin-1 

gene by hypoxia - Contributions of hypoxia-inducible 

factor-1, activator protein-1, 

GATA-2, and p300/CBP. Journal 

of Biological Chemistry 276:12645, 

2001. 

Yamashita, K, Kajstura, J, Discher, 

DJ, Wasserlauf, BJ, Bishopric, NH, 

Anversa, P and Webster, KA. Reperfusion-activated 

Akt kinase prevents 

apoptosis in transgenic mouse hearts 

overexpressing insulin-like growth factor- 

1. Circulation Research 88:609, 2001. 

INVENTIONS AND PATENTS 

Title: Conditional Silencing and 

Applications for Regulated Gene 

Delivery. Inventor: K.A. Webster. Filed 

12/18/99. 


• Dr. Webster’s team discovered that gene 

silencer or repressor elements can be 

used in gene therapy vectors to conditionally 

regulate the expression of a 

transgene. This will facilitate the development 

of protocols for the permanent 

treatment of diseases such as 

peripheral limb ischemia, myocardial 

ischemia, and perhaps some cancers using 

targeted and regulated gene therapy. 


Assistant Professor of 



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 


eceptor tyrosine kinase ErbB2. The 

mucin subunit ASGP-1 also has antiadhesive 

activity. The human MUC4 has 

corresponding transmembrane (MUC4 

beta) and mucin (MUC4 alpha) subunits, 

with similar growth factor domains 

and anti-adhesive potential. These characteristics 

suggest SMC/MUC4 play a 

functional role in normal cells by providing 

a direct protective barrier at the 

cell surface to limit adsorption 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 signalling via ErbB2. 

Disregulation of these functions 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 alpha component of 

the molecules result in reversible disruption 

of integrin-mediated cell adhesion 

to the extracellular matrix, and may be 

important in the development of metastatic 

potential of the transformed cell. 

Over-expression or disregulation of the 

ErbB2 oncoprotein and cell surface 

integrins have both been implicated in 

the initiation and progression of head 

and neck cancers. 

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 MUC4 is similarly 

expressed in the epithelia of the human 

upper aero-digestive 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 three-fold: 

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 of the upper 

aerodigestive tract, as well as in metastatic 

cervical lymph nodes. SMC/MUC4 is 

also 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. For squamous 

cell carcinomas, a trend towards 

decreased MUC4 staining in poorly differentiated 

tumors is seen. Ongoing studies 

seek to correlate MUC4 expression 

with clinical outcomes for head and neck 

squamous cell carcinoma and mucoepidermoid 

carcinoma of major and minor 

salivary glands. These studies may establish 

MUC4 as a potential molecular 

prognostic marker for these tumors. The 

cell surface location of differentially expressed 

or altered SMC/MUC4 as a potential 

tumor marker may, in turn, offer 

an important avenue for novel cancer 

treatments for head and neck malignancies. 

PUBLICATIONS 

Weed, DT, Carraway, K, Carvajal, 







121:87, 1999. 

Civantos, FJ, Roth, J, Goodwin, WJ 

and Weed, DT. Sensory recovery in 

myelolabial flaps used for oral cavity reconstruction. 

Otolaryngology Head 

Neck Surgery 122:509, 2000. 

Li, P, Arango, ME, Perez, RE, Reis, 

CA, Bonfante, EL, Weed, DT and 

Carraway, KL. Expression and localization 

of immunoreactive-sialomucin complex 

(Muc4) in salivary glands. Tissue 

and Cell 33:111, 2001. 

Catherine F. Welsh, M.D. 

Assistant Professor of Medicine 


Dr. Welsh is studying cell cycle progression 

through the G1 phase and 

its regulation by growth factor receptors 

and adhesion to the extracellular matrix. 

She 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 are also necessary. 

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. Furthermore, they are situated 

to play a key role in the regulation of 

adhesion-dependent cell cycle progression. 

18 


PUBLICATIONS 

Welsh, CF, Assoian, RK. A growing 

role for Rho family GTPases as intermediaries 

in growth factor- and adhesiondependent 

cell cycle progression. 

Biochimica et Biophysica Acta. 

1471(1):M21, 2000. 

Welsh, CF, Roovers, K. Villanueva, 

J. Liu, YQ. Schwartz, MA. Assoian, RK. 

Timing of cyclin D1 expression within 

G1 phase is controlled by Rho. Nature 

Cell Biology. 3(11):950, 2001. 


• Dr. Welsh’s studies indicate that 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. In addition, 

Rho proteins appear to be involved in 

determining the timing of cyclin D1 

expression within G1 phase. 


Professor of Biochemistry and 



Dr. Werner’s research focuses on the 

regulation of expression of 

connexin genes. Connexins are proteins 

that form cell-to-cell channels. Specifically, 

he is working on two connexins, 

(1) connexin32 expressed in the liver 

and in the nervous system, and (2) 

connexin43 expressed in the heart and 

uterus. 

A few years ago, Dr. Werner’s research 

team discovered that connexin32 

is expressed from two tissue-specific promoters 

leading to the production of two 

mRNA species that differ only in their 

5’-untranslated region (5’-UTR). While 

the liver-specific mRNA is translated efficiently 

in an in vitro translation system, 

the nerve-specific mRNA is translated 

efficiently in an in vitro translation system, 

the nerve-specific is not. They studied 

the molecular consequences of a 

5’-UTR mutation found in some patients 

with Charcot-Marie-Tooth disease 

(CMTX1) by generating transgenic mice 

with the mutation. They found that the 

mRNA is made, but the connexin32 protein 

is not. Thus, the mutation affects 

translatability of the mRNA. They then 

discovered that the nerve-specific 5’- 

UTR of the mRNA contains an internal 

ribosome entry site (IRES) and that the 

site is mutated in the CMTX patients. 

Connexin43 is found in both the 

heart muscle and in the uterus. The gene 

for connexin43 is expressed constitutively 

in the heart, whereas it is induced 

by estrogen in the myometrium or 

uterus. Dr. Werner’s team cloned a novel 

transcription factor that seems to participate 

in this regulation. They also found 

that the 5’-UTR of the gene is required 

for estrogen inducibility. Encouraged by 

their IRES results with connexin32, Dr. 

Werner’s research team looked for IRES 

activity in the 5’-UTR of the connexin43 

mRNA. They found a very active IRES 

element. In fact, it is possible that 

connexin43 mRNA accumulates in the 

uterus prior to parturition and is then 

quickly translated through activation of 

the IRES element allowing for the rapid 

appearance of gap junctions to allow labor 

to begin. 

PUBLICATIONS 

Schiavi, A, Hudder, A and Werner, 

R. Connexin43 mRNA contains a functional 

internal ribosome entry site. FEBS 

Letters 464:118, 1999. 

Werner, R. IRES elements in connexin 

genes: A hypothesis explaining the 

need for connexins to be regulated at the 

translational level. Iubmb Life 50:173, 

2000. 

Hudder, A and Werner, R. Analysis 

of a Charcot-Marie-Tooth disease mutation 

reveals an essential internal ribosome 

entry site element in the 

connexin-32 gene. Journal of Biological 

Chemistry 275:34586, 2000. 


• The discovery of an essential IRES element 

in the nerve-specific connexin32 

mRNA is the first published demonstration 

that IRES elements are functional 

in normal cellular mRNAs. IRES 

elements were originally discovered in 

RNA viruses (e.g., polio virus), however, 

they had never been shown conclusively 

to be functional. The CMTX 

mutation also is the first published 

mutation in an IRE element that causes 

a genetic disease. 


20 


TUMOR IMMUNOLOGY PROGRAM 



Professor of Microbiology and Immunology 


The Tumor Immunology Program 

presently consists of 16 faculty 

members from five 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 patient samples. The 

program investigates numerous aspects 

of the immune system in relation to the 

development and treatment of cancer. 


1) Elucidation of the mechanisms underlying 

the activities of innate and 

adaptive immune cells. 

2) Study of various aspects of stem cell 

biology and bone marrow transplantation. 

3) Analysis of the role of T cells in the 

host defenses against tumors. 

4) Mechanisms of tumor evasion of the 

immune system. 

5) Devise novel immunotherapeutic protocols. 

PARTICIPANTS 

Adkins, Rebecca D., Ph.D. 


Blomberg, Bonnie B., Ph.D. 


Hnatyszyn, H. James, Ph.D. 


Jurecic, Roland, Ph.D. 


Kraus, Gunter K., 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. 


Murray, Timothy G., M.D. 

Ophthalmology 

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


Riley, Richard L., Ph.D. 


Rosenblatt, Joseph D., M.D. 

Medicine 

Thomas, Giovanna R., M.D. 


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

Pathology 

HIGHLIGHTS 

• 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). 

(Blomberg) 

• Breast cancer patients show improved 

immune response after psychosocial 

intervention. (Blomberg) 

• Design and developed both hammerhead 

ribozymes and RNAse P molecules 

that target and effectively cleave 

the 1:19 breakpoint observed in some 

childhood leukemias. Received funding 

from the Leukemia Research Foundation 

to evaluate this gene therapy in 

leukemia cell lines and primary human 

leukemia cell samples. (Kraus, 

Hnatyszyn) 

• Design, construction, and current 

evaluation of several anti-telomerase 

ribozymes in human cancer cell lines. 

(Kraus, Hnatyszyn) 

• Direct activation of protein kinase C 

causes normal human hematopoietic 

CD34 + stem cells to differentiate into 

dendritic cells. (Lee) 

• Protein kinase C activation causes many 

myeloid leukemias to differentiate into 

immunologically functional “leukemic” 

dendritic cells. These cells have 

potential utility as “cellular” anti-leukemia 

vaccines. (Lee) 

• T cell activation may play a critical role 

in the pathogenesis of opportunistic 

infections. (Lee) 

• Discovery that after allogeneic bone 

marrow transplant, 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. 

(Levy) 

• Learned that lymphocytes, which 

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. 

(Levy) 

• 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. 

(Lichtenheld) 

• A unique peptide with immuno-enhancing 

properties has been identified 

in a secreted form of human MUC1 

and used in vaccination experiments. 

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. (Lopez) 

• The 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. (Lopez and 

Adkins) 

• IL-2 during in vitro priming promotes 

subsequent engraftment and successful 

adoptive tumor immunotherapy by 

persistent memory phenotypic CD8 + 

T cells. (Malek) 

• Heatshock fusion vaccines generate 

CD8 CTL without CD4 help; progress 

towards novel and efficient tumor specific 

vaccines. (Podack) 

• CD30 is identified as a major negative 

regulator of cytotoxic lymphocytes; 

blocking CD30 signals in vivo will dramatically 

enhance anti-tumor immune 

responses. (Podack) 

• Generation of the first murine gene 

knock in Florida: CD30-Ligand knock 

out in mice will serve as valuable model 

for tumor and autoimmunity studies. 

(Podack) 

• Innovative vaccine trial for lung adenocarcinoma. 

(Podack) 

• A role for perforin in lymphocyte homeostasis 

revealed: cytotoxicity by 

perforin is necessary to remove antigenpresenting 

cells and turn off T cell activation. 

(Podack) 

• The 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 (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. (Riley) 

• Development of novel antibodychemokine 

and antibody-costimulatory 

ligand fusion proteins with dual 

function and preserved targeting capabilities. 

(Rosenblatt) 

• Development of a novel strategy for 

gene therapy of HIV-1 using mutations 

introduced into tRNA LYS3 primers. 

(Rosenblatt) 

• Demonstration of the potential role for 

HSV amplicon vectors in gene therapy 

of malignancy, particularly CLL. 

(Rosenblatt) 

• Demonstration of trafficking and inhibition 

by defective HIV-1 as a novel 

approach to HIV-1 gene therapy. 

(Rosenblatt) 

Rebecca D. Adkins, Ph.D. 




Newborn animals succumb to infections 

and diseases that have little 

to no effect in adults. This disease susceptibility 

in early life is at least partially 

due to the failure to mount protective 

immune responses. To understand the 

basis for poor responsiveness, Dr. Adkins’ 

research is focusing on T cell function in 

neonates. In particular, the research compares 

the T helper (Th) activities that 

arise in situ in neonatal versus adult mice. 

Th cells can be functionally divided into 

Th1 and Th2 subsets. The Th1 subset 

produces IFN and mediates delayed-type 

hypersensitivity and protection against 

intracellular pathogens. The Th2 subset 

produces IL-4 and IL-5 and is important 

in humoral responses. Immune responses 

heavily skewed toward Th1 or 

Th2 function can exacerbate infectious 

diseases, allergic reactions, diabetes, and 

autoimmunity. Consequently, generating 

and maintaining the appropriate Th1/ 

Th2 balance is critical for protective immunity. 

This is particularly important for 

the very early stages of life, when exposure 

to many novel antigens occurs. The 

goal of Dr. Adkins’ lab is to understand 

how Th1/Th2 responses develop and 

persist in early life. 

These studies have revealed several 

interesting and important differences 

between the Th responses of newborns 

and adults. First, unlike in adults, newborn 

lymph node and spleen cells show 

different responses to immunization with 

protein antigen; lymph node cells develop 

a mature, mixed Th1/Th2 response 

whereas spleen cells show exclusive Th2 

development. Second, neonatal (not 

adult) Th2 function persists for a prolonged 

period following a single immunization. 

Lastly, animals initially 

immunized as neonates are “programmed” 

to have Th2-dominant 

memory responses, under conditions in 

which adults show Th1 dominance. 

These observations have made major 

contributions to the field of neonatal 

immunology for several reasons. First, 

they are the first demonstration that the 

nature of an immune response in early 

life is highly dependent on the site of 

initiation of the response (spleen versus 

lymph nodes). Second, this laboratory is 

unique in studying antigen specific responses 

in vivo during the first week of 

life. Thus, they have gained important 

new insights into the transition from 

primary to memory responses in 

neonates. 

22 


PUBLICATIONS 

Adkins, B. Apoptosis of näive murine 

neonatal T cells. International Review 

Immunology 18:465, 1999. 

Adkins, B. The functional capacities 

of T cells in newborn mice and humans. 

Immunology Today 20:330, 1999. 

Petito, CK, Adkins, B, Tracey, K, 

Roberts, B, Torres-Muñoz, J, McCarthy, 

M and Czeisler, C. Chronic systemic 

administration of tumor necrosis factor 

alpha and of HIV gp 120: Effects on 

adult rodent brain and blood-brain barrier. 

Journal of Neurovirology 5:314, 

1999. 

Adkins, B. Development of neonatal 

Th1/Th2 function. International Review 


Adkins, B, Bu, Y, Cepero, E and 

Perez, R. Exclusive Th2 primary effector 

function in spleens but mixed Th1/Th2 

function in lymph nodes of murine neonates. 

Journal of Immunology 164:2347, 

2000. 

Adkins, B, Charyulu, V, Sun, QL, 

Lobo, D and Lopez, DM. Early block in 

maturation is associated with thymic involution 

in mammary tumor-bearing 

mice. Journal of Immunology 164:5635, 

2000. 

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

The generation of Th memory in neonates 

versus adults: prolonged primary 

Th2 effector function and impaired 

development of Th1 memory effector 

function in murine neonates. Journal 

of Immunology 166:918, 2001. 

Plano, LRW, Adkins, B, Woischnik, 

M, Ewing, and Collins, CM. Toxin levels 

in serum correlate with the development 

of staphylococcal scalded skin 

syndrome in a murine model. Infection 

and Immunity 69:5193, 2001. 


• The 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 




by the direct or indirect effects of 

tumor-derived factors. 

Bonnie B. Blomberg, Ph.D. 




Dr. Blomberg currently is working 

on two projects in cancer research. 

One involves basic research on the molecular 

regulation of B lymphopoiesis in 

mice. Generation of B lymphocytes is 

important in those 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 Dr. Richard 

Riley in the Department of Microbiology 

and Immunology, research 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)λ5 and VpreB. 

Recent data from this laboratory indicate 

that this affects the antibody V H 

repertoire at the pre-B cell level, in other 

words, before antigen selection. 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. 

The second project being conducted 

in Dr. Blomberg’s laboratory involves 

clinical research with breast cancer patients. 

In collaboration with Dr. Michael 

Antoni and Dr. Charles Carver in the 

Department of Psychology, Dr. Sharlene 

Weiss 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 

the patients in response to psychosocial 

intervention (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 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. 

PUBLICATIONS 

Donohoe, ME, Beck-Engeser, GB, 

Lonberg, N, Karasuyama, H, Riley, RL, 

Jack, HM and Blomberg, BB. Transgenic 

human lambda5 rescues the murine 

lambda5 nullizygous phenotype. Journal 


Jin, Y, Fuller, L, Esquenazi, V, 

Blomberg, BB, Rosen, A, Tzakis, AG, 

Ricordi, C and Miller, J. Bone marrow 

cells inhibit the generation of autologous 

EBV-specific CTL. Human Immunology 

61:538, 2000. 


Jin, YD, Fuller, L, Wei, YT, 

Blomberg, BB, Miller, J and Esquenazi, 

V. Bone marrow cells promote TH2 polarization 

and inhibit virus-specific CTL 

generation. Human Immunology 

61:1233, 2000. 

Sherwood, EM, Xu, W, King, AM, 

Blomberg, BB and Riley, RL. The reduced 

expression of surrogate light chains 

in B cell precursors from senescent 

BALB/c mice is associated with decreased 

E2A proteins. Mechanisms of Aging and 

Development 118:45, 2000. 


• 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). 

• Breast cancer patients show improved 

immune response after psychosocial 

intervention. 

H. James Hnatyszyn, Ph.D. 




Dr. Hnatyszyn and his research team 

are focusing on a number of novel 

aspects with regards to cancer detection 

and therapeutic interventions. First, they 

are incorporating catalytic RNAs, such 

as ribozymes and RNAse P molecules, 

into strategies for cancer treatment using 

gene therapy. They have used these 

potent “molecular scissors” to target 

tumor-specific oncogenes in leukemias 

including BCR-ABL in CML and E2A- 

PBX1 in pre-B-ALL. Expression of these 

target-specific catalytic RNAs in cancer 

cells will reduce the oncogenic message, 

thereby rendering the cell more permissive 

to conventional therapies and/or permitting 

the cancer cell to enter a 

regulated replication cycle followed by 

programmed cell death. One application 

for these interventions is in the purging 

of stem cell grafts to remove residual leukemic 

cells, reducing the risk of relapse 

and making autologous transplantation 

a real possibility. Currently they are using 

this technology to develop gene 

therapies for human leukemias, multiple 

myeloma, and solid tumors including 

breast, prostate, ovarian, and cervical 

cancers. 

The second focus of Dr. Hnatyszyn’s 

research is to develop rapid, sensitive, and 

inexpensive assays for the detection of 

human malignancies. It is thought that 

early detection and subsequent intervention 

improves the prognosis and survival 

rate of patients with cancer. In collaboration 

with Dr. Gunter Kraus, Dr. 

Hnatyszyn’s laboratory utilizes real-time 

PCR and highly specific fluorogenic 

probes to design and evaluate detection 

assays that are very fast (less than 40 minutes), 

very sensitive, and rely on very little 

material from a patient sample (peripheral 

blood, tissue, or bone marrow). In 

the past six months, researchers in this 

lab have developed a number of rapid 

and sensitive assays designed to detect 

and identify a number of human malignancies. 

These assays can be used for 

diagnosis, tumor cell surveillance, monitoring 

treatment efficacy, and detection 

of residual disease in the patient and in 

transplant grafts. They also have expanded 

the application of these assays to 

encompass infectious diseases (e.g., tuberculosis, 

HIV/AIDS) including many 

pathogens that may contribute to the 

development of human cancers (e.g., 

HHV-8, HPV, HTLV). The speed and 

sensitivity of these assays in a clinical setting 

will permit clinicians to intervene 

early during cancer development and 

improve patient prognosis. 

PUBLICATIONS 

Hnatyszyn, H, Podack, ER, Young, 

AK, Seivright, R, Spruill, G and Kraus, 

G. The use of real-time PCR and 

fluorogenic probes for rapid and accurate 

genotyping of newborn mice. Molecular 

Cell Probes 15:169, 2001. 


• Design and development of both hammerhead 



the 1:19 breakpoint observed in some 

childhood leukemias. 

• Received funding from the Leukemia 

Research Foundation to evaluate this 

gene therapy in leukemia cell lines and 

primary human leukemia cell samples. 

Roland Jurecic, Ph.D. 




Since stem cells from various tissues 

(bone marrow, intestines, skin, liver, 

brain, testis) participate in tissue homeostasis 

by replacing differentiated cells lost 

to physiological turnover, disease, or injury, 

they hold tremendous promise as 

model systems for treatment of various 

diseases. 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. Research 

conducted in Dr. Jurecic’s laboratory 

focuses on 1) elucidation of genetic 

mechanisms that regulate the function 

of hematopoietic stem cells and development 

of blood cell diseases, and 

2) analysis of their in vivo developmental 

potential. The goal of this research is 

to enhance our understanding of HSC 

biology in order to achieve successful exvivo 

maintenance and genetic manipulation 

of HSC for more efficient clinical 

stem cell transplantation and gene 

therapy of genetic and acquired diseases. 

Molecular genetic analysis of HSC 

function encompasses identification, 

cloning, and functional genetic analysis 

of novel genes that regulate blood cell 

development and are also involved in leukemogenesis. 

They have created and 

screened total and subtracted cDNA libraries 

from mouse and human HSC and 

are also working on creating a stem cell 

24 


cDNA microarray in order to perform a 

global survey of differential gene expression 

during blood cell development and 

disease. So far they have identified a 

number of differentially expressed novel 

genes and have created knockout mice 

for three selected novel genes. In the second 

arm of the project, these researchers 

are trying to identify novel hematopoietic 

transcription factors. After performing 

a comprehensive cloning and expression 

analysis (cDNA array and 

Northern) of Cys 2 

-His 2 

type zinc finger 

(ZF) genes expressed in mouse HSC and 

progenitors, researchers have selected and 

cloned four novel zinc finger genes. Their 

role in blood cell development and leukemogenesis 

is currently being studied 

by generation of transgenic and knockout 

mouse models. 

Recent discovery that tissue-specific 

stem cells may have the capacity to develop 

into cells of unrelated tissue(s) 

could have important implications for 

designing new stem cell transplantation 

protocols for treatment of various diseases. 

The aim of this project is to analyze 

whether hematopoietic stem cells 

possess the potential for differentiation 

into cell types other than that of blood 

lineages. To study full developmental 

potential of HSC they have 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) and 

obtained preliminary evidence that 

mouse adult HSC have the capacity to 

develop into fetal CNS and heart muscle 

cells. If adult HSC can indeed develop 

into functional cells from unrelated tissues, 

this would open up the possibility 

of using autologous HSC to treat disorders 

affecting various tissues. 

PUBLICATIONS 

Infante, JL, Nachtman, RG, 

Abdullah, JM and Jurecic, R. Cloning 

and characterization of Vulcan, a novel 

zinc finger gene with developmentally 

regulated expression during differentiation 

of hematopoietic stem cells and progenitors 

into lymphoid and myeloid 

lineages. Blood 94:37, 1999. 

Nachtman, RG, Abdullah, JM, 

Infante, JL and Jurecic, R. Cloning and 

characterization of Tycho, a novel zinc 

finger gene, differentially expressed during 

lymphoid lineage commitment and 

differentiation of murine hematopoietic 

stem cells and progenitors. Blood 

94:131, 1999. 

Abdullah, JM, Jing, X, Spassov, DS, 

Nachtman, RG and Jurecic, R. Cloning 

and characterization of Hepp, a novel 

gene expressed preferentially in hematopoietic 

progenitors and mature blood 

cells. Blood Cells Molecules and Diseases 

27:667, 2001. 

Abdullah, JM, Li XY, Nachtman, 

RG and Jurecic, R. FLRF, a novel evolutionarily 

conserved RING finger gene, 

is differentially expressed in mouse fetal 

and adult hematopoietic stem cells and 

progenitors. Blood Cells Molecules and 

Diseases 27:320, 2001. 

Gunter K. Kraus, Ph.D. 




Dr. Kraus’ research interests overlap 

the areas of human malignancies 

and infectious diseases and include gene 

therapy, vaccines, and targeted delivery 

systems. The primary focus of Dr. Kraus’ 

research involves the design, development, 

and evaluation of novel gene therapies 

for human malignancies. A second 

area of research involves the design and 

development of safe and effective vaccines 

against both infectious diseases and 

various human cancers. 

Over the past year, Dr. Kraus has 

investigated the use of RNA enzymes, 

called ribozymes or RNAse P molecules, 

which may be used to prevent the expression 

of abnormal genes in human 

malignancies. His laboratory team has 

been working on several projects investigating 

this exciting gene therapy as a 

treatment for many human cancers including 

breast, prostate, ovarian, and 

cervical carcinomas, as well as leukemias 

and lymphomas. His group also has been 

examining the use of vaccines against 

several forms of cancer and other human 

diseases. Both DNA-based and peptide 

vaccines are under evaluation for their 

capacity to eliminate aberrant cancer cells 

and prevent infectious diseases. 

PUBLICATIONS 






Cell Probes 15:169, 2001. 


• Design and development of both hammerhead 



the one:19 breakpoint observed in 

some childhood leukemias. Received 

funding from the Leukemia Research 

Foundation to evaluate this gene 

therapy in leukemia cell lines and primary 

human leukemia cell samples. 

• Design, construction, and current 

evaluation of several anti-telomerase 

ribozymes in human cancer cell lines. 






Work 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 arises from hematopoietic progenitors 

and their intracellular/genetic characteristics. 

They 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 lab 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” 

anti-leukemia vaccines by reinfusion 

back into patients. This work aims to 

bring this approach to clinical trials. 

In addition to cognate antigen presentation 

by MHC to the T cell receptor 

(signal 1), other key molecular 

interactions underlie the ability of DC 

to activate (or inactivate) T cells. The 

most important of these is activation of 

T cell costimulatory receptors (including 

CD28, CD154 (CD40L), ICAM1) 

by their APC counter-receptors (CD80, 

CD86, CD40, LFA-3). They are studying 

what role costimulation plays in activation 

of immune responses (DNA 

vaccination), and conversely in tolerance 

induction (as therapy in organ transplantation 

and as a strategy used by cancers 

to evade immune destruction). These 

researchers also are examining what role 

of T cell activation plays in the pathogenesis 

of opportunistic infections, which 

are prevalent complications of immunosuppressive 

chemotherapy regimens. 

Hopefully, these studies will allow more 

effective manipulation of immune responses 

involved in all aspects of cancer 

treatment. 

PUBLICATIONS 

St. Louis, D, Woodcock, J, Fransozo, 

G, Blair, P, Carlson, LM, Murillo, ME, 

Wells, M, Williams, A, Smoot, D, 

Kaushal, S, Grimes, J, Harlan, DM, 

Chute, J, June, CH, Siebenlist, U and 

Lee, KP. Evidence from a human cell line 

model for distinct intracellular signaling 

pathways in CD34 + progenitor to dendritic 

cell differentiation. Journal of Immunology 

162:3237, 1999. 

Schlienger, K, Craighead, N, 

Francomano, T, Lee, KP, Levine, BL and 

June, CH. Efficient priming of protein 

antigen-specific human CD4(+) T cells 

by monocyte-derived dendritic cells. 

Blood 96:3490, 2000. 

Tadaki, DK, Kirk, AD, Craighead, 

N, Saini, A, Chute, JP, Lee, KP and 

Harlan, DM. Costimulatory molecules 

are active in the human xenoreactive T 

cell response but not in NK mediated 

cytotoxicity. Transplantation 70:162, 

2000. 


• Direct activation of protein kinase C 

causes normal human hematopoietic 

CD34 + stem cells to differentiate into 

dendritic cells. 

• Protein kinase C activation causes many 

myeloid leukemias to differentiate into 

immunologically functional “leukemic” 

dendritic cells. These cells have 

potential utility as “cellular” anti-leukemia 

vaccines. 

• T cell activation may play a critical role 

in the pathogenesis of opportunistic 

infections. 


Professor of Microbiology 

and Immunology 


Dr. Levy’s laboratory is studying 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 donormediated 

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 

26 


they are “doubly cytotoxic deficient”) 

they remain capable of inducing many 

GVHD symptoms and death in recipients. 

These researchers have recently 

found that highly purified populations 

of CD8 + or CD4 + T cells lacking these 

killing functions also induce lethal 

GVHD post-transplant. 

Researchers in Dr. Levy’s lab also are 

examining 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 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 effect 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 have also 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 are not necessary 

to establish early progenitor presence 

but are required for the establishment of 

long-term chimerism in the recipient. 

PUBLICATIONS 

Jiang, Z, Podack, ER and Levy, RB. 

Donor T cells which cannot mediate 

perforin dependent and FasL-dependent 

cytotoxicity can effect graft versus host 

reactivity following allogeneic bone 

marrow transplantation. Periodicum 

Biologorum 100:477, 1999. 

Ferrara, J, Choi, N and Levy, RB. 

Pathophysiologic mechanisms of acute 

GVHD. Biology of Blood and Bone 

Marrow Transplantation 5:347, 1999. 

Jones, M, Komatsu, M and Levy, 

RB. Cytotoxically impaired transplant 

recipients can efficiently reject major histocompatibility 

complex-matched bonemarrow 

allografts. Biology of Bone 

Marrow Transplant 6:456, 2000. 

Jiang, Z., Podack, E., Levy, RB. 

Major histocompatibility complex-mismatched 


using perforin and/or Fasligand 

double-defective CD4(+) donor 

T cells: involvement of cytotoxic function 

by donor lymphocytes prior to graftversus-host 

disease pathogenesis. Blood 

98:390, 2001. 


• Dr. Levy’s laboratory has discovered 

that 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. 

• They have learned that lymphocytes, 

which 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. 




Dr. Lichtenheld is interested in understanding 

how genes are essential 

for the effector function of lymphocytes 

and how their malignant transformation 

is turned on. The specific research 

focus is on cytotoxic lymphocytes and 

multiple myeloma. His research has 

shown that the activation and differentiation 

of cytotoxic lymphocytes involves 

the Stat signaling pathway activated by 

IL-2 receptor signals. These findings were 

based on the analysis of the induction of 

effector genes expressed exclusively by 

cytotoxic lymphocytes. 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 far-distal enhanceosomes. 

The immediate activation of Stat molecules 

and the slow process of differentiation 

implies that this pathway targets 

the effector genes directly and indirectly 

via the induction of additional genes. 

Such genes may control the differentiation 

process by opening up inaccessible 

chromatin structures of appropriate sets 

of genes, making them transparent for 

Stat proteins. To study the hierarchy of 

genes induced during the differentiation 

process, the laboratory has identified differentially 

expressed genes in a unique 

system in which cytokine receptor signals 

determine differentiation of cytotoxic 

lymphocytes but not their growth 

and survival. Further analysis of these 

genes is under investigation. 

Frequently, growth and survival 

signals from cytokine receptors or a 

dysregulation of their signaling pathways 

are an essential component of hematopoietic 

malignancies. One particular example 

is multiple myeloma, a malignancy 

of B-cells that involves IL-6 

and IL-6 receptor signals. The goal of this 

project is to develop new therapies de- 


fined at the molecular level by interfering 

with upstream components of the IL- 

6 receptor pathway, namely the ras and 

Stat pathways. 

PUBLICATIONS 

Zang ,J, Scordi, I, Smyth, MJ and 

Lichtenheld, MG. Interleukin 2 receptor 

signaling regulates the perforin gene 

through signal transducer and activator 

of transcription Stat5 activation of two 

enhancers. Journal of Experimental 

Medicine 190:1297, 1999. 

Lichtenheld, MG. Control of 

perforin gene expression: A paradigm for 

understanding cytotoxic lymphocytes? 

Cytotoxic Cells: Basic Mechanisms and 

Medical Applications, ed. M.V. Sitkovsky 

and P.A. Henkart. (Philadelphia: 

Lippincott Williams & Wilkins) pp.123- 

145, 1999. 

Malek, TR, Yu, A, Scibelli, P, 

Lichtenheld, MG and Codias, EK. 

Broad programming by IL-2 receptor signaling 

for extended growth to multiple 

cytokines and functional maturation of 

antigen-activated T cells. Journal of Immunology 

166:1675, 2001. 


• Dr. Lichtenheld’s laboratory has identified 

two essential enhancers of the 

perforin gene, demonstrating that they 

are under the control of Stat5 molecules. 

This work, which has shed molecular 

light on fundamental principles 

of effector gene activation in cytotoxic 

lymphocytes, was published in a prestigious 

journal. 





During mammary tumorigenesis, 

a profound dysregulation of cytokine 

production by various lymphoreticular 

cells has been documented. 

B lymphocytes from tumor bearers are 

cytotoxic against tumor targets and have 

an increased production of tumor necrosis 

factor (TNF-α). A greater stability of 

TNFα- RNA and a decreased rate of this 

cytokine RNA degradation was observed 

in tumor bearers’ B cells compared to 

those of normal mice. The TNF-α promoter 

contains regions that bind NF-B, 

which regulate the rate of transcription. 

Supershift assays for the NF-B region 

showed that there are p50-p65 

heterodimers and p50 homodimers in 

the nuclear extracts of the two types of B 

cells, while those from tumor bearers lack 

the c-Rel component that is present in 

normal B cells. These results indicate that 

abnormalities in binding and composition 

of the NF-B complexes may be 

involved in the increased TNF-α production 

by tumor bearers’ B cells. 

Recently, it has been found that lymphocytes 

from tumor-bearing mice have 

elevated levels of interleukin 6 (IL-6) at 

the transcriptional and translational levels, 

that are reflected systemically. The 

mammary tumor used in these studies 

constitutively produces several factors 

including granulocyte-macrophage 

colony stimulating factor (GM-CSF), 

prostaglandin E 2 

(PGE 2 

) and phosphatidyl 

serine (PS), which directly or indirectly 

can affect the cells of the immune 

system. In vitro addition of GM-CSF 

resulted in a dramatic increase in IL-6 

levels from B cells from normal mice. 

This effect does not appear to be due to 

elevated levels of TNF-α, known to 

upregulate IL-6. Rather, GM-CSF activates 

IL-6 production independently of 

TNF-α as demonstrated by neutralization 

studies using anti-TNF-α antibodies. 

Furthermore, the effect exerted by 

GM-CSF on IL-6 production by B lymphocytes 

appears to be direct, since pretreatment 

of cultures with anti-GM-CSF 

completely abrogated the elevated production 

of IL-6. The elevated levels of 

IL-6 and TNF-α in tumor bearers may 

contribute to the cachectic state observed 

in tumor bearing mice. 

Dr. Lopez’s laboratory has previously 

reported that mice implanted with mammary 

tumors show a progressive thymic 

involution which parallels the growth of 

the tumor. The involution is associated 

with a severe depletion of CD4 + 8 + thymocytes. 

In collaboration with Dr. 

Rebecca Adkins, three possible mechanisms 

leading to this thymic atrophy have 

been investigated: 1) increased apoptosis, 

2) decreased proliferation, or 3) disruption 

of normal thymic maturation. The 

levels of thymic apoptosis were determined 

by propidium iodide and Annexin 

V staining. A statistically significant, but 

minor, increase in thymic apoptosis of 

tumor-bearing mice was detected with 

propidium iodide and Annexin V staining. 

The levels of proliferation were assessed 

by in vivo labeling with BudR. The 

percentages of total thymocytes labeled 

one day following BudR injection were 

similar in control and tumor-bearing 

mice. Moreover, the percentages of CD4 - 

8 - thymocytes that incorporated BudR 

during a short-term pulse (five hour) of 

BudR were similar. Lastly, thymic maturation 

was evaluated by examining CD44 

and CD25 expression among CD4 - 8 - 

thymocytes. The percentage of CD44 + 

cells increased while the percentage of 

CD25 + cells decreased among CD4 - 8 - 

thymocytes from tumor-bearing versus 

control animals. Together, these findings 

suggest that the thymic hypocellularity 

seen in mammary tumor bearers is not 

due to a decreased level of proliferation, 

but to an arrest at an early stage of thymic 

differentiation along with a moderate 

increase in apoptosis. 

28 


PUBLICATIONS 

Charyulu, VI and Lopez, DM. Abnormal 

binding pattern and composition 

of the NF- B complex components are 

involved in increased TNF-α production 

by tumor bearers’ B cells. International 

Journal of Molecular Medicine 3:411, 

1999. 

Lopez, DM, Cheng, X and Handel-Fernandez, 

ME. Interferon γ- 

downregulation in mammary tumorbearing 

hosts: Implications for Tumor 

Progression and Immunotherapy. 

Proceedings of the 22nd Congress of the 

International Association for Breast Cancer 

Research (Ioannidou-Mouzaka, L., 

Agnantis, N.J., and Lopez, D.M. eds), 

Monduzzi Editore, Bologna, Italy, pp. 

11-15, 1999. 


Lobo, D and Lopez, DM. Early block 

in maturation is associated with thymic 

involution in mammary tumor-bearing 


2000. 

Charyulu, V and Lopez, DM. Elevated 

GM-CSF levels in tumor-bearing 

mice upregulates IL-6 production by B 

cells via a mechanism independent of 

TNF-α. International Journal of Oncology 

16:161, 2000. 

Lopez, DM. Alterations of macrophage 

functions during mammary 

tumor development. Mechanisms of 

Tumor Escape from Immune Recognition, 

(A. Oliva, ed). Harword Academic 

Publishers GMBH, Switzerland: 103- 

112, 2001. 


• The role of B lymphocytes in tumor 

progression has been thought to act 

mostly as producers of anti-tumor antibodies 

or as antigen presenting cells. 

Their work has demonstrated that in 

tumor bearers, these cells can be effectors 

of cytotoxicity against tumor targets, 

due to their production of TNF-α. 

Supershift assays showed that c-Rel is 

absent from the NF-κB complexes 

binding to the TNF-α promoter region, 

suggesting that although c-Rel has 

been implicated in the activation of 

some genes under specific in vitro conditions, 

it may be functioning as a negative 

regulator under in vivo circumstances. 

• 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 




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 experiments. 

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 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 

(IL)-2, -4, -7, -9, and -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 this 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 the 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 γc-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) They have used 

transgenic and gene knockout mouse 

models to define the molecular basis by 

which IL-7R regulates T cell development. 

These studies indicate that separate 

cytoplasmic domains of the IL-7Rγ 

chain differentially control distinct functions 

during T cell development, while 

normal IL-7R-dependent thymic development 

requires the integrated activity 

of all these domains. 5) They have uncovered 

a novel and unexpected role for 

IL-2 in thymic development, which is 

essential to prevent autoimmunity. 

6) This work illustrates that one important 

reason for failed anti-tumor immunity 

is that tumor-specific T cells are 

ignorant of the growing tumor. Importantly, 

a dendritic cell-based vaccine potently 

functioned to induce tumor 

immunity, which sometimes may lead to 

the rejection of the tumor. 

PUBLICATIONS 

Malek, TR, Porter, BO and He, Y- 

W. Regulation of T lymphocyte development 

by γc dependent cytokines. 


Porter, BO and Malek, TR. Prostaglandin 

E2 inhibits T cell activationinduced 

apoptosis and Fas-mediated 

cellular cytotoxicity by blockade of Fas- 

L. European Journal of Immunology 

29:2360, 1999. 

Maramor, MD, Bachmann, MF, 

Ohashi, PS, Malek, TR and Julius, M. 

Immobilization of GPI-anchored proteins 

inhibits T cell growth but not function. 

International Journal of Immunology 

11:1381, 1999. 

Porter, BO and Malek, TR. IL-2Rβ/ 

IL-7Rα doubly deficient mice recapitulate 

the thymic and intraepithelial lymphocyte 

(IEL) developmental defects of 

γc-/- mice: Roles for both IL-2 and IL- 

15 in CD8 IEL development. Journal of 

Immunology 163:5906, 1999. 

Li, XC, Ima, A, Li, Y, Zheng, XX, 

Malek, TR and Strom, TB. Blocking the 

common gamma-chain of cytokine receptors 

induces T cell apoptosis and longterm 

islet allograft survival. Journal of 

Immunology 164:1193, 2000. 

Malek, TR, Porter, BO, Codias, EK, 

Scibelli, P and Yu, A. Normal lymphoid 

homeostasis and lack of lethal autoimmunity 

in mice containing mature T cells 

with severely impaired IL-2 receptors. 

Journal of Immunology 164:2905, 2000. 

Codias, EK, Olosz, F and Malek, 

TR. Genomic organization and 5’ regulatory 

region of the mouse interleukin 2 

receptor beta-chain gene (IL-2Rb). Immunogenetics 

51:508, 2000. 

Dalyot-Hermans, N, Bathe, O and 

Malek, TR. Reversal of CD8(+) T cell 

ignorance and induction of anti-tumor 

immunity by peptide-pulsed APC. Journal 


Olosz, F and Malek, TR. Three 

loops of the common gamma chain 

ectodomain required for the binding of 

interleukin-2 and interleukin-7. Journal 


2000. 

Porter, BO and Malek, TR. Thymic 

and intestinal intraepithelial T lymphocyte 

development are each regulated by 

the gamma c-dependent cytokines II-2, 

IL-7, and IL-15. Seminars in Immunology 

12:465, 2000. 

Yu, AX, Olosz, F, Choi, CY and 

Malek, TR. Efficient internalization of 

IL-2 depends on the distal portion of the 

cytoplasmic tail of the IL-2R common 

gamma-chain and a lymphoid cell environment. 

Journal of Immunology 

165:2556, 2000. 

Li, XC, Demirci, G, Ferrari-Lacraz, 

S, Groves, C, Coyle A, Malek, TR and 

Strom, TB. IL-15 and IL-2: a matter of 

life and death for T cells in vivo. Nature 

Medicine 7:114, 2001. 

Malek, TR, Yu, AX, Scibelli, P, 

Lichtenheld, MG and Codias, EK. Broad 

programming by IL-2 receptor signaling 



antigen-activated T cells. Journal of Immunology 

166:1675, 2001. 

Porter, BO, Scibelli, P and Malek, 

TR. Control of T cell development in 

vivo by subdomains within the IL-7 receptor 

alpha-chain cytoplasmic tail. Journal 


Yu, AX and Malek, TR. The 

proteasome regulates receptor-mediated 

endocytosis of interleukin-2. Journal of 



Chairman and Professor of 



Perforin is one of the cytotlytic molecules 

critical for tumor rejection 

and viral defense. Creating perforindeficient 

mice with a combined deficiency 

for Fas-ligand (Fas-L) resulted in 

early death of double deficient mice due 

to uncontrolled expansion of cytotoxic 

T cells (CTL) and monocytes/macrophages 

and destruction of the pancreas and 

uterus. The function of perforin in homeostasis 

in the absence of Fas-L is the 

removal antigen presenting cells by activated 

CTL and thereby terminating the 

immune response. 

Negative regulators of CTL activity 

(with H. Muta) 

CTL are potent effectors of the immune 

system. Their uncontrolled activation 

and proliferation leads to severe disease 

and death as described above. Several 

molecules, including Fas-L and other 

death ligands, CTLA4 and TNF, are 

known to be involved in down regulation 

of CTL. They have discovered that 

CD30, a molecule transiently expressed 

on activated CTL can provide powerful 

negative regulation to suppress CTL. 

CD30 signals turn off cytotoxicity by 

suppressing Fas-L, perforin, and 

granzyme B expression. Proliferation of 

CTL is terminated by CD30 through 

30 


suppression of c-Myc. In addition CD30 

signals redirect CTL from tissues to 

lymph nodes by the upregulation of 

CCR7. Apoptosis is modulated by the 

upregulation of anti-apoptotic molecules 

TRAF1 and cIAP2 and the upregulation 

of proapoptotic molecules Fas, DR3 and 

TRAIL. 

Blocking CD30 signals therefore is 

an attractive way to increase the antitumor 

potential of CTL. Human trials 

using anti CD30 antibodies are initiated. 

In addition, mouse models are studied 

using CD30-L-deficient mice created at 

UM/Sylvester in 1999. 

The endoplasmic reticulum resident 

heat shock protein gp96 chaperons 

peptides, including those derived from 

tumor antigens, on their way to presentation 

by MHC class I. Replacement of 

the endoplasmic reticulum retention signal 

of gp96 with the Fc portion of murine 

IgG1 generated a secretory fusion 

protein of gp96, gp96-Ig. Tumor cells 

secreting gp96-Ig exhibited decreased 

tumorigenicity and increased immunogenicity 

in vivo and were rejected after 

initial growth. Rejection required CD8 

T cells during the priming and effector 

phase. CD4 T cells were not required for 

rejection in either phase. Carrageenan, a 

compound known to inactivate macrophages 

in vivo, did not diminish CD8- 

mediated tumor rejection. Therefore, 

immunization with tumors secreting 

gp96-Ig generates efficient tumor-rejecting 

CD8 CTL without requirement for 

CD4 or macrophage help. In contrast, 

immunization with purified, tumor-derived 

gp96 or with irradiated tumor cells 

requires both. Gp96-Ig based vaccines 

will be used in trials for the treatment of 

cervical carcinoma together with Dr. R. 

Mirashemi and Dr. B. Liu. 

Tumor-derived peptides presented 

by MHC class I molecules are targets for 

tumor rejection by CD8+ CTLs. MHCrestricted 

CD8+ CTLs also are required 

for the identification and characterization 

of tumor antigens that will be useful 

for immune therapy. For many 

human solid tumors, however, tumor antigens 

remain undefined because of the 

difficulty of generating MHC-restricted, 

tumor-specific CTLs required for their 

analysis. CD8+ CTL responses are 

modulated by CD4+ helper T cells and 

by antigen-presenting cells. In this study, 

highly purified CD8+ T cells were mixed 

with tumor cells in primary cultures in 

the absence of any other cells to reduce 

the complexity of CTL generation. Tumor 

cells were transfected with HLA-A1 

or HLA-A2 and used to stimulate partly 

matched HLA-A1- or HLA-A2-positive 

CD8+ T cells. Partial MHC class I 

matching of tumor and CD8+ T cells 

and omission of other cells in primary 

culture was highly effective in generating 

MHC class I-restricted CTL to 

poorly immunogenic small-cell lung 

carcinomas (SCLCs). Cytotoxicity was 

further enhanced by cotransfection of 

tumor cells with B7.1 (CD80). ICAM- 

1 (CD54) was not as effective as 

costimulation. SCLC cells presented 

tumor-specific peptides with HLA-A1 

and HLA-A2 and were lysed by A1- or 

A2-restricted CD8+ CTLs. A1- and A2- 

restricted CD8+ CTLs detected shared 

tumor antigens on unrelated SCLC tumor 

lines in addition to private antigens. 

The use of direct antigen presentation 

by MHC class I-transfected tumors to 

MHC class I-matched CD8+ T cells is 

an effective way to generate MHC class 

I-restricted CTLs toward poorly immunogenic 

tumors in vitro, permitting the 

molecular identification of their tumor 

antigens. 

A clinical trial for the treatment of 

lung adenocarcinoma is currently being 

conducted on the basis of these studies 

together with Dr. K. Sridhar † , Dr. N. 

Savaraj, and Dr. P. Cassileth. 

PUBLICATIONS 

Podack, ER. How to induce involuntary 

suicide: The need for dipeptidyl 

peptidase I. Proceedings National Academy 

of Science USA 96:8312, 1999. 

Strbo, N, Laskarin, G, Sotosek, V, 

Randic, LJ, Podack, ER and Rukavina, 

D. Modulation of perforin expression in 

the decidual and peripheral blood cytotoxic 

lymphocytes in culture. American 

Journal of Reproductive Biology 42:1, 1999. 

Lee, RK, Cai, JP, Deyev, V, Gill, PS, 

Cabral, L, Wood, C, Agarwal, RP, Xia, 

W, Boise, LH, Podack, ER and 

Harrington Jr, WJ. Azidothymidine and 

interferon-alpha induce apoptosis in herpes 

virus-associated lymphomas. Cancer 

Research 21:5514, 1999. 

Laskarin, G, Strbo, N, Sotosek, V, 

Rukavina, D, Faust, V, Szekeres-Bartho, 

J and Podack, ER. Progesterone directly 

and indirectly affects perforin expression 

in cytolytic cells. American Journal of 

Reproductive Immunology 5:312, 1999. 

Yamazaki, K, Spruill, G, Rhoderick, 

J, Spielman, J, Savaraj, N, and Podack, 

ER. Small-cell lung carcinomas express 

shared and private tumor antigens presented 

by HLA-A1 or HLA-A2. Cancer 

Research 18:4642, 1999. 

Chiarle, R, Podda, A, Prolla, G, 

Podack, ER, Thorbecke, GJ and 

Inghirami, G. CD30 overexpression enhances 

negative selection in the thymus 

and mediates programmed cell death via 

a Bcl-2-sensitive pathway. Journal of 


Yamazaki, K, Nguyen, T and 

Podack, ER. Cutting edge: tumor secreted 

heat shock-fusion protein elicits 

CD8 cells for rejection. Journal of Immunology 

10:5178, 1999. 

Schoell, WM, Mirhashemi, R, Liu, 

B, Janicek, MF, Podack, ER, Peñalver, 

MA and Averette, HE. Generation of 

tumor-specific cytotoxic T lymphocytes 

by stimulation with HPV type 16 E7 

peptide-pulsed dendritic cells: an approach 

to immunotherapy of cervical cancer. 

Gynecology Oncology 3:448, 1999. 

† 

deceased 





cytotoxicity can effect graft versus host 

reactivity following allogeneic bone 

marrow transplantation. Periodicum 

Biologorum 100:477, 1999. 

Petito, CK, Kerza-Kwiatecki, AP, 

Gendelman, HE, McCarthy, M, Nath, 

A, Podack, ER, Shapshak, P and Wiley, 

CA. Neuronal injury in HIV infection. 

Journal of Neurovirology 5:327, 1999. 

Prpic, L, Strbo, N, Sotosek, V, 

Gruber, F, Podack, ER and Rukavina, D. 

Assessment of perforin expression in peripheral 

blood lymphocytes in psoriatic 

patients during exacerbation of disease. 

Acta Dermato-Venereologica. Supplementum 

211:14, 2000. 

Muta, H, Boise, LH, Fang, L and 

Podack, ER. CD30 signals integrate expression 

of cytotoxic effector molecules, 

lymphocyte trafficking signals, and signals 

for proliferation and apoptosis. Journal 


Rukavina, D and Podack, ER. 

Abundant perforin expression at the 

maternal-fetal interface: guarding the 

semiallogeneic transplant. Immunology 

Today 21:160, 2000. 

Jiang, Z, Podack, ER, Levy, RB. 



using perforin and/or Fasligand 

double-defective CD4(+) donor 

T cells: involvement of cytotoxic function 



98:390, 2001. 

Ohshima, K, Kawasaki, C, Muta, H, 

Muta, K, Deyev, V, Haraoka, S, 

Suzumiya, J, Podack, ER and Kikuchi, 

M. CD10 and Bcl10 expression in diffuse 

large B-cell lymphoma: CD10 is a 

marker of improved prognosis. Histopathology 

39:156, 2001. 

Ohshima, K, Muta, H, Kawasaki, C, 

Muta, K, Deyev, V, Kanda, M, Kumano, 

Y, Podack, ER and Kikuchi, M. Bcl10 

expression, rearrangement and mutation 

in MALT lymphoma: Correlation with 

expression of nuclear factor-kappa B. 

International Journal of Oncology 

19:283, 2001. 






Cell Probes 15:169, 2001. 


• Heatshock fusion vaccines generate 

CD8 CTL without CD4 help: progress 

towards novel and efficient tumor specific 

vaccines. 

• CD30 is identified as a major negative 

regulator of cytotoxic lymphocytes: 

blocking CD30 signals in vivo will dramatically 

enhance anti-tumor immune 

responses. 

• Generation of the first murine gene 

knock in Florida: CD30-Ligand 

knock-out in mice will serve as a valuable 

model for tumor and autoimmunity 

studies. 

• Innovative vaccine trial for lung adenocarcinoma 

approved by FDA. 

• A role for perforin in lymphocyte homeostasis 

revealed: cytotoxicity by 

perforin is necessary to remove antigen 

presenting cells and turn off T cell 

activation. 





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 in the bone marrow. 

Dr. Riley’s laboratory has shown that 

the molecules, λ5 and VrpeB, which 

comprise the surrogate light chain component 

of the pre-B cell receptor, are reduced 

in pro-B/early pre-B cells both ex 

vivo and when derived in vitro from the 

bone marrow of 18-27-month-old 

BALB/c mice after stimulation with IL- 

7. Both λ5 and VpreB expression were 

decreased at the mRNA level as indicated 

by semi-quantitative RT-PCR; this suggests 

that the reduced surrogate light 

chains seen in senescent B cell precursors 

result from dysfunctional transcriptional 

regulation. The transcription of 

surrogate light chains is principally regulated 

by E2A (E47) and Early B cell Factor 

(EBF) gene products. EBF mRNA 

levels were estimated to be only slightly 

reduced in cultured senescent pro-B/ 

early pre-B cells (


• The 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 (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. 


Division Chief and Professor 

of Medicine 


Dr. Rosenblatt’s research currently is 

focused 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 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 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 antitumor 

immune response, particularly 

when combined with CD40L-induced 

costimulation. 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 EG-7 murine lymphoma expressing 

the target ovalbumin antigen, for effects 

on tumor-induced tolerance and the development 

of systemic immunity. 

In a separate effort, the utility of 

Herpes Simplex virus 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 TNF ligand family member 

LIGHT have been targeted to fresh CLL 

cells using the helper free HSV 

amplicons, and 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 seen with HSV 

helper virus containing preparations. 

Further preclinical development of the 

helper free HSV amplicon vector has 

been applied for under auspices of the 

NCI RAID mechanism. 

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 costimulatory 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 lignads have been synthesized 

and in vitro ability to bind to cognate 

antigenic targets and to deliver a 

local costimulatory signal documented. 

Currently, this 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. 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 further evaluated. 

The laboratory has also collaborated 

with the laboratory of Dr. Vicente 

Planelles at the University of Rochester 

on 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. Mechanisms of inhibition 

by mutant tRNA LYS3 , as well as 

by defective HIV-1 lentiviral vectors, are 

being further investigated for potential 

utility as a gene therapy approach. 

PUBLICATIONS 

Mahmood, K, Federoff, HJ, 

Challita-Eid, PM, Day B, Haltman, M, 

Atkinson, M, Planelles, V, and 

Rosenblatt, JD. Eradication of pre-established 

lymphoma using HSV amplicon 

vectors. Blood 93:643,1999. 

Amado, RG, Mitsuyasu, RT, 

Symonds, G, Rosenblatt, JD, Zack, J, 

Sun, LQ, Miller, M, Ely, J. Gerlach, W. 

A Phase I trial of autologous CD34+ 

hematopoietic progenitor cells transduced 

with an anti-HIV ribozyme. Human 

Gene Therapy 1;10 (13):2255, 

1999. 


Shostak, LD, Ludlow, J, Fisk, J, 

Pursell, S, Rimel, BJ, Nguyen, D, 

Rosenblatt, JD, Planelles V. Roles of p53 

and caspases in the induction of cell cycle 

arrest and apoptosis by HIV-1-vpr. Experimental 

Cell Research 251:156,1999. 

Penichet Manuel, L, Challita-Eid, 

PM, Shin, Seung-Uon, Sampogna, SL, 

Rosenblatt, JD, Morrison, SL. In vivo 

properties of three human HER2/neu 

expressing murine cell lines in immunocompetent 

mice. Laboratory Animals 

Science 73:2831, 1999. 

Klimatcheva, E, Rosenblatt, JD, 

Planelles, V. Lentiviral vectors and gene 

therapy. Frontiers in Bioscience 4:D481, 

1999. 

Mahmood, K, Tolba, K, Federoff, 

HJ, Rosenblatt, JD. The role of HSV 

amplicon vectors in cancer gene therapy. 

Gene Therapy and Molecular Biology, 

Boulikas T (ed), 4:209, 1999. 

Rimel, BJ, Rosenblatt, JD, 

Planelles, V. HTLV-II. Encyclopedia of 

Virology, Second Edition, Granoff, A, 

Webster, RG (eds), Academic Press, San 

Diego, CA, 1999. 

Ifthikharuddin, JJ, Mieles, LA, 

Rosenblatt, JD, Ryan, CK, Sahasrabudhe, 

DM. CD-20 expression in 

post-transplant lymphoproliferative disorders: 

Treatment with Rituximab. 

American Journal of Hematology 

65:171, 2000. 

Ifthikharuddin, JJ, Rosenblatt, JD. 

Type C oncoviruses-Human T-cell 

lymphotropic virus Types I and II. 

Principles and Practice of Infectious Diseases, 

5 th Edition, Volume 2. Eds: 

Mandell GL, Bennett, JE and Dolin, WB 

Saunders Co., Philadelphia, PA, 2000. 

Coliccio F, Griggs, J, Rosenblatt, 

JD. Basic concepts in drug development 

clinical trials. Clinical Oncology, Eighth 

Edition, Ed: Phillip Rubin. WB Saunders 

Co, Philadelphia 160, 2001. 

Rubin, Williams, Okunieff, Rosenblatt 

JD, Sitzmann. Statement of the 

clinical oncologic problem. Clinical 

Oncology, Eighth Edition, Ed: Phillip 

Rubin. WB Saunders Co, Philadelphia 

1, 2001. 

Tolba, K, Federoff, HJ, Rosenblatt, 

JD. Gene therapy for cancer. Clinical 

Oncology, Eighth Edition, Ed: Philip 

Rubin. WB Saunders Co, Philadelphia 

168, 2001. 

Maurer, C, Harrington, WJ, Gill, P, 

Kampe, CE, Rosenblatt, JD. Adult T- 

cell leukemia/lymphoma. Cancer Treatment, 

5 th Edition, Chapter 96, Ed: 

Haskell CM, WB Saunders Co, Philadelphia 

1474, 2001. 

Khorana, A, Rosenblatt, JD, Young, 

F. Immunopathogenesis of HIV and 

HTLV-1 infection: Mechanisms for 

Lymphomagenesis. Cancer Treatment 

and Research Series; HIV-Associated 

Malignancies. Ed: Joseph A. Sparano, 

M.D., Kluwer Academic Publishers, 

Norwell, MA, Chapter 2:19, 2001. 

Chen, Y, Pandya, K, Keng, PP, Feins, 

R, Raubertas, R, Smudzin, T, Rosenblatt 

JD, Okunieff P. Schedule-dependent 

pulsed Paclitaxel radiosensitization for 

thoracic malignancy. American Journal 

of Clinical Oncology 24(5): 432, 2001. 

Belly, RT, Rosenblatt, JD, 

Steinmann, M, Toner, J, Sun, J, Shehadi, 

J, Peacock, J, Raubertas, RF, Jani, N, 

Ryan, CK. Detection of mutated K-12 

ras in historically negative lymph nodes 

as an indicator of poor prognosis in stage 

II colorectal cancer. Clinical Colorectal 

Cancer 1:110, 2001. 

Renda, MJ, Rosenblatt, JD, 

Klimatcheva, E, Demeter, L, Bambara, 

R, Planelles, V. Mutation of the methylated 

tRNA Lys3 residue A58 disrupts reverse 

transcription and inhibitors 

replication of the Human Immunodeficiency 

Virus, Type 1. Journal of Virology 

75, 20:9671, 2001. 

Klimatcheva, E, Planelles, V, Day, 

S, Fulreader, F, Renda, MJ, Rosenblatt, 

JD. Defective lentiviral vectors are efficiently 

trafficked by HIV-1 and Inhibit 

its replication. Molecular Therapy 3:928, 

2001. 

Peniche, ML, De la Cruz, JS, 

Challita-Eid, PM, Rosenblatt, JD and 

Morrison, SL. A murine B cell lymphoma 

expressing human HER2/neu 

undergoes spontaneous tumor regression 

and elicits anti-tumor immunity. Cancer 

Immunology Immunotherapy 

49:649, 2001. 

Tolba, K.A., Bowers, Wm. J., 

Hilchey, S.P., Halterman, M.W., 

Howard, D.F., Giuliano, R.E., Federoff, 

H.J., Rosenblatt, JD. Development of 

HSV-1 Amplicon-based immunotherapy 

for Chronic Lymphocytic Leukemia. 

Blood 98:287, 2001. 

Karp, J, Lancet, J., Kaufman, S., 

End, D., Wright, J.J., Horak, I., Tidwell, 

M., Liesveld, J., Ange, D., Buddharaju, 

L., Gojo, I., Highsmith, W.E., Rybak, 

M.E., Rosenblatt, JD. Phase I Clinical 

trial of R115777 in adults with Acute 

Leukemia. Blood 97:3361, 2001. 


• Development of novel antibodychemokine 

and antibody-costimulatory 

ligand fusion proteins with dual 

function and preserved targeting capabilities. 

• Development of a novel strategy for 

gene therapy of HIV-1 using mutations 

introduced into tRNA LYS3 primers. 

• Demonstration of the potential role for 

HSV amplicon vectors in gene therapy 

of malignancy, particularly CLL. 

• Demonstration of trafficking and inhibition 

by defective HIV-1 as a novel 

approach to HIV-1 gene therapy. 

34 


Giovana R. Thomas, M.D. 




The primary goal of Dr. Thomas’ research 

is to develop immunologic 

approaches to treat head and neck squamous 

cell carcinoma in order to spare the 

functions of vital organs such as swallowing, 

speech, taste, and smell, and to 

prolong life of patients with these cancers. 

In the laboratory, efforts focus on 

mechanisms by which lack of expression 

of co-stimulatory molecules and expression 

of certain pro-inflammatory 

cytokines promote tumor growth during 

early tumor formation. Dr. Thomas also 

is collaborating with other investigators 

to determine immunologic mechanisms 

that may act synergistically with expression 

of co-stimulatory molecules in effecting 

greater regression of early 

squamous cell carcinoma. 

PUBLICATIONS 

Thomas, GR, Chen, Z, Loukinova, 

E, Oechsli, MN, Hendler, FJ, Van Waes, 

C. Decreased Expression of CD80 is a 

marker for increased tumorigenicity in a 

new murine model of oral squamous-cell 

carcinoma. International Journal of Cancer 

82:377, 1999. 

Luke, M, Darling, T, Hsu, R, Summers, 

R, Smith, J, Solomon, B, Thomas, 

GR, Yancy, K. “Mucosal morbidity in 

patients with Epidermolysis Bullosa 

Acquisita.” Archives of Dermatology; 

135:954, 1999. 

Moore, CE, Wiatrak, BJ, Mc- 

Clatchey, KD, Koopmann, CF, Thomas, 

GR, Bradford, CR, Carey, TE. High-risk 

human papillomavirus types and squamous 

cell carcinoma in patients with respiratory 

papillomas. Otolaryngology - 

Head and Neck Surgery 120(5):698, 

1999. 

Chen, Z, Malhotra, P, Thomas, GR, 

Ondrey, F, Duffey, D, Smith, C, 

Enamorado, I, Yeh, N, Kroog, G, Rudy, 

S, McCullagh, L, Mousa, S, Quezado, 

M, Herscher, L, Van Waes, C. Expression 

of pro-inflammatory cytokines in 

patients with Head and Neck Cancer.” 

Clinical Cancer Research 5:1369, 1999. 

Thomas, GR, Chen, Z, Enamorado, 

I, Bancroft, C, Van Waes, C. IL- 

12 and IL-2 induced tumor regression 

in a new murine model of oral squamous 

carcinoma is modulated by expression of 

CD80 co-stimulatory molecule and Interferon 

gamma. International Journal of 


Van Waes, C, Chen, Z, Callister, M, 

Colon, I, Ortiz, N, Smith, C, Thomas, 

GR, Dong, G. Cytokines in the pathogenesis 

and therapy of head and neck 

cancer. New Frontiers in Immunobiology, 

Edited by Veldman, Passali, and 

Lim. Kugler Publications, pp. 233, 2000. 

Takeda, N, Thomas, GR, Ludlow, 

CL. Aging effects on motor units in the 

human thyroarytenoid muscle. Laryngoscope 

110(6):1018, 2000. 

Loukinova, E, Dong, G, Enamorado, 

I, Thomas, GR, Chen, Z, Schreiber, 

H, Van Waes, C. Growth-regulated 

oncogene-alpha expression by murine 

squamous cell carcinoma promotes tumor 

growth, metastasis, leukocyte infiltration 

and angiogenesis by a host CXC 

receptor-2 dependent mechanism. 

Oncogene 19:3477, 2000. 

Bidus, KA, Thomas, GR, Ludlow, 

CL. Effects of adductor muscle stimulation 

on speech in abductor spasmodic 

dysphonia. Laryngoscope 110: 1943, 

2000. 

Sunwoo, JB. Herscher, LL. Kroog, 

GS. Thomas, GR. Ondrey FG. Duffey 

DC. Solomon BI. Boss C. Albert PS. 

McCullugh L. Rudy S. Muir C. Zhai S. 

Figg WD. Cook JA. Mitchell JB. Van 

Waes C. Concurrent paclitaxel and radiation 

in the treatment of locally advanced 

head and neck cancer. Journal of 

Clinical Oncology. 19(3):800, 2001. 

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




One of the most important goals of 

cancer research is to identify environmental 

and host factors that contribute 

to the malignant state. Human skin 

cancers are among the few human tumor 

types for which the predominant environmental 

carcinogen is known. Ultraviolet 

(UVB) light, a component of sunlight, 

is an important cause of skin cancer 

in humans. The specter of ozone 

depletion caused by environmental pollutants 

is upon us, raising the possibility 

that increasing amounts of UVB radiation 

will reach the surface of the earth. 

Under these circumstances, the potential 

exists in the near and distant future 

for higher frequencies of skin cancer 

as well as other UVB-related diseases. In 

humans and mice, the UVB radiation 

induces systematic and local immunosuppression. 

A consequence of that is 

inappropriate immune surveillance of 

somatic tissues for evidence of malignantly 

transformed cells. Even before the 

tumor develops in UVB-irradiated skin, 

the immunological system is impaired. 

The impairment of contact hypersensitivity, 

as it develops early and correlates 

well with the tumor frequency in various 

mouse strains, is used for more than 

15 years as a model of immunological 

events occurring in photocarcinogenesis. 

In mice, as well as humans, the UVB radiation-induced 

impairment of contact 

hypersensitivity is not uniform in all 

individuals; some individuals are susceptible 

to the deleterious effects of UVB 

(UVB-susceptible - UVB-S) whereas others 

are resistant to UVB (UVB-resistant 

- UVB-R). Preliminary experiments in 

this laboratory have shown that one of 

the genes (named UVB-1) determining 

UVB phenotypes is mapping within a 

180 kb long region on mouse chromosome 

17. The researchers in Dr. Vincek’s 

laboratory have physically isolated the 

complete region and identified a new 


gene within that region, named I6BL, a 

strong candidate for the UVB-1 gene. 

The goal of our research is to investigate 

whether the I6BL gene that was found is 

really the UVB-1 gene. If this is found 

to be true, the human homolog gene will 

be found and analyzed to determine its 

role in UVB induced immunosuppression 

and immunosurveillance. In case 

these experiments exclude the I6BL gene 

as the UVB-1 gene, they will search the 

UVB-1 region extensively for the presence 

of the UVB-1 gene and further analyze 

it once they find it. 

Once the UVB-1 gene has been isolated, 

researchers will be in the position 

to combine the current evidence regarding 

environmental carcinogens with our 

knowledge of genetic susceptibility factors 

so that they might improve the understanding 

of the pathogenesis of skin 

cancer and begin developing an approach 

for the early diagnosis and prevention of 

this disease. 

PUBLICATIONS 

Scordi, IA, Nassiri, M, Hanly, A and 

Vincek, V. Interleukin 11 (IL-11) reduces 

apoptosis in UVB irradiated mouse skin. 

Dermatology 199:296, 1999. 

Handel-Fernandez, ME, Kurimoto, 

I, Streilein, JW and Vincek, V. Genetic 

mapping and physical cloning of UVBsusceptibility 

region in mice. Journal of 

Investigative Dermatology 113:224, 

1999. 

Handel-Fernandez, ME and Vincek, 

V. Sequence analysis and expression of a 

mouse homologue of human I kappa BL 

gene. Biochimica et Biophysica Acta 

1444:306, 1999. 

Handel-Fernandez, ME and Vincek, 

V. Early cancer detection by microsatellite 

marker analysis. Medical Hypothesis 

53:114, 1999. 

Scordi, TA and Vincek, V. Timecourse 

study of UVB-induced cytokine 

induction in whole mouse skin. 

Photodermatology Photoimmunology 

Photomedicine 16:67, 2000. 

Walsh, PJ, Heitz, MJ, Campbell, 

CE, Cooper, GJ, Medina, M, Wang, YS, 

Goss, GG, Vincek, V, Wood CM and 

Smith CP. Molecular characterization of 

a urea transporter in the gill of the gulf 

toadfish. Journal of Experimental Biology 

203:2357, 2000. 

Handel-Fernandez, ME, Nassiri, M, 

Arana, M, Perez, MM, Fresno, M, Nadji, 

M and Vincek, V. Mapping of geneticdeletions 

on the long arm of chromosome 

22 in human pancreatic adenocarcinomas. 

Anticancer Research 20: 

4451, 2000. 

36 


VIRAL ONCOLOGY PROGRAM 



Professor of Medicine 

CO-PROGRAM LEADER 




The Viral Oncology Program is comprised 

of 11 faculty members from 

four different departments at the University 

of Miami School of Medicine and 

one member from the University of Nebraska. 

The program’s principal objective 

is to promote clinical and basic investigation 

of the pathogenesis of oncogenic 

viruses, AIDS-related malignancies, human 

T-cell leukemia viruses and herpes 

virus-associated cancers, and to develop 

and implement innovative therapies for 

treatment of these aggressive tumors. The 

investigators were recruited on the basis 

of productive track records in their respective 

disciplines and a commitment 

to innovative and complimentary 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, 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 through an NCI-sponsored 

training grant in viral oncology. 

Bench research conducted by members 

of the Viral Oncology Program has 

translated into novel clinical trials. A forum 

for such experimental trials exists 

through the NIH-sponsored AIDS Malignancy 

Consortium (AMC), and our 

center is a fully funded member. National 

trials for AIDS-related Central Nervous 

System Lymphoma (AMC 019) and 

Adult T-cell Lymphoma (AMC 033) 

originated at our institution. What’s 

more, the program is developing new 

approaches to cancer therapy utilizing 

oncolytic viruses as immunotherapeutic 

agents. The group also is investigating 

lymphomagenesis with a focus on 

cytokine dependence (IL-6) and pro- and 

anti-apoptotic gene expression. 

There is a concerted effort to extend 

the study of viral oncogenesis to developing 

nations such as Zambia and Brazil. 

These efforts are funded through 

Fogarty grants and the NCI. 

The University of Miami Sylvester 

Comprehensive Cancer Center is the 

ideal site for the study of viral oncology 

because of its diverse patient base and 

the large numbers of cases of HIV 

gamma herpesvirus and Human T 

Lymphotropic Virus Type I (HTLV-I) 

associated tumors. 


1) Investigate the regulation of programmed 

cell death, cytokine dependence, 

and viral and cellular gene 

expression in cancers occurring in 

immunocompromised patients. 

2) Devise novel therapeutic strategies for 

therapy of viral lymphoproliferative 

diseases and other cancers. 

3) Train physician scientists 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 

Agarwal, Ram P., Ph.D. 

Medicine 

Barber, Glen N., Ph.D. 


Boehmer, Paul E., Ph.D. 


Boise, Lawrence H., Ph.D. 


Downey, Kathleen M., Ph.D. 

Medicine 

Fischl, Margaret A., M.D 

Medicine 

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

Medicine 

Mian, Abdul M., Ph.D. 

Medicine 

Scott, Gwendolyn B., M.D. 

Pediatrics 

Scott, Walter A., Ph.D. 


So, Antero G., M.D., Ph.D. 

Medicine 

HIGHLIGHTS 

• The Viral Oncology Program has made 

good progress on several fronts, specifically 

in the identification of new targets 

for development of new therapies, 

the development of new therapeutic approaches, 

and the elucidation of molecular 

mechanism of combinational 

therapy in the treatment of cancer. 

• Dr. Barber and his colleagues study the 

mechanisms of host defense against viral 

and malignant disease. A key focus 

of Dr. Barber’s research is elucidating 

the mechanisms of interferons including 

their role in regulating apoptosis. 

His research team recently has 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 PKR/ 

interferon pathway being defective in 

susceptible cells. The research now has 

demonstrated in vivo that tumors defective 

in p53 function or transformed 

with myc or activated ras are also 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. 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. 

• Dr. Harrington focuses on the use of 

antiviral agents in viral-induced malignancies. 

He has found that antiviral 

thymidine analogues such as azidothymidine 

(AZT) induce marked apoptosis 

in Epstein Barr Virus (EBV) 

associated lymphomas. This therapy 

was very effective in eradicating AIDSrelated 

brain lymphoma and now is 

being tested in a nationwide clinical 

trial. More recently, Dr. Harrington 

found that AZT and Interferon alpha 

(IFNα) induce apoptosis in human 

herpes virus-8 (HHV-8) lymphoma 

lines. Interestingly, these agents have no 

effect on viral-negative lymphomas. 

The data demonstrates that IFNα potentially 

induces the death receptor 

ligand TRAIL. AZT acts by blocking 

NF-κB (p50, p65) translocation into 

the nucleus allowing for an unopposed 

death signal. A similar mechanism has 

been shown to occur in other viral-induced 

tumors such as adult T-cell leukemia 

(HTLV-I) and post-transplant 

lymphoma (EBV). Dr. Harrington’s 

team has initiated a new clinical trial 

for HHV-8 associated lymphomas that 

utilizes parenteral AZT and IFNα 

(these tumors are virtually always fatal). 

The only patient enrolled is in 

complete remission. Current studies are 

focused 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 

imuno-compromised patients (post 

transplant, hereditary immunodeficiencies). 

This work is done in collaboration 

with Dr. Mian and Dr. Agarwal. 

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. 

• Dr. Downey and Dr. So have recently 

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. Increasing 

evidence suggests that the 

cytokine IL-6 plays an important role 

in the pathogenesis of certain types of 

AIDS-related lymphomas. Recent 

studies have strongly 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 noncleaved 

cell lymphoma is preceded by 

elevated serum levels of IL-6. In addition, 

cell lines derived from HHV-8 associated 

AIDS Primary Effusion 

Lymphomas (PEL) constitutively secret 

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 

KSHV-infected primary effusion lymphoma 

cells. 

• Dr. Boise’s laboratory investigates 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 antiapoptotic 

proteins Bcl-2 or Bcl-x L 

are 

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 effect type 

I death receptor signaling when used 

in concert with inhibitors of signaling 

caspases. Interestingly, γ-herpes viruses 

associated with Kaposi’s sarcoma and 

primary effusion lymphomas (PEL) 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 our results we hypothesize 

that vBcl-2 and vFlip may work 

in concert to block complex death receptor 

signaling. This hypothesis is 

currently being tested through the introduction 

of these genes into TNFα- 

38 


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 a collaboration 

with Dr. Harrington on his 

studies to determine the mechanisms 

of antiviral induced apoptosis in AIDSrelated 

lymphomas that appear to be 

death receptor-mediated. 

Ram P. Agarwal, Ph.D. 

Associate Professor of Medicine 


Dr. Agarwal’s research is focused on 

the experimental therapeutics of 

anti-cancer and anti-AIDS drugs. Studies 

entail biochemical and molecular 

mechanisms of action, resistance, and 

toxicity of existing chemotherapeutic 

agents and development of new drugs 

and strategies. His research team also is 

involved in developing new and sensitive 

methods of monitoring drug concentrations 

and their metabolites in 

biological fluids and clinical samples to 

assess their pharmacokinetics and new 

ways of drug delivery. Information 

gained through these studies is used to 

reduce toxicity, circumvent resistance, 

and develop strategies to use these drugs 

and drug combinations to enhance their 

therapeutic efficacies. Currently, Dr. 

Agarwal’s studies are geared to understand 

host cell responses that determine 

the efficacy of anti-AIDS therapies of 

dideoxynucleosides. 

PUBLICATIONS 

Lee, RK, Cai, J-P, Deyev, V, Gil, PS, 


W, Boise, LH, Podack, E, and 

Harrington, Jr. WJ. Azidothymidine and 

interferon induced apoptosis in Herpes 

virus-associated lymphomas. Cancer Research 

59:5514, 1999. 

Agarwal, RP, Han, T and Fernandez, 

M. Collateral resistance of a dideoxycytidine-resistant 

cell line to fluoro- 

2’-de3oxyuridine. Biochemistry Biophysical 

Research Communication 

262:657, 1999. 

Agarwal, RP, Wang ,W, Yo, P, Han, 

T and Fernandez, M. Cross resistance of 

dideoxycytidine-resistant cell lines to 

azidothymidine. Biochemical Pharmacology 

58:1603, 1999. 


• Induced dideoxycytidine and arabinosylcytosine 

resistance in lymphocytic 

cell lines and showed that these analogs 

induced resistance by different 

mechanisms. If this also occurs in a 

clinic setting, these findings will have 

important implications in chemotherapy 

of these drugs. 

Glen N. Barber, Ph.D. 




Dr. Barber’s research interests focus 

on understanding the mechanisms 

of host defense against viral infection and 

malignant disease. Part of his research involves 

studying cytokines referred to as 

interferons, which are considered to play 

an important role in effectively preventing 

virus replication, and in mediating 

the activation and recruitment of potent 

immune responses that can help fight 

cancer. This research embraces the study 

of viruses recognized as contributing toward 

cancer, such as hepatitis C virus (liver 

cancer), human papilloma virus (cervical 

cancer), Epstein-Barr virus (lymphomas), 

and Human herpes virus-8 (sarcoma). 

Such viruses are known to inhibit mechanisms 

of host defense such as apoptosis 

and interferon-mediated antiviral activity. 

By understanding these cellular mechanisms, 

current therapies against viral and 

malignant disease may be improved as 

well as new therapeutic targets identified. 

PUBLICATIONS 

Taylor, D, Shi, ST, Romano, P, Barber, 

GN and Lai, M. Inhibition of the 

interferon-inducible protein kinase, 

PKR, by Hepatitis C virus E2 protein. 

Science 285:107, 1999. 

Balachandran, S, Roberts, PC, 

Kipperman, T, Bhalla, KN, Compans, 

RW, Archer, DR and Barber, GN. Alpha/Beta 

interferons potentiate virus-induced 

apoptosis through activation of the 

FADD/caspase 8 death signaling pathway. 

Journal of Virology 74:1513, 2000. 


Brown, LE, Truong, H, Pattnaik, AK, 

Archer, DR and Barber, GN. Essential 

role for the dsRNA-dependent protein 

kinase, PKR, in innate immunity to viral 

infection. Immunity 13:129, 2000. 

Barber, GN. The interferons and 

cell death: Guardians of the cell or accomplices 

of apoptosis? Seminars in Cancer 

Biology 10:103, 2000. 

Heylbroek, C, DeLuca, C, Lin, R, 

Balachandran, S, Barber, GN and 

Hiscott, J. The IRF-3 transcription factor 

is an essential mediator of virus induced 

apoptosis. Journal of Virology 74: 

3781, 2000. 

Balachandran, S and Barber, GN. 

Vesicular Stomatitis Virus, VSV, therapy 

of tumors. IUBMB Life 50:125, 2000. 

Saunders, LR, Perkins, DJ, 

Balachandran, S, Michaels, R, Ford, R, 

Mayeda, A and Barber, GN. Characterization 

of two evolutionarily conserved, 

alternatively spliced nuclear phosphoproteins, 

NFAR-1 and -2, that function 

in mRNA processing and interact with 

the double-stranded RNA-dependent 

protein kinase, PKR. Journal of Biological 

Chemistry 276:32300, 2001. 

Polyak, SJ, Khabar, KSA, Paschal, 

DM, Ezelle, HJ, Duverlie, G, Barber, 

GN, Levy, DE, Mukaida, N and Gretch, 

DR. Hepatitis C virus nonstructural 5A 

protein induces interleukin-8, leading to 

partial inhibition of the interferon-induced 

antiviral response. Journal of Virology 

75:6095, 2001. 


Ezelle, HJ, Balachandran, S, Sicheri, 

F, Polyak, SJ and Barber, GN. Analyzing 

the mechanisms of interferoninduced 

apoptosis using CrmA and hepatitis 

C virus NS5A. Virology 281:124, 

2001. 

Balachandran, S, Porosnicu, M and 

Barber, GN. Oncolytic activity of vesicular 

stomatitis virus is effective against 

tumors exhibiting aberrant p53, Ras, or 

Myc function and involves the induction 

of apoptosis. Journal of Virology 

75:3474, 2001. 

Barber, GN. Host defense, viruses 

and apoptosis. Cell Death and Differentiation 

8:113, 2001. 

Lin, RT, Genin, P, Mamane, Y, 

Sgarbanti, M, Battistini, A, Harrington, 

WJ, Barber, GN and Hiscott, J. HHV- 

8 encoded vIRF-1 represses the interferon 

antiviral response by blocking 

IRF-3 recruitment of the CBP/p300 

coactivators. Oncogene 20:800, 2001. 

Saunders, LR, Jurecic, V, and Barber, 

GN. The 90-and 110-kDa human 

NFAR proteins are translated from two 

differentially spliced mRNAs encoded on 

chromosome 19p13. Genomics 71:256, 

2001. 

Paul E. Boehmer, Ph.D. 

Associate Professor of Biochemistry 



Enzymology of DNA Replication 

and Recombination: Helicases and 

Accessory Proteins 

Dr. Boehmer’s laboratory is using herpes 

simplex virus type-1 (HSV-1) as a 

model system to study the enzymology 

of DNA replication and recombination 

with particular emphasis on helicases and 

their accessory proteins. Helicases catalyze 

DNA unwinding thereby converting 

inert duplex DNA into template 

information for DNA replication or creating 

single-stranded DNA for strandtransfer 

reactions in homologous recombination. 

HSV-1 is a large double-stranded 

DNA virus that is extremely widespread 

in the human population. HSV-1 causes 

a variety of primary and recurrent infections 

ranging from rather benign cold 

sores to corneal blindness and encephalitis. 

HSV-1 infections are particularly 

severe in immuno-compromised individuals 

such as AIDS patients. 

HSV-1 encodes its own DNA polymerase, 

a multi-faceted single-strand 

DNA-binding protein (SSB), and two 

DNA helicases. The first helicase possesses 

sequence-specific DNA-binding 

activity that targets it to the origins of 

replication to initiate replication. The 

second helicase is a multi-subunit enzyme 

that is responsible for concomitant 

unwinding and priming at the DNA replication 

fork. His team is interested in 

studying the molecular mechanisms by 

which these helicases unwind DNA and 

how they interact with other DNA replication 

factors notably SSB and DNA 

polymerase. In addition, they are interested 

in solving the crystal structures of 

these proteins. 

They are also using HSV-1 to study 

the enzymology of homologous recombination. 

In HSV-1 it is predicted that 

homologous recombination proceeds by 

a single-strand annealing mechanism. 

Consequently, we are interested in studying 

the role of the HSV-1 DNA helicases 

and SSB in promoting stand annealing 

and branch migration reactions. 

Finally, Dr. Boehmer’s team is using 

the HSV-1 DNA replication enzymes to 

study the mechanism of translesion replication. 

Using lesions produced by the 

anticancer drug cisplatin, they hope to 

demonstrate that interactions between 

replication fork enzymes can lead to 

mutagenic bypass of cisplatin lesions and 

thus account for the mutagenic properties 

of this drug. 

These studies will increase our understanding 

of how DNA helicases perform 

essential tasks during DNA 

replication and recombination and may 

also contribute to the development of 

novel anti-viral compounds targeted 

against herpes virus infections. 

PUBLICATIONS 

Bastide, L, Boehmer, PE, Villani, G 

and Lebleu, B. Inhibition of a DNAhelicase 

by peptide nucleic acids. Nucleic 

Acids Research 27:551, 1999. 

Lehman, IR and Boehmer, PE. Replication 

of Herpes Simplex Virus DNA. 

Journal Biological Chemistry 274: 

28059, 1999. 

White, EJ and Boehmer, PE. 

Photoaffinity labeling of the herpes simplex 

virus type-1 single-strand DNAbinding 

protein (ICP8) with oligodeoxyribonucleotides. 

Biochemical Biophysical 

Research Communications 

264:493, 1999. 

Gourves, A-S, Tanguy, Le Gac, N, 

Villani, G, Boehmer, PE and Johnson, 

NP. Equilibrium binding of single 

stranded DNA with HSV-1 coded single 

stranded DNA binding protein. ICP8. 


10864, 2000. 

Sampson, DA, Arana, ME and 

Boehmer, PE. Cysteine 111 affects coupling 

of single-stranded DNA binding 

to ATP hydrolysis in the Herpes simplex 

virus type-1 origin-binding protein. Journal 


2000. 

Arana, ME, Haq, B, Le, Gac, NT 

and Boehmer, PE. Modulation of the 

herpes simplex virus type-1 UL9 DNA 

helicase by its cognate single-strand 

DNA-binding protein, ICP8. Journal of 


40 


Lawrence H. Boise, Ph.D. 

Assistant Professor of Microbiology 



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’s team has found cooperativity between 

overexpression of Bcl-2 family 

members and inhibition of caspases in 

the prevention of TNFa-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. Dr. Boehmer and his 

research team 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. 

A second area of investigation in his 

laboratory is the regulation of bcl-x expression. 

bcl-x L 

, can function in a similar 

fashion as bcl-2, yet displays a different 

pattern of expression. Specifically in lymphocytes 

Bcl-2 is expressed at high levels 

regardless of the activation state of the 

cell while Bcl-x L 

is expressed only upon 

cell activation. In addition, upregulation 

of bcl-x but not bcl-2 occurs in tumor 

cells following irradiation or induction 

of multidrug resistance. To address these 

differences and to determine the mechanism 

of bcl-x regulation, a fragment of 

genomic DNA which extends 9 kb 5’ of 

the start methionine has been isolated. 

These researchers are characterizing the 

promoter to determine the elements required 

for bcl-x expression in response 

to various signals. In addition, the cloned 

fragment contains a GC rich region that 

displays differential methylation in drug 

sensitive and drug resistant cell lines. 

While bcl-x overexpression has not been 

shown to lead to any specific tumors, its 

expression has been demonstrated in several 

types of tumors including breast, 

prostrate, multiple myeloma and the 

Reed-Sternberg cells of Hodgkin’s lymphoma. 

Understanding the mechanisms 

by which bcl-x is controlled may result 

in the development of ways to increase 

the efficacy of cancer chemotherapy 

through decreasing the apoptotic threshold 

of the tumor cell. 

As a product of the studies of bcl-x 

expression in drug resistant tumors, researchers 

in Dr. Boehmer’s laboratory 

became interested in the study of arsenic 

trioxide as a potential therapeutic agent 

in the treatment of multiple myeloma. 

This team is studying the mechanism by 

which this agent can kill chemo refractory 

myeloma cells. These studies have 

led to a new clinical trial initiated at UM/ 

Sylvester that will gather correlary scientific 

information from the patients on 

this trial. 

PUBLICATIONS 

Johnson, BW and Boise, LH. Bcl-2 

and caspase inhibition cooperate to inhibit 

Tumor Necrosis Factor-induced cell 

death in a Bcl-2 cleavage-independent 

fashion. Journal of Biological Chemistry 

274:18552, 1999. 

Wang, S, Wang, Z, Boise, LH and 

Grant, S. Circumvention of Bcl-x L 

-mediated 

inhibition of paclitaxel-induced 

mitochondrial dysfuntion and apoptosis 

by bryostatin 1 in human myelomonocytic 

leukemia cells (U937). Leukemia 

13:1564, 1999. 

Wang, S, Wang, Z, Boise, LH, Dent 

P and Grant S. Loss of the Bcl-2 phosphorylation 

loop domain increases resistance 

of human leukemia cells (U937) 

to Paclitaxel-mediated mitochondrial 

dysfunction and apoptosis. Biochemical 

and Biophysical Research Communications 

259:67, 1999. 



W, Boise, LH, Podack, ER, and 

Harrington, WJ Jr. Azidothymidine 

and interferon induced apoptosis in 

Herpes virus associated lymphomas. 

Cancer Research 59:5514, 1999. 







Grad, JM, Zeng, XR and Boise, LH. 

Regulation of Bcl-x(L): a little bit of this 

and a little bit of STAT. Current Opinion 

in Oncology 12:543, 2000. 

Johnson, BW, Cepero, E and Boise, 

LH. Bcl-x(L) inhibits cytochrome c release 

but not mitochondrial depolarization 

during the activation of multiple 

death pathways by tumor necrosis factor-alpha. 


275:31546, 2000. 

Tang, L, Boise, LH, Dent P and 

Grant S. Potentiation of 1-beta-Darabinofuranosylcytosine-mediated 

mitochondrial 

damage and apoptosis in 

human leukemia cells (U937) overexpressing 

Bcl-2 by the kinase inhibitor 7- 

hydroxystaurosporine (UCN-01). Biochemical 


Grad, JM, Bahlis, NJ, Reis, I, 

Oshiro, MM, Dalton, WS and Boise, 

LH. Ascorbic acid enhances arsenic trioxide-induced 

cytotoxicity in multiple 

myeloma cells. Blood 98:805, 2001. 

Cepero, E, Johnson, BW and Boise, 

LH. Cloning and analysis of Bcl-2 family 

genes. Methods in Cell Biology 66:29, 

2001. 


Jost, M, Huggett, TM, Kari, C, 

Boise, LH and Rodeck, U. Epidermal 

growth factor receptor-dependent control 

of keratinocyte survival and Bcl-x(L) 

expression through a MEK-dependent 

pathway. Journal of Biological Chemistry 

276:6320, 2001. 

Kathleen M. Downey, Ph.D. 





Dr. Downey and Dr. So are interested 

in the molecular mechanism 

by which cell proliferation (DNA replication) 

is regulated during the cell cycle. 

Their approach has been to elucidate the 

mechanism of DNA replication and its 

regulation, and the mechanisms by 

which replication fidelity is maintained 

in mammalian cells. 

The major focus of their studies is 

DNA polymerase δ (pol δ) and its 

processivity factor, the proliferating cell 

nuclear antigen (PCNA). Pol δ was discovered 

in their laboratory in 1976 as a 

new species of mammalian DNA polymerase. 

It was distinct from all other 

mammalian DNA polymerases known at 

the time (α, β, and γ) in one important 

property, i.e., it had an intrinsic 3' to 5' 

exonuclease activity and was therefore 

capable of editing errors made during 

DNA synthesis. This highly faithful enzyme 

is now believed to be the principal 

DNA polymerase required for the replication 

of chromosomal DNA. Pol δ is 

also thought to be involved in post-replication 

mismatch repair and nucleotide 

excision repair. PCNA was first identified 

in their laboratory as a processivity 

factor for DNA polymerase δ in 1986. 

PCNA enables pol δ to synthesize long 

stretches of DNA without dissociating 

from the template, by tethering the polymerase 

to the DNA template/primer. 

PCNA has been suggested to be a coordinator 

of cell cycle progression with 

DNA replication and repair. 

PUBLICATIONS 

Zaika, A, Mozzherin, DJ, Tan, C- 

K, Downey, KM and Fisher, PA. A twodimensional 

support for selective binding 

of polyhistidine-tagged proteins: identification 

of a proliferating cell nuclear 

antigen point mutant with altered function 

in vitro. Annals of Biochemistry 

268:193, 1999. 

Mozzherin, DJ, Tan, C-K, Downey, 

KM and Fisher, PA. Architecture of the 

active DNA polymerase δ-proliferating 

cell nuclear antigen-template-primer 

complex. Journal of Biological Chemistry 

274:19862, 1999. 

Kramata, P and Downey, KM. 9- 

(2-phosphonylmethoxyethyl)derivatives 

of purine nucleotide analogs: a comparison 

of their metabolism and interaction 

with DNA synthesis. Molecular Pharmacology 

56:1262, 1999. 

Meyer, PR, Matsuura, SE, Mian, 

AM, So, AG and Scott, WA. A mechanism 

of AZT-resistance: An increase in 

nucleotide-dependent primer unblocking 

by mutant HIV-1 reverse transcriptase. 

Molecular Cell 4:35, 1999. 

Meyer, PR, Matsuura, SE, Schinazi, 

RF, So, AG and Scott, WA. Differential 

removal of thymidine nucleotide analogues 

from blocked DNA chains by 

human immunodeficiency virus reverse 

transcriptase in the presence of physiological 

concentrations of 2’-deoxynucleoside 

triphosphates. Antimicrobial 

Agents and Chemotherapy 44:3465, 

2000. 




Dr. Harrington’s research efforts center 

on understanding the mechanisms 

of antiviral mediated apoptosis of 

viral mediated malignancies. His team 

found that interferon potently induces 

death receptor ligands in certain unique 

viral mediated lymphomas. This had led 

to a novel therapeutic approach for these 

deadly tumors. EBV related Burkitts and 

primary CNS lymphoma, HHV-8 associated 

primary effusion lymphoma, and 

HTLV-I associated adult T-cell leukemia 

are all refractory to conventional chemotherapy 

yet remarkably sensitive to antiviral 

therapy. Clinical trials have been 

designed and implemented that exploit 

this phenomenon. Dr. Harrington’s 

AIDS related brain lymphoma study now 

is a national trial run through UM/ 

Sylvester’s NCI cooperative group. The 

three principal projects currently underway 

include: 

• To map the apoptotic pathways induced 

in viral associated lymphomas. 

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 pathways in resistant tumors are 

also being studied. 

• Another project focuses on the regulation 

of the antiapoptotic factor, cellular 

inhibitor of apoptosis or c-IAP in 

EBV mediated lymphomas. Their work 

suggests that these may be overcome 

by inhibition of the transcription factor 

NFKB. Agents such as CD-40 

ligand, which has promise in the 

therapy of B cell lymphomas are also 

being studied. 

• Another project assigned to a new fellow 

from his NCI-funded viral oncology 

training program focuses on the 

mechanism of type I interferon-medi- 

42 


ated apoptosis in adult T-cell leukemia 

(ALT). Dr. Harrington’s research lab recently 

demonstrated that IFNα induces 

trial in vivo in ALT patients. This 

directly correlates with tumor regression. 

PUBLICATIONS 

Barbosa, HS, Bittencourt, AL, 

Barreto de Arauji, I, Pereira Filho, CS, 

Furlan, R, Pedrosa, C, Lessa G, 

Harrington, WJ Jr and Galvao, Castro 

B. Adult T-cell leukemia/lymphoma in 

northeastern Brazil: A clinical, histopathologic, 

and molecular study. Journal 

of Acquired Immune Deficiency 

Syndrome and Human Retrovirology 

1:65, 1999. 

Yamashita, M, Veronesi, R, Menna- 

Barreto, M, Harrington, WJ Jr, Sampio, 

C, Brites, C, Badaro, R, Andrade-Filho, 

AS, Okhura, S, Igarashi, T, Takehisa, J, 

Miura, T, Chamone, D, Bianchini, O, 

Jardim, C, Sonoa, S and Hayami, M. 

Molecular epidemiology of human T-cell 

leukemia virus type I (HTLV-1) Brazil: 

The predominant HTLV-1s in South 

America differ from HTLV-1s of Japan 

and Africa, as well as those of Japanese 

immigrants and their relatives in Brazil. 

Virology 261:59, 1999. 

Lee, RKL, Cai, J-P, Deyev, V, Gill, 

P, Cabral, L, Wood, C, Agarwal RP, Xia 

W, Boise LH, Podack, E and Harrington, 

WJ Jr. Azidothymidine and interferon 

alpha induce apoptosis in herpesvirusassociated 

lymphomas. Cancer Research 

59:5514, 1999. 

Raez, L, Cabral, L, Cai, J-P, Landy, 

H, Sfakianakis, G, Byrne, Jr GE, Hurley, 

J, Scerpella, E, Jayaweera, D and 

Harrington, WJ Jr. Treatment of AIDS 

related primary central nervous system 

lymphoma with zidovudine, ganciclovir, 

and interleukin-2. AIDS Research and 

Human Retroviruses 15:713, 1999. 

Ratner, L, Lee, J, Tang, SH, Redden, 

D, Hamzeh, F, Herndier, B, 

Scadden, D, Kaplan, L, Ambinder, R, 

Levine, A, Harrington, WJ Jr, Grochow, 

L, Flexner, C, Tan, B and Straus D. Chemotherapy 

for human immunodeficiency 

virus-associated non-Hodgkin’s 

lymphoma in combination with highly 

active antiretroviral therapy. Journal of 

Clinical Oncology 19:2171, 2001. 

Scott, D, Cabral, L and Harrington, 

WJ Jr. Treatment of HIV-associated multicentric 

Castleman’s disease with oral 

etoposide. American Journal of Hematology 

66:148, 2001. 

Abdul M. Mian, Ph.D. 



Dr. Mian’s research focuses on the 

use of anti-viral nucleosides for the 

treatment of AIDS associated lymphomas. 

Lymphomas in immunocom-promised 

individuals are frequently associated 

with the herpes virus. Therapeutic outcome 

of these lymphomas when treated 

with AZT is dependent upon the presence 

of EBV and/or levels of BCL-2. The 

effects of AZT in EBV-positive lymphomas 

are mediated via apoptosis, whereas, 

in EBV-negative lymphomas, it failed to 

induce apoptosis as determined by 

Annexin V staining methodology. It is 

therefore, reasonable to postulate that 

EBV plays a role in inhibiting the tumor 

growth by this anti-viral drug in sensitive 

cells. However, AIDS lymphomas 

that over-express BCL-2 (an antiapoptotic 

protein) even when EBV is 

positive is resistant to AZT mediated 

apoptosis. Thus, absence of EBV infection 

and/or higher expression of BCL-2 

render these lymphomas resistant to the 

treatment of AZT. 

In order to improve the therapeutic 

outcome of these tumors, Dr. Mian’s 

laboratories are engaged in discovering: 

1) new and more effective congeners, 

2) the mechanism of growth inhibition, 

and 3) metabolism of the active anti-viral 

molecule(s). Thus, by utilizing the primary 

cultures from the responding and 

non-responding AZT treated patients as 

well as established cultures lines, they are 

evaluating the new and modified antiviral 

compounds for their growth inhibitory 

properties. The metabolism studies 

are being carried out in EBV positive and 

negative tissue cultures. The aim of Dr. 

Mian’s research is to decipher the active 

metabolite(s) and to establish the probable 

site of inhibition by AZT. The results 

from these experiments may provide 

better understandings and improved 

agents to combat this malignancy. 

PUBLICATIONS 

Mehta, P, Perez-Stable, C, Nadji, M, 

Mian, AM, Asotra, K and Roos, BA. 

Suppression of human prostate cancer 

cell growth by forced expression of 

connexin genes. Developmental Genetics 

24:91, 1999. 







Walter A. Scott, Ph.D. 

Professor of Biochemistry 



The antiretroviral drug 3'-azidothymidine 

(AZT) is phosphorylated 

by cellular kinases to form the nucleoside 

triphosphate derivative. The reverse 

transcriptase (RT) of human immunodeficiency 

virus (HIV) is able to use this 

nucleotide in place of the normal nucleotide 

substrate (dTTP) which results in 

chain termination and inhibition of further 

DNA synthesis. Because of this, 

AZT is a potent inhibitor of viral replication. 

Antiviral therapy with AZT leads 

to the selection of resistance mutations 

in the viral RT gene. The biochemical 

mechanism of this resistance has been the 

subject of investigation in several laboratories 

over the past several years since 

the virus carrying these mutations is 

highly resistant to AZT in cell culture 

assays, whereas in vitro incorporation 


experiments showed little difference between 

purified wild type and mutant RT. 

In 1998, Dr. Scott’s laboratory discovered 

and reported a new reaction catalyzed 

by HIV RT that led to removal of 

chain terminating residues from the 3' 

end of blocked DNA chains (Meyer et 

al., 1998). In the presence of ribonucleotide 

di- or triphosphate, the 3' residue 

was transferred to free nucleotide to form 

a novel low molecular weight product 

and an unblocked DNA chain that can 

be extended with normal dNTPs. The 

structure of the novel product was determined 

and shown to consist of two 

nucleoside residues connected by three 

or four phosphate residues (dinucleoside 

polyphosphate). The activity is related to 

pyrophosphorolysis except that the 3' 

nucleotide is transferred to a nucleotide 

acceptor rather than to pyrophosphate. 

Other RTs also had low levels of nucleotide-dependent 

pyrophosphorolysis activity. 

However, the activity was not 

detected in other DNA polymerases that 

were tested. 

These results suggested a mechanism 

for AZT resistance. Recombinant wild 

type and mutant RTs were prepared and 

characterized for the nucleotide-dependent 

pyrophosphorolysis activity. The 

AZT-resistant mutant (D67N, K70R, 

T215F, K219Q) had substantially elevated 

levels of this activity in comparison 

with wild type enzyme (Meyer et al., 

1999). Dr. Scott’s team showed that this 

increase was cumulative over a short segment 

of DNA that had multiple potential 

sites for incorporation of dTMP since 

AZTMP incorporated at the first position 

could subsequently be removed in 

the presence of ATP and the chains further 

extended to the next position where 

AZTMP could again be incorporated 

and removed. The removal reaction was 

inhibited by the next complementary 

dNTP which induced formation of a 

dead-end complex with RT, chain-terminated 

primer/template and dNTP. DNA 

chains terminated with most chain-terminating 

nucleotides such as ddAMP 

and d4TMP were very sensitive to this 

inhibition. By contrast, DNA chains terminated 

with AZTMP was insensitive to 

this inhibition. This provides an explanation 

for why the AZT resistance mutations 

show very little cross resistance 

to other chain-terminating drugs. 

PUBLICATIONS 







Meyer, PR, Matsuura, SE, Schinazi, 

RF, So, AG and Scott, WA. Differential 

removal of thymidine nucleotide analogues 

from blocked DNA chains by 

human immunodeficiency virus reverse 

transcriptase in the presence of physiological 


triphosphates. Antimicrobial 

Agents and Chemotherapy 44:3465, 

2000. 


• HIV reverse transcriptase (as well as 

other reverse transcriptases) catalyzes a 

novel reaction (nucleotide-dependent 

pyrophosphorolysis activity) that produces 

a dinucleoside polyphosphate 

and unblocked primer/template. 

• AZT resistant mutants of HIV have 

increased ability to remove the chain 

terminator after it has been incorporated. 

This is due to increased nucleotide-dependent 

pyrophosphorolysis 

activity. 

44 


CANCER PREVENTION AND CONTROL PROGRAM 



Professor of Psychology 


The Cancer Prevention and Control 

Program includes research in cancer 

etiology, prevention, early detection, 

education and outreach, cancer genetics, 

psychoneuroimmunology, and biobehavioral 

interventions. During the past 

year, there have been exciting discoveries 

in many of these areas. 

Major research efforts by the Cancer 

Prevention and Control Program 

have built on earlier work. This includes 

work in relation to tobacco use, assessment 

of quality of life among persons 

who have been treated for cancer, investigations 

of cancer incidence in Florida, 

outreach to Hispanic populations, and 

implementation of cancer-control strategies. 

The projects performed by the 

members of this group vary substantially. 

Some are purely behavioral or psychosocial 

in their aims; others examine neuroendocrine 

and immunological end 

points. Most of these projects entail collaboration 

among behavioral scientists, 

surgeons, and oncologists. Others entail 

further collaborations with immunologists 

and other biomedical scientists. 


1) To determine how genetic, molecular, 

behavioral, and/or environmental 

exposures explain differences in 

cancer morbidity and mortality 

among minority populations. 

2) To develop, implement, and evaluate 

hypothesis-driven interventions (of 

various types) to prevent and “control” 

cancer in clinical or community 

populations. 

3) To develop and evaluate psychosocial 

interventions toward reducing stress, 

enhancing quality of life, and improving 

compliance as well as other 

health-related behaviors. 

4) To examine the interactive effects of 

stress, behavior, and psychosocial 

components on neuroendocrine, hormonal, 

and immune function in cancer 

patients, and to determine how 

these vary across sites, gender, age, 

race/ethnicity, and prognostic variables. 

5) To improve the quality of life of persons 

who are currently under treatment 

for cancer or have been treated 

in the past. 

6) To gain a better understanding of potential 

psychosocial influences on biological 

processes that may be involved 

in cancer recurrence. 

PARTICIPANTS 

Antoni, Michael H., Ph.D. 

Psychology 

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

Pediatrics 

Carver, Charles S., Ph.D. 

Psychology 

Fleming, Lora E., M.D., Ph.D., 

M.P.H., M.Sc. 


Fletcher, Maryann, Ph.D. 

Medicine 

Goodman, Kenneth W., Ph.D. 

Bioethics 

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


Kirsner, Robert, M.D. 

Dermatology 

Kumar, Adarsh M., Ph.D. 

Psychiatry and Behavioral Sciences 

Kumar, Mahendra, Ph.D. 


Lee, David J., Ph.D. 


Penedo, Frank J., Ph.D. 

Psychology 

Trapido, Edward, Sc.D. 


Weiss, Sharlene M., Ph.D. 

Medicine 

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


HIGHLIGHTS 

• Breast Cancer: African-American 

women with a family history of breast 

cancer have characteristic mutations 

and polymorphic variants not observed 

in Caucasians, and that the frequency 

of BRCA1 and BRCA2 germ-line “deleterious” 

mutations is much less than 

that observed in Caucasians. 

• 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 risks, compared 

to white non-Hispanics. Black 

children have significantly decreased 

incidences and risk. Results for lymphoid 

leukemia were similar. The 

incidence of lymphoma in Florida’s 

Hispanic children (primarily Cuban 

and Central American origin) differ 

from similar reports from Texas and 

California, where Hispanics are primarily 

of Mexican origin. 

• Hepatocellular Carcinoma: Florida 

blacks and Hispanics are at significantly 

increased risk for Hepatocellular Carcinoma 

(HCC) incidence compared 

with Florida whites. These results have 


implications for preventive HCC recommendations 

in growing racial and 

ethnic subpopulations in the United 

States. 

• Prostate Cancer: A vitamin D analog 

has been developed that significantly 

inhibits prostate cancer metastasis in 

vivo and does not produce cachexia or 

unacceptable hypercalcemia. 

• Head and Neck Cancer: Supplemental 

beta-carotene has no significant effect 

on second head and neck cancer mortality 

or lung cancer mortality. 

• Breast Cancer Screening: After controlling 

for demographic variables traditionally 

related to breast cancer 

screening rates, there are ethno-regional 

differences in breast cancer screening 

practices among Cubans, Mexican 

Americans, Puerto Ricans, and Central 

and South Americans across the United 

States. In these groups, social integration 

appears to influence cancer-screening 

participation of Hispanic women. 

The modest effect is not universal 

across Hispanic groups and is stronger 

for Pap smear than for mammography 

screening behavior. 

• Among women enrolled in the Breast 

Cancer Early Detection Program, predictors 

of recent mammograms were 

having had a checkup in the past year. 

Women who named their physician as 

an important source of information 

about health and prevention also were 

more likely to have had a recent examination 

(OR 1.85; 95 percent CI 1.27- 

2.69). 

• There are significant differences in the 

adjusted frequency of dense breast 

among women of different racial and 

ethnic groups. The extent to which 

these differences may account for racial 

and ethnic differences in the incidence 

and presenting stage of breast 

cancer remains to be investigated. 

• Tobacco: 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 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 the law enforcement efforts. 

Evaluation of the media campaign 

shows an association between more 

recall of anti-tobacco messages and 

less tobacco use. Further, when antitobacco 

community partnerships/coalitions 

were most active, there were 

greater decreases in youth tobacco use 

than when the activities were fewer. 

• 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. 

• Hormone Use: Hormone replacement 

therapy (HRT), which includes progestins, 

ameliorates but does not completely 

abolish the estrogen-related 

components of replacement therapy 

associated risk. Survival in patients with 

endometrial cancer is better for those 

who have used estrogen, but this does 

not reassure potential hormone users, 

who obviously prefer to avoid endometrial 

cancer entirely. 

• Biopsychosocial Research: Studies have 

demonstrated that elevated life stress 

predicts greater promotion and persistence 

of squamous intraepithelial lesions 

(sil) and greater decline in natural 

killer (NK) cell percentages over a oneyear 

prospective period in women coinfected 

with HIV and HPV. 

• Researchers have established an immunologic 

battery for the NCI-funded 

project “facilitating positive adaptation 

in women with breast cancer,” which 

included lymphoproliferative responses 

to CD3 cross linking and associated 

th1- and th2- like cytokine production 

and cytokine-stimulated NKCC to 

K562 targets and breast cancer-related 

cell lines. 

• Investigators have developed an experimental 

intervention “cognitive-based 

stress management” (CBSM) to be 

tested on a variety of patients with different 

cancer diagnoses. 

• Studies have demonstrated that early 

stage breast cancer patients assigned to 

the experimental intervention CBSM 

showed increases in positive growth and 

optimism and a decreased prevalence 

of clinical depression, decreases in 

plasma cortisol, and increases in lymphocyte 

proliferative responses to anti- 

CD3 cross linking. 

• Researchers have been funded by NCI 

for a five-year randomized trial “facilitating 

positive adaptation in women 

with breast cancer,” which tests the effects 

of a cognitive-based stress management 

intervention in newly 

diagnosed breast cancer patients. 

• Investigators also have been funded by 

NCI for a five-year P50 Center for 

Psycho-Oncology Research, which will 

conduct behavioral, psychological, social, 

and biomedical research on the interrelationships 

between cognition, 

emotions, biological processes, and 

physical health. Populations include 

those at high risk for cancer and those 

dealing with cancer diagnoses. The 

grant includes funding for four clinical 

trials, four core laboratories, and 

multiple pilot studies focusing on 

psycho-oncology research. 

46 




Sharlene M. Weiss, Ph.D. 



Dr. Antoni’s research interests in the 

Division of Health Psychology 

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, 

and HIV infection. He also has 

examined some of the psychobiological 

mechanisms that might explain the ways 

in which stressful events and psychosocial 

interventions contribute to the 

adjustment to 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). 

Dr. Weiss collaborates with Dr. 

Antoni in projects supported by NCI 

R01s and a large NCI-funded P50 Center 

grant (NCI-1P50CA84944) titled 

“Center for Psycho-Oncology Research” 

(CPOR). A separate R01 project (NCI- 

R011CA64710) titled “Facilitating Positive 

Adaptation in Women with Breast 

Cancer” is a five-year randomized trial 

testing the effects of Cognitive 

Behavioral Stress Management (CBSM) 

intervention on positive growth, psychosocial 

adjustment, and immune function 

in white, Hispanic (both English and 

Spanish-speaking), and black women 

who are newly diagnosed with and 

treated for early/middle stage breast cancer 

(Stages I-III). The project will further 

examine the impact of positive 

contributions (as well as distress), by examining 

the effects of CBSM in a variety 

of life spheres at three months and 

nine months after the intervention. The 

intervention is hypothesized to improve 

psychosocial adjustment and foster a 

sense of positive growth, foster a more 

rapid return to prediagnosis quality of 

life, indexed by levels of positive and 

negative mood, fatigue symptoms and 

sleep quality, and disturbances in social 

and psychosexual functioning. The investigators 

also will examine how changes 

in these spheres are paralleled by changes 

in aspects of immune functioning relevant 

for future risk of disease recurrence, 

including lymphocyte subpopulations; 

lymphoproliferative responses to anti- 

CD3; interleukin-2 (IL-2) and interferon-gamma 

(IFN-γ) production during 

lymphoproliferative challenge; and recombinant 

(r)IL-2- and rIFN-γ-stimulated 

natural killer cell cytotoxicity to 

K562 targets, and three breast-cancer 

lines, MB453, SKBR3, and MCF-7. 

The CPOR P50 also will conduct 

behavioral, psychological, social, and biomedical 

research on the interrelationships 

among cognition, emotion, biological 

processes, and physical health in patients 

with different forms of cancer including 

breast cancer, prostate cancer, and AIDSrelated 

cervical neoplasia. The CPOR 

will systematically evaluate the efficacy 

of the group-based CBSM intervention 

in Projects 1, 2, and 3, and a pharmacological 

hormonal treatment in Project 4, 

for improving quality of life and physical 

health in patients with different types 

of cancer or carcinogenic processes associated 

with reproductive health or hormonal 

functioning. Dr. Weiss’ prior work 

has shown that CBSM intervention can 

improve mood, change cognitions, and 

build coping resources; that it modulates 

the output of sympathetic nervous system 

(SNS), Hypothalamic Pituitary Adrenal 

(HPA), and Hypothalamic Pituitary 

Gonadal (HPG) hormones; and that 

it helps normalize immunologic status in 

different populations. Recent work suggests 

that these effects may generalize to 

patients with certain types of cancer and 

that the psychosocial and physiologic 

changes may influence quality of life and 

physical health in cancer patients as well. 

The CPOR also supports and conducts 

pilot studies of interventions in men and 

women with other cancers and will also 

develop and test other forms of intervention 

as well as Spanish translations of 

CBSM for Spanish-speaking breast and 

prostate cancer patients. 

Generally speaking, most of the researchers’ 

efforts have focused on using 

information derived from studies of 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, our researchers 

also conduct generalizability 

studies designed to see how well the interventions 

work in diverse patients 

groups (e.g., inner city HIV-positive 

women at risk for cervical cancer, 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 

chronic diseases. 

PUBLICATIONS 

Cruess, DG, Antoni, MH, Kumar, 

M, Ironson, G, McCabe, P, Fernandez, 

JB, Fletcher, M and Schneiderman, N. 

Cognitive-behavioral stress management 

buffers decreases in dehydroepiandrosterone 

sulfate (DHEA-S) and increases 

in the cortisol/DHEA-S ratio and 

reduces mood disturbance and perceived 

stress among HIV-seropositive men. 

Psychoneuroendocrinol 24:537, 1999. 

Antoni, MH, Carver, CS, Boyers, 

A., McGregor, B, Arena, P, Kilbourn, K, 

Lehman, J, Harris, S, Price, A, Alferi, S, 

Culver, J and Cruess, D. Cognitive behavioral 

stress management intervention 

increases positive adaptation to breast 

cancer. Psychosomatic Medicine, 61:94, 

1999. 


Cruess, D, Antoni, MH, McGregor, 

B, Boyers, A, Alferi, S, Kilbourn, K, 

Schneiderman, N, Kumar, M, Fernandez, 

J and Carver, CS. Cognitive behavioral 

stress management reduces serum 

cortisol levels and enhances feelings of 

positive personal growth in women with 

breast cancer. Psychosomatic Medicine 

61:94, 1999. 

Lutgendorf, S and Antoni, MH. 

Emotional and cognitive processing in a 

trauma disclosure paradigm. Cognitive 

Therapy and Research 23:423, 1999. 

Alferi, S, Culver, J, Carver, CS, 

Arena, P and Antoni, MH. Religiosity, 

religious coping and distress: A prospective 

study of catholic and evangelical 

Hispanic women in treatment for early 

stage breast cancer. Journal of Health 

Psychology 4:343, 1999. 


Arena, P and Antoni, MH. Religious 

orientation, religious coping and distress 

among Hispanic early stage breast cancer 

patients: A prospective study. Psychosomatic 

Medicine 61:118, 1999. 

Spencer, S, Lehman, J, Wynings, C, 

Arena, P, Carver, CS, Antoni, MH, 

Derhagopian R, Ironson G, and Love N. 

Concerns about breast cancer and relations 

to psychological well-being in a 

multi-ethnic sample of early stage patients. 

Health Psychology 18:159, 1999. 

Alferi, S, Carver, CS, Antoni, MH, 

Weiss, S and Duran, R. Types, sources, 

and timing of social support: A prospective 

study of social support and distress 

among Hispanic breast cancer patients. 

Psychosomatic Medicine 62:104, 2000. 

Antoni, MH, Cruess, S, Cruess, 

DG, Kumar, M, Lutgendorf, S, Ironson, 

G, Dettmer, E, Williams, J, Klimas, N, 

Fletcher, MA and Schneiderman, N. 


reduces distress and 24-hour urinary free 

cortisol output among symptomatic 

HIV-infected gay men. Annals of Behavioral 

Medicine 22:29, 2000. 

Cruess DG, Antoni, MH, Kumar 

M and Schneiderman N. Reductions in 

salivary cortisol are associated with mood 

improvement during relaxation training 

among HIV-seropositive men. Journal 

of Behavioral Medicine 23:107, 2000. 

Alferi, SM, Carver, CS, Antoni, 

MH, Weiss, S and Duran, RE. An exploratory 

study of social support, distress, 

and life disruption among low-income 

Hispanic women under treatment for 

early stage breast cancer. Health Psychology 

20:41, 2001. 

Antoni, MH, Lehman, JM, 

Kilbourn, KM, Boyers, AE, Culver, JL, 

Alferi, SM, Yount, SE, McGregor, BA, 

Arena, PL, Harris, SD, Price, AA and 

Carver, CS. Cognitive-behavioral stress 

management intervention decreases the 

prevalence of depression and enhances 

benefit finding among women under 

treatment for early-stage breast cancer. 


Dixon, D, Cruess, S, Kilbourn, K, 

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

Baum, A, Schneiderman N and Antoni, 

MH. Social support mediates loneliness 

and human herpes virus type 6 (HHV- 

6) antibody titers. Journal of Applied 

Social Psychology 31:1111, 2001. 

McGregor, BA, Carver, CS, Antoni, 

MH, Weiss, S, Yount, SE and Ironson, 

G. Distress and internalized homophobia 

among lesbian women treated for 

early stage breast cancer. Psychology of 

Women Quarterly 25:1, 2001. 

Penedo, FJ, Antoni, MH, 

Schneiderman, N, Ironson, GH, Malow, 

RM, Cruess, S, Hurwitz, B and 

LaPerriere, A. Dysfunctional attitudes, 

coping, and depression among HIV-seropositive 

men who have sex with men. 

Cognitive Therapy and Research 25:591, 

2001. 

Schneiderman, N, Antoni, MH, 

Saab, PG and Ironson, G. Health psychology: 

Psychosocial and bio-behavioral 

aspects of chronic disease management. 

Annual Review of Psychology 52:555, 

2001. 


• Life stress and stress management in the 

promotion of human papillomavirus to 

cervical neoplasia. Studies 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 relations 

between life stress, pessimism, emotional 

expression, natural killer cell cytotoxicity, 

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. Studies indicated that elevated 

life stress predicts greater promotion 

and persistence of SIL and greater declines 

in natural killer (NK) cell percentages 

over a one-year prospective 

period in women co-infected with HIV 

and HPV. The reductions in NK percent 

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 in 200 HIV-positive HPV-positive 

women. 

• Psychosocial intervention after surgery for 

breast cancer. Through an NCI-funded 

project titled “Facilitating Positive Adaptation 

in Women with Breast Cancer,” 

researchers can examine effects of 

group-based cognitive behavioral stress 

management 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 pilot work also showed that 

48 


women assigned to CBSM showed increases 

in positive growth and optimism 

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 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. 

Lisa L. Baumbach-Reardon, Ph.D. 

Associate Research Professor of 

Pediatrics 


Dr. Baumbach-Reardon and her collaborators 

focus their research on 

the analysis of genetic risk factors for 

breast/ovarian cancer in African-American 

women. 

Among women under age 50, breast 

cancer (BC) incidence and mortality rate 

in African-Americans exceeds that in 

Caucasians. This excess among young 

black women may be due to increased 

exposure to known or unknown risk 

factors, decreased exposure to protective 

factors, and/or genetic factors. With the 

discovery of BRCA1 and BRCA2, associated 

with increased risk for breast 

cancer, technology exists to analyze the 

distribution and prevalence of gene alterations 

in at-risk groups. Prevalence of 

BRCA1 and BRCA2 germ-line mutations 

in African-American breast cancer patients 

is controversial. Although such 

mutations have been reported in several 

at-risk African-American patients, recent 

evidence suggests that the prevalence 

in unselected African-American patients 

is low. 

Over the last two years, Dr. 

Baumbach-Reardon has focused her efforts 

on the analysis of BRCA1 and 

BRCA2 mutations in 20 African-American 

families with high to moderate risks 

for breast cancer, and have completed 

these analyses at the end of this year. In 

this family cohort, “deleterious” (i.e. protein-truncating) 

germ-line mutations 

were detected in a very small percentage 

of families (10 percent for BRCA1; 5 

percent for BRCA2), observations which 

are both substantially, and statistically, 

lower than those percentages reported in 

at-risk Caucasian women with similar 

positive family histories. However, interestingly, 

Dr. Baumbach-Reardon and 

others have detected a number of other 

genetic “variants” (missense mutations, 

splice site alterations, “silent polymorphisms” 

in both of these genes more so 

in BRCA2) in 13/20 families which otherwise 

do not have a detectable deleterious 

mutation. Three of the 20 families 

analyzed (two high-risk, one moderaterisk) 

remain without any detectable genetic 

variant in BRCA1 or BRCA2. Similar 

results from three other independent 

laboratories have recently been reported. 

In summary, Dr. Baumbach-Reardon 

and colleagues previously published reports—as 

well as the soon-to-be published 

observations discussed above— 

suggest that African-American women 

with a family history of breast cancer 

have characteristic mutations and polymorphic 

variants not so far observed in 

Caucasians, and that the frequency of 

BRCA1 and BRCA2 germ-line “deleterious” 

mutations in the study groups, including 

at-risk families, is much less than 

that observed in Caucasians. Their current 

efforts focus on the identification 

of additional genetics factors and alterations 

that may contribute to breast cancer 

in African-American women. 

PUBLICATIONS 

Gayol, L, Scholl, T, Basterrechea, H, 

Pfeifer, I, Davies, J, Perera, E, Smith, S, 

Arena, JF, and Baumbach, LL. BRCA1 

mutation analysis in at-risk African- 

American families: results and implications. 

American Journal of Human 

Genetics 65(4):A127(676), 1999. 

Mefford, HC, Baumbach, LL, 

Panguluri, RCK, Whitfield-Broome, C, 

Szabo, C, Smith, S, King, M-C, 

Dunston, G, Stoppa-Lyonnet, D, and 

Arena, JF. Evidence for a BRCA1 

founder mutation in families of West 

African ancestry. American Journal of 

Human Genetics 65:575, 1999. 

Eisenberg, I, Avidan, N, Potikha, T, 

Hochner, H, Chen, M, Olender, T, 

Barash, M, Shemesh, M, Sadeh, M, 

Grabov-Nardini, G, Shmilevich, I, 

Friedmann, A, Karpati, G, Bradley, WG, 

Baumbach, LL, Lancet, D, Ben Asher, 

E, Beckmann, JS, Argov, Z and Mitrani- 

Rosenbaum, S. The UDP-N-acetylglucosamine 

2-epimerase/N-acetylmannosamine 

kinase gene is mutated in recessive 

hereditary inclusion body myopathy. 



• Dr. Baumbach-Reardon’s research team 

has completed analysis of BRCA1 and 

BRCA2 in 20 at-risk African-American 

breast cancer patients/families. To date, 

these analyses have only detected two 

deleterious mutations in BRCA1 and 

one deleterious mutation in BRCA2. 

Based on control experiments, their 

mutation detection rate (using the described 

methodology) is 95 percent. 

• Different polymorphic variants have 

been detected in both BRCA1 and 

BRCA2 in these families, representing 

both missense and silent mutations. A 

large number of “variants” were detected 

in BRCA2 in these families, with 

the vast majority of these occurring in 

the absence of a detectable BRCA1 or 

BRCA2 deleterious mutation. Selected 

variants were further analyzed for their 

presence in African-American controls 


and ranged in frequency from one to 

five percent. 

• Their data support a low germ-line “deleterious” 

BRCA1 and BRCA2 mutation 

rate in African-American patients and 

suggest a possible role for African- 

American specific variants in modulating 

breast cancer risk. 

• At the completion of these studies, the 

group will have a collection of families 

with BRCA1/BRCA2 mutations, which 

will be useful for further investigations. 

Families who do not contain BRCA1/ 

BRCA2 mutations also can be used to 

help identify additional genes and/or 

factors contributing to breast cancer in 

African-American patients. 

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 also 

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). 

He also is a collaborator in research that 

provides cancer patients with psychosocial 

interventions—ten-week group sessions 

in cognitive-behavioral stress 

management—and examines the effects 

of those interventions over the subsequent 

year. His research team’s first study 

on that topic examined only psychosocial 

outcomes (PI, Adjustment to Breast 

Cancer Among Younger Women, NCI 

grant R01-CA64710). However, pilot 

data collected in that study has led to 

further work, specifically examining the 

impact of the intervention on immune 

function (Co-PI, Facilitating Positive 

Adaptation to Breast Cancer, NCI grant 

R01-CA64710). 

PUBLICATIONS 




study of catholic and evangelical 









Medicine 61:118, 1999. 



Derhagopian, R, Ironson, G and Love, 

N. Concerns about breast cancer and 

relations to psychological well-being in 

a multiethnic sample of early stage patients. 



A, McGregor, B, Arena, P, Kilbourn, K, 





cancer. Psychosomatic Medicine 61:94, 

1999. 





stress management reduces serum cortisol 

levels and enhances feelings of positive 

personal growth in women with 


61:94, 1999. 






Medicine 61:118, 1999. 







Carver, CS and Scheier, MF. Scaling 

back goals and recalibration of the 

affect system are processes in normal 

adaptive self-regulation: Understanding 

“response shift” phenomena. Society of 

Scientific Medicine 50:1715, 2000. 


• Dr. Carver’s team completed interviews 

with 90 cancer survivors, working toward 

the development of a measure of 

psychosocial adjustment aimed specifically 

at cancer survivors. The interview 

phase was followed by an itemdevelopment 

phase. The items are then 

tested on another sample of cancer 

survivors. 

• Other members of this team, particularly 

Dr. Spencer, found that concerns 

about recurrence and death were more 

salient even to early stage breast cancer 

patients than concerns about anything 

else related to the cancer experience. 

That study also found that Hispanic 

women reported more intense concerns 

of several sorts than did non-Hispanic 

whites or blacks. Concerns about existential 

issues, concerns about sexuality, 

and concerns about rejection from others 

all played roles in predicting various 

aspects of quality of life. 

• Dr. Susan Alferi, another colleague of 

Dr. Carver, studied a sample of low SES 

Hispanic breast cancer patients. That 

study found substantial differences 

between women who identified themselves 

as Catholic and those who identified 

themselves as fundamentalist 

Christians. Among the Catholic 

50 


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. 

Lora E. Fleming, M.D., Ph.D., 

M.P.H., M.Sc. 

Associate Professor of Epidemiology 

and Public Health 


Dr. Fleming is the only board-certified 

and licensed occupational and 

environmental medicine physician and 

epidemiologist in South Florida. Her 

areas of research interest are occupational 

and environmental medicine and epidemiology. 

Dr. Fleming has performed funded 

research on the health effects of methyl 

mercury contamination in the Everglades 

(ATSDR and Florida Department of 

Health); 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 (Florida 

Department of Health); 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 (Florida Department 

of Health); and several studies on the 

human health effects of the marine toxin 

diseases (NIEHS, CDC, and Florida 

Department of Health), as well as a 

NIOSH Career Development studying 

the chronic health effects of a large cohort 

of licensed Florida Pesticide Applicators. 

Dr. Fleming is Director of Outreach 

and Education at the NIEHS Marine 

and Freshwater Biomedical Sciences 

Center at the University of Miami and 

the Director of the Epidemiology Core 

for the NIOSH Deep South Agricultural 

Center at the University of South Florida. 

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, 

as well as being the vice chair of the 

International ACGIH TLV Committee 

that recommends voluntary occupational 

standards used worldwide to protect 

workers. 

Cancer-Related Activities 

Dr. Fleming is the Director of Research 

for the Florida Cancer Data System 

(FCDS), Florida’s incident tumor 

registry at UM/Sylvester. 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. This work has led to several national 

presentations on Florida cancer 

issues, including work on childhood lymphoma 

in Florida, Cancer Information 

Services Evaluation, and cancer among 

Hispanics. 

Based on her research into the human 

health effects of marine and freshwater 

toxins, Dr. Fleming is currently 

performing a study on the possible association 

between blue green algal toxins 

in drinking water and the risk of hepatocellular 

carcinoma in Florida. 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 are evaluating the risk 

of liver cancer in Florida for persons living 

near surface water treatment plants 

with possible blue green algal toxin contamination. 

This study is being performed 

in collaboration with the FCDS 

and 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; the Florida Harmful Algal 

Bloom Taskforce at the Florida Marine 

Research Institute provides funding for 

this study. 

Based on her work studying the 

chronic health effects among a large cohort 

of licensed Florida Pesticide Applicators, 

Dr. Fleming is currently performing 

a study to examine the levels of the 

pesticide DDT in the blood of licensed 

Florida pesticide applicators with and 

without prostate cancer. DDT is an organochlorine 

pesticide. In addition to 

being very environmentally persistent, 

there is some evidence that these organochlorine 

pesticides may act like the 

female hormone, estrogen, and induce 

prostate and testicular cancer. The 

Florida licensed pesticide applicators 

were heavily exposed to organochlorines 

in the past and they have an increased 

risk of both prostate and testicular cancer. 

This work is in collaboration with 

the FCDS, the Department of Chemistry 

and the Pesticide Laboratory of the 

University of Quebec. The study is 

funded by a gift for research in pesticides 

made to UM/Sylvester. 

PUBLICATIONS 

Fleming, LE, Easom, J, Baden, D, 

Rowan, A and Levin, B. Emerging harmful 

algal blooms and human health: 

Pfiesteria and related organisms. Toxicology 

Pathology 27:573, 1999. 

Fleming, LE, Bean, JA, Rudolph, M 

and Hamilton, K. Mortality in Florida 

pesticide applicators. Journal of Occupational 

Environmental Medicine 56:14, 

1999. 

Fleming, LE, Bean, JA, Rudolph, M 

and Hamilton, K. Cancer incidence in 


Florida pesticide applicators. Journal of 

Occupational Environmental Medicine 

41:279, 1999. 

Fleming, LE, Oquendo, S, Bean, JA, 

Tamer, R, Finn, S and Wanner, A. A pilot 

study of screening for alpha one antitrypsin 

deficiency. American Journal of 


Shea, KA, Fleming, LE, Wilkinson, 

JD, Wohler-Torres, B and McKinnon, 

JA. Hepatocellular carcinoma incidence 

in Florida-ethnic and racial distribution. 


Wilkinson, JD, Fleming, LE, 

MacKinnon, J, Voti, L, Wohler-Torres, 

B, Peace, S and Trapido, E. Lymphoma 

and lymphoid leukemia incidence in 

Florida children-ethnic and racial distribution. 


Kenneth W. Goodman, Ph.D. 

Director, UM Bioethics Program 

Director, Clinical and Research 

Ethics Education, UMHC/SCCC 

Vice Chair, UMHC/SCCC Bioethics 

Committee 


Dr. Goodman continues his focus on 

ethical issues in health informatics 

and epidemiology and public health, 

which further cemented the University 

of Miami’s reputation as an international 

leader in these areas, especially regarding 

bioinformatics. An additional emphasis 

on end-of-life care was also 

productive and led to University of Miami 

and other Florida partners being 

awarded a Robert Wood Johnson Foundation 

grant as part of its Community 

Relationships to Improve Care of the 

Dying. Additionally, an NIH grant 

awarded in 1999 will support the development 

of a short course, “Especially 

Difficult Ethical Problems in Epidemiology 

and Clinical Research Ethics,” to 

be offered annually for three years. 

PUBLICATIONS 

Goodman, KW. Philosophy as 

news: Bioethics, journalism and public 

policy. Journal of Medicine and Philosophy 

24:181, 1999. 

Goodman, KW. Bioinformatics: 

Challenges revisited. MD Computing 

16:17, 1999. 

Goodman, KW. Commentary: National 

living wills and local politics. 

ASBH Exchange (newsletter of the 

American Society for Bioethics and Humanities) 

Summer: 6, 1999. 

Goodman, KW. Health care ethics. 

Responses to an Aging Florida, Summer: 

5, 1999. 

Goodman, KW. Health informatics 

and the hospital ethics committee. MD 

Computing 16:17, 1999. 

Goodman, KW et al. IRB review: 

Necessary, nice or needless? (Letter.) 

Annals of Epidemiology 9:68, 1999. 

Goodman, KW. Pentostatin (Nipent) 

and high-dose cyclophosphamide 

for the treatment of refractory autoimmune 

disorder. Seminars Oncology 

27:67, 2000. 


Professor of Otolaryngology 

Director, Sylvester Comprehensive 

Cancer Center 


Dr. Goodwin’s research has focused 

on the prevention and treatment 

of squamous cell carcinoma of the upper 

aerodigestive tract. In particular, he 

has been interested in the potential of 

several micronutrients to inhibit the development 

of these cancers. Various aspects 

of a recently completed Phase III 

clinical trial, investigating the activity of 

beta-carotene, are currently being analyzed 

and published. 

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 Dr. Frank Penedo, Dr. 

Goodwin also is interested in the effect 

of stress and depression on survival and 

quality of life in this group of patients. 

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. 

PUBLICATIONS 

Mayne, ST, Carmel, B, Silva, F, Kim, 

SC, Fallon, BG, Briskin, K, Zheng, T, 

Baum, M, Shor-Posner, G and Goodwin, 

WJ. Plasma lycopene concentrations in 

humans are determined by lycopene intake, 

plasma cholesterol concentrations 

and selected demographic factors. The 

Journal of Nutrition 129:849, 1999. 

Rhee, JS, Davis, RE and Goodwin, 

WJ. Minimizing deformity from parotid 

gland surgery. Current Opinion in Otolaryngology 

and Head and Neck Surgery 

7:90, 1999. 

Goodwin, WJ. Outcomes analysis 

in patients with head and neck cancer: 

Peer reviewed editorial. Archives of Otolaryngology-Head 

and Neck Surgery 

126:335, 2000. 

Goodwin, WJ. Salvage surgery for 

patients with recurrent squamous cell 

carcinoma of the upper aerodigestive 

tract: When do the ends justify the 

means? Laryngoscope 93:1, 2000. 

Civantos, FJ, Roth, J, Goodwin, 

WJ, Weed, DT and Shiralkar, P. Sensory 

recovery in melolabial flaps used for 

oral cavity reconstruction. Archives of 

Otolaryngology-Head and Neck Surgery 

122:509, 2000. 

Mayne, ST, Cartmel, B, Baum, M, 

Shor-Posner, G, Fallon, BG, Briskin, K, 

Bean, J, Zheng, TZ, Cooper, D, Friedman, 

C and Goodwin, WJ. Randomized 

trial of supplemental beta-carotene 

to prevent second head and neck cancer. 


52 


Adarsh M. Kumar, Ph.D. 

Research Associate Professor of 



Breast Cancer and Stress, 

Neurohormonal Dysregulation 

Intervention with Guided Imagery 

and Music (GIM) 

The main objective of this project is to 

investigate the effectiveness of Bonny 

method of guided imagery and music 

(GIM) in reducing the levels of stress and 

stress-related neurohormones in breast 

cancer survivors. 

Women with breast cancer suffer 

from stress, anxiety, and depression. Diagnosis 

as well as treatment of breast 

cancer including radiation and chemotherapy 

are extremely stressful and are 

known to cause physiological as well as 

emotional disturbances. Although the 

effect of radiation and chemotherapy 

begins to taper off in six months, the 

breast cancer survivor continues to remain 

under stress, which may contribute 

to depression and compromise the 

quality of life. 

Recent research provides strong evidence 

that stress causes alteration in functions 

of hypothalamic-pituitary-adrenal 

(HPA) axis, as well as neurotransmitter 

systems in the brain. Stress initiates activation 

of the HPA-axis, leading to the 

release of cortisol from the adrenal cortex. 

Dysfunction in serotonergic system 

and the pineal gland hormone, melatonin, 

in response to stress have also been 

reported. The hormones in central nervous 

systems including those of stress 

related hormones of the HPA-axis interact 

with serotonergic and other neurotransmitter 

systems in the normal 

course of functions and stress may be one 

of the leading causes of dysfunction in 

the activity of all interacting neuronal 

pathways. Among various interventions 

currently used in alleviating the effects 

of stress on health, music therapy is considered 

as an important method of choice 

for stress intervention, for elevating general 

mood, improving sleep and appetite 

in the elderly, reducing fear, panic and 

depressed mood, and, improving the 

overall quality of life. 

The results of their recently published 

study (Kumar et al., Alternative 

Therapies in Health and Medicine, 5:49- 

57,1999) demonstrate that music 

therapy given to Alzheimer’s patients resulted 

in an increase in the levels of serum 

melatonin and changes in other 

neurotransmitter systems as well as had 

beneficial effects on health such as improvement 

in their sleep, social interactions, 

and other behaviors. 

The present pilot project is investigating 

the influence of GIM on changes 

in the levels of stress-related hormones, 

melatonin, and cortisol and on melatonin/cortisol 

ratio, as markers of stress 

reduction, as well as on profile of mood 

state (POMS) in breast cancer patients 

age 40 years and older, who are six 

months or more post breast cancer (stage 

I or II) surgery, radiation, and chemotherapy. 

Dr. Kumar’s team is investigating 

two groups of subjects. Subjects in 

group one individually receive six sessions 

of GIM once every two weeks. Test scores 

of POMS, as well as samples of saliva, 

are collected from each subject before and 

after each session and at four weeks after 

GIM has been discontinued. For the 

purpose of comparison the subjects of 

group two will wait until the end of the 

study for receiving GIM as a complementary 

treatment but are expected to 

provide saliva samples and POMS scores 

at the same time points as the GIM group 

one. Cortisol and melatonin in samples 

of saliva will be assayed simultaneously 

after all the samples have been collected. 

POMS score and their relationship with 

changes in salivary hormones will be 

evaluated. This study is in progress. 

PUBLICATIONS 

Kumar, AM, Berger, JR, Eisdorfer, 

C, Fernandez, JB, Goodkin, K and 

Kumar, M. Cerebrospinal fluid 5-hydroxytryptamine 

and 5-hydroxyindoleacetic 

acid in HIV-1 infection. 

Neuropsychobiology 44:13, 2001. 


Vice Chair and Professor of 



Since tobacco use is the leading cause 

of preventable disease and death and 

is responsible for more than one-third of 

all cancer deaths, Dr. Trapido’s research 

in the last year has focused on determining 

what types of youth tobacco-use prevention 

programs are most effective. 

Working with the state of Florida’s Tobacco 

Pilot Program, his team has been 

assessing the effectiveness of a mass media 

campaign, 13 educational programs, 

enforcement of tobacco laws related to 

youth sales and possession, and grassroots 

coalitions involved with anti-tobacco 

activities. The goal of the program is to 

reduce the prevalence of smoking among 

youth. Furthermore, Dr. Trapido’s research 

is related to determining what 

works and what does not. In other areas, 

Dr. Trapido’s work has included the expansion 

of the Cancer Information Service 

of Florida and Puerto Rico to cover 

the U.S. Virgin Islands and the continuation 

of three additional programs—the 

National Hispanic Leadership Initiative 

on Cancer, the Florida Cancer Data System, 

and the Early Breast Cancer Detection 

Program. 

PUBLICATIONS 

Ramirez, A, Suarez, L, McAlister, A, 

Villareal, R, Trapido, E, Talavera, G, 

Perez-Stable, E and Marti, J. Cervical 

Cancer Screening in Regional Hispanic 

Populations. American Journal of Behavioral 

Health 24:181, 2000. 


Lai, H, Lai, SH, Shor-Posner, G, 

Ma, FC, Trapido, E and Baum, MK. 

Plasma zinc, copper, copper: zinc ratio 

and survival in a cohort of HIV-1-infected 

homosexual men. Journal of Acquired 

Immune Deficiency Syndromes 

27:56, 2001. 

Perez-Stable, EJ, Ramirez, A, 

Villareal, R, Talavera, GA, Trapido, E, 

Suarez, L, Marti, J and McAlister, A. 

Cigarette smoking behavior among US 

Latino men and women from different 

countries of origin. American Journal of 

Public Health 91:1424, 2001. 

Sly, DF, Hopkins, RS, Trapido, E 

and Ray, S. Influence of a counteradvertising 

media campaign on initiation 

of smoking: The Florida “Truth” Campaign. 

American Journal of Public 

Health. 91:233, 2001. 





Florida children-Ethnic and racial distribution. 



• The Florida Tobacco Pilot Program 

(TPP) was implemented in 1998 to 

prevent and reduce youth tobacco use 

through coordinated programs of 

school and non-school-based education, 

a media campaign, implementation 

of anti-tobacco community-based 

activities through county partnerships 

and enforcement of youth-related tobacco 

laws. 

• There have been significant decreases 

in tobacco use by middle and high 

school students (54 percent and 24 percent 

respectively, between 1998 and 

2000). Among these students, the 

prevalence of use fell by 45 percent, 26 

percent, and 13 percent among eighth, 

tenth, and twelfth graders, respectively 

(when examined cross-sectionally). 

Among younger students, i.e., fourth 

to seventh graders, tobacco use remained 

low, but non-significant increases 

in use among the 1998 seventh 

grade cohort were observed. 

• Furthermore, there were also small nonsignificant 

increases in the proportion 

of youth who had a least one best friend 

who smoked, among eighth and ninth 

grade students in 1999 who had been 

in seventh and eighth grades, the year 

before. Among middle and high school 

students, there were significant increases 

in awareness of the TPP’s media 

campaign, reaching 95 percent 

awareness and attitudes about tobacco 

industry manipulation (a major theme 

of the campaign) also improved. In 

addition, campaign exposure was significantly 

associated with non-smokers 

remaining non-smokers. It is interesting 

to note, however, that among 

fourth to seventh graders, awareness of 

the advertisements produced by the 

Philip Morris Company substantially 

exceeded those of the TPP. 

• With respect to community-based partnerships, 

activity level was directly associated 

with decreased tobacco use, 

and also with a lower percentage of 

stores selling tobacco products. Regarding 

education, youth receiving “comprehensive 

tobacco use prevention 

education” were more likely to be committed 

to maintaining their non-smoking 

behavior than students receiving 

any education on tobacco use. However, 

exposure to such programs was 

lower than desired. Taken as a whole, 

the programs in the TPP appear to be 

positively related to decreases in tobacco 

use among middle and high 

school students. However, the success 

among certain groups, such as fourth 

to seventh graders, is less clear. 

54 


CLINICAL ONCOLOGY RESEARCH PROGRAM 

(DEVELOPING PROGRAM) 

ACTING PROGRAM LEADER 


Associate Professor of Microbiology and Immunology and Medicine 


The Clinical Oncology Research Program 

is a developing effort at the 

University of Miami Sylvester Comprehensive 

Cancer Center. The broad objective 

of this program is to organize 

research that involves bi-directional flow 

between clinic and laboratory by enhancing 

the relevance to human cancer of 

UM/Sylvester’s basic science laboratories 

and the utilization of clinical trials to gain 

insights into cancer biology. 

At present, the majority of the clinical 

research conducted at UM/Sylvester is 

coordinated in disease base teams—13 

distinct multidisciplinary groups that work 

together to provide care for our cancer 

patients and conduct clinical research. 

Multidisciplinary Site-Based 

Oncology Groups 

Genitourinary Oncology 

Group Leader 

Soloway, Mark S., M.D. 

Urology 

Gynecologic Oncology 

Group Leaders 

Mirhashemi, Ramin, M.D. 

Obstetrics and Gynecology 

Wolfson, Aaron H., M.D. 

Radiation Oncology 

Head and Neck Oncology 

Group Leader 

Weed, Donald T., M.D. 


Hematologic Malignancies 

Group Leader 

Fernandez, Hugo F., M.D. 

Medicine 

Neurological Oncology 

Group Leaders 

Heros, Deborah O., M.D. 

Neurology 

Landy, Howard J., M.D. 

Neurological Surgery 

Developing Multidisciplinary 

Site-Based Oncology Groups 

Breast Cancer Group Leaders 

Franco, Sandra X., M.D. 

Medicine 

Moffat, Jr., Frederick L., M.D. 

Surgery 

Colorectal Cancer Group Leader 

Hellinger, Michael D., M.D. 

Surgery 

Lung Cancer Group Leaders 

Raez, Luis E., M.D. 

Medicine 

Thurer, Richard J., M.D. 

Surgery 

Melanoma Group Leaders 

Elgart, George W., M.D. 

Dermatology 

Feun, Lynn G., M.D. 

Medicine 

Sarcoma Group Leader 

Temple, H. Thomas, M.D. 

Orthopaedics and Rehabilitation 

Upper Gastrointestinal Oncology 

Group Leaders 

Ardalan, Bach, M.D. 

Medicine 

Franceschi, Dido, M.D. 

Surgery 

Genitourinary Oncology 

Multidisciplinary Site-Based Group 

Leader 

Mark S. Soloway, M.D. 

Urology 

PARTICIPANTS 

Urologic Oncology 

Norman L. Block, M.D. 

Urology 

Bruce R. Kava, M.D. 

Urology 

Raymond J. Leveillee, M.D. 

Urology 

Mark S. Soloway, M.D. 

Urology 

Pathology 

Merce Jorda, M.D., Ph. D. 

Pathology 

Hematology Oncology 

Pasquale W. Benedetto, M.D. 

Medicine 

Basic Research 

Balakrishna L. Lokeshwar, Ph.D. 

Urology 

Atwar Ganju Krishan, Ph.D. 


Epidemiology 





The Genitourinary Site Disease 

Group is actively involved in improving 

detection, treatment, and outcomes 

of genitourinary tumors. This is 

illustrated by performing cancer screening, 

educating the general community, 

and researching ways to diagnose cancers 

earlier and more accurately. Many protocols 

have been developed to improve 

treatment for genitourinary malignancies 

such as multimodality treatments for 

locally advanced prostate cancer. By 

combining chemotherapy and surgery, 

patients with locally advanced prostate 

cancer can become surgical candidates, 

thereby increasing their potential for a 

cancer cure. 

The group also is trying to decrease 

the impact of cancer treatments on patients’ 

quality of life. This is one of the 

few urological cancer programs that is 

active in the new field of minimally invasive 

laparoscopic surgery. Kidney surgery 

for tumors is routinely performed 

laparoscopically. The group also is actively 

involved in performing laparoscopic 

prostatectomies and bladder 

removal. Recovery time and pain from 

surgery is greatly diminished utilizing 

these innovative surgical techniques. 

New minimally invasive forms of nonsurgically 

treating small kidney tumors 

also are being developed. 

This group also is committed to the 

equalization of cancer treatment outcomes 

in all sexes and races. In conjunction 

with the epidemiology department, 

the team is trying to determine differences 

in cancer treatment outcomes between 

the sexes and races. By identifying 

differences, they can better understand 

the barriers to care and try to diminish 

them, increasing the likelihood of early 

diagnosis and successful treatment of 

urological malignancies. 

On the basic science realm, Dr. 

Lokeshwar’s research is focused on the 

mechanism of prostate cancer metastasis 

and its control by novel chemotherapeutic 

drugs. His research on mechanism 

of cancer metastasis and extracellular 

matrix biology is supported by a fouryear 

grant from the National Institutes 

of Health, National Cancer Institute, a 

30-month grant from the U.S. Department 

of Army Medical Research and Materials 

Command, and by UM/Sylvester. 

He has identified a novel chemically 

modified non-antimicrobial tetracycline 

(COL-3) as an effective anti-metastatic 

drug with potential to treat prostate cancer 

metastatic to bone. The National 

Cancer Institute has completed the Phase 

I trial of this drug and awaiting further 

trials. (A full description of Dr. Lokeshwar’s 

research can be found in the 

Tumor Cell Biology Program section of 

this report.) 

Dr. Krishan leads another area of 

basic research in the group. Most of Dr. 

Krishan’s ongoing work is focused on 

tumor growth inhibitory effects of anticancer 

drugs used alone or in combination. 

In collaboration with Dr. Leblanc 

of the chemistry department, Dr. Krishan 

and his colleagues are studying the effects 

of some novel peptides, which have 

pronounced growth inhibitory effects 

on human prostate tumors grown in 

athymic mice. Current work is focused 

on the synthesis of small peptides, which 

could be used to arrest the growth of 

prostate tumors. The team’s major 

strength is the expert use of laser flow 

cytometry for monitoring growth and 

drug transport in human tumor cells. 

Two major techniques developed in this 

lab for cell cycle analysis and monitoring 

of drug resistance are universally used 

in cancer research. Recently, this lab has 

developed laser flow cytometric techniques 

for monitoring the expression of 

hormone receptors in human breast and 

prostate tumors. 

CLINICAL PROTOCOLS 

NCI/SWOG Trial 

S0000, Selenium, and Vitamin E Prostate 

Cancer Prevention Trial (SELECT) 

Prostate Cancer 

Randomized Prospective Study of Adjuvant 

Androgen Ablation in Radical Prostatectomy 

Patients at High Risk for 

Disease Recurrence 

A Phase II Study of Temozolomide in 

the Treatment of Patients with Metastatic 

Prostate Cancer 

Psycho-Oncology Study to Evaluate Behavior 

Stress Management in Patients 

with Prostate Cancer 

A Phase II Evaluation of Weekly Taxol 

and E-Mcyt (estramustine phosphate) in 

Patients with Hormone Refractory Prostate 

Cancer 

A Randomized, Double Blind, Placebo 

Controlled, Multi-Center Comparative 

Safety Efficacy Study of Intravenous 

Zoledronate (four and eight mg) in Prostate 

Cancer Patients with Metastatic 

Bone Lesions Receiving Antineoplastic 

Therapy 

A Randomized, Double Blind Placebo 

Controlled Phase III Trial Evaluating 

Zoledronate plus Standard Therapy Versus 

Placebo + Standard Therapy in Patients 

with Recurrent Carcinoma of the 

Prostate who are Asymptotic with Castrate 

Levels of Testosterone 

Kidney Cancer 

A Multi-Center, Randomized Phase III 

Study of Adjuvant Oncophage Versus 

Observation in Patients with High Risk 

of Recurrence after Surgical Treatment 

for Renal Cell Carcinoma 

Radiofrequency Ablation of Renal Tumors 

Utilizing A Saline Electrode During 

Traditional Radical Nephrectomy to 

Determine Effects on Tumor and Normal 

Tissue 

56 


PUBLICATIONS 

Lokeshwar, BL, Schwartz, GG, 

Seizer, MG, Burnstein, K, Zhuang, S and 

Block, NL. Inhibition of metastasis by 

1α, 25-[OH]2 vitamin D, and EB1089, 

α vitamin D analogue, in a prostate 

cancer model. Cancer Epidemiology 

Biomarkers and Prevention 8:241, 1999. 

Zhu, BQ, Block, NL and Lokeshwar, 

BL. Organ-specific stromal cells and 

their extracellular matrix modify the response 

of tumor cells to antitumor drugs. 

Annals NY Academy of Science 878:642, 

1999. 

Selzer, MG, Zhu, BQ, Block, NL 

and Lokeshwar, BL. CMT-3, a chemically 

modified tetracycline inhibits bony 

metastases and delays the development 

of paraplegia in a rat model of prostate 

cancer. Annals of NY Academy of Science 

878:678, 1999. 


HAse urine test. A sensitive and specific 


evaluating its grade. Urology Clinics of 



HT, Wei, D, Young, MJ, Duncan, RC, 





163:348, 2000. 

Garde, SV, Basrur, VS, Li, L, 

Finkelman, MA, Krishan, A, Wellham, 

L, Ben-Josef, E, Haddad, M, Taylor, JD, 

Porter, AT, and Tang, DG. Prostate secretory 

protein (PSP94) suppresses the 

growth of androgen-independent prostate 

cancer cell line (PC3) and xenografts 

by inducing apoptosis. Prostate 38:118, 

1999. 

Krishan, A, Oppenheimer, A, You, 

W, Dubbin, R, Sharma, D, and Lokeshwar, 

BL. Flow cytometric analysis of 

androgen receptor expression in human 

prostate tumors and benign tissues. 


Krishan, A, Sridhar, KS, Mou, C, 

Stein, WD, Lyubimov, E, Hu, YP and 

Fernandez, H. Synergistic effect of 

prochlorperazine and dipyridamole on 

the cellular retention and cytotoxicity of 

doxorubicin. Journal Clinical Cancer 

Research 6:1508, 2000. 

Choy, N, Blanco, B, Wen, J, 

Krishan, A and Russell, KC. Photochemical 

and thermal bergman cyclization 

of a pyrimidine enediynol and 

enediynone. Organic Letters 2:3761, 

2000. 

Krishan, A. Monitoring of cellular 

resistance to cancer chemotherapy: drug 

retention and efflux. Methods Cell Biology 

164:193, 2001. 

Thomas, RA, Krishan, A, Robinson, 

DM, Sams, C and Costa, F. NASA/ 

American Cancer Society high-resolution 

flow cytometry project-I. Cytometry 

43:2, 2001. 

Wen, J, Krishan, A and Thomas, 

RA. NASA/American Cancer Society 

high-resolution flow Cyometry project - 

II. Effect of pH and DAPI concentration 

on dual parametric analysis of DNA/ 

DAPI fluorescence and electronic nuclear 

volume. Cytometry 43:12, 2001. 

Krishan, A, Wen, J, Thomas, RA, 

Sridhar, KS and Smith, WI Jr. NASA/ 


flow Cyometry project - III. Multiparametric 

analysis of DNA content and electronic 

nuclear volume in human solid 

tumors. Cytometry 43:16, 2001. 

Frankfurt, OS and Krishan, A. Identification 

of apoptotic cells by formamide-induced 

DNA denaturation in 

condensed chromatin. J Histochemistry 

Cytochemistry 49:369, 2001. 

Frankfurt, OS and Krishan, A. Enzyme-linked 

immunosorbent assay 

(ELISA) for the specific detection of 

apoptotic cells and its application to 

rapid drug screening. J Immunology 

Methods 253:133, 2001. 

Lokeshwar, BL, Escatel, E, Houston-Clark, 

HL and Zhu, BQ Rapid induction 





Therapeutic Strategies. W. J. Whelan, et 

al: Advances in Gene Technol. Miami 

Nature Biotechnology Short Reports. Vol 

10:117a. Oxford U. Press, 1999. 



Science 878:271, 1999. 


KL, Lokeshwar, BL and Holick, MF. 

The in vitro evaluation of 25-hydroxy vitamin 




6:901, 2000. 

Lokeshwar, BL, Escatel, E and Zhu, 

B. Cytotoxic activity and inhibition of 

tumor cell invasion by derivatives of a 



8:271, 2001. 


Burnstein, KL. Correspondence re: S. E., 

Blutt, T. C., Polek, L. V. Stewart, M. W., 

Kattan, and N. L., Weigel, A. Calcitriol 



Research 61:4294, 2001. 








276:11922, 2001. 

Obek, C, Shelfo, SW, Korman, HJ 

and Soloway, MS. Intravesical therapy 

for transitional cell carcinoma of the 

bladder: The community practice. Urology 

53:82, 1999. 

Obek, C, Neulander, E, Sadek, S 

and Soloway, MS. Is there a role for digital 

rectal examination in the follow up 

of patients after radical prostatectomy. 


Sadek, S, Soloway, MS, Hook, S and 

Civantos, F. The value of upper tract 

cytology after transurethral resection of 

bladder tumor in patients with bladder 

transitional cell cancer. Journal of Urology 

161:77, 1999. 

Obek, C, Louis, P, Civantos, F and 

Soloway, MS. Comparison of digital rectal 

examination and biopsy results with 

the radical prostatectomy specimen. 



Obek, C, Lai, S, Sadek, S, Civantos, 

F and Soloway, MS. Age as a prognostic 

factor for disease recurrence after radical 

prostatectomy. Journal of Urology 

54:533, 1999. 

Neulander, EZ, Duncan, RC, 

Tiguert, R, Posey, JT and Soloway, MS. 

Deferred treatment of localized prostate 

cancer in the elderly: The impact of the 

age and stage at the time of diagnosis on 

the treatment decision. British Journal 

of Urology International 85:699, 2000. 


HT, Wei, D, Young, MJ, Duncan, RC, 





163:348, 2000. 

Soloway, MS and Obek, C. Periprostatic 

local anesthesia before ultrasound 

guided prostate biopsy. Journal of Urology 

163:172, 2000. 

Rubinowicz, DM, Soloway, MS, 

Lief, M and Civantos, F. Hemospermia 

and expressed tumor in the urethra: An 

unusual presentation of ductal carcinoma 

of the prostate. Journal of Urology 

163:915, 2000. 

Posey, JT, Neulander, EZ, Soloway, 

MS and Civantos, F. Signet ring cell carcinoma 

of a pulled-through sigmoid colon 

mimicking a primary invasive 

bladder tumor: Case report and review 

of the literature. Urology 55:949, 2000. 

Ciancio, G, Hawke, C and Soloway, 

MS. The use of liver transplant techniques 

to aid in the surgical management 

of urological tumors. Journal of Urology 

164:665, 2000. 


local anesthesia before ultrasound 

guided prostate biopsy. Journal of Urology 

163:172, 2000. 



Leaders 

Ramin Mirhashemi, M.D. 


Aaron H. Wolfson, M.D. 


PARTICIPANTS 


Hervy E. Averette, M.D. 


Ramin Mirhasehmi, M.D. 


Manuel Peñalver, M.D. 


Leo B. Twiggs, M.D. 



Christiane Takita, M.D. 




Medical Oncology 


Medicine 

Diagnostic Radiology 

Marco A. Amendola, M.D. 

Radiology 

Pathology 

Parvin Ganjei-Azar, M.D. 

Pathology 

Mehrdad Nadji, M.D. 

Pathology 

Basic Research Radiation Biology 

Paul G. Braunschweiger, Ph.D. 


Radiation Experimental 

Therapeutics 

Atwar Ganju Krishan, Ph.D. 



The Gynecologic Oncology Multidisciplinary 

Site-Based Group at 

UM/Sylvester is dedicated to the ongoing 

investigation of the optimal method 

of treating patients with malignant tumors 

of the female reproductive organs 

such as the uterus, cervix, ovaries, fallopian 

tubes, vulva, and vagina. Emphasis 

is placed on a collaborative approach 

among physicians, nurses, basic scientists, 

and data managers in achieving this 

goal. In addition, efforts are underway 

not only to cure patients with female 

genital tract cancers but also to preserve 

their pelvic organs with as much normal 

functioning as possible. 

On the basic science area, Dr. Braunschweiger’s 

research team is investigating 

the use of nitric oxide as a radiationenhancing 

agent for patients with invasive 

cancer of the cervix and the study of 

glucose transporters in ovarian and cervical 

cancers. 

Dr. Krishan and Dr. Wolfson are 

working on a study of DNA abnormalities 

for predicting the survival of patients 

with invasive cancer of the cervix that 

have treatment with both radiation and 

chemotherapy. This project is funded by 

RTOG and seeks to use high resolution 

flow cytometry for the analysis of aneuploidy 

and cell cycle distribution in human 

cervical cancer. 

On the clinical research area the 

group is working on the development of 

a new type of radiation delivery system 

to improve the treatment of patients with 

invasive cancer of the cervix that undergo 

low-dose-rate brachytherapy as a portion 

of their radiotherapy. 


Evaluation of DNA Aneuploidy and 

S-Phase Fraction as Indicators of Response 

to Chemoradiotherapy in Patients 

with Invasive Cervical Carcinoma. Aaron 

H. Wolfson, M. 

Phase II Non-Randomized Study of 

Carboplatin and Topetecan in Patients 

with Stage III and IV Ovarian Epithelial 

Cancer. Ricardo Estape, M.D. 

58 


Phase III Randomized Study of 

Whole Abdominal Radiotherapy versus 

Combination Ifosfamide-Mesna with 

Cisplatin in Optimally Debulked Stage 

I, II, III, or IV Carcinosarcoma of the 

Uterus. Aaron H. Wolfson, M.D. Gynecologic 

Oncology Group (GOG#150) 

Trials 

Role of Radiation in the Pretreatment 

Evaluation of Invasive Cervical 

Cancer. Marco Amendola, Ricardo 

Estape, M.D.M.D. ACRIN (GOG 

#6651). 

PUBLICATIONS 

Gomez-Fernandez, CR, Ganjei- 

Azar, P, Capote-Dishaw, J, Averette, HE 

and Nadji, M. Reporting normal endometrial 

cells in pap smears: An outcome 

appraisal. Gynecology Oncology 

74:381, 1999. 

Hou, Y, Wang, J, Andreana, PR, 

Cantauria, G, Tarasia, S, Sharp, L, 

Braunschweiger, PG and Wang, PG. 

Targeting nitric oxide to cancer cells: 

cytotoxicity studies of glyco-Snitrosothiols. 

Bioorganic and Medicinal 

Chemistry Letters 9:2255, 1999. 

Cantauria, G, Magalhaes, A, 

Peñalver, MA, Angioli, R, Braunschweiger, 

PG, Gomez-Marin, O and Kanhoush, 

R. Expression of GLUT-1 glucose 

transporter in borderline and malignant 

epithelial tumors of the ovary. Gynecologic 

Oncology 79:33, 2000. 

Mendez, LE, Joy, S, Angioli, R, 

Estape, RE and Peñalver, MA. Primary 

uterine angiosarcoma Gynecolgic Oncology 

75:272, 1999. 

Cantuaria, G, Angioli, R, Nahmias, 

J, Estape, RE and Peñalver, MA. Primary 

malignant melanoma of the uterine cervix: 

case report and review of the literature. 

Gynecolgic Oncology 75:170, 

1999. 







Research 6:1508, 2000. 

Choy, N, Blanco, B, Wen, J, 

Krishan, A and Russell, KC. Photochemical 

and thermal bergman cyclization 

of a pyrimidine enediynol and 

enediynone. Organic Letters 2:3761, 

2000. 

Krishan, A. Monitoring of cellular 

resistance to cancer chemotherapy: drug 

retention and efflux. Methods Cell Biology 

164:193, 2001. 





43:2, 2001. 

Wen, J, Krishan, A and Thomas, 

RA. NASA/American Cancer Society 

high-resolution flow Cyometry project - 

II. Effect of pH and DAPI concentration 







flow Cyometry project - III. Multiparametric 





of apoptotic cells by formamide-induced 




Frankfurt, OS and Krishan, A. Enzyme-linked 

immunosorbent assay 

(ELISA) for the specific detection of 

apoptotic cells and its application to 

rapid drug screening. J Immunology 

Methods 253:133, 2001. 

Mirhashemi, R, Schoell, WM, 

Estape, RE, Angioli, R and Averette, 

HE. Trends in the management of pelvic 

abscesses. Journal of the American 

College of Surgeons 188:567, 1999. 

Mirhashemi, R, Averette, HE, 

Deepika, K, Estape, R, Angioli, R, Martin, 

J, Rodriguez, M and Peñalver, MA. 

The impact of intraoperative autologous 

blood transfusion during type III radical 

hysterectomy for early-stage cervical 

cancer. American Journal of Obstetrical 

Gynecology 81:1310, 1999. 

Schoell, WM, Mirhashemi, R, Liu, 

B, Janicek, MF, Podack, ER, Peñalver, 

MA, and Averette, HE. Generation of 

tumor-specific cytotoxic T lymphocytes 

by stimulation with HPV type 16 E7 

peptide-pulsed dendritic cells: An approach 

to immunotherapy of cervical 

cancer. Gynecology Oncology 3:448, 

1999. 

Cantuaria, G, Magalhaes, A, 

Angioli, R, Mendez, L, Mirhashemi, R, 

Wang, P, Peñalver, MA, Averette, H and 

Braunschweiger, PG. Antitumor activity 

of a novel glyco-nitric oxide conjugate 

in ovarian carcinoma. Cancer 88: 

381, 2000. 

Corn, BW, Mehta, MP, Buatti JM, 

Wolfson, AH, et al. Stereotactic Irradiation: 

A potential new modality in the 

management of brain metastases from 

ovarian cancer. American Journal of 


Wolfson, AH. Conventional radiation 

therapy of cervical cancer. Seminars 

Surgical Oncology 16:242, 1999. 

Head and Neck Oncology 

Multidisciplinary 

Site-Based Group 

Leader 



PARTICIPANTS 

Head and Neck Surgery 

David J. Arnold, M.D. 


Francisco J. Civantos, M.D. 




David T. Huang, M.D., Ph.D. 


Giovanna R. Thomas, M.D. 






Mercedes Porosnicu, M.D. 

Medicine 

Luis E. Raez, M.D. 

Medicine 


David T. Huang, M.D., Ph.D. 


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




Radiology 

Rita G. Bhatia, M.B.B.S. 

Radiology 

Pathology 

Carmen R. Gomez-Fernandez, M.D. 

Pathology 



Anatomy and Cell Biology 

Sheldon Greer, Ph.D. 




Abdul M. Mian, Ph.D. 

Medicine 


Patients with head and neck cancers 

are cared by a multidisciplinary 

team of surgeons, radiation oncologists, 

medical oncologists, dentists, prosthodontists, 

speech pathologists, and clinical 

nurse specialists. Head and neck 

cancers are treated with multimodality 

therapy that may include various combinations 

of surgery, radiation treatments, 

and chemotherapy as part of 

standard treatment protocols or as participants 

in clinical trails using investigational 

therapies or combinations of 

therapies. Each patient’s treatment regimen 

is individualized in this context of 

multidisciplinary care through the 

mechanisms of readily available consultations 

from each of the various treatment 

disciplines available at UM/Sylvester, 

as well as by evaluation at a multidisciplinary 

Head and Neck Tumor 

Board that meets weekly. 

The head and neck division at UM/ 

Sylvester is involved in a number of basic 

science and clinical research projects. 

Dr. Weed, in collaboration with Dr. 

Carraway, is involved in the study of a 

cell surface molecule known as MUC4, 

a human mucin that has been associated 

with other types of malignancies such as 

breast and pancreas tumors. MUC4 may 

be involved in the processes that change 

a non-cancerous cell to an immortal cancer 

cell, as well as the mechanisms of tumor 

spread or metastasis to other sites 

in the body. MUC4 has not previously 

been studied in head and neck cancers, 

and Dr. Weed’s preliminary work suggests 

it may change in important ways 

in head and neck tumors. While the significance 

of these changes are not yet 

known, preliminary data may implicate 

MUC4 as a marker by which aggressiveness 

of a particular tumor may be gauged. 

Another cell surface molecule, CD44, is 

being studied by Dr. Franzmann, a fellow 

in head and neck oncology, in collaboration 

with Dr. Bourguignon and 

Dr. Weed. As with MUC4, CD44 may 

play significant roles in cancer growth 

and metastasis for head and neck tumors. 

Other work involves the study of novel 

ways to enhance the body’s immune response 

as a means of treating head and 

neck cancers. This work is being carried 

out under the direction of the newest 

member of the Department of Otolaryngology, 

Dr. Thomas, in collaboration 

with Dr. Lopez. 

Dr. Greer’s laboratories have been 

fully engaged in developing 5-halogenated 

pyrimidines to improve radiation 

effects on tumors relative to normal tissues. 

The effectiveness of this class of 

compounds is greatly dependent upon 

their ability and extent of incorporation 

into DNA strands. As deoxyuridine analogs 

are rapidly catabolized by serum and 

tissue phosphorylases, thereby limiting 

their incorporation, the use of CldC with 

a deaminase inhibitor, i.e. tetrahydrouridine, 

has been shown to be superior 

as a radiosensitizing agent. CldC is 

anabolized and incorporated selectively 

into tumor DNA, mostly because the 

two pivotal enzymes (deoxycytidine kinase 

and deoxycytidine monophospate 

deaminase) are elevated many-fold on 

most human malignant tumors when 

compared to the adjacent normal tissue. 

In collaboration with Dr. Sridhar, Dr. 

Goodwin, Dr. Arnold, and Dr. Mian, Dr. 

Greer currently is conducting these enzyme 

studies in head and neck tumor 

patients as a prelude to Phase I clinical 

trails. They are also evaluating the stability 

of CldC in the presence of 

sulphydrl agents including amifostine 

(generally given to the cancer patient 

undergoing radiation). Preliminary studies 

show that this molecule was stable 

after 72 hours of exposure. Dr. Mian and 

Dr. Greer also are establishing the HPLC 

assay conditions to undertake the pharmacokinetic 

and drug metabolism studies 

needed in conjunction with Phase I 

clinical trails. 

These ongoing collaborative efforts 

are aimed in developing the rationale as 

well as the needed methodologies to carry 

out the clinical evaluation of CldC and 

tetrahydrouridine as a selective radiosensitizer. 

More clinically oriented studies are 

also being carried out both with the confines 

of the medical center as well as in 

the context of national clinical trails and 

studies. Dr. Civantos is studying the applicability 

of lymphoscintigraphy to cancers 

of the mouth and tongue as a 

possible means of selective detection of 

early spread of these tumors to cervical 

lymph nodes. If this technique is successful, 

more extensive operations to remove 

multiple lymph nodes in the neck might 

not be necessary for certain early cancers. 

Dr. Civantos has initiated this study 

at UM/Sylvester and currently is working 

with the American College of 

Surgeons to expand this study as a multiinstitutional 

national trail. The group is 

also involved in a number of studies investigating 

the speech and swallowing 

outcomes and quality of life outcomes 

that result from the type of extensive sur- 

60 


gical resections and reconstructions routinely 

performed in the treatment of head 

and neck cancers. These studies are 

multi-institutional, originating from 

Northwestern University and led here at 

UM/Sylvester by Donna Lundy, M.A., 

a speech pathologist. The disciplines of 

head and neck surgical oncology, radiation 

oncology, and medical oncology 

participate in a number of national clinical 

trials investigating novel combinations 

of chemotherapeutic agents and 

radiation treatments, as well as novel 

therapeutic strategies involving antibodies 

to tumor growth receptors and gene 

therapy strategies for advanced unresectable 

head and neck tumors. Gene 

therapy trials have focused in 

intratumoral injections of wild-type p53 

gene using an adenoviral vector, and are 

led at UM/Sylvester by Dr. Goodwin. 

PUBLICATIONS 



D, Guy, PM, Carvajal, ME, Fregien, N, 





Chemistry 274:5263, 1999. 



and Motor Proteins. T. Kreis and R.D. 




125:15, 2000. 

Civantos, FJ, Roth, J, Goodwin, WJ 

and Weed, DT. Sensory recovery in 


Otolaryngology, Head and 

Neck Surgery 122:509, 2000. 

Telischi, FF, Bustillo, A, Whiteman, 

ML, Serafini, AN, Reisberg, MJ, Gomez- 

Marin, O, Civantos, FJ and Balkany, FJ. 

Octreotide scintigraphy for the detection 

of paragangliomas. Otolaryngology 

Head Neck Surgery 122:358, 2000. 

Rhee, JS, Davis, RE and Goodwin, 

WJ. Minimizing deformity from parotid 



7: 90, 1999. 

Goodwin, WJ. Outcomes analysis 

in patients with head and neck cancer: 

Peer reviewed editorial. Archives of Otolaryngology-Head 


126:335, 2000. 

Goodwin, WJ. Salvage surgery for 

patients with recurrent squamous cell 

carcinoma of the upper aerodigestive 

tract: When do the ends justify the 

means? Laryngoscope 93:1, 2000. 

Mayne, ST, Cartmel, B, Baum, M, 

Shor-Posner, G, Fallon, BG, Briskin, K, 

Bean, J, Zheng, TZ, Cooper, D, Friedman, 

C and Goodwin, WJ. Randomized 

trial of supplemental beta-carotene to 

prevent second head and neck cancer. 


Ress, BD, Sridhar, KS, Balkany, TJ, 

Waxman, GM, Stagner, BB and 

Lonsbury-Martin, BL, Krishan, A. Effects 

of cis-platinum chemotherapy on 

otoacoustic emissions: The development 

of an objective screening protocol. Otolaryngology 

Head Neck Surgery 121: 

693, 1999. 







Research 6:1508, 2000. 

Thomas, GR, Chen, Z, Loukinova, 

E, Oechsli, MN, Hendler, FJ, Van Waes, 





82:377, 1999. 

Moore, CE, Wiatrak, BJ, McClatchey, 

KD, Koopmann, CF, Thomas, 

GR, Bradford CR, Carey TE. High-risk 

human papillomavirus types and squamous 


papillomas. Otolaryngology - 

Head and Neck Surgery 120(5):698, 

1999. 







patients with Head and Neck Cancer. 


Thomas, GR, Chen, Z, Enamorado, 

I, Bancroft, C, Van Waes, C. IL- 

12 and IL-2 induced tumor regression 

in a new murine model of oral squamous 

carcinoma is modulated by expression of 









Edited by Veldman, Passali, and 

Lim. Kugler Publications, pp. 233, 2000. 

Takeda, N, Thomas, GR, Ludlow, 

CL. Aging effects on motor units in the 

human thyroarytenoid muscle. Laryngoscope 

110(6):1018, 2000. 

Loukinova E, Dong, G, Enamorado, 

I, Thomas, GR, Chen, Z, Schreiber, 

H, Van Waes, C. Growth regulated oncogene-alpha 

expression by murine squamous 

cell carcinoma promotes tumor 

growth, metastasis, leukocyte infiltration 

and angiogenesis by a host CXC receptor-2 

dependent mechanism. Oncogene 

19:3477, 2000. 

Bidus, KA, Thomas, GR, Ludlow, 

CL. Effects of adductor muscle stimulation 

on speech in abductor spasmodic 

dysphonia. Laryngoscope 110: 1943, 

2000. 

Sunwoo, JB. Herscher, LL. Kroog, 

GS. Thomas, GR. Ondrey, FG. Duffey, 

DC. Solomon, BI. Boss, C. Albert, PS. 

McCullugh, L. Rudy, S. Muir, C. Zhai, 

S. Figg, WD. Cook, JA. Mitchell, JB. 

Van Waes, C. Concurrent paclitaxel and 

radiation in the treatment of locally advanced 



Weed, DT, Carraway, K, Carvajal, 








121:87, 1999. 

Li, P, Arango, ME, Perez, RE, Reis, 

CA, Bonfante, EL, Weed, DT and 

Carraway, KL. Expression and localization 

of immunoreactive-sialomucin complex 

(Muc4) in salivary glands. Tissue 

and Cell 33:111, 2001. 

Hematologic/Malignancies 


Leader 

Hugo F. Fernandez, M.D. 

Medicine 

PARTICIPANTS 

Hematology/Oncology 

John J. Byrnes, M.D. 

Medicine 

Hugo F. Fernandez, M.D. 

Medicine 

Mark S. Goodman, M.D. 

Medicine 


Laurence H. Boise, Ph.D. 


H. James Hnatyszyn, Ph.D. 


Norma S. Kenyon, Ph.D. 

Medicine 

Gunter K. Kraus, Ph.D. 







The Hematological Malignancy/ 

Blood and Marrow Transplantation 

Site Based Oncology Group is focused 

on developing new treatments for patients 

with leukemia, lymphoma, multiple 

myeloma, and other hematologic 

disorders. The groups’ therapy is based 

on standard approaches with the development 

of novel chemotherapeutic and 

62 

immunologic treatments of these diseases. 

High-dose chemotherapy and stem 

cell transplantation is used to further 

enhance these treatment modalities. 

Research in the group includes testing 

new agents for the treatment of chemotherapy 

resistant multiple myeloma, 

development of anti-leukemia vaccines, 

understanding the mechanisms of graft 

versus host disease following bone marrow 

transplantation, developing cuttingedge 

molecular diagnosis, detecting leukemia-related 

genes, enhancing bone 

marrow stem cell, collecting and conditioning/engrafting 

techniques to improve 

bone marrow transplantation, and preventing 

graft rejection following transplantation. 

Several of these studies have 

shown significant promise in the laboratory 

and now are being tested in patients. 

Researchers in the Leukemia Group 

presently are testing a novel treatment 

using a familiar drug to fight a deadly 

cancer of the blood called multiple myeloma. 

The treatment was developed by 

UM/Sylvester researchers and sponsored 

by the National Cancer Institute, to test 

the effectiveness of arsenic trioxide and 

vitamin C in destroying myeloma cells 

that have become resistant to the effects 

of standard chemotherapy. Multiple myeloma, 

primarily a disease of the blood 

and bone marrow, is the second-most 

common blood malignancy behind leukemia. 

More than 13,000 people in the 

United States are diagnosed with the disease 

each year, and its incidence—particularly 

among adults age 50 to 70—is 

increasing. Chemotherapy has traditionally 

been the treatment for multiple myeloma, 

but over time, the disease becomes 

resistant to the cancer-fighting drugs. 

Doctors have attempted to slow that 

progression with escalating doses of 

chemotherapy followed by bone marrow 

transplantation. The treatment often extends 

life, but eventually the myeloma 

cells continue to grow unchecked and the 

disease becomes fatal. 

While the toxic properties of arsenic 

are legendary, these researchers have developed 

a novel way to target its strength 

in a positive way. Vitamin C appears to 

boost the cancer-killing effect of arsenic, 

so relatively small quantities of the drug 

can achieve effective results. In addition, 

arsenic kills multiple myeloma cells in a 

different manner than traditional chemotherapy, 

with a different range of tolerable 

side effects. 

The clinical trial, the only one of its 

kind under way in the United States, was 

developed by a team of UM/Sylvester scientists 

and clinicians led by Dr. Lee. The 

initial phases of the clinical trial will determine 

the combination of arsenic trioxide 

and vitamin C that is most effective 

in the treatment of patients with relapse 

or chemo-resistant multiple myeloma. 

Researchers also hope to find clues about 

why nearly 90 percent of myeloma becomes 

resistant to chemotherapy over 

time and how they can overcome that 

resistance. The two-year trial, a community-wide 

effort, will enroll up to 25 patients 

at UM/Sylvester and three other 

community hospitals. 

CLINICAL TRIALS 

Arsenic trioxide and vitamin C as therapy 

for relapsed/refractory multiple myeloma. 

K. Lee. 

Phase III evaluation of three induction 

regimens and the addition of Mylotarg 

prior to autologous transplants for patients 

with acute myeloid leukemia- 

ECOG Study. H. Fernandez. 

Phase III trial to evaluate the use of Holmium–DOMP 

in patients with multiple 

myeloma. M. Goodman. 

Phase I trial for the evaluation of safety 

and pharmacokinetics of intravenous 

Busulfan on a twice a day and daily 

schedule. H. Fernandez. 

Phase I/II trial of Mylotarg, Busulfex, and 

cyclophosphamide for high-risk and relapsed 

AML M. Goodman. 


PUBLICATIONS 

Johnson, BW and Boise, LH. Bcl-2 

and caspase inhibition cooperate to inhibit 

Tumor Necrosis Factor?-induced 

cell death in a Bcl-2 cleavage-independent 

fashion. Journal of Biological 

Chemistry 274:18552, 1999. 

Wang, S, Wang, Z, Boise, LH and 

Grant, S. Circumvention of Bcl-x L 

-mediated 

inhibition of paclitaxel-induced 

mitochondrial dysfuntion and apoptosis 

by bryostatin 1 in human myelomonocytic 


13:1564, 1999. 

Wang, S, Wang, Z, Boise, LH, Dent 

P and Grant S. Loss of the Bcl-2 phosphorylation 





and Biochemical Research Communications 

259:67, 1999. 

Lee, RK, Cai, J-P, Deyev V, Gil, PS, 



Harrington, WJ Jr. Azidothymidine and 


virus associated lymphomas. Cancer Research 

59: 5514, 1999. 

Muta, H, Boise, LH, Fang, L, 

Podack, E. CD30 signals integrate expression 





Grad, JM, Bahlis, NJ, Reis, I, 

Oshiro, MM, Dalton, WS and Boise, 

LH. Ascorbic acid enhances arsenic trioxide-induced 

cytotoxicity in multiple 

myeloma cells. Blood 98:805, 2001. 

Cepero, E, Johnson, BW and Boise, 

LH. Cloning and analysis of Bcl-2 family 

genes. Methods in Cell Biology 66:29, 2001. 

Jost, M, Huggett, TM, Kari, C, 

Boise, LH and Rodeck, U. Epidermal 

growth factor receptor-dependent control 

of keratinocyte survival and Bcl-x(L) 

expression through a MEK-dependent 

pathway. Journal of Biological Chemistry 

276:6320, 2001. 

Restrepo, A, Albrecht, F, Raez, LE, 

Fernandez, HF, Nassiri M, Byrne GE Jr 

and Cassileth PA. Post-liver transplantation 

lymphoproliferative disorders with 

and without infusions of donor bone 

marrow cells. Critical Review Oncogenes 

10:239, 1999. 

St., Louis, D, Woodcock, J, Fransozo, 

G, Blair, P, Carlson, LM, Murillo, ME, 








162(6):3237, 1999. 

Tadaki, DK, Kirk, AD, Craighead, 

N, Saini, A, Chute, JP, Lee, KP and 

Harlan, DM. Costimulatory molecules 

are active in the human xenoreactive T- 

cell response but not in NK mediated 

cytotoxicity. Transplantation 70:162, 

2000. 

Jiang, Z, Podack, E and Levy, RB. 

Donor T-cells which cannot mediate 


cytotoxicity can effect graft vs. host reactivity 

following allogeneic bone marrow 

transplantation. Periodicum Biologorum 

100:477, 1999. 

Ferrara, J, Choi, N and Levy, RB. 

Pathophysiologic mechanisms of acute 



Jones, M, Komatsu, M and Levy, 

RB. Cytotoxically impaired transplant 

recipients can efficiently reject major histocompatibility 


allografts. Biology of Bone 

Marrow Transplant 6:456, 2000. 

Jiang, Z., Podack, E., Levy, RB. 



using perforin and/or Fas 

ligand double-defective CD4(+) donor 

T-cells: involvement of cytotoxic function 



98:390, 2001. 

Neurological Oncology 


Leaders 

Deborah O. Heros, M.D. 

Neurology 

Howard J. Landy, M.D. 


PARTICIPANTS 

Neurosurgery 

Howard J. Landy, M.D. 


Nizam Razack, M.D. 




Medicine 


Medicine 

Neurology 

Deborah O. Heros, M.D. 

Neurology 

Priscilla Potter, M.D., Ph.D. 

Neurology 


Avis M. Bernstein, Ph.D. 


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


B-Chen Wen, M.D. 






Recent research activities have involved 

study of radiation sensitizers 

vitamin D and MRI in high-grade 

glioma. The group has been studying the 

use of estramustine, a chemotherapy 

agent currently used for prostate cancer, 

as a radiosensitizer in the treatment of 

high-grade gliomas with radiation 

therapy and Gamma Knife stereotactic 

radiosurgery. Approximately 20 patients 

have been treated thus far with encouraging 

preliminary results. Laboratory 

studies utilizing glioma cells in tissue 

culture have shown promotion of tumor 

cell death by apoptosis when the cells are 

exposed to vitamin D. 

The Neuro-Oncology Laboratory, 

headed by Dr. Savaraj, is investigating the 

use of vitamin D to treat brain tumor 

patients. Dr. Savaraj has discovered a 

novel membrane protein in the tumors 

of patients with malignant glioma, which 

may predict which patients may respond 

to vitamin D therapy. A cellular receptor 

involved in the process has been identified. 

Based on this data, a clinical trial 

of vitamin D use in patients with highgrade 

glioma is being developed. A group 

of patients with high-grade gliomas has 

been identified with initially misleading 

findings on MRI scans. Analysis of these 

patients has led to a publication describing 

guidelines for the radiographic evaluation 

of these patients. 


SCCC 1995008: Gamma Knife radiosurgery, 

radiation therapy, and estramusline 

for high-grade glioma. 

SCCC 1998070: CPT-11 and VM-26 

for high-grade glioma. 

PUBLICATIONS 

Landy, HJ: Localization and brain 

tumor surgery. Advances in Clinical Neurosciences 

9:13, 1999. 

Zou, J, Landy, HJ, Xu, R, Lampidis, T, 

Feun L, Wu, CJ, Furst, AJ, Savaraj, N: 

A unique 220-kd protein correlates with 

vitamin D sensitivity in glioma cells, Biochemical 


Landy, HJ, Lee, TT, Potter, P, 

Feun, L, Markoe, A: Early MRI findings 

in high-grade glioma. Journal of 

Neuro-Oncology 47:65, 2000. 

Abdel-Wahab, M, Corn, B, Wolfson, 

A, Raub, W, Gaspar, LE, Curran, W 

Jr, Bustillo, P, Rubinton, P and Markoe, 

A. Prognostic factors and survival in patients 

with spinal cord gliomas after radiation 

therapy. American Journal of 


Breast Cancer Multidisciplinary 

Site-Based Group (Developing) 

Leaders 

Sandra X. Franco, M.D. 

Medicine 


Surgery 

PARTICIPANTS 

Surgical Oncology 


Surgery 


Surgery 

Jodeen E. Powell, M.D. 

Surgery 


Sandra X. Franco, M.D. 

Medicine 

Judith Hurley, M.D. 

Medicine 


Medicine 


Medicine 

Orlando Silva, M.D. 

Medicine 

Catherine F. Welsh, M.D. 

Medicine 


Cristiane Takita, M.D. 


Radiology 

Joyce C. Lentz, M.D. 

Radiology 

Maria V. Velasquez, M.D. 

Radiology 

Pathology 

Carmen Gomez-Fernandez, M.D. 

Pathology 

Merce Jorda, M.D., Ph.D. 

Pathology 

Familial Breast and Ovarian 

Cancer Center 

Fernando Arena, M.D., Ph.D. 


Talia R. Donnenberg, M.S., C.G.C. 


Ramin Mirhashemi, M.D. 



Between Jackson Memorial Hospital 

and UM/Sylvester, 600 new cases 

of breast cancer are diagnosed each year. 

More than 100 additional breast cancer 

patients are seen after their initial diagnosis 

for treatment. This large cohort of 

patients provides a wide opportunity for 

research in breast cancer. 

The research of the breast cancer site 

disease group can be broken down into 

four categories: 1) Psycho-Oncology; 2) 

Epidemiologic; 3) Clinical; and 4) Basic 

Research. 

Psychosocial Research 

In the area of Psycho-Oncology research, 

members of the group collaborate 

with researchers in the Cancer 

Control Program (Dr. Antoni and Dr. 

Carver) on studies focusing on the ef- 

64 


fects of stressors and stress management 

interventions on the adjustment to and 

physical course of diseases such as breast 

cancer. 

Dr. Antoni’s research examines some 

of the psychobiological mechanisms that 

might explain the ways in which stressful 

events and psychosocial interventions 

contribute to the adjustment 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). 

Dr. Carver’s 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. A 

detailed description of the research is 

available in the Cancer Prevention and 

Control section of this report. 

Epidemiologic Research 

With the creation of the Familial 

Ovarian/Breast Cancer Center through 

the Department of Obstetric and Gynecology, 

the ability to perform epidemiologic 

and preventive research in the area 

of breast cancer has expanded. For example, 

one of the group’s ongoing studies, 

in collaboration with Dr. Baumbach- 

Reardon from the Cancer Control Program, 

focuses on the analysis of genetic 

risk factors for breast/ovarian cancer in 

African-American women. This research 

suggests that novel genetic mutations 

may underlay the susceptibility of minority 

patients to familial breast cancer 

as compared to better-studied populations 

such as Ashkenazi Jewish women. 

A detailed description of the research is 

available in the Cancer Control section 

of this report. 


Basic research using breast cancer 

models is a major focus in the Tumor 

Immunology and Tumor Cell Biology 

research programs. The focus of the individual 

studies varies widely. Researchers 

in the Tumor Cell Biology Program 

are involved in investigations related to 

the ultrastructural analyses of proteins, 

understanding metastasis of tumors and 

how signaling pathways and molecules 

transmit and integrate information, 

which determines cell fate, including cell 

structure and function. 

Dr. Carraway’s primary research effort 

for much of the past decade, for example, 

has been concerned with the role 

of cell surface glycoproteins in mammary 

cancer, focusing on a particular glycoprotein 

complex (sialomucin complex, 

SMC, rat Muc4) that his laboratory discovered 

about 20 years ago. 

Dr. Fregien’s research is directed towards 

understanding the molecular basis 

for the progression of noninvasive 

tumor cells into highly aggressive, metastatic 

cancer cells. 

Dr. Welsh’s research focuses on the 

study of cell cycle progression through 

the G1 phase and its regulation by 

growth factor receptors and adhesion to 

the extracellular matrix. Her team 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. 

The role of Rho B signaling in relation 

to cyclin D1 expression and cell cycle 

progression is being actively investigated. 

In the Tumor Immunology Program, 

researchers are investigating numerous 

aspects of the immune system in relation 

to the development and treatment of 

cancer. For example, Dr. Kraus and Dr. 

Hnatyszyn focus their research on the 

design, development, and evaluation of 

novel gene therapies for human malignancies 

including breast cancer. A second 

area of research involves the design 

and development of safe and effective 

vaccines against various human cancers. 

Dr. Lopez’s research relates to the role 

of cell-mediated immunity in breast tumors 

progression, focusing on the effect 

of tumor-derived factors and tumorinduced 

cytokines. 

The laboratory of Dr. Rosenblatt is 

currently focused 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 SLC, 

DC-CK1 and /or RANTES respectively, 

on the development of an anti-tumor 

response. In addition, his laboratory has 

synthesized 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 and has 

documented the ability to bind to cognate 

antigenic targets and to deliver a 

local costimulatory signal to tumors bearing 

her2/neu in vivo. In addition the 

laboratory has synthesized antibody fusion 

proteins with fused chemokine domains 

such as RANTES, which can also 

localize to tumor. The potential for local 

delivery of a chemotactic signal is currently 

being investigated using a novel 

B-cel deficient mouse model that allows 

the testing of humanized antibody fusion 

proteins targeting human xenogeneic 

tumors in the mouse model. 

Detailed descriptions of each of the 

studies mentioned above can be found 

in the Tumor Cell Biology and Tumor 

Immunology sections of this report. 

Clinical Research 

One of the main clinical interests of 

the group has been the treatment of patients 

with locally advanced breast cancer. 

Clinical researchers in the group are 

investigating new treatment modalities 

for patients with high risk of recurrence 

such as Herceptin, used in combination 

with chemotherapeutic agents such as 

platinum salts and taxanes. This combination 

is extremely potent in laboratory 

studies and excellent clinical responses in 

the neoadjuvant setting have been witnessed 

using a combination of cis-platinum, 

Taxotere, and Herceptin. 

The group participates in the National 

Surgical Adjuvant Breast and 


Bowel Project (NSABP) under the leadership 

of Dr. Moffat. Since 1996, Dr. 

Moffat’s research interest primarily has 

been focused on the development of sentinel 

lymph node biopsy (SLNB) in cutaneous, 

colorectal, and breast cancers. 

The sentinel lymph node (SLN) is that 

one, two, or few lymph nodes in a regional 

lymphatic nodal basin, which are 

first in line to receive lymph drainage 

from a primary cancer. It is hypothesized 

that cancer cells metastasizing through 

the lymphatics will first seed out in the 

SLN(s) before reaching the other nodes 

in that basin. Therefore, if the SLN(s) 

can be accurately identified or localized 

and removed, the pathological status of 

such node(s) will accurately reflect the 

status of that regional lymph node basin. 

Thus, if localized SLNs are found 

by the pathologist to be free of tumor, 

the cancer patient can be spared major 

expensive, morbidity-prone radical/ 

therapeutic lymphadenectomy. 

Dr. Moffat was one of 11 surgeons 

who participated in the only multicenter 

validation trial of SLNB in early 

invasive breast cancer published to date. 

This trial demonstrated a highly satisfactory 

SLN localization rate, but a disturbingly 

high false-negative rate as well. 

A follow-up trial is now underway under 

the auspices of NSABP. The 11 surgeons 

who completed the validation trial 

are training approximately 5,000 surgeons 

across North America in the SLNB 

technique to allow them to participate 

in this new study (NSABP B-32 protocol). 


A series of innovative trials has been initiated 

at both JMH and UM/Sylvester. 

These include both intramural trials as 

well as pharmaceutical and cooperative 

group trials. A unique aspect of clinical 

research at JMH has been the inclusion 

of a high proportion of minority patients 

including Hispanic and African-American 

patients in trials, relative to other institutions. 

Active trials are listed below: 

Phase III randomized double-blind 

evaluation of LY353381 compared with 

Tamoxifen in women with locally advanced 

or metastatic breast cancer. S. 

Franco 

Phase II trial of neoadjuvant Herceptin, 

Taxotere and Cisplatinum in the treatment 

of locally advanced breast cancer. 

J. Hurley 

Phase II trial of neoadjuvant Carboplatinum 

and Taxotere in the treatment of 

locally advanced and inflammatory 

breast cancers that do not overexpress 

HER-2. J. Hurley. 

Pilot trial of local injection of human 

chorionic gonadotropin in early breast 

cancer: measurement of apoptotic and 

proliferative index before and after 

therapy 9939GCC-treatment. J. Hurley. 

NSABP B-30: A three-arm randomized 

trial to compare adjuvant Adriamycin 

and Cyclophosphamide followed by 

Taxotere, Adriamycin, Taxotere, and 

Cyclophosphamide in breast cancer patients 

with positive axillary lymph nodes. 

F. Moffat. 

NSABP: Study of Tamoxifen and 

Raloxifene (STAR) for the prevention of 

breast cancer. F. Moffat. 

NSABP B-32: A randomized, Phase III 

clinical trial to compare sentinel node 

resection to conventional axillary dissection 

in clinically node-negative breast 

cancer patients. F. Moffat. 

NSABP B-31: A randomized trial comparing 

the safety and efficacy of 

Adriamycin and Cyclophosphamide followed 

by Taxol (AC-T) to that of 

Adriamycin and Cyclophosphamide followed 

by Taxol plus Herceptin (AC-T+) 

in node-positive breast cancer patients 

who have tumors that overexpress HER2. 

F. Moffat. 

A clinical trial to identify the first draining 

lymph nodes (sentinal node) and to 

determine the prognostic value of the 

status of this lymph node. F. Moffat. 

ECOGE5194: Local excision alone for 

selected patients with DCIS of the breast. 

S. Richman. 

ECOGJMA.17: A Phase III randomized 

double blind study of Letrozole versus 

placebo in women with primary breast 

cancer completing five or more years of 

adjuvant Tamoxifen. S. Richman. 

Pain management skills for minority 

breast cancer patients. S. Richman. 

PUBLICATIONS 


A., McGregor, B, Arena, P, Kilbourn, K, 





cancer. Psychosomatic Medicine, 61:94, 

1999. 









61:94, 1999. 




study of Catholic and evangelical 





Arena, P and Antoni, MH. Religious orientation, 

religious coping and distress 



Medicine 61:118, 1999. 

Spencer, S, Lehman J, Wynings, C, 


Derhagopian, R, Ironson, G, and Love, 

66 




a multiethnic sample of early stage patients. 



MH, Weiss, S and Duran, R. Types, 

sources, and timing of social support: A 

prospective study of social support and 

distress among Hispanic breast cancer 

patients. Psychosomatic Medicine 

62:104, 2000. 


MH, Weiss, S and Duran, RE. An exploratory 

study of social support, distress, 

and life disruption among low-income 

Hispanic women under treatment for 

early-stage breast cancer. Health Psychology 

20:41, 2001. 

Antoni, MH, Lehman, JM, 

Kilbourn, KM, Boyers, AE, Culver, JL, 

Alferi, SM, Yount, SE, McGregor, BA, 

Arena, PL, Harris, SD, Price, AA and 

Carver, CS. Cognitive-behavioral stress 

management intervention decreases the 

prevalence of depression and enhances 

benefit finding among women under 

treatment for early-stage breast cancer. 










Arena, JF, and Baumbach, L. BRCA1 


American Families: results and implications. 


Genetics 65(4):A127(676), 1999. 




Dunston, G, Stoppa-Lyonnet, D, and 

Arena, JF. Evidence for a BRCA1 founder 

mutation in families of West African 

ancestry. American Journal of Human 

Genetics 65:575-578, 1999. 

Bathe, OF, Boggs, JE (Powell), 

Kaklamanos, IG, Franceschi, D, Moffat, 

FL and Livingstone AS. Metastasectomy 

as a cytoreductive strategy for treatment 

of isolated pulmonary and hepatic metastases 

from breast cancer. Surgical Oncology 

8:35, 1999. 

Huang, J, Zhang, B-T, Li, Y, Mayer, 

B, Carraway, KL and Carraway, CAC. 

c-Src association with and phosphorylation 

of p58 gag , a membrane- and microfilament-associated 

retroviral gag-like 

protein in a xenotransplantable rat mammary 

tumor. Oncogene 18:4099, 1999. 


Zhu, X and Komatsu, M. Regulation of 

expression of sialomucin complex (rat 





1999. 

Fregien, N, Carraway, CAC and 

Carraway, KL. An intramembrane 

modulator of the ErB2 receptor tyrosine 

kinase that potentiates neuregulin signaling. 


274:5263, 1999. 

Price-Schiavi, SA, Zhu, X, Aquinin, 

R, and Carraway, KL. Sialomucin complex 


growth factor beta in mammary 

gland by a novel post-translational 

mechanism. Journal of Biological Chemistry 

275:17800, 2000. 

Zhu, X, Price-Schiavi, SA and 

Carraway, KL. Extracellular regulated 

kinase (ERK)-dependent regulation of 

sialomucin complex/rat Muc4 in mammary 


2000. 


components in the mammary 

gland and breast cancer - Preface. Journal 


Neoplasia 6:249, 2001. 

Carraway, KL. Price-Schiavi, SA. 

Komatsu, M. Jepson, S. Perez, A. 





Li, P, Price-Schiavi, SA, Rudland, PS 


(rat Muc4) transmembrane subunit 

binds the differentiation marker peanut 

lectin in the normal rat mammary gland. 

Journal of Cellular Physiology 186:397, 

2001. 

Rodriguez Cuevas, S, Macias 

Carmen, G, Franceschi, D, Labastida, S. 

Breast carcinoma presents a decade earlier 

in Mexican women than in women 

in the United States or European countries. 

Cancer 863, 2001. 

Hurley, J, Lee, Y, Boggs, J (Powell) 

and Franco, S. Breast Cancer and Human 

Immunodeficiency Virus: A Report 

of Sixteen Cases. Breast Cancer Research 

and Treatment 57, 1999. 

Hurley, J, Franco, S, Gomez- 

Fernandez, C, Reis, I, Velez, G, Doliny, 

P, Harrington, W, Wilkerson and Lee. 

Breast Cancer and Human Immunodeficiency 

Virus: A Report of 20 Cases. 

Clinical Breast Cancer 2: 215, 2001. 

Guatam and Hurley, J. Phase II 

Study of Neoadjuvant Herceptin, 

Taxotere and Cisplatin in the Treatement 

of Locally Advanced and Inflammatory 

Breast Cancer. Advances in Breast Cancer 

3:5, 2001. 

Hurley, J, Doliny, P, Velez, G, Reis, 

I, Silva, O, Gomez-Fernandez, C, Velez, 

G, Lee, Y and Franco, S. High Rate of 

Axillary Node Clearance with Neoadjuvant 

Herceptin, Taxotere and Cisplatin 

in Locally Advanced and Inflammatory 

Breast Cancer. Breast Cancer Research 

and Treatment 69: 516, 2001. 

Lopez, DM, Cheng, X and Handel- 

Fernandez, ME. Interferon g- 

downregulation in mammary tumor 

bearing hosts: Implications for Tumor 

Progression and Immunotherapy. Proceedings 

of the 22nd Congress of the International 

Association for Breast Cancer 

Research (Ioannidou-Mouzaka, L., 

Agnantis, N.J., and Lopez, D.M. eds), 

Monduzzi Editore, Bologna, Italy, pp. 

11-15, 1999. 


Lobo, D and Lopez, DM. Early block 

in maturation is associated with thymic 

involution in mammary tumor-bearing 


2000. 



functions during mammary tumor 

development. Mechanisms of 

Tumor Escape from Immune Recognition, 

(A. Oliva, ed.). Harword Academic 

Publishers GMBH, Switzerland: 103- 

112, 2001. 

Averette, HE, Mirhashemi, R and 

Moffat, FL. Pregnancy after breast cancer: 

The ultimate medical challenge. 


Moffat, FL and Serafini, N. Sentinel 

lymph node biopsy for breast cancer: 

A new minimally invasive staging 

procedure. Contemporary Diagnostic 

Radiology 22:1, 1999. 

Moffat, FL, Gulec, SA, Sittler, SY, 

Serafini, AN, Sfakianakis, GN, Boggs, 

JE (Powell), Franceschi, D, Pruett, CS, 

Pop, R, Gurkok, C, Livingstone, AS and 

Krag, DN. Unfiltered sulphur colloid and 

sentinel node biopsy for breast cancer. Technical 

and kinetic considerations. Annals 

of Surgical Oncology 6:746, 1999. 

Krag, DN, Ashikaga, T, Moss, TJ, 

Kusminsky, RE, Feldman, S, Carp, NZ, 

Moffat, FL, Beitsch PD, Frazier, TG, 

Gaskin, TA, Shook, JW, Harlow, SP and 

Weaver, DL. Breast cancer cells in the 

blood. Breast Journal 5:354, 1999. 

Kalish, ED, Iida, N, Moffat, FL and 

Bourguignon, LYW. A new CD44v3- 

containing isoform is involved in tumor 

cell growth and migration during human 

breast carcinoma progession. Frontiers in 

Bioscience 4:1, 1999. 

Moffat, FL. Sentinel lymph node 

biopsy. Krag DN (Ed.) Handbook in 

Surgical Oncology, Landes Bioscience 

Publishers, Austin, TX 2000. 

Moffat, FL and Krag, DN. Sentinel 

node biopsy for breast cancer: Showtime 

or dress rehearsal? In Vivo 14:255, 2000. 

Moffat, FL. Sentinel node biopsy is 

not an alternative to axillary dissection 

in breast cancer. Journal of Surgical Oncology 

– Supplement 77:153, 2001. 

Bland, KI. Moffat, FL. Morris, DM. 

Klimberg, S. Foster, R. McMasters, KM. 

Dermal injection of radioactive colloid 

is superior to peritumoral injection for 

breast cancer sentinel lymph node biopsy: 

Results of a multi-institutional 

study – Discussion. Annals of Surgery 

233:684, 2001. 

Anderson, KO, Mendoza, TR, 

Valero, V, Richman, SP, Russell, C, 

Hurley, J, DeLeon, C, Washington, P. 

Palos, G, Payne, R, Cleeland, CS. Minority 

cancer patients and their providers: 

pain management attitudes and 

practice. Cancer 88:1929, 2000. 

Welsh, CF, Assoian, RK. A growing 

role for Rho family GTPases as intermediaries 

in growth factor- and adhesiondependent 

cell cycle progression. Biochimica 

et Biophysica Acta. 1471(1): 

M21, 2000. 

Welsh, CF, Roovers K. Villanueva 

J. Liu YQ. Schwartz MA. Assoian RK. 



Cell Biology. 3(11):950, 2001. 

Colorectal Cancer 

Multidisciplinary Site-Based 

Group (Developing) 

Leader 

Michael D. Hellinger, M.D. 

Surgery 

PARTCIPANTS 

Surgery 

Michael D. Hellinger, M.D. 

Surgery 

Laurence R. Sands, M.D. 

Surgery 


Bach Ardalan, M.D. 

Medicine 




Gastroenterology 

Jose A. Garrido, M.D. 

Medicine 


The Colorectal Malignancies Multidisciplinary 

Site-Based Group currently 

is involved in an NIH-sponsored 

multicenter prospective randomized trial 

of laparoscopic versus open surgery for 

colon cancer. In addition, they are working 

with the same group in establishing 

a similar protocol for rectal cancer. The 

group also is investigating trials for 

therapy of locally advanced rectal cancer. 

PUBLICATIONS 

Bathe, OF, Franceschi, D, Livingstone, 

AS, Moffat, FL, Tian, E and 

Ardalan, B. Increased thymidylate synthase 

gene expression in liver metastases 

from colorectal carcinoma: Implications 

for chemotherapeutic options and survival. 

Cancer Journal Scientific American 

5:34, 1999. 

Lung Cancer Multidisciplinary 


Leaders 


Medicine 

Richard J. Thurer, M.D. 

Surgery 

PARTICIPANTS 



Medicine 

Surgery 

Richard J. Thurer, M.D. 

Surgery 

Basic Science 




Medicine 

68 



Lung Cancer Vaccine: Tumor-derived 

peptides presented by MHC class I 

molecules are targets for tumor rejection 

by CD8+ CTLs. MHC-restricted CD8+ 

CTLs also are required for the identification 

and characterization of tumor 

antigens that will be useful for immune 

therapy. For many human solid tumors, 

however, tumor antigens remain undefined 

because of the difficulty of generating 

MHC-restricted, tumor-specific 

CTLs required for their analysis. CD8+ 

CTL responses are modulated by CD4+ 

helper T-cells and by antigen-presenting 

cells. In this study, highly purified CD8+ 

T-cells were mixed with tumor cells in 

primary cultures in the absence of any 

other cells to reduce the complexity of 

CTL generation. Tumor cells were transfected 

with HLA-A1 or HLA-A2 and 

used to stimulate partly matched HLA- 

A1- or HLA-A2-positive CD8+ T-cells. 

Partial MHC class I matching of tumor 

and CD8+ T-cells and omission of other 

cells in primary culture was highly effective 

in generating MHC class I-restricted 

CTL to poorly immunogenic small cell 

lung carcinomas (SCLCs). Cytotoxicity 

was further enhanced by cotransfection 

of tumor cells with B7.1 (CD80). 

ICAM-1 (CD54) was not as effective as 

costimulation. SCLC cells presented tumor-specific 

peptides with HLA-A1 and 

HLA-A2 and were lysed by A1- or A2- 

restricted CD8+ CTLs. A1- and A2-restricted 

CD8+ CTLs detected shared 

tumor antigens on unrelated SCLC tumor 

lines in addition to private antigens. 

The use of direct antigen presentation 

by MHC class I-transfected tumors to 

MHC class I-matched CD8+ T-cells is 

an effective way to generate MHC class 

I-restricted CTLs toward poorly immunogenic 

tumors in vitro, permitting the 

molecular identification of their tumor 

antigens. A clinical trial for the treatment 

of lung adenocarcinoma is currently conducted 

on the basis of these studies together 

with Dr. Sridhar, Dr. Savaraj, and 

Dr. Cassileth. 

Research activities continue in the 

area of multimodality treatment in advance 

stage lung cancer. New drug and 

radiation treatment approaches are being 

evaluated along with surgical resection 

in patients with pulmonary malignancies. 

Pioneering work done in collaboration 

with Kasi Sridhar, M.D., in developing 

the combination modality approach continues 

with follow-up of an initial group 

of patients treated more than ten years ago. 

Studies involving early stage disease 

are underway. Preoperative evaluation of 

early stage patients involving a search for 

micrometastatic disease are underway. 

These efforts are in collaboration with 

Dr. Sridhar and Dr. Katariya of the Division 

of Cardiothoracic Surgery. This 

has involved participation in the American 

College of Surgeons Oncology 

Group (ACOSOG) protocols evaluating 

the benefits of radical lymph node dissection 

in Stage I lung cancer and developing 

studies to indicate which patients 

with apparent early disease might benefit 

from adjuvant therapy. Participation 

in additional studies sponsored by the 

ACOSOG is planned. 

Studies continue regarding malignancies 

of the lung in patients with immune 

deficiencies in an effort to 

determine the appropriate treatment modalities 

for this group. 

PUBLICATIONS 


suicide: The need for dipeptidyl 

peptidase I. Proceedings National Academy 

of Science USA 96:8312, 1999. 


Gate L, Cossum, P and Lampidis, TJ. 


and MDR tumor cells systems. Anticancer 

Research 19:1277, 1999. 

Yamazaki, K, Spruill, G, Rhoderick, 

J, Spielman, J, Savaraj, N, and Podack, 

ER. Small-cell lung carcinomas express 

shared and private tumor antigens presented 

by HLA-A1 or HLA-A2. Cancer 

Research 18:4642, 1999. 







Research 6:1508, 2000. 

Katariya, K, Thurer, RJ. Malignancies 

associated with the immunocompromised 

state. Chest Surgery Clinics of 

North America 9:2:63, 1999. 

Katariya, K, Thurer, RJ. Thoracic 

malignancies Associated with AIDS 

Seminars in Thoracic and Cardiovascular 

Surgery. 12(2):148, 2000. 

Melanoma Multidisciplinary 


Leaders 

George W. Elgart, M.D. 

Dermatology 


Medicine 

PARTICIPANTS 



Medicine 

Surgery 


Surgery 

Dermatology 

Robert Johr, M.D. 

Dermatology and Cutaneous Surgery 

Robert S. Kirsner, M.D. 


Keyvan Nouri, M.D. 


Dermopathology 

George W. Elgart, M.D. 




Major research interests include 

studying angiogenesis factors 

such as VEGF (vascular endothelial 

growth factor) in tumor samples of melanoma. 

This may serve as a basis for the 

use of antiangiogenesis drugs to treat 

melanoma or as an adjuvant. The group 

has presented preliminary findings at a 

national cancer meeting. 

A Phase II trial of intravenous 

Navelbine with oral Tamoxifen has been 

completed. This study demonstrated that 

this regimen has antitumor activity in 

patients with malignant melanoma. The 

results have been published in Cancer. A 

Phase II trial of biochemotherapy in 

melanoma patients with promising results 

is currently being conducted. 

Another laboratory study involves 

the synergistic effects of green tea with 

the chemotherapy to treat melanoma 

patients. Green tea has chemopreventive 

activities and can inhibit carcinogenesis. 

Green tea can induce apoptosis in certain 

tumor cells as well. It also has been 

found that green tea can potentiate certain 

chemotherapeutic agents against 

melanoma cells. A clinical protocol is 

currently being prepared to use green tea 

with chemotherapy to treat melanoma 

patients. The laboratory findings were 

presented at the last AACR meeting. 

Current clinical research protocol is 

based upon our laboratory investigations 

in melanoma. They have found that 

cyclosporine can increase the toxicity of 

chemotherapy when used with interleukin 

2 and interferon. This appears to 

initiate an autoimmune response against 

the patient’s melanoma. The protocol is 

entitled “A pilot study of the initiation 

of an autoimmune reaction to tumor in 

melanoma patients by cyclosporine A, 

Alpha interferon, and interleukin 2 following 

chemotherapy with BCNU, 

DTIC, cisplatin and tamoxifen.” 


Pilot study of the initiation of an 

autoimmune reaction to tumor in melanoma 

patients by cyclosporine A, Alpha 

interferon, and interleukin 2 following 

chemotherapy with BCNU, DTIC, 

cisplatin and tamoxifen. 

Phase II trial of biochemotherapy in 

melanoma patients. 

PUBLICATIONS 

Feun, LG, Savaraj, N, Hurley, J, 

Marini, A, Lai, SA: Clinical trial of intravenous 

navelbine in advanced malignant 

melanoma. Cancer 88: 584, 2000. 

Federman, DG, Reid, MC, Feldman, 

SR, Greenhoe, J and Kirsner, RS. 

The primary care provider and the care 

of skin disease - The patient’s perspective. 

Archives of Dermatology 137:25, 

2001. 

Sarcoma Multidisciplinary 


Leader 

H. Thomas Temple, M.D. 


PARTICIPANTS 

Orthopaedic Oncology 

Theodore I. Malinin, M.D. 


Walid Mnaymneh, M.D. 


H. Thomas Temple, M.D. 



Pasquale W. Benedetto, M.D. 

Medicine 

Jonathan L. Cohen, M.D. 

Medicine 


Medicine 

Pathology 

Merce Jorda, M.D., Ph.D. 

Pathology 

Miguel A. Suarez, M.D. 

Pathology 





The group has focused on new modalities 

to assess the response to chemotherapeutic 

intervention for both 

high-grade bone and soft tissue sarcomas 

using MRI spectroscopy. A pilot study is 

ongoing and preliminary data is being 

collected. A database is being set up, and 

it is anticipated that this project will be 

completed by June 2001. Other ongoing 

clinical studies include: “Treatment 

Outcomes in Patients with Unplanned 

Surgical Resections,” “The Efficacy of 

Chemotherapy in the Treatment of Soft 

Tissue Sarcomas,” and “MR Evaluation 

of Shoulder Pain in Patients Presenting 

with Proximal Humeral Enchondromas.” 

Data from the group was presented 

at the American Academy of Orthopaedic 

Surgeons on “Intercalary Allograft 

Reconstruction Following Tumor Resection” 

and “Reconstructive Salvage of Failed 

Allograft Implants.” The group also is interested 

in looking at the expression of proliferation 

markers immuno-histochemically 

pre- and post-chemotherapy in patients 

with high-grade soft tissue sarcomas. 

70 


Clinical Oncology Research 

Program (Developing) 

DESCRIPTION OF DEVELOPMENT 

The blueprint for the development 

of the Clinical Oncology Research 

Program (CORP) at UM/Sylvester is described 

below: 

Goal: Develop and Support High- 

Level Investigator Initiated Clinical 

Trials at UM/Sylvester. 

Areas of potential strength for novel clinical 

trials at University of Miami: 

• Molecular diagnostics (real time PCR 

via Roche LightCycler). 

• Small molecule clinical trials (arsenic, 

busulfan, vitamin D, nucleoside analogs 

(cytochlor)). 

• Immunotherapy (vaccines, dendritic 

cells, T-cells) utilizing existing cGMP 

facilities. 

• Bone marrow transplantation (stem cell 

purification, etc.) using existing cGMP 

facilities. 

• Biomolecules (antibodies, etc.) in conjunction 

with the DRI (with planned 

cGMP facility). 

Specific Aims of the CORP 

• Serve as the major conduit by which 

promising basic and preclinical research 

is translated into clinical trials. 

• Develop and support investigator-initiated 

clinical trials. 

• Provide CORP members priority access 

to unique “clinical grade” CORP 

core resources for the development of 

innovative trials. 

• Serve as UM/Sylvester’s scientific review 

body and sole access point by 

which investigators can access University-wide 

clinical resources (General 

Clinical Research Center, Cellular 

Therapies, and Tissue Engineering Initiative). 

Components of the CORP 

• Members 

• Clinical and Translational Research 

Committee (CTRC) 

• Phase I/II Clinical Trials Development 

Office (in the Clinical Research Services 

Office, CRS) 

• Core Resources 

a) Cell Purification and Processing 

Core (consisting of the current Research 

Apheresis Unit + Hematopoiesis 

Core (cGMP cell purification 

and ex vivo manipulation (bone 

marrow stem cells, immune cells)). 

b) Molecular Diagnostics Core (real 

time PCR and sequencing, currently 

the Vector Core (Kraus, Hnatyszyn). 

• GCRC/CTTEI Scientific Review Panel 

for the Cancer Center. 

OPERATIONAL PLAN 

Specific Aim 1 

• Serve as the major conduit by which 

promising basic and preclinical research 

is translated into clinical trials. 

a) Clinical and Translational Research 

Committee: The CTRC will review 

and fund promising translational research 

projects as it is currently doing. 

b) Dedicated Phase I/II Development 

Office in the CRS: Establishment of 

this office (with integrated Biostatistical 

and Database support) to help 

“convert” preclinical studies into appropriately 

designed clinical trials 

protocols. 


• Develop and support investigatorinitiated 


a) Funding support (through the 

CTRC and Programmatic). 

b) Dedicated Phase I/II Development 

Office in the CRS, with integrated 

Biostatistics and Data Management 

components. 


• Provide unique “clinical grade” core 

resources for the development of innovative 

trials. 

a) Core Facilities: CORP member would 

have priority access to these CORP 

Core Facilities, which would include 

cGMP cell processing and molecular 

diagnostics. 

b) Microarray analysis (through the UM/ 

Sylvester-Incyte contractural agreement). 

c) The CORP also would serve as the 

sole access point through which 

cancer center investigators can access 

to the clinical trial resources of 

the General Clinical Research Center 

(GCRC) and Cellular Therapies 

and Tissue Engineering Initiative (if 

these are funded). Both the GCRC 

and CTTEI will require scientific 

review and approval of protocols 

submitted for support, which would 

be the function of the CORP review 

committee. 

d) The GCRC is an NIH-funded center. 

The GCRC resources are available 

to approved trials that are 

nationally peer-review funded, or are 

in-house investigator initiated. 

These resources include: 

• Research MRI 

• Chemistry Core (serum 

biochemistry and metabolism 

assays) 

• Immunology Core (immune 

assays) 

• Physiology Core (metabolic 

functional assays, noninvasive 

cardiology) 

• Funding for routine laboratory 

tests, inpatient and outpatient 

hospitalization, specialized 

nursing requirements, etc. 

e) Cellular Therapies and Tissue Engineering 

Initiative. This is a University 

of Miami research initiative 

through the provost’s office. Resources 

include: 

• cGMP Cell Purification Core 

(in conjunction with the CORP 

Core) 

• cGMP Biomolecules Production 

Facility (clinical-grade antibodies, 

other biomolecules) 

• Histology Core 


72 



DESCRIPTION 

Shared Resources are available to all 

University of Miami Sylvester Comprehensive 

Cancer Center members. 

They provide access to technologies, services, 

and scientific consultation that facilitate 

interaction and enhance scientific 

productivity. Shared Resources provide 

a measure of stability, reliability, costeffectiveness, 

and quality control that 

would be difficult to achieve otherwise. 

UM/Sylvester investigators with peerreviewed, 

funded projects are the primary 

beneficiaries of all shared resources and 

services. A brief description of the Shared 

Research Resources supported by UM/ 

Sylvester follows. 

Gene KnockOut and Transgene 

Facility 

MANAGER 


Vice Chair and Professor of 


PURPOSE 

The purpose of this facility is to produce 

transgenic and knockout mice and to 

train investigators in this technology for 

application to their research. The major 

goal of the facility is to provide this 

technological capability to the peerreviewed 

funded cancer researchers at 

UM/Sylvester. 

SERVICES 

1) Set-up breeding of donor and recipient 

mice and to subsequently check 

plugs to confirm mating. 

2) Perform vasectomies of male mice 

for the recipient colony. 

3) Collect fertilized eggs or blastocytes. 

4) Sort and culture eggs. 

5) Prepare microinjection needles. 

6) Microinject eggs with DNA or 

blastocytes with cells. 

7) Inject donor and recipient mice with 

hormones. 

8) Perform microsurgery to re-implant 

eggs or blastocysts. 

9) Provide investigators with tissue biopsy 

to screen for transmission of 

transgene. 

10) Advise investigators in the production 

of transgenic and gene knockout 

constructs. 

11) Advise investigators in culturing and 

gene targeting embryonic stem cells. 

DNA Core Facility 

MANAGER 


Professor of Biochemistry 


PURPOSE 

To make DNA sequencing services available 

to UM/Sylvester members in support 

of their peer-reviewed funded 

research. 

SERVICES 

This facility provides UM/Sylvester investigators, 

in support of their peerreviewed 

funded research, with the following 

services: 

1) DNA Sequencing: The investigator 

provides the purified DNA for analysis 

and receives a sequence within 

three to five days. The sequence data 

is about 98 percent accurate. Some 

investigators do 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 double-stranded 

DNA, the facility also provides sequencing 

of PCR products. The results 

for this analysis are usually 

superior to those obtained from cloning 

DNA. 

2) Coordinate orders for synthesis of 

oligonucleotides from commercial 

sources for UM/Sylvester members. 

Flow Cytometry Resource 

MANAGER 




PURPOSE 

To provide 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 to train investigators 

in the use of flow cytometry for 

their research. 

SERVICES 

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 heterogenous mixtures. 

3) DNA content 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 

analytical flow cytometer, 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. 

Media Facility 

MANAGER 

Arba Ager, Ph.D. 



PURPOSE 

To support UM/Sylvester investigators 

in their use of cell cultures. To achieve 

this goal, the facility centralized distribution 

of cell culture media, salt solutions, 

enzymes, and antibiotics. The 

resource also maintains a stock of cell 

lines. 

Protein Analysis Facility 

MANAGER 

Vladimir A. Malinovskii, M.D., Ph.D. 

Research Assistant Professor of 


PURPOSE 

To make protein analysis services available 

to UM/Sylvester members in support of 

their peer-reviewed funded research. 

SERVICES 

1) Protein/Peptide Sequencing 

2) Peptide Synthesis 

3) Mass Spectrometry 

4) Amino Acid Analysis 

5) Protein Fragmentation 

6) High Performance Liquid 

Chromatography 

7) Electrophoresis/Blotting 

Cell Purification and 

Banking Facility 

MANAGER 


Associate Professor of Microbiology 

and Immunology and Medicine 

PURPOSE 

For many cancer researchers, the transition 

from small animal to human studies 

is prevented by the inability to obtain 

primary human cells, whether they are 

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, 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. 

Analytical Imaging Core 

MANAGER 

Alberto Pugliese, M.D. 

Research Associate Professor, 

Medicine 

PURPOSE 

The current Analytical Imaging Core is 

a joint Diabetes Research Institute and 

UM/Sylvester Comprehensive Cancer 

Center effort that represents a major 

upgrade over past imaging resources. 

The Analytical Imaging Core is housed 

in 460 square feet of dedicated laboratory, 

office, and storage space in the recently 

remodeled sixth floor of the Diabetes 

Research Institute. Approximately 

$1.2 million have been invested by the 

Diabetes Research Institute and UM/ 

Sylvester just to equip the core with the 

following key instruments: 

• Zeiss LSM-510 Confocal Laser Scanning 

Microscope (CLSM) 

• Atto Instruments Spinning Disk Confocal 

Microscope (CARV) 

• Laser Scanning Cytometer (LSC) 

• Leica DMIRB Epifluorescent Inverted 

Microscope 

• MetaMorph Imaging System (MIS) 

• Laser Capture Dissection Microscope 

(LCM) 

The core equipment also includes 

computers and peripherals attached to 

the above instruments, such as digital 

cameras and printers. Of note, the core 

equipment includes a professional grade 

Fujix 3000 printer (cost $10,000) that 

produces publication quality prints and 

is suitable for high volume output. The 

histology laboratory located at the Diabetes 

Research Institute supports the 

basic handling and processing of biological 

specimens and preparation for analysis. 

The facility also has some space and 

equipment (freezers, hoods, and incubators) 

for sample preparation and live cell 

work. 

SERVICES 

Confocal microscopy has become a standard 

technique of cell biology, offering 

many advantages over standard fluorescent 

microscopy including an increased 

sensitivity and effective resolution, and 

the ability to image relatively thick, 

fluorescently labeled biological specimens 

in two or three dimensions. Before 

the advent of confocal microscopy, images 

often appeared blurry by eye and 

proved technically challenging or impossible 

to capture on film because light 

from above and below the focal plane 

overwhelmed the image. 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 

74 


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 in our core is the Zeiss 

LSM-510, which is regarded as the premier 

instrument on the market. Designed 

to be a flexible instrument for use 

in multiple imaging techniques, the 

LSM-510 is ideal for a core laboratory. 

As equipped in our facility, the LSM-510 

can detect up to 5 channels, 4 fluorescent 

channels simultaneously, from UV 

to far red plus a separate detector for 

transmitted light. The outstanding beam 

control afforded by the 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 is also equipped with an 

Atto Instruments Spinning Disk Confocal 

Microscope (CARV), which is a 

mercury vapor lamp 3 color confocal 

instrument that is particularly suited for 

live cell analysis and video-rate (30 frames 

per second) imaging. The system can be 

upgraded to perform ratio imaging for 

the quantitation of calcium, sodium, 

cyclic AMP, and pH at 30 full frame ratio 

images per second. This capability is 

particularly useful in direct imaging of 

signal transduction pathways. Designed 

as a simple to use system optimized for 

imaging of live cells, the CARV system 

is an excellent complement to the LSM- 

510. 

Standard epifluorescence microscopy 

is available using a Leica DMIRB 

Inverted microscope equipped to perform 

triple fluorescence, phase contrast, 

and light microscopy, etc. This microscope 

is also equipped with an Eppendorf 

micro-manipulator. 

The core is equipped with a Laser 

Scanning Cytometer (LSC) from Compu- 

Cyte. This instrument 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 are made on each 

cell. Possible applications for the LSC 

include detection and quantitation of 

apoptosis (TUNEL, annexin), in situ 

hybridization (FISH), the study of cell 

adhesion, cell cycle, and DNA content, 

etc. 

Our ability to capture and analyze 

images through the above instruments is 

further enhanced by the availability of 

the MetaMorph Imaging System (MIS). 

This system consists of hardware and 

software that enables capture and analysis 

of microscopy or macro digital images 

obtained using the instruments 

described above. This allows for sophisticated 

analysis of live cell imaging, 

multi-label fluorescence, confocal microscopy, 

motion analysis, and co-localization 

studies, FISH, FRET, FRAP, live/ 

dead cell, and morphometric assay. 

The Analytical Imaging Core offers 

access to a Leica 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 

disease, where only small amounts 

of fixed tissue may be available for study. 

Clinical Research Services 

Resource 

MANAGER 



PURPOSE 

The purpose of the Clinical Research 

Services Resource is to provide UM/ 

Sylvester investigators with broad-based 

support for their clinical research activities, 

i.e., to: 

1) Evaluate the clinical trial protocol design, 

scientific merit, and patient carerelated 

issues through the Protocol 

Review Committee. 

2) Provide support services for screening, 

evaluating, recruiting, tracking, 

protecting, and maintaining patients 

on clinical protocols. 

3) 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. 

4) Assure compliance with guidelines for 

investigational drug use and toxicity 

reporting and maintain quality data 

management. 

5) Develop a data safety and monitoring 

board to monitor institutional 


6) Support national cooperative group 

activities and interact with UM/ 

Sylvester affiliates. 

7) Develop, operate, and maintain a 

computerized protocol data management 

system. 

8) Budget clinical trial expenditures and 

negotiate contracts with clinical trail 

sponsors. 


SERVICES 

1) Regulatory Office: This office handles 

all activities involving activation of 

clinical trials, which includes preparation 

of documents and presentation 

to both the UM/Sylvester 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 Clinical Research Services 

personal and office expenditures 

and negotiates the contracts with the 

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 DSMB. 

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. 

Core Research Histology Laboratory 

Developing Shared Resource 

MANAGER 

Carol K. Petito, M.D. 

Professor of Pathology 

PURPOSE 

In collaboration with the department of 

pathology, UM/Sylvester has recently 

supported the establishment of a Core 

Research Histology Laboratory to make 

histology services available to UM/ 

Sylvester researchers in support of their 

peer-reviewed funded research. 

SERVICES 

The facility currently provides the following 

services: 

1) Processing of fixed material into paraffin 

blocks. 

2) Tissue sectioning for routine hematoxylin-eosin 

stains. 

3) Tissue sectioning for immunohistochemistry. 

76 


DIVISION OF BIOSTATISTICS 

DIVISION CHIEF 


PROFESSIONAL EXPERTISE 


Division Chief 

Clarice Frankel 

Staff Associate 

Kara Hamilton, M.P.H. 

Biostatistician 

Isildinha M. Reis, Dr. PH. 


Gail R. Walker, Ph.D. 


Cheng Wang, M.S. 

Research Associate 

Jiuhua Wu, M.D., M.S. 


PURPOSE 

The Division of Biostatistics provides 

statistical expertise in the study, 

design, and data analysis for UM/ 

Sylvester members. Statisticians in the 

unit collaborate on developing protocols 

for clinical trials, work together on research 

proposals for laboratory-based 

investigations, and conduct epidemiologic 

studies. They also perform statistical 

analyses and substantively interpret 

their results, as well as author or co-author 

papers for publication. Biostatistics 

is committed to applying statistical and 

computational methods to improve the 

means by which clinical trials and translational 

research are conducted within 

UM/Sylvester and to developing statistical 

methodology that aids cancer research. 

Role in UM/Sylvester Research 

Collaboration: Members of the division 

seek to establish enduring collaborations 

with UM/Sylvester investigators 

to advance the 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. 

Consulting: In contrast to collaborations, 

which involve long-term collegial 

relationships in planning studies or 

analyzing data from them, 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. 

Current Activities: Members of the 

Division of Biostatistics are involved in 

developing protocols for Phase I and 

Phase II clinical trials and grant proposals 

for external funding. Statisticians in 

the division serve on UM/Sylvester’s Protocol 

Review Committee through rotating 

membership. 

The Divison of Biostatistics participates 

in audits by Clinical Research Services 

of investigator-initiated clinical 

trials. As a team, the division has developed 

an infrastructure for statistical 

work, including solutions to recurring 

statistical problems, development of statistical 

software, and the creation of a 

technical reference library. 

The division’s personnel also engage 

in teaching fellows who work on cancerrelated 

projects in clinical departments. 

Collaborative and consulting activities 

with UM/Sylvester members have resulted 

in the development of Phase I and 

Phase II oncology clinical trials, analyses 

of clinical oncology data, and publications 

on cancer-related projects. 

Examples of Biostatistical Expertise 

• Study design. The Division of Biostatistics 

can formulate study objectives 

and endpoints in terms that are appropriate 

for statistical analysis, recommend 

alternative study designs, 

determine the sample size needed to 

address study objectives at an appropriate 

level of significance and power, 

and develop and write plans for statistical 

analyses. The division has the tools 

to implement randomization procedures 

where needed, and can recommend 

alternative strategies and 

statistical methods for dose escalation/ 

de-escalation in Phase I trials. The unit 

also has the capability of applying interim 

stopping rules to clinical trials if 

proper data management has been established. 

• Data analysis. After study data have 

been collected, the Division of Biostatistics 

can perform exploratory and 

final statistical analyses, provide graphical 

and tabular reports of the results, 

substantively interpret the findings, and 

coauthor papers for publication. 


78 


DIVISION OF INFORMATICS 

DIVISION CHIEF 


SOFTWARE AND SYSTEMS DEVELOPMENT 

Carmen J. Schwelm, M.S. 

Manager 

Oscar Arevalo, B.S. 

Systems Analyst 

Maguys Casuso, M.S. 

Senior Systems Analyst 

Anabel Fernandez, B.S. 

Senior Systems Analyst 

Qin He, M.S. 

Senior Programmer Analyst 

Ming-Hung Shao, M.S. 


Yueping Yu, M.S. 


NETWORK SUPPORT 

Huntson Lam, B.S. 

Manager 

Johnny Joa, B.S. 

Systems Analyst 

PURPOSE 

The role of the Division of Informatics 

at UM/Sylvester is to facilitate 

information integration for patient 

care, research, education, and administration. 

To achieve the implementation 

of this vision, there are the following 

specific aims: 

• Create integrated information resources 

that facilitate research and patient care 

by: 

1) Constructing a data warehouse 

that draws upon data and images 

from electronic media (Electronic 

Medical Record) and other 

transactional databases required 

for translational and clinical 

research 

2) Providing a network that is 

accessible from a standardized 

desktop and then link together 

information tools for research, 

patient care, administration, and 

education. 

• Creating shareable high-speed computing 

tools that will facilitate the basic 

science research that drives new discoveries. 

• Continue to build the infrastructure to 

support the development of Clinical 

Cancer Information Systems (CCIS) 

by: 

1) Ongoing provision and organization 

of the human, information, 

and technology resources required 

for the infrastructure of CCIS 

2) Periodic evaluation of planning 

and implementation efforts 

3) Identification of funding opportunities 

to support CCIS in the 

future. 

Informatics supports such diverse 

data sets as patient medical records, laboratory 

animal pedigrees, laboratory process 

and reagent data, biospecimen 

tracking data, epidemiological data, clinical 

registry information required by various 

professional and regulatory groups, 

information on DNA and RNA sequences 

and features, genetic markers, 

and phenotypic variations, etc. 

Associated with these data sets are 

complex process-based interactions between 

researchers, clinicians, and support 

staff. Informatics must model these interactions 

as well as the raw data. Ultimately, 

all aspects of the collection, 

storage, analysis, transmission, and dissemination 

of this information within 

UM/Sylvester’s network are aided by 

computers and computer technology. 

Supporting this information flow re- 

quires a substantial investment of both 

manpower and equipment for computing 

infrastructure and infrastructurerelated 

activities. 

ORGANIZATIONAL STRUCTURE 

The Division of Informatics is led by 

Dr. Dido Franceschi, a surgical oncologist 

who devotes 50 percent of his time 

to clinical activities and 50 percent to the 

Informatics Program. Boris Djokic, 

Ph.D., reports to Dr. Franceschi and acts 

as assistant director. The Division of 

Informatics working groups and managers 

are as follows: 

Software and Systems Development 

Carmen J. Schwelm, M.S. 

Manager 

Provides support for clinical, basic, and 

population research at UM/Sylvester and 

research administration. 

Networking, Web Communications, 

and Desktop Support 

Huntson Lam, B.S. 

Manager 

Provides support for the connectivity to 

medical center and other data networking 

and web systems. Additionally they 

assist in the selection, acquisition, and 

deployment of desktop hardware and 

software for UM/Sylvester members and 

employees. 

INFORMATICS STEERING 

COMMITTEE 

The Division of Informatics has an internal 

advisory structure to provide 

broad-based oversight for programs strategic 

plan. The steering committee is a 

major policy-setting committee charged 

with the responsibility to develop 

informatics priorities for UM/Sylvester. 

At a macro level, the committee focuses 

on the major issues of data standardiza- 


tion, data integration, assessments of information 

needs, data betterment, and 

provides the supervision for, consulting 

to, and integration of the user groups. 

The day-to-day operation of the division 

occurs through a network of work 

groups organized around the needs of the 

two UM/Sylvester divisions. There is a 

principle work group for both the hospital 

and research division with a communication 

and networking group that 

supports both divisions. A brief description 

of these groups including their functions 

and staffing follows. 

RESEARCH DIVISION 

Clinical Research: The Clinical Research 

Services Division coordinates intervention-based 

clinical research studies 

in all oncology disciplines and population 

sciences. The Clinical Research Services 

office is developing objective and 

verifiable data management procedures 

for clinical studies, web-enabled database 

applications for protocol management, 

automation of the tracking of patient 

accrual data, and the appropriate secure 

dissemination of relevant reports and 

data analysis to investigators, internal 

review boards, and appropriate regulatory 

agencies. 

Bioinformatics: This is a facility under 

development that will support 

biosciences computing and data management 

for laboratory-based science, particularly 

as it relates to DNA and protein 

sequence analysis, structure, and function. 

It is anticipated that the facility will 

provide advanced support in the use of 

shared genome science and molecular 

biology data resources, such as sequence 

databases. It will also provide biosciences 

computer programming, relational database 

systems for laboratory data acquisition, 

image analysis, and web information 

systems integration. 

Cancer Clinical Information Systems 

(CCIS): The CCIS is a secure intranet 

Web-based clinical data warehouse designed 

to facilitate the organization and 

presentation of clinical data collected 

throughout the medical center campus 

at a single source. 

General Research Support Systems: 

This is a specialized work group that supports 

a variety of peer-reviewed and 

funded biomedical research projects. 

Population Informatics: This is a specialized 

group that supports a variety of 

peer-reviewed and funded epidemiological 

and population-based research 

projects. 

Administrative Computing: This 

work group provides infrastructure support 

for the administration of databases 

relating to the research portfolio of UM/ 

Sylvester, human resources, accounting, 

development, education, and training. 

Web Systems: This is an infrastructure 

support group with responsibility 

for the technical aspects of the UM/ 

Sylvester’s website as well as its Intranet. 

Networking, Web Communications, 

and Desktop Support: This group provides 

infrastructure support for medical center 

connectivity and other data networking 

and web systems including UM/ 

Sylvester’s central computing hardware 

and firewall security systems. 

HOSPITAL DIVISION 

Medical Information Systems: Medical 

Information Systems is a hospital division 

that incorporates its traditional 

medical records office with the 

Informatics development of an Electronic 

Medical Record (EMR). 

80 


SCIENTIFIC REPORT PUBLICATIONS 1999-2001 

Adkins, B. Apoptosis of näive murine 

neonatal T cells. International Review 


Adkins, B. The functional capacities of 

T cells in newborn mice and humans. 


Petito, CK, Adkins, B, Tracey, K, Roberts, 

B, Torres-Munoz J, McCarthy, M 

and Czeisler, C. Chronic systemic administration 

of tumor necrosis factor alpha 

and of HIV gp 120: Effects on adult 

rodent brain and blood-brain barrier. 


Adkins, B. Development of neonatal 

Th1/Th2 function. International Review 


Adkins, B, Bu ,Y, Cepero, E and Perez, 

R. Exclusive Th2 primary effector function 

in spleens but mixed Th1/Th2 function 

in lymph nodes of murine neonates. 


Adkins, B, Charyulu V, Sun QL, Lobo 

D and Lopez DM. Early block in maturation 

is associated with thymic involution 

in mammary tumor-bearing mice. 


Adkins, B, Bu Y and Guevara P. The generation 

of Th memory in neonates versus 

adults: prolonged primary Th2 

effector function and impaired development 

of Th1 memory effector function 

in murine neonates. Journal of Immunology 

166:918, 2001. 

Plano, LRW, Adkins, B, Woischnik, M, 

and Collins, CM. Toxin levels in serum 

correlate with the development of staphylococcal 

scalded skin syndrome in a murine 

model. Infection and Immunity 

69:5193, 2001. 







59:5514, 1999. 

Agarwal, RP, Han, T and Fernandez, M. 

Collateral resistance of a dideoxycytidineresistant 

cell line to fluoro-2’-de3oxyuridine. 

Biochemistry Biophysical 

Research Communication 262:657, 

1999. 

Agarwal, RP, Wang, W, Yo, P, Han, T 

and Fernandez, M. Cross resistance of 

dideoxycytidine resistant cell lines to 

azidothymidine. Biochemical Pharmacology 

58:1603, 1999. 

Cruess, DG, Antoni, MH, Kumar, M, 

Ironson, G, McCabe, P, Fernandez, JB, 

Fletcher, M and Schneiderman, N. Cognitive-behavioral 

stress management 






Psychoneuroendocrinology 24:537, 

1999. 

Antoni, MH, Carver, CS, Boyers, A., 

McGregor, B, Arena, P, Kilbourn, K, 






1999. 

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