SCIENTIFIC REPORT 2004
RESEARCH ACTIVITIES 2002-2003
INTRODUCTION AND PROGRESS REPORT
TABLE OF CONTENTS
INTRODUCTION AND
PROGRESS REPORT
LEADERSHIP
i
vii
MULTIDISCIPLINARY RESEARCH
PROGRAMS
Cancer Prevention and
Control Program
1
Clinical Oncology Research Program
33
Tumor Cell Biology Program
65
Tumor Immunology Program
103
Viral Oncology Program
129
SHARED RESOURCES
Analytical Imaging Core
143
Biostatistics
145
Cell Purification and Banking Facility
146
Clinical Research Services Resource
147
DNA Core Facility
148
EDITOR
Flow Cytometry Resource
149
W. Jarrard Goodwin, M.D., F.A.C.S.
Gene Knockout and Transgene Facility
150
Director, University of Miami
Histology Research Lab Core
151
Sylvester Comprehensive Cancer Center
Informatics
152
Molecular Analysis Core
153
PRODUCTION COORDINATION
Population Research Core
154
Office of Research Administration
PUBLICATIONS
155
GLOSSARY
191
Office of Marketing and Communications
Sabia Communications
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
INTRODUCTION AND PROGRESS REPORT
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
INTRODUCTION AND PROGRESS REPORT
INTRODUCTION AND
PROGRESS REPORT
W. Jarrard Goodwin, M.D., F.A.C.S.
Director, University of Miami Sylvester Comprehensive Cancer Center
INTRODUCTION
S
ince publishing our last Scientific Report in
2002, much has changed at the University of
Miami Sylvester Comprehensive Cancer Center.
We have recruited more than 25 new faculty
members, most of whom are physician-scientists,
reflecting our commitment to translational
research. Our Institutional Review Board has
approved and opened 160 therapeutic clinical trials. We have strengthened our five multidisciplinary
research programs and opened new shared
resources, most notably the Population Research
Core that supports population-based cancer
prevention and control research at UM/Sylvester.
With assistance from the Population Research
Core, we are increasing the diversity of clinical
trial participants to represent the racial, ethnic,
and socioeconomic composition of South
Florida’s diverse and unique community. Much
of this has been done under the thoughtful leadership of Joseph D. Rosenblatt, M.D., associate
director, clinical and translational research, and
the several senior scientists he’s already brought
to South Florida. Dr. Rosenblatt joined the
University of Miami School of Medicine in 2001
as division chief of Hematology-Oncology.
His presence can be felt everywhere.
UM/Sylvester’s Best Friend
Many of you may have known or heard about Jay
W. Weiss, whom we often describe as the “best
friend UM/Sylvester will ever have.” As chairman
of the board of governors, Jay led UM/Sylvester
during its most challenging years, and did so with
integrity, tenacity, and grace. Jay’s vision and
leadership continually invigorated and inspired us
to reach new heights. To Jay, who lost his battle
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
with cancer earlier this year, and the many others
who continue to support UM/Sylvester each and
every day, we dedicate this report. As we continue
our quest to cure cancer and to ensure the best
possible quality of life for those suffering from
this disease, we know we do so with the support
of many friends and colleagues. During the past
two years, UM/Sylvester has been the proud recipient of nearly $56 million in cancer-related
research grants and more than $17 million in
philanthropy (to support research). We continually are expanding our research and clinical facilities and planning for the day when we can start
building much-needed new infrastructure.
Cancer Incidence and Death Rates
Despite all the success we’ve had as a nation and
the important research that’s underway across
the globe, cancer remains a threat to this society.
According to the American Cancer Society, 1.3
million new cancer cases will be reported this
year, and Florida stands second only to California, projecting more than 96,000 new cancer
cases in 2004. But we have made progress, which
I highlight below. According to the Annual
Report to the Nation,1 Americans’ risk of getting
and dying from cancer continues to decline
and survival rates for many cancers continue
to improve:
• Both overall observed cancer incidence rates
and death rates from all cancers combined have
dropped.
• We’ve seen the first ever drops in lung cancer
incidence rates in women.
• The percentage of patients who have survived
more than five years post-diagnosis has
increased in the past two decades.
i
INTRODUCTION AND PROGRESS REPORT
• Among men, cancer incidence rates have
recently declined for seven of the top 15 cancer
sites: lung, colon, oral cavity, leukemia, stomach, pancreas, and larynx.
• In addition to lung cancer, incidence rates
among women also have declined in: colon,
cervix, pancreas, ovary, and oral cavity cancers.
• Childhood cancers have shown some of the
largest improvements in cancer survival during
the past 20 years.
• There are, however, wide variations in survival
associated with race and ethnicity; in every
racial and ethnic population, with the exception
of Asian/Pacific Islander women, the risk of
cancer death from all cancer sites combined was
higher than the risk of death for non-Hispanic
white patients.
The State of Florida, the citizens of South
Florida, and the University of Miami are investing heavily in translational research—with ideas
flowing from the laboratory bench to the patient’s
bedside and back again—which is the essence
of a comprehensive cancer center, the essence of
UM/Sylvester. I am proud to tell you about the
important translational research underway at
UM/Sylvester and the equally important basic
science and cancer prevention and control
research that undergirds and strengthens our
efforts.
ii
PROGRESS REPORT
S
cientists at UM/Sylvester are grouped into
five multidisciplinary research programs that
reflect our strengths and our priorities—Cancer
Prevention and Control, Clinical Oncology Research, Tumor Cell Biology, Tumor Immunology,
and Viral Oncology. Our scientists work within
the established research programs and with physicians in UM/Sylvester’s 15 multidisciplinary, sitebased oncology groups. Together we design and
conduct the clinical trials necessary to test the
value of new prevention, screening, diagnosis,
and treatment protocols. Examples of significant
research currently taking place at UM/Sylvester
are included in this report, which is organized
by multidisciplinary research program. We
also have provided descriptions of each of our
shared resources and a list of publications by
author. Several research projects of particular
note are highlighted here:
Research Highlights
Note: More information also can be found at
www.sylvester.org.
• UM/Sylvester is expanding the use of a vaccine
for patients with non-small cell lung cancer.
It now will be administered to two new groups
of patients: those who have surgery to remove
lung tumors and those who complete their
first cycle of standard chemotherapy. The lung
cancer vaccine was developed by Eckhard R.
Podack, M.D., Ph.D., UM/Sylvester’s Associate
Director, Basic Science and Chairman of
Microbiology and Immunology, and has been
available in research protocols at UM/Sylvester
for more than three years. UM/Sylvester is the
only facility in the United States that does immunotherapy using the B7.1 vaccine for lung
cancer. Luis Raez, M.D., F.A.C.P., asssitant
professor of Medicine and Epidemiology and
Public Health, administered the vaccine to 19
people who had an expected survival of less
than six months; six or them are still diseasefree and three have surpassed the three-year
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
INTRODUCTION AND PROGRESS REPORT
mark with no sign of relapse. This disease is
lethal and the average survival for this diagnosis
is less than one year. The results of the threeyear study were published on July 15 in the
Journal of Clinical Oncology.
• A study just published in the New England Journal of Medicine could have huge implications
for the thousands of children diagnosed with
cancer every year, raising hope they can avoid
potentially fatal cardiac problems caused by
their treatment. Steven E. Lipshultz, M.D.,
professor and chairman of Pediatrics at the University of Miami School of Medicine, is the lead
author of the study, which reveals that using a
heart-protective drug dexrazoxane (under the
brand name Zinecard) before chemotherapy
sharply lowered the amount of heart damage.
The drug works by soaking up spare iron in the
blood that normally would bind with the chemotherapy drug to produce compounds known
to destroy heart muscle. The study, which began in 1995, tracked 200 childhood leukemia
patients in the United States and Canada for
three years.
• Howard T. Petrie, Ph.D., professor of Microbiology and Immunology at the University of
Miami School of Medicine, has identified a
key step in the path that stem cells take in
supporting the body’s immune system. His
work was published in the June 16 issue of the
journal Immunity. Finding a way to cultivate
T-cell growth could lead to new therapies that
strengthen the immune system in patients with
a variety of illnesses.
• A seven-year international study revealed that
less-invasive laparoscopic surgery for colon
cancer is just as effective as traditional open
surgery when performed by an experienced surgeon—but with faster recovery times and fewer
complications. Three UM/Sylvester colorectal
surgeons were involved in the study, published
in the New England Journal of Medicine in May
2004—Michael D. Hellinger, M.D., F.A.C.S.,
F.A.S.C.R.S., division chief of Colon and Rectal
Surgery at the University of Miami School of
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Medicine; Laurence R. Sands, M.D., F.A.C.S.,
F.A.S.C.R.S., and Rene F. Hartmann, M.D.,
F.A.C.S., F.A.S.C.R.S. The study compared
patient outcomes at three and five years after
surgery and found no significant difference in
recovery, relapse, or survival between the two
techniques.
• Izidore Lossos, M.D., associate professor of
Medicine, is the lead author of a landmark
lymphoma study published in April 2004 in
the New England Journal of Medicine. The study
identifies six genes that can predict whether a
patient’s lymphoma will respond to standard
treatment. This finding by researchers at the
University of Miami School of Medicine,
Stanford University School of Medicine, and
Applied Biosystems could result in the first
gene-based screening to identify people who
need aggressive therapy.
• Glen N. Barber, Ph.D., professor of Microbiology and Immunology and co-leader of the Viral
Oncology Program at UM/Sylvester, is conducting research into using the tumor destroying
properties of viruses for therapeutic purposes.
This research has focused on a recombinant
vesicular stomatitis virus (VSV) that expresses
virus-like particles (VLP). VLP may be used
for immunizing, preventing, or treating viral
infections. Dr. Barber has demonstrated the
feasibility of generating large amounts of VLP,
including human T-lymphotropic virus, type 1
and human papilloma virus-like particles using
VSV, which is innocuous in humans. Furthermore, he has shown that the VLP can be delivered to dendritic cells, which in turn process
and present antigens. This approach may lead
to novel immunization and treatment modalities for a variety of viral infections and new
approaches to cancer.
• UM/Sylvester has opened a phase II clinical
trial to investigate a novel treatment for metastatic melanoma. Pegylated arginine deiminase
(ADI-PEG) is an amino acid enzyme inhibitor,
which interferes with the ability of melanoma
tumor cells to proliferate. Lynn G. Feun, M.D.,
iii
INTRODUCTION AND PROGRESS REPORT
professor of Medicine at the University of
Miami School of Medicine, is leading the
investigation. ADI-PEG is a targeted approach
to fighting cancer, which focuses on enzymes
that are very common in all melanoma cell
lines. ADI-PEG attaches to arginine, an amino
acid in the blood, which malignant tumor cells
rely on to grow. The ADI-PEG degrades the
arginine, making it impossible for the cancer
to synthesize and use. This has significant advantages over previous treatments. Because
this treatment is not chemotherapy, it can be
administered as an outpatient treatment with
a single weekly injection, rather than requiring
a hospital stay or a long infusion.
• Sheldon Greer, Ph.D., professor of Microbiology and Immunology at the University of
Miami School of Medicine, has made many
important discoveries in the course of his distinguished scientific career. An experimental
radiosensitizer developed by Dr. Greer will
shortly enter a phase I clinical trial for head
and neck cancer patients. Cytochlor, developed
by Dr. Greer and NCI-approved for patient
trials to be conducted by Luis E. Raez, M.D.,
F.A.C.P., enters tumor cells and renders them
much more susceptible to low-dose radiation.
This enables a much higher success rate against
cancer cells and the potential for reducing
patient side effects.
• Theodore J. Lampidis, Ph.D., professor of Cell
Biology and Anatomy, has discovered one way
to attempt to tackle the problem of targeting
non-dividing tumor cells that are resistant to
chemotherapy and/or radiation. He has
found that slow dividing cells located in the
middle of the tumor grow under low oxygen
conditions (hypoxia) and differ in their metabolism of glucose from normal cells in the body.
To exploit this difference, he has shown that by
simply using a false sugar—2-Deoxyglucose
(2-DG)—instead of glucose, the slow growing
tumor cells take up more 2-DG than the slow
growing normal cells and consequently starve to
death. Luis E. Raez, M.D., F.A.C.P., and Shou-
iv
Ching Tang, M.D., Ph.D., have initiated the
first clinical trials in lung cancer patients using
this highly novel approach.
• A unique peptide (IEP11) was defined by
Diana M. Lopez, Ph.D., professor of Microbiology and Immunology and leader of UM/Sylvester’s Tumor Immunology Program. This
peptide appears to elicit a powerful immune
response in mice that have been injected with
various types of tumor cells. Subsequent studies
indicate that those animals that were “IEP11
immunized” were found to form tumors at a
greatly reduced rate. This suggests that the
peptide could serve as an adjuvant treatment to
enhance many cancer vaccine therapies in the
treatment of a variety of tumor types. Viragen,
a new biotechnology company located in
Plantation, Florida, will collaborate with the
University’s team to develop the peptide for
use in human clinical trials.
• Azorides Morales, M.D., chairman of Pathology
at the University of Miami School of Medicine,
has devised a way to use microwave radiation
to reduce tissue pathology processing from
one day to about one hour. The Jackson Health
System and UM/Sylvester are the only institutions in the world offering this technique. This
is not frozen section pathology, but accelerated
tissue processing patented by the University of
Miami, which may revolutionize the way tissues
are processed, while allowing pathologists to
extract vital molecular information in ways not
previously possible.
• Eckhard R. Podack, M.D., Ph.D., has developed a new antibody that can be used to target
Hodgkin’s and non-Hodgkin’s lymphoma cells.
The development of this novel antibody called
SGN30, which identifies a protein on the surface of the cancer cells and “labels” the cells
with an antibody therapy, allows the immune
system to target them for destruction. This is a
more “intelligent” treatment and should have
fewer side effects than with traditional chemotherapy. Joseph D. Rosenblatt, M.D., and
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
INTRODUCTION AND PROGRESS REPORT
Hugo F. Fernandez, M.D., have initiated
a clinical trial using SGN30 in lymphoma
patients. UM/Sylvester has collaborated
with Seattle Genetics to further the investigation of SGN30.
• The future of cancer treatment also may use
vaccines to boost the immune system so it
recognizes and kills cancer cells. Luis E. Raez,
M.D., F.A.C.P., and Richard J. Thurer, M.D.,
are among the physicians working with
UM/Sylvester physician-scientist Eckhard R.
Podack, M.D., Ph.D., to develop several new
revolutionary vaccines for the treatment of
lung cancer. This approach also may lead to
vaccines for other cancers. Dr. Thurer is a professor of Surgery and director of the Thoracic
Surgery Section.
• Joseph D. Rosenblatt, M.D., UM/Sylvester’s
Associate Director, Clinical and Translational
Research and Division Chief of HematologyOncology, opened a phase I clinical trial of a
novel combination therapy for patients with
certain types of leukemia and lymphoma.
The idea of this trial is to use an antibody,
which has had some success in the treatment
of these disorders, and to try and augment the
effects of that antibody in combination with
interleukin-2 (IL-2). Campath-1H, also called
alemtuzumab, is an approved form of treatment
for patients with efractory/relapsed B-cell
chronic lymphocytic leukemia, T-prolymphocytic
leukemia, and cutaneous T-cell lymphomas
(Sezary syndrome). By using IL-2 and
alemtuzumab in combination it may hasten
the return of the immune system to normal
by enhancing the recovery of T cells and
reducing post-treatment infectious complications. The idea of combining these two drugs
was developed by Dr. Rosenblatt, Edgardo
Santos, M.D., and their colleagues in the
department of Medicine at the University of
Miami School of Medicine.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Joseph D. Rosenblatt also is leading studies
related to the development of novel immunotherapeutic and gene therapy strategies for
human malignancy. Dr. Rosenblatt and
Khaled Tolba, M.D., assistant professor of
Medicine, have studied the ability of gene
therapy “vectors” derived from herpes simplex
virus called HSV amplicons to augment the
immune response to tumors. Together with
Seung-Uon Shin, Ph.D., an expert in antibody
engineering, Dr. Rosenblatt’s laboratory has
developed a variety of antibody fusion proteins
with potential utility in human malignancy.
These include fusions with immune effector
molecules such as T-cell costimulatory ligands,
and/or molecules that can recruit immune cells
such as chemokines. Dr. Shin also is studying
a fusion of anti-tumor antibody with an antiangiogenic agent called endostatin, which
improves upon the performance of either an
anti-her2/neu antibody or endostatin alone
in the setting of breast cancer in preclinical
tumor models.
• Joyce M. Slingerland, M.D., Ph.D., professor
of Medicine, is directing research efforts in
breast cancer and also serves as director of the
Braman Family Breast Cancer Institute at
UM/Sylvester, a multidisciplinary translational
research institute devoted to advancing research
in cancer prevention, diagnosis, and treatment.
Dr. Slingerland is a recognized authority on cell
cycle regulation in relation to breast cancer,
with particular emphasis on the p27 cell cycle
regulator. She heads a major laboratory effort
and has continued to recruit key individuals
to increase expertise in the areas of molecular
pathology, epidemiology, and clinical trials in
breast cancer.
v
INTRODUCTION AND PROGRESS REPORT
National Cancer Institute Designation
I am pleased to tell you that UM/Sylvester will
seek National Cancer Institute designation in
2005. Comprised of a distinguished group of
physicians and scientists, the External Advisory
Committee has visited UM/Sylvester twice
within the past year to evaluate the progress in
our multidisciplinary research programs and
research initiatives. They were highly complimentary of UM/Sylvester’s continuing efforts and
recommended application for the NCI-Comprehensive Cancer Center designation next year.
The EAC will meet with us again during the
fall of 2004; their advice and assistance has been
invaluable.
Research is curing cancer, and to further
achieve that goal, UM/Sylvester continues to
build upon its excellent multidisciplinary research
programs and shared resources already in place.
We are especially invested in the development of
home grown clinical trials based on science and
technology developed at the University of Miami.
We continue working to bring research discoveries from the laboratory bench to the patient bedside more quickly than ever before.
In Closing
These are exciting times at UM/Sylvester, and
I am proud to be part of such a dynamic and
dedicated team. Together with support from our
senior vice president for medical affairs and dean
of the school of medicine, John G. Clarkson,
M.D., and University of Miami President Donna
E. Shalala, Ph.D., we take steps toward winning
the war against cancer every day. We also work
very hard to ensure the best possible quality of
life for our patients. But we must continue to
do more.
I hope you find this report interesting and
inspiring. I want to assure you that UM/Sylvester,
South Florida’s only university-based cancer center, is making a difference in the lives of South
Florida citizens and that we are committed to
this noble cause.
Thank you for your time and attention.
W. Jarrard Goodwin, M.D., F.A.C.S.
Director
University of Miami
Sylvester Comprehensive Cancer Center
1 NCI: http://www.cancer.gov and the SEER Homepage: http://www.seer.cancer.gov. Click on “1975-2001 Report to the Nation.”
vi
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
LEADERSHIP
LEADERSHIP
UNIVERSITY OF MIAMI
Donna E. Shalala, Ph.D.
President
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
John G. Clarkson, M.D.
Senior Vice President for Medical Affairs and Dean
John M. Deeley
Vice President for Administration, Operations and Planning
Minor W. Anderson
Associate Vice President for Medical Affairs and Managing Director, University of Miami
Medical Group
UM/ SYLVEST ER CO MPRE HE NSI VE CANCE R CENT ER
As of year end, FY 2004
EXECUTIVE COMMITTEE
W. Jarrard Goodwin, M.D., F.A.C.S.
Director
Eckhard R. Podack, M.D., Ph.D.
Associate Director, Basic Science
Michael H. Antoni, Ph.D.
Associate Director,
Cancer Prevention and Control
Robert S. Powell, M.Ed.
Associate Director, Administration
Dido Franceschi, M.D.
Division Chief, Informatics
Kelvin P. Lee, M.D.
Program Co-Leader,
Clinical Oncology Research
Joseph A. Lucci, III, M.D.
Director, Clinical Research Services Resource
Joseph D. Rosenblatt, M.D.
Associate Director,
Clinical and Translational Research
James J. Schlesselman, Ph.D.
Division Chief, Biostatics
Joyce M. Slingerland, M.D., Ph.D.
Director, Braman Family Breast Cancer Institute
at UM/Sylvester
Arnold M. Markoe, M.D., Sc.D.
Professor and Chairman, Radiation Oncology
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
vii
LEADERSHIP
MULTIDISCIPLINARY RESEARCH
PROGRAM LEADERSHIP
Roland Jurecic, Ph.D.
Molecular Analysis Core
Michael H. Antoni, Ph.D.
Cancer Prevention and Control Program
Michael H. Antoni, Ph.D.
Dorothy F. Parker, M.H.S.
Population Research Core
Joseph D. Rosenblatt, M.D.
Kelvin P. Lee, M.D.
Clinical Oncology Research Program
SCIENTIFIC STEERING COMMITTEE
Kermit L. Carraway, Ph.D.
Tumor Cell Biology Program
Diana M. Lopez, Ph.D.
Tumor Immunology Program
William J. Harrington, Jr., M.D.
Glen N. Barber, Ph.D.
Viral Oncology Program
Eckhard R. Podack, M.D., Ph.D., Chair
Microbiology and Immunology
Michael H. Antoni, Ph.D.
Psychology
Glen N. Barber, Ph.D.
Microbiology and Immunology
Kermit L. Carraway, Ph.D.
Cell Biology and Anatomy
SHARED RESOURCE LEADERSHIP
Murray P. Deutscher, Ph.D.
Biochemistry and Molecular Biology
Alberto Pugliese, M.D.
Beata R. Frydel, Ph.D.
Analytical Imaging Core
Marilyn Stern Emas, M.Ed.
Development
James J. Schlesselman, Ph.D.
Biostatistics
Kelvin P. Lee, M.D.
Cell Purification and Banking Facility
Joseph A. Lucci, III, M.D.
James D. Hanlon, Jr., R.N.
Clinical Research Services Resource
Rudolf K. Werner, Ph.D.
DNA Core Facility
Richard L. Riley, Ph.D.
Flow Cytometry Resource
Thomas R. Malek, Ph.D.
Gene Knockout and Transgene Facility
Carol K. Petito, M.D.
Histology Research Lab Core
Dido Franceschi, M.D.
Informatics
viii
Lora E. Fleming, M.D., Ph.D., M.P.H., M.Sc.
Epidemiology and Public Health
W. Jarrard Goodwin, M.D., F.A.C.S.
Otolaryngology
James D. Hanlon, Jr., R.N.
Clinical Research Services Resource
William J. Harrington, Jr., M.D.
Medicine
Judith B. Hayden, M.B.A.
Marketing and Communications
Denise M. Korniewicz, D.N.Sc., R.N., F.A.A.N.
Nursing
David J. Lee, Ph.D.
Epidemiology and Public Health
Kelvin P. Lee, M.D.
Microbiology and Immunology
Robert B. Levy, Ph.D.
Microbiology and Immunology
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
LEADERSHIP
Diana M. Lopez, Ph.D.
Microbiology and Immunology
BOARD OF GOVERNORS
Joseph A. Lucci, III, M.D.
Obstetrics and Gynecology
Joaquin F. Blaya, Chair
Rose Ellen Greene, Vice Chair
Thomas B. Levinson, Vice Chair
Diane Abrams
William H. Allen, Jr.
Minor Anderson
Cynthia L. Augustyn, J.D.
Jose P. Bared
Gloria Berkowitz
Norman L. Braman
Minette Brown
John G. Clarkson, M.D.
Diane M. Cook
John M. Deeley
Denny Feinsilver
Michael B. Fernandez
Thomas J. Fitzpatrick
Bernard J. Fogel, M.D.
Gail Gidney
W. Jarrard Goodwin, M.D., F.A.C.S.
Mark Halpern
Peggy Hollander
Mark Levitats
Alan S. Livingstone, M.D., F.A.C.S.
Jayne S. Malfitano
George Mencio, Jr.
Eugene K. Montoya
Marvin O’Quinn
Dennis Patin, M.D.
Nilda P. Peragallo, Dr.P.H., R.N., F.A.A.N.
Joseph D. Rosenblatt, M.D.
Joan Scheiner
John Schulte
Anne Smith, R.N., M.B.A.
Richard Spring
David L. Stansberry, M.S.
Barbara Weintraub
Gary S. Margules, Ph.D.
Technology Transfer
Robert S. Powell, M. Ed.
Administration
Joseph D. Rosenblatt, M.D.
Medicine
Antonieta Sauerteig, M.S.
Research Administration
James J. Schlesselman, Ph.D.
Epidemiology and Public Health
Joyce M. Slingerland, M.D., Ph.D.
Medicine
Richard Spring
UM/Sylvester Board of Governors
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
ix
LEADERSHIP
EXTERNAL ADVISORY COMMITTEE
Albert F. LoBuglio, M.D.
Evalina B. Spencer Professor of Oncology
University of Alabama at Birmingham
James J. Mulé, Ph.D.
Associate Center Director, Translational Science and
Technology Development
Director, UAB Comprehensive Cancer Center
Michael McGillicuddy Endowed Chair, Melanoma
Research and Treatment
David W. Golde, M.D.
Enid A. Haupt Chair of Hematologic Oncology
H. Lee Moffitt Cancer Center & Research Institute
Memorial Sloan-Kettering Cancer Center
Joyce C. Niland, Ph.D.
Chair and Professor, Division of Information
Sciences
Head, Laboratory of Molecular and Cellular
Hematology
Director, Department of Biostatistics
Harvey Herschman, Ph.D.
Director for Basic Research
City of Hope National Medical Center
Professor, Department of Biological Chemistry
Paul Okunieff, M.D.
Chair and Philip Rubin Professor of Radiation
Oncology
Professor, Department of Pharmacology
UCLA-Jonsson Comprehensive Cancer Center
Paul B. Jacobsen, Ph.D.
Professor of Psychology and Oncology
University of South Florida
Program Leader, Psychosocial and Palliative
Care Program
University of Rochester
Max S. Wicha, M.D.
Director, University of Michigan Cancer Center
Distinguished Professor of Oncology
University of Michigan Cancer Center
Program Leader, Health Outcomes and Behavior
H. Lee Moffitt Cancer Center & Research Institute
James F. Lynch, M.B.A.
Vice President, Hospital and Medical Science
Administration
Fox Chase Cancer Center
Nancy Mueller, Sc.D.
Professor of Epidemiology
Associate Director for Population Sciences
Dana-Farber/Harvard Cancer Center
x
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
CANCER PREVENTION AND
CONTROL PROGRAM
PROGRAM LEADER
Michael H. Antoni, Ph.D.
Professor of Psychology
DESCRIPTION OF PROGRAM
T
he Cancer Prevention and Control Program
is composed of 23 faculty members in nine
different departments at the University of Miami.
The program, which builds on earlier work,
includes research in cancer etiology, prevention,
early detection, education/outreach, cancer
genetics, quality of life, survivorship, psychoneuroimmunology, and biobehavioral
interventions.
Specific studies underway at this time
include the use of tobacco, assessment of quality
of life among persons who have been treated for
cancer, stress management intervention in persons recently diagnosed with cancer, investigations of cancer incidence in Florida, outreach
to Hispanic populations, and implementation
of cancer control strategies.
The projects performed by members of the
Cancer Prevention and Control Program vary
substantially. Some are purely behavioral or psychosocial in their aims; others examine neuroendocrine and immunological mechanisms relevant
for disease promotion and/or progression. Most
of these projects entail collaboration among behavioral scientists, surgeons, and oncologists.
Others involve collaboration among psychologists, epidemiologists, immunologists, biochemists, and other biomedical scientists.
GOALS OF PROGRAM
1) Determine the predictors of cancer risk behavior in vulnerable populations and then develop
and evaluate culturally competent interventions to prevent cancer in clinical and community populations.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
2) Develop and evaluate psychosocial interventions designed to reduce stress, enhance quality of life, and improve compliance as well as
other health-related behaviors and biological
processes associated with health outcomes.
3) Examine the interactive effects of stress, behavior, and psychosocial components on neuroendocrine and immune function in cancer
patients and in at-risk populations. Determine
how these vary across sites, gender, age, race/
ethnicity, and prognostic variables.
4) Better understand the risk factors for recurrence, enhancing quality of life, the role of the
family in survival, preventing second malignancies and the sequelae of cancer treatment,
and gain a better understanding of potential
psychosocial influences on biological processes
that may be involved in cancer recurrence.
5) Develop and evaluate methods of disseminating cancer information and education for
diverse communities.
PARTICIPANTS
Antoni, Michael H., Ph.D.
Psychology
Armstrong, F. Daniel, Ph.D.
Pediatrics
Baumbach-Reardon, Lisa L., Ph.D.
Pediatrics
Blomberg, Bonnie B., Ph.D.
Microbiology and Immunology
Carver, Charles S., Ph.D.
Psychology
Fleming, Lora E., M.D., Ph.D., M.P.H., M.Sc.
Epidemiology and Public Health
1
CANCER PREVENTION AND CONTROL PROGRAM
Fletcher, Mary Ann A., Ph.D.
Microbiology and Immunology
Goodman, Kenneth W., Ph.D.
Medicine
Goodwin, W. Jarrard, M.D., F.A.C.S.
Otolaryngology
Ironson, Gail H., M.D., Ph.D.
Psychology
Kirsner, Robert S., M.D.
Dermatology and Cutaneous Surgery
Kumar, Mahendra, Ph.D.
Psychiatry and Behavioral Sciences
Lechner, Suzanne C., Ph.D.
Psychiatry and Behavioral Sciences
Lee, David J., Ph.D.
Epidemiology and Public Health
Levis-Dusseau, Silvina, M.D.
Medicine
McCoy, Clyde B., Ph.D.
Epidemiology and Public Health
Penedo, Frank J., Ph.D.
Psychology
Roos, Bernard A., M.D.
Medicine
Schlesselman, James J., Ph.D.
Epidemiology and Public Health
Schneiderman, Neil, Ph.D.
Psychology
Shor-Posner, Gail S., Ph.D.
Psychiatry and Behavioral Sciences
Twiggs, Leo B., M.D.
Obstetrics and Gynecology
Wilkinson, James D., M.D., M.P.H.
Epidemiology and Public Health
2
HIGHLIGHTS
Breast Cancer
African-American women with pre-menopausal
breast cancer have characteristic mutations and
polymorphic variants not observed in Caucasians.
In addition, the frequency of BRCA1 and
BRCA2 germ-line “deleterious” mutations is
much less than that observed in Caucasians.
Overall, breast cancer in African-American
women occurs at a younger age, is more often
estrogen receptor negative, and more frequently
exhibits aggressive biological behaviors.
Breast Cancer Screening
After controlling for demographic variables traditionally related to breast cancer screening rates,
there are ethno-regional differences in breast cancer screening and Pap smear practices among Cubans, Mexican-Americans, Puerto Ricans, Central
Americans, and South Americans across the United
States. Social integration appears to influence
participation in cancer screening among Hispanic
women. The modest effect is not universal across
Hispanic groups and is stronger for Pap smear
than for mammography screening behavior.
Florida Comprehensive Cancer Control
Initiative
The Florida Comprehensive Cancer Control Initiative (FCCCI) was established in October 2000
as the result of a federal appropriation and funding from the CDC’s Comprehensive Cancer
Control Program. The CDC’s funding ended in
June 2003, but the program continues as a departmental resource for expanding UM/Sylvester’s
community-based cancer control research program.
During the two and one-half years the FCCCI
was funded by CDC, it established four regional
cancer control collaboratives that cover the entire
state of Florida. Each collaborative engaged in a
strategic planning process and developed a comprehensive cancer control plan for their respective
regions (http://fccci.med.miami.edu). More than
200 individuals and 100 organizations participated in the planning process, which has been
integrated into the state’s cancer control planning
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
activities. The regional collaboratives form a
unique infrastructure that continues under the
leadership of cancer centers and universities:
UM/Sylvester is the lead agency for the Southeast
Regional Collaborative; the H. Lee Moffitt Cancer Center and Research Institute is sponsoring
the Southwest Regional Collaborative; the M.D.
Anderson Cancer Center in Orlando is sponsoring the Northeast Regional Collaborative; and
the Northwest Regional Collaborative is led by a
collaborative effort involving Florida State University, Florida A&M University, and the Coastal
Cancer Information Service Partnership Program.
Membership in the regional collaboratives, implementation of the regional plans, and integration
into state activities, are ongoing.
In addition to establishing the collaboratives
and developing the regional plans, the FCCCI
has conducted the following pilot studies:
• Telephone survey on attitudes and barriers to cancer screening and education—a random statewide
phone survey that asked participants their reasons for obtaining or not obtaining specific
cancer screening tests and information about
cancer.
• Miami-Dade Cancer Prevention Project—addresses cancer disparities in the Haitian-American community in north Miami-Dade County,
which has a high percentage of late stage diagnoses for breast, cervical, prostate, colorectal,
and lung cancers.
• Sun protection in Miami-Dade County public
schools—a survey in elementary and middle
public schools to determine current policies and
procedures for protecting students and staff
from sun exposure and skin cancer risk.
• Small area analysis of cancer and demographic
data for Miami-Dade County (funded by an
American Cancer Society Florida Division
grant; Robert S. Kirsner, M.D., is the principal
investigator)—developed a methodology to
correlate late stage diagnosis with sociodemographic variables and identify geographic areas
of the county at greatest need of interventions
to reduce late diagnosis.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Head and Neck Cancer
Supplemental beta-carotene has no significant
effect on second head and neck cancer mortality
or lung cancer mortality.
Hepatocellular Carcinoma
Florida Blacks and Hispanics are at significantly
increased risk for hepatocellular carcinoma (HCC)
incidence when compared with Whites from
Florida. These results have implications for preventive HCC recommendations in growing racial
and ethnic subpopulations in the United States.
Hodgkin’s Disease
The incidence of Hodgkin’s and non-Hodgkin’s
lymphoma is significantly higher among Florida’s
Hispanic children, with 30 percent increased relative risk, compared to White non-Hispanics.
Black children have significantly decreased incidence and risk. Results for lymphoid leukemia
were similar. Incidence of lymphoma in Florida’s
Hispanic children (primarily those of Cuban and
Central American origin) differ from similar reports from Texas and California, where Hispanics
are primarily of Mexican origin.
Tobacco Use
Results of the evaluation of Florida’s Tobacco Pilot Program show that there has been a decrease
in the prevalence of smoking among middle and
high school students by approximately 40 percent
and 18 percent, respectively, statewide since
1988. Exposure to tobacco use prevention education has been associated with lower proportions
of youth who smoke, as has been the intensity of
law enforcement efforts. Evaluation of the media
campaign shows an association between more
recall of anti-tobacco messages and less tobacco
use. Further, when anti-tobacco community partnerships/coalitions were most active, there were
greater decreases in youth tobacco use than when
the activities were less active.
Cigarette smoking may be a gateway drug to
illegal drug use. Persons who had smoked cigarettes were far more likely to use cocaine, heroin,
crack, and marijuana.
3
CANCER PREVENTION AND CONTROL PROGRAM
MICHAEL H. ANTONI, PH.D.
Professor of Psychology
DESCRIPTION OF RESEARCH
D
r. Antoni’s research interests over the past
decade have focused on examining the effects of stressors and stress management interventions on the adjustment to, and physical course
of, diseases such as breast cancer, cervical cancer,
prostate cancer, chronic fatigue syndrome, and
HIV infection. He also has examined some of the
psychobiological mechanisms that might explain
ways in which stressful events and psychosocial
interventions contribute to the adjustment to,
and physical course of, these diseases looking specifically at psychological intervening variables
(stress appraisal processes, coping behaviors, and
social resources) and biological/physiological variables (endocrine and immune system functioning).
For the past four years, Dr. Antoni has been
funded by the NCI through a five-year P50 Center for Psycho-Oncology Research (CPOR) grant,
which conducts bio-psychosocial research on the
inter-relationships between cognition, emotions,
biological processes, and physical health in the
context of several cognitive-behavioral stress
management (CBSM) randomized clinical trials.
Populations include those at high risk for cancer
and those dealing with cancer diagnoses including cervical neoplasia, breast cancer, and prostate
cancer. The grant includes funding for four clinical trials, five core laboratories dedicated to providing psychosocial and biological mechanism
and outcome data, as well as statistical/data management for the four clinical trials. A number of
UM/Sylvester investigators including those from
the departments of Microbiology and Immunology, Psychology, and Medicine, have ongoing
pilot studies designed to elaborate on biopsychosocial pathways being explored in the
CPOR parent trials.
4
Generally speaking, most of Dr. Antoni’s research efforts have focused on using information
derived from studies examining the effects of field
and laboratory stressors to develop stress reduction interventions that are specifically tailored to
the disease-related issues, educational levels, and
cultural characteristics of the target groups. This
has resulted in the development of treatment
manuals used for conducting intervention
groups, which are in turn used to test the efficacy
of treatment programs in the context of randomized clinical trials. In addition to testing the efficacy of these interventions in homogeneous
populations, this program also will conduct
generalizability studies designed to see how well
the interventions work in diverse patients groups
(e.g., inner city HIV+ women at risk for cervical
cancer and Spanish-speaking breast cancer patients). The overarching goal is to develop theoretically driven and empirically supported
psychosocial interventions with utility for secondary and tertiary prevention in persons diagnosed and treated for cancer.
SELECTED PUBLICATIONS
2002
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naïve T cells
(CD4(+)CD45RA(+)CD29(+)). American Journal of Psychiatry 159:143-45, 2002.
Knippels, HM, Goodkin, K, Weiss, JJ, Wilkie,
FL, and Antoni, MH. The importance of cognitive self-report in early HIV-1 infection: validation of a cognitive functional status subscale.
AIDS 16:259-67, 2002.
Culver, JL, Arena, PL, Antoni, MH, and Carver,
CS. Coping and distress among women under
treatment for early stage breast cancer: comparing
African Americans, Hispanics and non-Hispanic
Whites. Psycho-oncology 11:495-504, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
Cruess, S, Antoni, MH, Hayes, A, Penedo, F,
Ironson, G, Fletcher, MA, Lutgendorf, S, and
Schneiderman, N. Changes in mood and depressive symptoms and related change processes
during cognitive behavioral stress management
in HIV-Infected Men. Cognitive Therapy and
Research 26:373-392, 2002.
Kumar, M, Kumar, AM, Waldrop, D, Antoni,
MH, Schneiderman, N, and Eisdorfer, C. The
HPA axis in HIV-1 infection. Journal of Acquired Immune Deficiency Syndromes 31
Supplement 2:S89-93, 2002.
2003
Antoni, MH. Stress management and psychoneuroimmunology in HIV infection. CNS
Spectrums 8:40-51, 2003.
Perna, FM, Antoni, MH, Baum, A, Gordon, P,
and Schneiderman, N. Cognitive behavioral
stress management effects on injury and illness
among competitive athletes: a randomized clinical trial. Annals of Behavioral Medicine 25:6673, 2003.
Antoni, MH. Psychoneuroendocrinology and
psychoneuroimmunology of cancer: Plausible
mechanisms worth pursuing? Brain, Behavior and
Immunity 17 (1 Supplement):S84-91, 2003.
Antoni, MH and Pitts, M. Journal of Psychosomatic Research, special issue. Journal of Psychosomatic Research 54:179-83, 2003.
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates the
association between psychological distress and
immune status among HIV-positive men and
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-89,
2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptom-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
atic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Petronis, VM, Carver, CS, Antoni, MH, and
Weiss, S. Investment in body image and psychosocial well-being among women treated for early
stage breast cancer: partial replication and extension. Psychology & Health 18:1-13, 2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life
stress and cervical squamous intraepithelial lesions in women with human papillomavirus and
human immunodeficiency virus. Psychosomatic
Medicine 65:427-34, 2003.
Weiss, JL, Mulder, CL, Antoni, MH, De
Vroome, EM, Garssen, B, and Goodkin, K. Effects of a supportive-expressive group intervention on long-term psychosocial adjustment in
HIV-infected gay men. Psychotherapy and Psychosomatics 72:132-40, 2003.
McGregor, BA, Antoni, MH, Boyers, A, Alferi,
SM, Blomberg, BB, and Carver, CS. Cognitive
behavioral stress management increases benefit
finding and immune function among women
with early stage breast cancer. Journal of Psychosomatic Research 54:1- 8, 2003.
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,
and Schneiderman, N. Psychological distress is
associated with decreased memory helper T-cell
and B-cell counts in pre-AIDS HIV seropositive
men and women but only in those with low viral
load. Psychosomatic Medicine 65:627-35, 2003.
O’Cleirigh, C, Ironson, G, Antoni, MH,
Fletcher, MA, McGuffey, L, Balbin, E,
Schneiderman, N, and Solomon, G. Emotional
expression and depth processing of trauma and
their relation to long-term survival in patients
with HIV/AIDS. Journal of Psychosomatic Research 54:225-35, 2003.
5
CANCER PREVENTION AND CONTROL PROGRAM
Robbins, M, Szapocznik, J, Tejeda, M, Samuels,
D, Ironson, G, and Antoni, MH. The protective
role of the family and social support network in a
sample of HIV+ African American women:
results of a pilot study. Journal of Black Psychology 29:17-37, 2003.
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,
Schneiderman, N, Brondolo, E, Tobin, J, and
Weiss, S. Cognitive-behavioral interventions improve quality of life in women with AIDS. Journal of Psychosomatic Research 54: 253-261,
2003.
Lechner, SC, Zakowski, SG, Antoni, MH,
Greenhawt, M, Block, K, and Block, P. Do
sociodemographic and disease-related factors influence benefit-finding in cancer patients?
Psycho-oncology 12: 491-499, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-2, 2003.
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni,
MH, Malow, R, Costa, P, and Schneiderman, N.
Personality, quality of life and HAART adherence
among men and women living with HIV/AIDS.
Journal of Psychosomatic Research 54:271-8,
2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological distress among symptomatic HIV+ men who have
sex with men. Annals of Behavioral Medicine
25:203-13, 2003.
6
HIGHLIGHTS/DISCOVERIES
• Life stress and stress management in the promotion
of human papillomavirus to cervical neoplasia—
researchers have been investigating the interaction of viral and psychosocial risk factors for
cervical cancer among African American
women who are co-infected with HIV-1 and
high versus low-risk human papillomavirus
(HPV) types. One study specifically examines
the relationships between life stress, pessimism,
emotional expression, natural killer cell cytotoxicity (NKCC), and cytotoxic-suppressor
T cells, and the development of squamous
intraepithelial lesions (SIL) and cervical carcinoma in women co-infected with HIV and one
or more HPV types. Dr. Antoni’s laboratory
recently found that elevated life stress predicts
greater promotion and persistence of SIL,
greater numbers of genital herpes virus outbreaks, and greater declines in NK cell percentages over a one-year prospective period in
women co-infected with HIV and HPV. The
reductions in NK percentage appeared to explain the association between elevated life stress
and SIL promotion. This work led to one of the
projects in the CPOR, which evaluates the effects of CBSM intervention on distress, quality
of life, NK cells, and their cytotoxicity, and the
promotion of SIL and indices of clinical disease
progression in HIV+HPV+ women.
• Psychosocial intervention after surgery for breast
cancer—the laboratory has an NCI-funded
project titled “Facilitating Positive Adaptation
in Women with Breast Cancer,” which examines the effects of group-based CBSM intervention on psychosocial adjustment in 200
early-stage breast cancer patients in the weeks
following surgery. Pilot work over the prior year
established an immunologic battery for this
study, which includes lymphoproliferative responses to CD3 crosslinking and associated
Th1- and Th2-like cytokine production, and
cytokine-stimulated NKCC to K562 targets
and breast-cancer related cell lines. This work
also showed that women assigned to CBSM
showed increases in positive growth and optiUM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
mism and a decreased prevalence of clinical depression, decreases in plasma cortisol, and increases in lymphocyte proliferative responses to
anti-CD3 crosslinking.
• International breast cancer research—additional
work with the Helen Dowling Institute in
Rotterdam, Holland, focused on developing
new assessment strategies for measuring emotional expression patterns and acute responses
to emotionally-arousing laboratory challenges
in breast cancer patients and how these change
during the course of psychotherapy. They are
collecting data for a Dutch Cancer Foundation
(NKB)-funded study titled “Effects of group
psychotherapy compared with group support in
patients with early-stage breast cancer,” which is
modeled after the recently funded NCI study
noted above. These researchers found evidence
that psychosocial intervention reduced cortisol
levels and modulated the NK cell response to
laboratory challenges.
• Psychosocial intervention after adjuvant therapy
for breast cancer—together with a team led by
Gail H. Ironson, M.D., Ph.D., and Ron E. F.
Durán, Ph.D., the CPOR is investigating the
effects of CBSM in a randomized trial among
women who completed adjuvant therapy for
breast cancer within the last year. Preliminary
results suggest that the intervention produces
similar psychological and physiological effects
to those observed in women receiving CBSM
shortly after surgery.
• Psychosocial intervention after surgery for prostate
cancer—together with a team led by Neil
Schneiderman, Ph.D., and Frank J. Penedo,
Ph.D., the CPOR is investigating the effects of
CBSM in a randomized trial among men recently undergoing surgery for early-stage prostate cancer. Preliminary results suggest that the
intervention is successful in increasing quality
of life in this population. Studies now are underway examining the biological changes that
may occur concurrently with these quality of
life improvements.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
F. DANIEL ARMSTRONG, PH.D.
Professor of Pediatrics
DESCRIPTION OF RESEARCH
D
r. Armstrong’s major interests in cancer
research are in the areas of neurocognitive
late effects in children treated for brain tumors
and acute lymphocytic leukemia, quality of life
assessment in childhood cancer, interventions for
cognitive late effects in childhood cancer survivors, and health behavior outcomes in long-term
survivors of childhood cancer.
SELECTED PUBLICATIONS
2002
Lemanek, KL, Brown, RT, Armstrong, FD,
Hood, C, Pegelow, CH, and Woods, G. Dysfunctional eating patterns and symptoms of pica in
children and adolescents with sickle cell disease.
Clinical Pediatrics 41:493-500, 2002.
Perrin, E and the Committee on Psychosocial
Aspects of Child and Family Health, American
Academy of Pediatrics. (Armstrong, FD, co-author), Technical Report: Co-parent or secondparent adoption by same-sex parents. Pediatrics
109:341-344, 2002.
2003
Thompson, RJ, Jr., Armstrong, FD , Link, CL,
Pegelow, CH, Moser, F, and Wang, W. A prospective study of the relationship over time of behavior problems, intellectual functioning, and family
functioning in children with sickle cell disease:
a report from the Cooperative Study of Sickle
Cell Disease. Journal of Pediatric Psychology
28:59-65, 2003.
7
CANCER PREVENTION AND CONTROL PROGRAM
LISA L. BAUMBACH-REARDON, PH.D.
Associate Professor of Pediatrics
DESCRIPTION OF RESEARCH
D
r. Baumbach’s laboratory is involved in
breast cancer research focusing on a better
understanding of the genetic basis of breast cancer in African-American women. The laboratory
is completing two major projects. The first is the
development of a specific BRCA1 and BRCA2
mutation/variants panel for women of African
ancestry with either breast cancer or a significant
family history of breast/ovarian cancer. Development of such a panel will allow its incorporation
into clinical practice with clear improvement
of genetic counseling for this minority and
underserved population. Based on their preliminary data, supplemented with a thorough review
of all published English literature, the laboratory
has identified 13 reported mutations and 13 reported unclassified variants in BRCA1, and six
mutations and ten variants in BRCA2 in African
Americans. Some of these genetic changes are
specific to an individual; others are recurrent in
the African Americans studied. A screening panel
for such BRCA1 and BRCA2 mutations/variants
will be designed to develop an efficient assay for
eventual use in clinical practice.
The second project, which complements the
first, is a genome-wide analysis of all genetic
changes in breast cancer tissues collected from
African-American patients. These studies will use
state-of-the art technology of DNA microarray
analysis. The combined information from these
studies will provide significant new insights into
the genetic basis of African-American breast cancer, thus providing important new information
regarding diagnosis and possible therapies.
8
HIGHLIGHTS/DISCOVERIES
• Identified 13 reported mutations and 13 reported unclassified variants in BRCA1, and six
mutations and 10 variants in BRCA2 in African
Americans.
• Made significant progress in the development of
the mutation screening panel-streamlined
methodology for mutation detection.
• Filed for a patent to protect information related
to the development of the mutation screening
panel, through the University of Miami Office
of Technology Transfer.
• Conducted further detection and population
screening for African-American BRCA1 and
BRCA2 missense mutations.
BONNIE B. BLOMBERG, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
R
esearch in Dr. Blomberg’s laboratory focuses
on two projects. One of these projects
involves basic research on the molecular regulation of B lymphopoiesis in mice. Generation of
B lymphocytes is important in cancer patients
receiving bone marrow as well as in the normal
production of the humoral (antibody) response.
Aged humans and other mammals have a poorer
immune response to pathogens.
In collaboration with Richard L. Riley,
Ph.D., in the department of Microbiology and
Immunology, Dr. Blomberg has shown that aged
mice, those greater than or equal to about 80
percent of their full life span, have a substantial
decrease in the number of precursor B lymphocytes as well as the amount of the precursor B-cell
receptor (preBCR) including the surrogate light
chain (SLC)g5 and VpreB. Their data indicate
that this affects the antibody VH repertoire at the
pre-B cell level, i.e., before antigen selection.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
More recent data indicate that the transcription
factor, E2A, is reduced in not only precursor B
cells but also in mature B cells in peripheral
lymphoid organs in aging, leading to defects in
Ig class switch and humoral immunity. Current
studies will reveal the molecular and cellular
causes of these defects in the aged humoral
immune response and attempt to reverse these
defects. These studies are important for cancer
for two reasons: 1) the depressed immune
response seen in aged humans likely contributes
to increased susceptibility to cancer, and 2) bone
marrow transplantation given to many types of
cancer patients requires generation of mature
B lymphocytes from the precursors in the bone
marrow. Knowledge about the cellular and
molecular requirements for B lymphopoiesis
in young and aged individuals should lead to
improvements in the humoral immune system
of cancer patients.
Another project in Dr. Blomberg’s laboratory
involves clinical research with breast cancer patients. In collaboration with Michael H. Antoni,
Ph.D., and Charles S. Carver, Ph.D., in the department of Psychology, Sharlene Weiss, Ph.D.,
in the department of Medicine, and members of
the Cancer Prevention and Control Program at
UM/Sylvester, Dr. Blomberg’s laboratory is
measuring the status of various immune parameters in patients in response to psychosocial intervention (e.g., group therapy, stress reduction).
Preliminary experiments have shown that intervention patients have an improved immune
response as seen by the ability of their T cells
to proliferate in response to an antigen-specific
receptor stimulus (anti-CD3). Current studies are
measuring T, natural killer (NK), and lymphokine-activated killer (LAK) cytotoxic function
as well as potential TH1/TH2 differences by
cytokine production resulting from T-cell stimulation. These studies are important to allow optimal immune response in cancer patients, which
will better detect/destroy residual cancer and
allow for better patient survival.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SELECTED PUBLICATIONS
2002
Jin, Y, Fuller, L, Carreno, M, Esquenazi, V,
Blomberg, BB , Wei, YT, Ciancio, G, Burke, GW
3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional and phenotypic properties of peripheral T
cells anergized by autologous CD3(+) depleted
bone marrow cells. Human Immunology 63:56775, 2002.
Burke, GW, Ciancio, C, Blomberg, BB , Rosen,
A, Suzart, K, Roth, D, Kupin, W, Esquenazi, V,
and Miller, J. Randomized trial of three different
immunosuppressive regimens to prevent chronic
renal allograft rejection. Transplantation Proceedings 34:1610-11, 2002.
Blomberg, BB , Mathew, J, Fainman, H, Hussini,
S, Carreno, M, Hnatyszyn, H, Garcia-Morales,
R, Fuller, L, Vallone, T, Rosen, A, Esquenazi, V,
Ricordi, C, Tzakis, A, and Miller, J. Human bone
marrow cells retrovirally transduced with the allogeneic class II gene, HLA-DR3beta, down regulate anti-allogeneic responses of autologous
lymphoid cells. Human Immunology 63:S19,
2002.
2003
Mathew, JM, Blomberg, BB , Fuller, L, Burke,
GW, Ciancio, G, Kenyon, N, Ricordi, C, Tzakis,
AG, Esquenazi, V, and Miller, J. A novel microcell-mediated lympholytic assay for the evaluation of regulatory cells in human alloreactive
CTL responses. Journal of Immunological Methods 272:67-80, 2003.
Blomberg, BB , Hussini, S, Fainman, H, Mathew,
JM, Hernandez, A, Carreno, M, Hnatyszyn, HJ,
Garcia-Morales, R, Fuller, L, Rosen, A, Ricordi,
C, Tzakis, A, Miller, J, and Esquenazi, V.
Retroviral transduction of an allogeneic class II
gene into human bone marrow down regulates
allo-immune reactivity. Human Immunology
64:S128, 2003.
9
CANCER PREVENTION AND CONTROL PROGRAM
Hernandez, A, Lindner, I, Blomberg, BB ,
Hussini, S, Burger, M, Mathew, JM, Carreno, M,
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,
Lee, KP, Miller, J, and Esquenazi, V. Suppression
of allogeneic T cell proliferation through blocking of NF-KB in the differentiation process of
human dendritic cells. Human Immunology
64:S128, 2003.
McGregor, BA, Antoni, MH, Boyers, A, Alferi,
SM, Blomberg, BB , and Carver, CS. Cognitive
behavioral stress management increases benefit
finding and immune function among women
with early stage breast cancer. Journal of Psychosomatic Research 54:1- 8, 2003.
Mathew, JM, Alvarez, S, Vallone, T, Blomberg,
BB, Joshua, M, and Esquenazi, V. A humanSCID-mouse-islet transplant model for the evaluation of the regulatory activity of donor bone
marrow cells. Human Immunology 64:S7, 2003.
• Compromised humoral immune response in
aged individuals may be at least partially explained by antibody VH repertoire differences at
the pre-B cell level (before antigen selection).
Van Der Put, E, Sherwood, EM, Blomberg, BB ,
and Riley, RL. Aged mice exhibit distinct B cell
precursor phenotypes differing in activation, proliferation, and apoptosis. Experimental Gerontology 38:1137-47, 2003.
Frasca, D, Nguyen, D, Van Der Put, E, Riley,
RL, and Blomberg, BB . The Age-related decrease
in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrowderived B cell precursors. Frontiers in Bioscience
8:A110-16, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Effects of aging on proliferation and E47
transcription factor activity induced by different
stimuli in murine splenic B cells. Mechanisms of
Ageing and Development 124:361-69, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Frasca, D, Van der Put, E, Riley, RL, and
Blomberg, BB . Reduced Ig class switch in aged
mice correlates with decreased E47 and activation-induced cytidine deaminase. Journal of Immunology 172:2155-62, 2003.
10
HIGHLIGHTS/DISCOVERIES
• Decreased transcription factor E2A is important
for decreased Ig class switch and optimal humoral immunity.
• Demonstrated improved immune response in
breast cancer patients after psychosocial intervention.
CHARLES S. CARVER, PH.D.
Professor of Psychology
DESCRIPTION OF RESEARCH
D
r. Carver’s cancer-related research concerns
the role of psychosocial variables in cancer
morbidity and quality of life in cancer patients,
in terms of emotional disturbance, psychosexual
disturbance, and disruption of normal life activities. He is interested in the influences of vulnerability and resilience factors such as personality
and perceptions of availability of social support.
Dr. Carver also is interested in coping processes
of various sorts and their influence on adaptation
to diagnosis and treatment of cancer. Over time,
his work has expanded to include studies of quality of life among long-term survivors of cancer
and studies of relations between psychosocial
variables at diagnosis and recurrence over the
years following treatment (PI, Quality of Life
in Adult Cancer Survivors, NCI grant R01CA78995). Dr. Carver is a collaborator in
research that provides cancer patients with
psychosocial interventions—ten-week group
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
sessions in cognitive-behavioral stress management—and examines effects of those interventions over the subsequent year. His first study on
that topic examined only psychosocial outcomes
(PI, Adjustment to Breast Cancer Among Younger
Women, NCI grant R01- CA64710). Pilot data
collected in that study, however, have led to further work in which he and his colleagues also are
examining the impact of the intervention on immune function (Co-PI, Facilitating Positive Adaptation to Breast Cancer, NCI grant
R01-CA64710).
SELECTED PUBLICATIONS
2002
Perczek, RE, Burke, MA, Carver, CS, Krongrad,
A, and Terris, MK. Facing a prostate cancer diagnosis: who is at risk for increased distress? Cancer
94:2923-29, 2002.
Culver, JL, Arena, PL, Antoni, MH, and Carver,
CS. Coping and distress among women under
treatment for early stage breast cancer: Comparing African Americans, Hispanics, and non-Hispanic Whites. Psycho-oncology 11:495-504,
2002.
2003
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life
stress and cervical squamous intraepithelial lesions in women with human papillomavirus and
human immunodeficiency virus. Psychosomatic
Medicine 65:427-34, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
McGregor, BA, Antoni, MH, Boyers, A, Alferi,
SM, Blomberg, BB, and Carver, CS. Cognitive
behavioral stress management increases benefit
finding and immune function among women
with early stage breast cancer. Journal of Psychosomatic Research 54:1-8, 2003.
Carver, CS, Lehman, JM, and Michael, HA. Dispositional pessimism predicts illness. Journal of
Personality and Social Psychology 84:813-21,
2003.
Petronis, VM, Carver, CS, Antoni, MH, and
Weiss, S. Investment in body image and psychosocial well-being among women treated for early
stage breast cancer: partial replication and extension. Psychology & Health 18:1-13, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-2, 2003.
HIGHLIGHTS/DISCOVERIES
• Completed interviews with 90 cancer survivors,
while working toward the development of a
measure of psychosocial adjustment aimed
specifically at cancer survivors. The interview
phase was followed by an item-development
phase. The items were then tested on another
sample of cancer survivors, resulting in a measure termed the Quality of Life in Adult Cancer
Survivors (QLACS).
• Investigated ethnic differences in reactions to
the cancer experience. One study found that
Hispanic women reported a variety of more
intense concerns of several sorts than did nonHispanic Whites or Blacks, along with greater
levels of distress. Concerns about existential
issues, sexuality, and rejection from others all
played roles in predicting various aspects of
quality of life in this study. Two other studies
determined that Hispanic and African-American women use more religious coping than do
non-Hispanic White women. Non-Hispanic
White women, it was found, use more humor.
11
CANCER PREVENTION AND CONTROL PROGRAM
• Studied a sample of low socioeconomic status
(SES) Hispanic breast cancer patients. This
study, led by Dr. Carver’s colleague, Susan
Alferi, Ph.D., found substantial differences
between women who identified themselves as
Catholic and those who identified themselves
as fundamentalist Christians. Among the
Catholic women, greater involvement in
religious coping was related to greater emotional distress. Among the other women the
opposite pattern emerged. Clearly, the effect
of religious involvement varies with the nature
of the religious involvement.
• Examined the effects of early portions of the
experience on the quality of life of long-term
survivors (five years or more). This research has
found that higher levels of distress during the
period surrounding treatment related strongly
to higher levels of distress five to 15 years later.
One of these studies also found that women
who reported finding benefit in the cancer experience during the first year post-treatment
had better emotional quality of life four to
seven years later.
LORA E. FLEMING, M.D., PH.D., M.P.H.,
M.Sc.
Professor of Epidemiology
and Public Health
DESCRIPTION OF RESEARCH
D
r. Fleming’s research interests are focused in
occupational and environmental medicine
and epidemiology. She is the only board-certified
and licensed occupational and enviromental
medicine physician and epidemiologist in South
Florida.
Dr. Fleming has performed funded research
on the health effects of methyl mercury contamination in the Everglades (Agency for Toxic Substances and Disease Registry and the Florida
Department of Health (FDOH)); a study of fumigation workers with the National Institute of
Occupational Safety and Health (NIOSH); a
12
study of pesticide levels and Parkinson’s disease
(University of Miami Glaser Award); an evaluation of reported health effects of the fumigant
Benlate (FDOH); an evaluation of the human
health effects of hazardous waste incineration
(Florida Department of Environmental Protection); an evaluation of the occupational health
effects of solid waste work (Center for Solid and
Hazardous Waste); back injury prevention in
firefighters (FDOH); several studies on the human health effects of the marine toxin diseases
(National Institute of Environmental Health Sciences, CDC, and the FDOH); a NIOSH Career
Development Award studying the chronic health
effects of a large cohort of licensed Florida pesticide applicators; and has recently finished a large
cohort study of certified Florida firefighters
funded by NIOSH.
Dr. Fleming is associate director of the
NIEHS Marine and Freshwater Biomedical Sciences Center at the University of Miami and director of outreach and education at the center.
She serves and has served on numerous task
forces and committees, including the Florida
Birth Defects Registry, Florida Harmful Algal
Bloom Taskforce, and the Florida Pesticide Advisory Committee.
Cancer-Related Activities
At UM/Sylvester, Dr. Fleming is the director of
research and project director for the Florida Cancer Data System (FCDS), Florida’s incident tumor registry. As part of her work with FCDS, Dr.
Fleming interacts with investigators, students, and
FCDS personnel to increase research opportunities and educational outreach at the FCDS. With
her colleagues, Dr. Fleming has investigated the
cancer experience of Florida’s Hispanic population,
the risk of subsequent cancers among persons with
ovarian cancer, the risk of cancer among Florida’s
children, and the stage at which poor women in
Florida present for diagnosis of breast cancer.
Based on her research, which focuses on the
human health effects of marine and freshwater
toxins, Dr. Fleming has studied the possible asso-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
ciation between blue green algal toxins in drinking water and the risk of hepatocellular carcinoma in Florida.
With NIOSH funding, Dr. Fleming has assisted Fangchao Ma, M.D., and other colleagues
to examine the cancer risks associated with
firefighting in Florida. A retrospective cohort
study was conducted among 34,796 male and
2,017 female firefighters certified between 1972
and 1999. Age- and gender-specific cancer incidence rates in the general Florida population
were used as comparisons in calculating the standardized incidence ratios (SIR). A total of 1,032
cases of cancer among Florida firefighters (970
male and 52 female) were identified by linkage
with the FCDS as of December 31, 1999. The
overall risk of cancer among male firefighters was
significantly lower compared to that of the general Florida population (age adjusted SIR=0.84;
95 perecent CI=0.79-0.90) as well as for cancers
of buccal (0.67; 0.47-0.91), stomach (0.50; 0.250.90), lung (0.65; 0.54-0.78), and brain (0.58;
0.31-0.97). Significantly increased cancer incidence was observed among male firefighters for
bladder (1.29; 1.01-1.62), testes (1.60; 1.202.09), and thyroid cancers (1.77; 1.08-2.73). Female firefighters had significantly increased
overall risk (1.63; 1.22-2.14), and increased incidence for thyroid cancers (3.97; 1.45-8.65) and
Hodgkin’s disease (6.25; 1.26-18.26).
SELECTED PUBLICATIONS
2002
Dewailly, E, Furgal, C, Knap, A, Galvin, J,
Baden, D, Bowen, B, Depledge, M, Duguay, L,
Fleming, LE, Ford, T, Moser, F, Owen, R, Suk,
WA, and Unluata, U. Indicators of ocean and
human health. Canadian Journal of Public
Health 93: S34-8, 2002.
Grant, P, Skinner, HG, Fleming, LE, and Bean,
JA. Influence of structured encounter forms on
documentation by community pediatricians.
Southern Medical Journal 95:1026-31, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Knap, A, Dewailly, E, Furgal, C, Galvin, J,
Baden, D, Bowen, RE, Depledge, M, Duguay, L,
Fleming, LE, Ford, T, Moser, F, Owen, R, Suk,
WA, and Unluata, U. Indicators of ocean health
and human health: developing a research and
monitoring framework. Environmental Health
Perspectives 110:839-45, 2002.
Zhou, O, Shimoda, H, Gao, B, Oh, S, Fleming,
LE, and Yue, G. Materials science of carbon
nanotubes: fabrication, integration, and properties of macroscopic structures of carbon
nanotubes. Accounts of Chemical Research
35:1045-53, 2002.
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, and Peace, S. Cancer among Hispanic women in South Florida: an
18-year assessment: a report from the Florida
Cancer Data System. Cancer 95:1752-58, 2002.
2003
Oberstein, EM, Fleming, LE, Gomez-Marin, O,
and Glassberg, MK. Pulmonary Lymphangioleiomyomatosis (LAM): Examining Oral Contraceptive Pills and the Onset of Disease. Journal
of Women’s Health (Larchmont) 12:81-5, 2003.
Entzel, PP, Fleming, LE, Trepka, MJ, and
Squicciarini, D. The health status of newly
arrived refugee children in Miami-Dade County,
Florida. American Journal of Public Health
93:286-8, 2003.
Fleming, LE, Gomez-Marin, O, Zheng, D, Ma,
F, and Lee, D. National Health Interview Survey
mortality among US farmers and pesticide applicators. American Journal of Industrial Medicine
43:227-33, 2003.
Varela, JE, Gomez-Marin, O, Fleming, LE, and
Cohn, SM. The risk of death for Jehovah’s Witnesses after major trauma. Journal of Trauma
54:967-72, 2003.
13
CANCER PREVENTION AND CONTROL PROGRAM
HIGHLIGHTS/DISCOVERIES
• Research on human health effects of marine and
freshwater toxins—blue green algae, or
cyanobacteria, are microorganisms at the base
of the food and oxygen chain. The blue green
algae easily grow in fresh water reservoirs, sometimes producing large amounts of toxins. These
natural toxins can be carcinogenic and have
been associated with an increased risk of liver
cancer in animals and humans in China; furthermore, normal drinking water treatment
does not completely remove these toxins.
Therefore, using the technology of geographic
information systems (GIS) to store, analyze,
and display the data, Dr. Fleming and her colleagues showed that there may be an increased
risk of liver cancer in Florida for persons living
near surface water treatment plants with possible blue green algal toxin contamination. This
study was performed in collaboration with the
FCDS, the University of Miami NIEHS Marine and Freshwater Biomedical Sciences Center, and the Rosenstiel School of Marine and
Atmospheric Sciences, as well as the St. Johns
River Management District. Funding for this
study was provided by the Florida Harmful Algal Bloom Taskforce at the Florida Marine Research Institute.
• Examination of the cancer risks associated with
firefighting in Florida—this study did not find
evidence of an excess risk of lung or brain cancer in firefighters as documented in prior mortality studies. The study does, however, suggest
that a significantly increased risk of bladder
cancer among male firefighters might be related
to occupational exposure, rather than tobacco
use. This is the largest known study of
firefighters to date.
14
MARY ANN A. FLETCHER, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
D
r. Fletcher is interested in studying immunologic changes during stress management in
breast cancer and cervical neoplasia. She has collaborated with Michael H. Antoni, Ph.D., Gail H.
Ironson, M.D., Ph.D., and Neil Schneiderman,
Ph.D., for the past 17 years on NIH-funded
projects examining the immunological effects of
stress management in persons with HIV infection, women at risk for cervical cancer, and
women undergoing treatment for early-to-midstage breast cancer.
Dr. Fletcher is the director of the E.M.
Papper Laboratory of Clinical Immunology. This
laboratory has been an important core facility for
mind-body research at the University of Miami
for many years. Much of their research has been
cancer related. Currently, the laboratory supports
the P50 Center for Psycho-Oncology Research
(CPOR), which is assessing the effects of cognitive-behavioral stress management (CBSM) on
both psychological and biological parameters in
patients with breast cancer and prostate cancer
and with cervical hyperplasia. The laboratory
functions as a Biological Assessment Core to
coordinate the collection, storage, and assaying
of immune indices of cytotoxic and helper cell
function (cytokine-stimulated natural killer cytotoxicity (NKCC), ELISPOT, quantitative flow
cytometric measurement of surface and intracellular molecules, including activation and differentiation markers as well as cytokines, perforin, and
granzymes). By ELISA assays, the laboratory
measures Th1 (g-IFN, IL-2, IL-12), Th2 (IL-4,
IL-5, IL-6, and IL-10), and proinflamatory (IL-1,
IL-6, and TNF-α) cytokines as well as receptors
of these cytokines in body fluids and lymphocyte
culture supernatants. Standardized assays are used
for soluble markers of disease activity (CA 15.3,
PSA, VEGF, etc.) in blood samples collected
from cancer patients and controls.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
SELECTED PUBLICATIONS
HIGHLIGHTS/DISCOVERIES
2002
• Dr. Fletcher’s primary areas of focus include
examining quantitative indices of lymphocyte
subpopulations and qualitative indices of function including NKCC and IgG antibodies to
latent herpes viruses, and how these respond to
stressors and stress management interventions
in these populations.
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American Journal of Psychiatry 159:143-45, 2002.
2003
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates the
association between psychological distress and
immune status among HIV-positive men and
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-89,
2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,
NG, Fletcher, MA , Antoni, MH, LeBlanc, WG,
and Schneiderman, N. Psychological distress is
associated with decreased memory helper T-cell
and B-cell counts in pre-AIDS HIV seropositive
men and women but only in those with low viral
load. Psychosomatic Medicine 65:627-35, 2003.
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,
MA, McGuffey, L, Balbin, E, Schneiderman, N,
and Solomon, G. Emotional expression and
depth processing of trauma and their relation to
long-term survival in patients with HIV/AIDS.
Journal of Psychosomatic Research 54:225-35,
2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Her laboratory currently is exploring the mechanics of cytotoxicity (e.g., perforin and
granzyme production) and how these relate to
psychosocial factors via hypothalamic pituitary
adrenal hormone changes.
KENNETH W. GOODMAN, PH.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
W
ork on ethics and evidence-based practice
constitutes a natural extension of efforts to
explore ethical issues in health informatics, epidemiology, and public health. The University of
Miami’s reputation as a leader in under-addressed
areas of clinical and research ethics continues to
expand. The University continues to work on
issues in the use of information technology, especially in public health. Moreover, the University’s
ethics programs include international research
ethics among the core foci, even as the University
continues work on end-of-life care, environmental health and ethics, and genetics. Efforts to develop ethics curricula for scientists and others
continue.
Dr. Goodman is director of the University of
Miami’s Bioethics Program, director of clinical and
research ethics education at UM/Sylvester, and
vice chair of UM/Sylvester’s Bioethics Committee.
15
CANCER PREVENTION AND CONTROL PROGRAM
SELECTED PUBLICATIONS
2002
Green, RM, DeVries, KO, Bernstein, J,
Goodman, KW, Kaufmann, R, Kiessling, AA,
Levin, SR, Moss, SL, and Tauer, CA. Overseeing
research on therapeutic cloning: a private ethics
board responds to its critics. Hastings Center Report 32:27-33, 2002.
2003
Markovitz, BP and Goodman, KW. Case reports
on the web redux: confidentiality still in jeopardy.
Proceedings of the AMIA Annual Symposium
926, 2003.
W. JARRARD GOODWIN, M.D., F.A.C.S.
Professor of Otolaryngology
DESCRIPTION OF RESEARCH
D
r. Goodwin’s research focuses on the prevention and treatment of squamous cell carcinoma (SCCA) of the upper aerodigestive tract.
Cancer Prevention and Control
Dr. Goodwin has had a long-term interest in the
potential of several micronutrients to inhibit the
development of these cancers. Currently, various
aspects of an extensive database from a phase III
chemo-prevention trial, investigating the activity
of beta-carotene, are being analyzed and published. He also is collaborating with investigators
at the University of Florida on an NCI-funded
oral cavity cancer control project. Disparities in
mortality and stage at time of presentation for
under-served populations is a developing interest.
ing various treatment interventions. Working
with Frank J. Penedo, Ph.D., he also is interested
in the effect of stress and depression on survival
and quality of life in this group of patients.
Therapy
Finally, Dr. Goodwin is actively involved in clinical trials studying the effect of P-53 gene therapy,
alone and in combination with chemotherapy, for
recurrent cancers of the oral cavity, pharynx, and
larynx.
SELECTED PUBLICATIONS
2003
Civantos, FJ, Gomez, C, Duque, C, Pedroso, F,
Goodwin, WJ, Weed, DT, Arnold, D, and
Moffat, F. Sentinel node biopsy in oral cavity
cancer: correlation with PET scan and immunohistochemistry. Head & Neck 25:1-9, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45,
2003.
HIGHLIGHTS/DISCOVERIES
• Established, as one of the first investigators, the
efficacy of selenium and retinoic acid in inhibiting carcinogenesis in an animal tumor model
relevant to SCCA of the upper aerodigestive
tract.
• Published definitive outcomes studies analyzing
the results of salvage treatment for recurrent
cancer of the upper aerodigestive tract and for
the treatment of Stage IV cancer.
Quality of Life
In addition, Dr. Goodwin studies the impact of
treatment decisions on the quality of life experienced by patients with head and neck cancer.
Current studies include collaborative investigations of speech and swallowing function follow-
16
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
GAIL H. IRONSON, M.D., PH.D.
Professor of Psychology
DESCRIPTION OF RESEARCH
Predictors of Long-Term Survivorship
Dr. Ironson’s work focuses on identifying psychosocial characteristics of persons who become
long-term survivors of HIV and cancer.
Psychosocial Interventions to Improve
Survivorship
Parallel work by Dr. Ironson’s colleagues is evaluating the effects of interventions designed to
boost emotional awareness and expression, build
social support, and benefit breast cancer survivors
and HIV-infected persons. This work is funded
by two NIH/NIMH R01’s and an NCI P50.
SELECTED PUBLICATIONS
2002
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American Journal of Psychiatry 159:143-5, 2002.
Ironson, G, Freund, B, Strauss, JL, and Williams,
J. Comparison of two treatments for traumatic
stress: a community-based study of EMDR and
prolonged exposure. Journal of Clinical Psychology 58:113-28, 2002.
Ironson, G, Solomon, GF, Balbin, EG,
O’Cleirigh, C, George, A, Kumar, M, Larson, D,
and Woods, TE. The Ironson-Woods Spirituality/
Religiousness Index is associated with long survival, health behaviors, less distress, and low cortisol in people with HIV/AIDS. Annals of
Behavioral Medicine 24:34-48, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Freedland, KE, Skala, JA, Carney, RM,
Raczynski, JM, Taylor, CB, Mendes De Leon,
CF, Ironson, G, Youngblood, ME, Rama
Krishnan, KR, and Veith, RC. The Depression
Interview and Structured Hamilton (DISH): Rationale, development, characteristics, and clinical
validity. Psychosomatic Medicine 64:897-905,
2002.
2003
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates the
association between psychological distress and
immune status among HIV-positive men and
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-9,
2003.
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Stanley, H,
Ironson, G, Schneiderman, N, Brondolo, E,
Tobin, JN, and Weiss, S. Cognitive-behavioral
interventions improve quality of life in women
with AIDS. Journal of Psychosomatic Research
54:253-61, 2003.
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,
MA, McGuffey, L, Balbin, E, Schneiderman, N,
and Solomon, G. Emotional expression and
depth processing of trauma and their relation to
long-term survival in patients with HIV/AIDS.
Journal of Psychosomatic Research 54:225-35,
2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
17
CANCER PREVENTION AND CONTROL PROGRAM
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life
stress and cervical squamous intraepithelial lesions in women with human papillomavirus and
human immunodeficiency virus. Psychosomatic
Medicine 65:427-34, 2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and Psychological
Distress Among Symptomatic HIV+ Men Who
Have Sex With Men. Annals of Behavioral Medicine 25:203-13, 2003.
HIGHLIGHTS/DISCOVERIES
• Identified in her long-term survivorship studies
a number of cognitive appraisal, emotional expression, and spiritual-related predictors that
characterize HIV and cancer populations.
• Used this information to relate these psychosocial characteristics to relevant physiological
indicators (e.g., cortisol and natural killer cell
toxicity (NKCC)) that may explain their association with extended survival and optimal
health outcomes.
ROBERT S. KIRSNER, M.D.
Associate Professor of Dermatology and
Cutaneous Surgery
DESCRIPTION OF RESEARCH
D
r. Kirsner’s research interests encompass skin
cancer, health services research, and epidemiology. Specifically, he focuses on primary and
secondary prevention of skin cancer. With regard
to primary prevention efforts, his laboratory is
evaluating the policies and procedures in the Miami-Dade County school system related to sun
protection and studying the attitudes and behaviors of Hispanic students toward skin cancer prevention. His research will evaluate predictors of a
school-based education program aimed at skin
cancer education. Dr. Kirsner’s research efforts
18
regarding secondary prevention is aimed at determining prevalence of screening being performed
in various settings, patient preferences regarding
screening, and predictors of when skin cancer
screening will occur. Dr. Kirsner’s work in health
services research is aimed at determining the role
of a health care delivery system for outcomes for
skin cancer and other screenable cancers such as
breast, colon, and cervical cancer. Researchers in
this laboratory also are evaluating the effect of
poverty and access to cancer-related services on
cancer outcomes. Finally, Dr. Kirsner’s interest in
epidemiology has focused on the role of ultraviolet light in the development and mortality of skin
cancer and lymphoma.
SELECTED PUBLICATIONS
2002
Kirsner, RS , Fastenau, J, Falabella, A, Valencia, I,
Long, R, and Eaglstein, WH. Clinical and economic outcomes with graftskin for hard-to-heal
venous leg ulcers: a single-center experience. Dermatologic Surgery 28:81-82, 2002.
Federman, DG, Kravetz, JD, and Kirsner, RS .
Skin cancer screening by dermatologists: prevalence and barriers. Journal of the American Academy of Dermatology 46:710-14, 2002.
Federman, DG and Kirsner, RS . The patient
with skin disease: an approach for nondermatologists. Ostomy/Wound Management 48:22-8;
quiz 29-30, 2002.
Harrison-Balestra, C, Eaglstein, WH, Falabela,
AF, and Kirsner, RS . Recombinant human platelet-derived growth factor for refractory nondiabetic ulcers: a retrospective series. Dermatologic
Surgery 28:755-59; discussion 759-60, 2002.
Sullivan, TP, Elgart, GW, and Kirsner, RS . Pemphigus and smoking. International Journal of
Dermatology 41:528-30, 2002.
Sullivan, TP and Kirsner, RS . Surgical pearl:
punch technique to improve granulation over
exposed tendons in chronic wounds. Journal of
the American Academy of Dermatology 47:43940, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
Trent, JT and Kirsner, RS. Diagnosing necrotizing fasciitis. Advances In Skin & Wound Care
15:135-38, 2002.
Zacur, H and Kirsner, RS. Debridement: Rationale and Therapeutic Options. Wounds 14:2E7E, 2002.
Geren, SM, Kerdel, FA, Falabella, AF, Kirsner,
RS. Infliximab: A treatment option for ulcerative
pyoderma gangrenosum. Wounds 15:49-53,
2003.
Kirsner, RS . Infection and Intervention. Wounds
15:127-28, 2003.
2003
Kirsner, R . New approaches to a timeless dilemma. Ostomy/Wound Management 49:12-14,
2003.
Li, J, Zhang, YP, and Kirsner, RS . Angiogenesis
in wound repair: angiogenic growth factors and
the extracellular matrix. Microscopy Research
and Technique 60:107-14, 2003.
Trent, JT, Kirsner, RS , Romanelli, P, and Kerdel,
FA. Analysis of intravenous immunoglobulin for
the treatment of toxic epidermal necrolysis using
SCORTEN: The University of Miami Experience. Archives of Dermatology 139:39-43, 2003.
Trent, JT and Kirsner, RS . Wounds and malignancy. Advances in Skin & Wound Care 16:3134, 2003.
Jacob, SE, Lodha, R, Cohen, JJ, Romanelli, P,
and Kirsner, RS . Paraneoplastic eosinophilic
fasciitis: a case report. Rheumatology International 23:262-4, 2003.
Martin, LK and Kirsner, RS . Ulcers caused by
bullous morphea treated with tissue-engineered
skin. International Journal of Dermatology
42:402-04, 2003.
Ayyalaraju, RS, Finlay, AY, Dykes, PJ, Trent, JT,
Kirsner, RS , and Kerdel, FA. Hospitalization for
severe skin disease improves quality of life in the
United Kingdom and the United States: a comparative study. Journal of American Academy of
Dermatology 49:249-54, 2003.
Banta, MN, Eaglstein, WH, and Kirsner, RS .
Healing of refractory sinus tracts by dermal matrix injection with Cymetra. Dermatologic Surgery 29:863-66, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
HIGHLIGHTS/DISCOVERIES
• Found that differences in the stage of melanoma between patients enrolled in fee for
service compared to HMO is related to patient
access.
• Described the correlation between melanoma
in Black and Hispanic patients with UV exposure (the first to do so), suggesting a rationale
of skin cancer prevention in darkly pigmented
populations.
• Established that a history of skin cancer is the
most important predictor for determining
whether a patient will have skin cancer screening performed by his primary care provider.
MAHENDRA KUMAR, PH.D.
Professor of Psychiatry and
Behavioral Sciences
DESCRIPTION OF RESEARCH
D
r. Kumar is the director of the Molecular
Neuroendocrinology and Neurotransmitters
Laboratory in the department of Psychiatry and
Behavioral Sciences at the University of Miami.
He has been a close collaborator with Michael H.
Antoni, Ph.D., Gail H. Ironson, M.D., Ph.D.,
and Neil Schneiderman, Ph.D., over the past 15
years in various research investigations including
most recently, the Center for Psycho-Oncology
Research (CPOR), funded by the NCI. Dr. Kumar
conducts several neuroendocrinological protocols
within the CPOR and is responsible for carrying
out all the required assays to understand the mediating effects of stress hormones on health and
immunological indices during cognitive-behavioral stress management (CBSM) intervention.
19
CANCER PREVENTION AND CONTROL PROGRAM
SELECTED PUBLICATIONS
2002
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American Journal of Psychiatry 159:143-5, 2002.
Ironson, G, Solomon, GF, Balbin, EG,
O’Cleirigh, C, George, A, Kumar, M, Larson, D,
and Woods, TE. The Ironson-Woods Spirituality/
Religiousness Index is associated with long survival, health behaviors, less distress, and low cortisol in people with HIV/AIDS. Annals of
Behavioral Medicine 24:34-48, 2002.
Kumar, M, Kumar, AM, Waldrop, D, Antoni,
MH, Schneiderman, N, and Eisdorfer, C.
The HPA axis in HIV-1 infection. Journal of
Acquired Immune Deficiency Syndromes 31
Supplement 2:S89-93, 2002
2003
Mitchell, A and Kumar, M . Psychological coping
and cancer. Search strategy used is inadequate.
British Medical Journal 326:598; author reply
598, 2003.
HIGHLIGHTS/DISCOVERIES
• Made available urinary, blood, and salivary cortisol measurements that help in the understanding of the acute and more enduring effects of
this form of stress management on different
cancer populations studied at UM/Sylvester.
• Installed a real time polymerase chain reaction
(PCR) facility, which has been used to quantify
viral loads for HPV 16 and 18 sub-strains in
HIV+ women at-risk for cervical neoplasia in
one CPOR project. In fact, viral loads samples
have been obtained from the participants.
20
SUZANNE C. LECHNER, PH.D.
Assistant Professor of Psychiatry and
Behavioral Sciences
DESCRIPTION OF RESEARCH
D
r. Lechner’s research in psycho-oncology
focuses on two different themes: positive
adaptation to breast cancer and the causes of late
presentation to clinic following the detection of a
breast cancer symptom. With regard to the first,
Dr. Lechner is involved in clinical trials and correlational research studies to examine how people
adjust to illness, and whether there are variables
that can predict which patients will adapt well
and which will require psychotherapeutic intervention. Within the context of all of these studies, she is interested in the complex relationships
between positive adjustment and psychosocial
and immunological/endocrine variables. The
laboratory’s ongoing clinical intervention studies
are examining the effects of a ten-week cognitivebehavioral stress management (CBSM) intervention versus a one-day stress management seminar
on immunological, endocrine, and psychological
outcomes for women with early stage breast cancer. In addition, Dr. Lechner is the primary investigator of another ongoing correlational research
study, funded by the American Psychological Association Division 38, which will examine the
correlates and consequences of benefit-finding
(i.e., the belief that having cancer has led to positive life changes, such as better relationships with
family and friends, a stronger sense of self-efficacy, and personal strength and redirected
priorities).
Dr. Lechner’s research also focuses on another topic: delayed presentation to clinic following the detection of a breast cancer symptom.
Early detection and treatment has been shown to
result in a significant reduction in breast cancer
mortality. In spite of the importance of early detection, some women delay seeking consultation
after they detect a suspicious breast cancer symp-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
tom, such as a palpable breast lump or nipple
discharge. Women who delay in seeking medical
advice are more likely to present with advanced
disease, thus limiting available treatment options
and substantially impacting mortality. Previous
studies have indicated that breast cancer patients
who delayed as long as three to six months had
poorer prognoses than those who sought treatment within three months of symptom detection.
The reasons for delayed presentation are not well
understood, but may include such factors as
symptom-related information, sociodemographic
variables, ethnicity-related factors (e.g., fatalism),
attitudes and beliefs of the person’s social network
or religion, psychological attributes, and knowledge-related factors. The percentage of women
who present to the clinic with late stage breast
cancer in the metropolitan Miami-Dade area is
disproportionate to state and national averages,
leading to the hypothesis that late presentation
may be a significant health problem in this geographical area.
SELECTED PUBLICATIONS
2003
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,
Schneiderman, N, Brondolo, E, Tobin, J, and
Weiss, S. Cognitive-behavioral interventions improve quality of life in women with AIDS. Journal of Psychosomatic Research 54:253-61, 2003.
Lechner, SC, Zakowski, SG, Antoni, MH,
Greenhawt, M, Block, K, and Block, P. Do
sociodemographic and disease-related factors influence benefit-finding in cancer patients?
Psycho-oncology 12:491-99, 2003.
HIGHLIGHTS/DISCOVERIES
Development of Benefit-Finding in Cancer
Survivors
One study examined patients’ perceptions that
having cancer led to positive life changes, or
benefit-finding, e.g., improved relationships,
enhanced appreciation of life, increased resilience,
and self-reliance. The laboratory investigated
the relationship between benefit-finding and
sociodemographic (e.g., gender, age, marital
status, education, and income) and diseaserelated variables (e.g., severity of disease, or
cancer stage, or time since diagnosis).
• As hypothesized, benefit-finding was greater in
younger patients, and also differed by stage of
disease in a curvilinear fashion. Individuals with
Stage II disease had significantly higher benefitfinding scores than those with Stage IV or Stage
I cancer.
• Time since diagnosis and treatment status
(i.e., currently in treatment, completed treatment, or no treatment) were not related to
benefit-finding.
• Findings suggest that stage of disease is an important factor to consider when investigating
positive perceptions of disease in individuals
with cancer.
Another study examined whether various
measures of positive thinking (i.e., Life Orientation Test-Revised for Optimism) and found
meaning (Benefit-Finding Scale) measured over a
one-year period following surgery for early stage
breast cancer were associated with adjustment
(i.e., Profile of Mood States, Quality of Life
(QOL), and CES-Depression).
• Controlling for baseline levels of adjustment,
greater optimism at one-year follow-up was associated with concurrent higher vigor, better
QOL, fewer depressive symptoms, less anxiety,
depression, anger, and fatigue.
• One-year follow-up benefit-finding was correlated with concurrent higher vigor, better QOL,
fewer depressive symptoms, and less anxiety
when baseline adjustment scores were controlled.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
21
CANCER PREVENTION AND CONTROL PROGRAM
• Findings suggest that maintaining a positive
attitude may relate to psychological well-being
over the year post surgery.
An additional study revealed that there were
complex relationships between benefit-finding
and coping over the one-year period following
surgery for early stage breast cancer.
• During the early period of dealing with the diagnosis of and treatment for breast cancer, for
example, benefit-finding is associated with
greater positive reframing, religious coping, selfdistraction, substance use, examining emotions,
and seeking less social support. By mid-treatment (three months later), active coping and
religious coping were important correlates of
benefit-finding, while after treatment completion (six months), higher benefit-finding was
related to greater active coping, examining emotions, seeking social support, religious coping,
and reduced use of acceptance coping. However, by one year after surgery, greater benefitfinding was associated with using positive
reframing and planning coping strategies.
• Thus, effective coping strategies early on may be
those that help women modulate their emotions and maintain hope. Later on, the most
effective strategies appear to be those that help
them move on and plan for the future.
• The research outcome suggests that finding
benefits in cancer may be differentially related
to the coping strategies women employ at different points during the treatment trajectory,
which may have important implications for tailoring psychosocial interventions across medical
treatment.
22
DAVID J. LEE, PH.D.
Associate Professor of Epidemiology and
Public Health
DESCRIPTION OF RESEARCH
D
r. Lee is a chronic disease epidemiologist
with a long-standing interest in the prevalence of, and morbidities associated with, sensory-related diseases and impairments. In the past
two years, he has published findings that examined cancer mortality risk in community-residing
adults with visual impairment and glaucoma. Previous research has suggested an association between cancer risk and eye disease. Dr. Lee and his
colleagues found, however, that detection bias, in
part, might be responsible for this association.
Their findings were of sufficient merit to warrant
publication of an accompanying editorial by a
leading ophthalmic epidemiologist.
Dr. Lee entered the field of tobacco control
research in 2000, where he now devotes 60 percent of his research efforts. Since this career shift,
he has served as co-investigator of the Florida
Youth Cohort Study that is following a sample of
Florida adolescents in order to monitor changes
in tobacco-related attitudes/beliefs and behaviors.
He also is the lead author on three papers reporting results from this work. Dr. Lee also is the
principal investigator of two Flight Attendant
Medical Research Institute (FAMRI)-funded
grants to study the influence of second-hand
smoke on the health of adolescents. Using
UM/Sylvester developmental funds, Dr. Lee
fielded a school-based pilot study in 2004 that
examined second-hand smoke exposure and cancer risk factors in an ethnically diverse group of
middle-school students. Findings from this study
will be used to develop an intervention designed
to reduce cancer risk factors in this population.
It will be submitted for possible funding to the
NCI in February 2005.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
Dr. Lee also has developed an interest in the
identification of cancer risk factors in adults. For
example, he recently co-authored a paper examining cancer mortality risk in pesticide applicators.
He served as the dissertation chair for a project
examining cancer risk in Florida firefighters. Two
papers examining cancer mortality and cancer
incidence in this occupational group are presently
under peer review. In 2003, Dr. Lee and his colleagues published a lead article in the journal
Ophthalmology examining the association between
glaucoma and cause-specific mortality including
cancer. Dr. Lee’s most recent tobacco-related
publication focused on trends in smoking rates
among 209 of the largest worker groups in the
United States. This paper was published in the
Journal of Occupational and Environmental
Medicine in 2004.
A novel non-nicotine replacement therapy
smoking cessation strategy for older adults with
chronic disease, including cancer patients, is
presently under review by the NCI. A cognitive
behavioral smoking cessation program directed
at military recruits prior to entry into basic
training is also under review at the Department
of Defense.
SELECTED PUBLICATIONS
Lee, DJ, Gomez-Marin, O, Ma, F, and Lam, BL.
Uncorrected binocular distance visual acuity
impairment and survival: The National Health
and Nutrition Examination Survey I. Ethnicity
and Disease 13:485-91, 2003.
Lee, DJ, Trapido, E, and Rodriguez, R. Secondhand smoke and earaches in adolescents: The
Florida Youth Cohort Study. Nicotine and Tobacco Research 5:1-4, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated an association between exposure
to second-hand smoke and self-reported earaches in adolescents, which is novel in that
these associations have typically been reported
in younger children and infants. The two
FAMRI-funded studies will help to determine if
biologically confirmed exposure to second-hand
smoke is related to both reported earaches and
clinically confirmed indicators of middle ear
problems.
SILVINA LEVIS-DUSSEAU, M.D.
Professor of Medicine
2002
DESCRIPTION OF RESEARCH
Lee, DJ, Gomez-Marin, O, Lam, BL, and Zheng,
DD. Visual acuity impairment and mortality in
U.S. adults. Archives of Ophthalmology
120:1544-50, 2002.
or the last ten years, Dr. Levis-Dusseau, director of the Osteoporosis Center, a joint venture
between the University of Miami School of
Medicine and the Miami Veterans Administration Medical Center, has been conducting clinical
trials testing the effectiveness of different drugs in
the treatment of osteoporosis. Currently, she is
conducting an NIH-sponsored trial that will
evaluate the effectiveness of estrogens derived
from soy in preventing menopausal symptoms
and bone loss. Her research interests also include
improving muscle function and bone mass in
elderly individuals with vitamin D deficiency.
Dr. Levis-Dusseau has collaborated with Bernard
A. Roos, M.D., Michael H. Antoni, Ph.D., and
Neil Schneiderman, Ph.D., for the past three
Lee, DJ, Trapido, E, and Rodriguez, R. Self-reported school difficulties and tobacco use among
fourth- to seventh-grade students. Journal of
School Health 72:368-73, 2002.
2003
Fleming, LE, Gomez-Marin, O, Zheng, D, Ma,
F, and Lee, DJ. National Health Interview Survey
mortality among U.S. farmers and pesticide
applicators. American Journal of Industrial
Medicine 43:227-33, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
F
23
CANCER PREVENTION AND CONTROL PROGRAM
years to conduct a clinical trial testing the effects
of low-dose estrogen treatment on quality of life,
osteoporosis risk, and other physical indicators in
men who had undergone androgen deprivation
therapy for metastatic prostate cancer. This
project is funded by the NCI as part of the
Center for Psycho-Oncology Research (CPOR),
which is directed by Michael H. Antoni, Ph.D.
SELECTED PUBLICATIONS
2002
Levis, S, Quandt, SA, Thompson, D, Scott, J,
Schneider, DL, Ross, PD, Black, D, Suryawanshi,
S, Hochberg, M, and Yates, J. Alendronate reduces the risk of multiple symptomatic fractures:
results from the fracture intervention trial. Journal of the American Geriatric Society 50:409-15,
2002.
2003
Hernandez-Cassis, C, Vogel, CK, Hernandez, TP,
Econs, MJ, Iglesias, M, Iglesias, A, Levis, S,
Roos, BA, Howard, GA, and Gamarra, AI. Autosomal dominant hyperostosis/osteosclerosis with
high serum alkaline phosphatase activity. Journal
of Clinical Endocrinology & Metabolism
88:2650-55, 2003.
HIGHLIGHTS/DISCOVERIES
• Discovered that vitamin D deficiency in South
Florida residents is higher than expected: approximately 25 percent in young adults and 30
percent in the elderly.
24
FRANK J. PENEDO, PH.D.
Assistant Professor of Psychology
Psycho-Oncology, Psychology of Aging and
Immunosenescence in Chronically Ill Older
Adults
Within the fields of health psychology and behavioral medicine, cancer and the human immunodeficiency virus (HIV) have provided unique
opportunities to evaluate the role of psychosocial
factors in disease acquisition and progression
among various populations. Part of Dr. Penedo’s
research is examining the role of psychosocial factors such as stress, coping, and personality style in
psychological distress and physical health status
in three specific populations: 1) HIV+ ethnically
diverse men who have sex with men (MSM) and
heterosexual older men with a history of substance use, 2) men treated with radical prostatectomy or radiation for localized prostate cancer,
and 3) men and women diagnosed with Stages IIII of head and neck cancer.
Dr. Penedo’s research with these chronic disease groups is focused primarily on evaluating the
efficacy of group- and individual-based stress
management interventions on reducing distress
and improving quality of life (QOL) and physical
health status among older cancer or HIV populations (50 years and older). Dr. Penedo is particularly interested in how psychosocial factors such
as stress, coping, and personality style may interact with health behaviors (e.g., treatment adherence), neuroendocrine function, and the agerelated decrements in immune function (i.e.,
immuno-senescence) seen in older populations.
More specifically, he is interested in how stress
and other psychosocial factors may interact with,
and exacerbate, age-related decrements in immune function on the one hand, and disease
progression in older cancer and HIV populations
on the other.
Several of the research questions involved in
Dr. Penedo’s work aim to answer: 1) whether psychosocial factors impact neuroendocrine and immune parameters in chronically ill older adults
(e.g., Does psychological stress-related activation
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
of the HPAC-axis lead to suppressed immunity,
particularly shifts in specific T-cell and cytokine
subpopulations and angiogenic factors?), 2) the
extent to which age-related decrements in immunity can be exacerbated (or buffered) by psychosocial factors (e.g., Are there protective
psychosocial factors such as coping repertoires or
personality styles that may buffer the effects of
distress on immune function or age-related decrements in immunity? Can psychosocial interventions modify these factors in an aim to sustain or
enhance immunity as well as ameliorate disease
progression?), and 3) the clinical implication of
the impact of psychosocial factors on neuroendocrine and immune function in older chronically
ill populations (e.g., What is the clinical significance—disease progression, improved physical
health status—of the relationship between
psychosocial factors and neuroendocrine and
immune function in older adults?).
In an effort to answer these questions,
Dr. Penedo is involved in several biopsychosocial
HIV and cancer studies evaluating the role of
psychosocial factors and psychosocial interventions on QOL, immune function, and health
status.
SELECTED PUBLICATIONS
2003
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-22, 2003.
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M,
Malow, R, Costa, P, and Schneiderman, N. Personality, quality of life and HAART adherence
among men and women living with HIV/AIDS.
Journal of Psychosomatic Research 54:271-78,
2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological distress among symptomatic HIV+ men who have
sex with men. Annals of Behavioral Medicine
25:203-13, 2003.
BERNARD A. ROOS, M.D.
Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Roos’ current clinical research involves
adult stem cells as well as hormone and exercise therapy in men and women, particularly frail
elderly. One project is directed at the role of estrogen in the aging male and the other on the
restorative effects of resistance exercise in frail
elderly. In addition, there are several major research and training initiatives in geriatrics.
SELECTED PUBLICATIONS
2002
Yang, ES, Maiorino, CA, Roos, BA, Knight, SR,
and Burnstein, KL. Vitamin-D mediated growth
inhibition of an androgen-ablated LNCaP cell
line model of human prostate cancer. Molecular
and Cellular Endocrinology 186:69–79, 2002.
D’Ippolito, G, Schiller, PC, Balkan, W, Roos,
BA, and Howard, GA. Cooperative anabolic actions of HGF and 1,25-dihydroxyvitamin D3 in
osteoblastic differentiation of human vertebral
marrow stromal fibroblasts. Bone 31:269–75,
2002.
Perez-Stable, CM, Schwartz, GG, Farinas, A,
Finegold, M, Binderup, L, Howard, GA, and
Roos, BA. The Gγ/T-15 transgenic mouse model
of androgen-independent prostate cancer: target
cells of carcinogenesis and the effect of the vitamin D analog EB 1089. Cancer Epidemiology,
Biomarkers and Prevention 1555–63, 2002.
25
CANCER PREVENTION AND CONTROL PROGRAM
Signorile, JF, Carmel, MP, Czaja, SJ, Asfour, SS,
Morgan, RO, Khalil, TM, Ma, F, and Roos, BA.
Differential increases in average isokinetic power
by specific muscle groups of older women due to
variations in training and testing. Journal of Gerontology: Medical Sciences 57:M683–M690,
2002.
Signorile, JF and Roos, BA. Resistance training
for power, strength, and functionality: a longterm prescription. American Journal of the Medical Sciences 398-402, September/October, 2002.
2003
Hernandez-Cassis, C, Vogel, CK, Hernandez, TP,
Econs, MJ, Iglesias, M, Iglesias, A, Levis, S,
Roos, BA, Howard, GA, and Gamarra, AI. Autosomal dominant hyperostosis/osteosclerosis with
high serum alkaline phosphatase activity. Journal
of Clinical Endocrinology & Metabolism
88:2650-55, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-22, 2003.
HIGHLIGHTS/DISCOVERIES
• The laboratory’s research on exercise and nutrition continues to improve the prescription of
exercise and nutrition in the frail and vulnerable
elderly. They have completed preliminary studies of a speed-training method to improve mobility that revealed a special role for neural
coordination. Important physical function correlates with vitamin deficiency, and a clinical
trial has demonstrated the effects of correcting
vitamin deficiency on the mobility of older
persons.
26
• Osteoporosis therapy approaches have emerged
from studies of normal human stem cells and
studies of artificial matrix that can support their
growth and mineralization. Researchers in Dr.
Roos’ laboratory have discovered a unique combination of matrix, hormones, vitamins, and
growth factors that promotes the maturation
and growth of stem cells that forms bone in tissue culture and in animal transplants. Tissue
engineering approaches also are being examined
as they address the many safety issues that will
ultimately allow the application of these new
technologies to persons with osteoporosis.
• Hormonal changes in aging individuals continue to offer the opportunity—through hormone replacement therapy—to slow the aging
process. Following up on earlier studies of sex
hormone deficiency and concerns over the
many diverse complications of sex hormone
replacement, researchers in this laboratory have
begun to evaluate various nutritional supplements such as soy protein chemicals that can act
as sex hormone replacements without causing
increased risk of cancer. Moreover, the initial
studies of vitamins in aging persons have been
completed, reporting that 20 percent of older
ambulatory South Floridians are vitamin D
deficient. Planning for several studies to assess
the dose and effects of successful vitamin D
replacement in older persons is underway. The
initial focus is on benefits of vitamin D replacement on gait, balance, and other mobilityrelated factors.
• New hormonal interventions that can improve
the mood of men undergoing hormone-deprivation therapy for advancing prostate cancer are
now being examined. The laboratory, through
an NCI-funded study, will aim to demonstrate
that low-dose estrogen replacement might benefit men with prostate cancer. Similar studies
based on the use of estrogen-like nutritional
compounds, such as soy isoflavones, also are
being considered.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
NEIL SCHNEIDERMAN, PH.D.
Professor of Psychology
DESCRIPTION OF RESEARCH
D
r. Schneiderman’s research focuses on improving the quality of life (QOL) in men
who have undergone radical prostatectomy or
beam radiation treatment for localized prostate
cancer. As project leader of a study titled “Cognitive-Behavioral Stress Management and Prostate
Cancer” on Center Grant P50 CA84944 (under
Michael H. Antoni Ph.D.’s direction as principal
investigator), Dr. Schneiderman’s laboratory is
conducting studies comparing a ten-week cognitive-behavioral stress management (CBSM)
program versus a one-day CBSM seminar. They
are examining QOL indicators and immune
system status (e.g., natural killer cell cytotoxicity
(NKCC)) throughout a 12-month follow-up
period.
SELECTED PUBLICATIONS
2002
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American Journal of Psychiatry 159:143-45, 2002.
Kumar, M, Kumar, AM, Waldrop, D, Antoni,
MH, Schneiderman, N, and Eisdorfer, C.
The HPA axis in HIV-1 infection. Journal of
Acquired Immune Deficiency Syndromes 31
(Supplement 2):S89-93, 2002.
Williams, R, Schneiderman, N, Relman, A, and
Angell, M. Resolved: psychosocial interventions
can improve clinical outcomes in organic disease—rebuttals and closing arguments. Psychosomatic Medicine 64:564-67, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Williams, RB and Schneiderman, N. Resolved:
psychosocial interventions can improve clinical
outcomes in organic disease (pro). Psychosomatic
Medicine 64:552-57, 2002.
Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB,
Evans, JD, McDonald, PA, and Schneiderman,
N. Hemodynamic response patterns: responder
type differences in reactivity and recovery. Psychophysiology 39:739-46, 2002.
2003
Perna, FM, Antoni, MH, Baum, A, Gordon, P,
and Schneiderman, N. Cognitive behavioral
stress management effects on injury and illness
among competitive athletes: a randomized clinical trial. Annals of Behavioral Medicine 25:6673, 2003.
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates
the association between psychological distress and
immune status among HIV-positive men and
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-89,
2003.
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,
and Schneiderman, N. Psychological distress is
associated with decreased memory helper T cell
and B cell counts in pre-AIDS HIV seropositive
men and women but only in those with low viral
load. Psychosomatic Medicine 65:627-35, 2003.
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,
MA, McGuffey, L, Balbin, E, Schneiderman, N ,
and Solomon, G. Emotional expression and
depth processing of trauma and their relation to
long-term survival in patients with HIV/AIDS.
Journal of Psychosomatic Research 54:225-35,
2003.
27
CANCER PREVENTION AND CONTROL PROGRAM
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,
Schneiderman, N, Brondolo, E, Tobin, J, and
Weiss, S. Cognitive-behavioral interventions improve quality of life in women with AIDS. Journal of Psychosomatic Research 54:253-61, 2003.
Fernander, AF, Durán, REF, Saab, PG, Llabre,
MM, and Schneiderman, N. Assessing the reliability and validity of the John Henry Active
Coping Scale in an urban sample of African
Americans and White Americans. Ethnicity &
Health 8:147-61, 2003.
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M,
Malow, R, Costa, P, and Schneiderman, N. Personality, quality of life and HAART adherence
among men and women living with HIV/AIDS.
Journal of Psychosomatic Research 54:271-78,
2003.
Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB,
Evans, JD, McDonald, PAG, and Schneiderman,
N. Hemodynamic response patterns: Responder
type differences in reactivity and recovery. Psychophysiology 39:739-46, 2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological distress among symptomatic HIV+ men who have
sex with men. Annals of Behavioral Medicine
25:203-13, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-22, 2003.
Berkman, LF, Blumenthal, J, Burg, M, Carney,
RM, Catellier, D, Cowan, MJ, Czajkowski, SM,
DeBusk, R, Hosking, J, Jaffe, A, Kaufmann, PG,
Mitchell, P, Norman, J, Powell, LH, Raczynski,
JM, and Schneiderman, N. Enhancing Recovery
in Coronary Heart Disease Patients Investigators
(ENRICHD). Effects of treating depression and
low perceived social support on clinical events
after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients
(ENRICHD) Randomized Trial. Journal of the
American Medical Association 289:3106-16,
2003.
Watkins, LL, Schneiderman, N, Blumenthal, JA,
Sheps, DS, Catellier, D, Taylor, CB, and
Freedland, KE; ENRICHD Investigators. Cognitive and somatic symptoms of depression are associated with medical comorbidity in patients
after acute myocardial infarction. American Heart
Journal 146:48-54, 2003.
28
HIGHLIGHTS/DISCOVERIES
• Maintaining an optimistic outlook is associated
with greater NKCC by way of greater emotional expression.
• Perceived stress management skills mediate
improvements in mood and QOL during the
CBSM intervention.
• Intervention-related gains in QOL may be
paralleled by gonadal hormone (testosterone)
changes.
GAIL S. SHOR-POSNER, PH.D.
Professor of Psychiatry and Behavioral
Sciences
DESCRIPTION OF RESEARCH
D
r. Shor-Posner is funded by the NCI as part
of the Women’s Intervention Nutrition
Study (WINS). She received this funding for the
Low Fat Diet and Breast Cancer Recurrence/Outcome Trial. The goal of this multi-site project is
to determine whether a program of dietary fat
intake reduction, provided in addition to defined
adjuvant therapy, will effectively prolong diseasefree survival for patients between 48 and 78 years
of age with early stage breast cancer. The study is
ongoing, and a proposal has been submitted for
continuation until 2007.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
Dr. Shor-Posner is the principal investigator
of the Fogarty International Center (FIC) AIDS
and TB International Training and Research Program, funded by the NIH/FIC. The AIDS training curriculum is an international program
designed to contribute to research capacity building in targeted developing countries, to facilitate
the ability of scientists/clinicians to slow HIV-1
disease progression, prevent maternal-to-child
transmission, and enhance survival. This program
also seeks to provide training to qualified health
professionals from two countries that are currently experiencing the most dramatic increases
in TB and multi-drug resistant TB (MDR-TB)
in the Americas, Honduras, and the Dominican
Republic.
Dr. Shor-Posner also is the mentor of Florida
Department of Health-funded research titled,
“Pulmonary Complications in Tobacco Users Infected With the Human Immunodeficiency Virus: Therapeutic Implications.” This proposal is
for evaluation of the frequency of tobacco use
among HIV+ individuals hospitalized at Jackson
Memorial Hospital and the impact of tobacco use
on the risk of developing lower respiratory infections.
Additionally, Dr. Shor-Posner is the nutrition director of the NIH-funded General Clinical
Research Center (GCRC). The GCRC, while
located in several locations, functions as a single
integrated department/unit with single program
leadership and coordination. This clinical research infrastructure provides a conduit for the
enhancement of multi-specialty projects.
SELECTED PUBLICATIONS
2002
Miguez-Burbano, MJ, Pineda-Medina, L,
Lecusay, R, Page, JB, Castillo, G, Burban, X,
Rodriguez, A, Rodriguez, N, and Shor-Posner,
G. Continued high risk behaviors in HIV infected drug abusers. Journal of Addictive Diseases
21:67-80, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Shor-Posner, G , Miguez, MJ, Pineda, LM,
Rodriguez, A, Ruiz, P, Castillo, G, Burban, X,
Lecusay, R, and Baum, M. Impact of selenium
status on the pathogenesis of mycobacterial disease in HIV-1-infected drug users during the era
of highly active antiretroviral therapy. Journal of
Acquired Immune Deficiency Syndromes
29:169-73, 2002.
Miguez-Burbano, MJ, Burbano, X, Rodriguez, A,
Lecusay, R, Rodriguez, N, and Shor-Posner, G .
Development of thrombocytosis in HIV+ drug
users: impact of antiretroviral therapy. Platelets
13:183-85, 2002.
Miguez, MJ, Burbano, X, Archer, H, and
Shor-Posner, G . Limited impact of highly active
antiretroviral therapy in thrombocytopenia.
Journal of Acquired Immune Deficiency
Syndromes 30:260-61, 2002.
Miguez-Burbano, MJ, Navas, R, Forero, MG,
Burbano, X, Rodriguez, N, and Shor-Posner, G .
Evaluation of HIV prevention and counseling
practices of obstetrician/gynecologists in Bogota,
Colombia: impact on women’s knowledge and
risk practices. AIDS Education and Prevention
14:72-80, 2002.
Shor-Posner, G , Lecusay, R, Morales, G, Campa,
A, and Miguez-Burbano, MJ. Neuroprotection in
HIV-positive drug users: implications for antioxidant therapy. Journal of Acquired Immune Deficiency Syndromes 31 Supplement 2:S84-88,
2002.
Burbano, X, Miguez-Burbano, MJ, McCollister,
K, Zhang, G, Rodriguez, A, Ruiz, P, Lecusay, R,
and Shor-Posner, G . Impact of a selenium
chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clinical
Trials 3:483-91, 2002.
Shor-Posner, G , Lecusay, R, Miguez-Burbano,
MJ, Morales, G, and Campa, A. Neuroprotection
in HIV+ drug users: implications for antioxidant
therapy. Journal of Acquired Immune Deficiency
Syndromes 31:S84-S88, 2002.
29
CANCER PREVENTION AND CONTROL PROGRAM
2003
Miguez-Burbano, MJ, Archer, H, Rodriguez, M,
and Shor-Posner, G . Discontinuation of secondary prophylaxis and the risk of Pneumocystis
carinii pneumonia. AIDS 17:140-41, 2003.
Shor-Posner, G , Lecusay, R, Miguez, MJ,
Moreno-Black, G, Zhang, G, Rodriguez, N,
Burbano, X, Baum, M, and Wilkie, F. Psychological burden in the era of HAART: impact of
selenium therapy. International Journal of Psychiatry in Medicine 33:55-69, 2003.
Miguez, MJ, Shor-Posner, G , Morales, G,
Rodriguez, A, and Burbano, X. HIV treatment in
drug abusers: impact of alcohol use. Addiction
Biology 8:33-37, 2003.
Miguez-Burbano, MJ, Burbano, X, Ashkin, D,
Pitchenik, A, Allan, R, Pineda, L, Rodriguez, N,
and Shor-Posner, G . Impact of tobacco use on
the development of opportunistic respiratory
infections in HIV seropositive patients on
antiretroviral therapy. Addiction Biology
8:39-43, 2003.
Perez-Then, E, Peña, R, Tavarez-Roja, M, Peña,
C, Quiñonez, S, Buttler, M, Ammann, A,
Hernandez, W, Goyanes, M, Miguez, MJ, ShorPosner, G, and PMTCT Group. Preventing
mother-to-child HIV transmission in a developing country: the Dominican Republic experience.
Journal of Acquired Immune Deficiency Syndromes 34:506-11, 2003.
30
LEO B. TWIGGS, M.D.
Professor and Associate Dean of Women’s
Health, Interim Chairman of Obstetrics and
Gynecology, and Medical Director, Institute
for Women’s Health
DESCRIPTION OF RESEARCH
D
r. Twiggs, who also is the Dean of Women’s
Health at the University of Miami School of
Medicine, has tested the efficacy of a vaccine for
human papillomavirus (HPV) as a method of
controlling the risk of cervical cancer. He also
collaborates with Michael H. Antoni, Ph.D., and
Mary Josephine O’Sullivan, M.D., to conduct
studies of the effects of stressors and stress management on health behaviors and cervical neoplasia in women co-infected with HIV and HPV.
SELECTED PUBLICATIONS
2002
Wright, TC Jr., Cox, JT, Massad, LS, Twiggs,
LB, and Wilkinson, EJ. ASCCP-Sponsored Consensus Conference. 2001 Consensus Guidelines
for the management of women with cervical cytological abnormalities. Journal of the American
Medical Association 287:2120-29, 2002.
2003
Wright, TC Jr., Cox, JT, Massad, LS, Carlson, J,
Twiggs, LB , and Wilkinson, EJ. American Society for Colposcopy and Cervical Pathology 2001
consensus guidelines for the management of
women with cervical intraepithelial neoplasia.
American Journal of Obstetrics and Gynecology
189:295-304, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CANCER PREVENTION AND CONTROL PROGRAM
HIGHLIGHTS/DISCOVERIES
SELECTED PUBLICATIONS
• Cancer control research—The Institute for
Women’s Health has an active cancer control
research program. Dr. Twiggs, Timothy De
Santis, M.D., and Nahida Chakhtoura, M.D.,
have been collaborating with two medical device companies utilizing spectroscopic measures
in cervical precursors in an effort to diagnose
and prevent cervical cancer. This collaboration
in an Institutional Review Board (IRB)approved research setting resulted in the
evaluation of more than 300 women with
abnormal Pap smears in three separate clinical
research protocols.
2002
JAMES D. WILKINSON, M.D., M.P.H.
Associate Professor of Epidemiology and
Public Health
DESCRIPTION OF RESEARCH
D
r. Wilkinson’s research focuses on epidemiological studies of cancer examining differential cancer risks among U.S. Hispanics for both
adults and children. The results of this research
are intended to better inform cancer control and
prevention efforts in Florida among various subpopulations. Currently, Dr. Wilkinson is part of a
collaborative team, led by investigators from the
International Agency for Research on Cancer, to
study prostate cancer genetics in Cuban men,
comparing populations from Havana and Miami.
An application for project funding to the NCI is
planned for 2004.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, Voti, L, and Peace,
S. Cancer trends among Hispanic men in South
Florida, 1981-1998. Cancer 94:1183-90, 2002.
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, and Peace, S. Cancer among Hispanic women in South Florida: an
18-year assessment: a report from the Florida
Cancer Data System. Cancer 95:1752-58, 2002.
HIGHLIGHTS/DISCOVERIES
• Florida’s Hispanic children have a 30 percent
increased risk of lymphoma and lymphoid leukemia compared to non-Hispanic White children.
• Cancer incidence is decreased for both Hispanic
men and women in South Florida compared to
non-Hispanic Whites.
• Lung cancer is now the third most common
cancer among Hispanic women in South
Florida.
• Similarly, cancer mortality is decreasing among
the Hispanic and non-Hispanic populations of
South Florida.
31
CANCER PREVENTION AND CONTROL PROGRAM
32
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
CLINICAL ONCOLOGY RESEARCH
PROGRAM
PROGRAM LEADER
Joseph D. Rosenblatt, M.D.
Professor of Medicine and Division Chief of Hematology-Oncology
PROGRAM CO-LEADER
Kelvin P. Lee, M.D.
Associate Professor of Microbiology and Immunology
PROGRAM DESCRIPTION
GOALS OF PROGRAM
T
T
he Clinical Oncology Research Program
(CORP) is composed of 23 faculty members
as well as associate faculty members from accross
the University of Miami School of Medicine. Faculty are specifically selected for their involvement
in research that has significant translational potential and may lead to improvements in cancer
prevention, diagnosis, and treatment. Program
members must have peer-reviewed cancer-related
research funding or be newly recruited investigators with the potential to apply for and receive
funding. Associate program members generally
are clinical faculty who are selected based on
significant involvement in the overall clinical
research effort at the University, such as involvement in clinical trials and/or correlative studies.
The program was organized in January 2003
to address the need for a broad-based clinical
research program distinct from the four multidisciplinary research programs at the University
of Miami Sylvester Comprehensive Cancer Center. Nearly half of the program members are
newly recruited faculty.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
he overall goal of the CORP is to translate
findings from UM/Sylvester’s basic research
programs into new therapeutic, diagnostic, and/
or prognostic interventions, as well as develop
novel and innovative clinical trials.
Specific goals include:
1) Translating UM/Sylvester’s basic science efforts
into the clinical arena. This includes the preclinical and clinical development of novel diagnostic and therapeutic strategies and their
implementation in the form of clinical protocols by CORP investigators.
2) Integrating clinical research efforts across
departmental lines. This includes support for
site-based disease approaches encompassing
tissue procurement for analysis and validation,
improved mechanisms for tissue preservation
to facilitate analysis of gene expression,
proteomics, and coordination of efforts
involving basic scientists, surgical staff,
and pathologists.
3) Developing the institutional intramural trial
portfolio in an effort to provide novel clinical
options for UM/Sylvester patients and to
develop pilot phase I/II trials for subsequent
validation in the cooperative group setting.
33
CLINICAL ONCOLOGY RESEARCH PROGRAM
Several shared interests connect researchers
and create natural liaisons with other UM/Sylvester
programs. Areas of interest include:
• Development of gene and cellular therapies for
cancer.
PARTICIPANTS
• Development of novel pharmacological agents
and/or combinations.
Ganju-Krishan, Awtar, Ph.D.
Radiation Oncology
• Identification of new prognostic and/or therapeutic targets.
Greer, Sheldon, Ph.D.
Microbiology and Immunology
• Creation of mechanisms for tissue procurement
and/or correlative studies.
Koniaris, Leonidas G., M.D., F.A.C.S.
Surgery
CORP members are involved in the development and management of several shared resources
including Clinical Research Services; tumor banks
and databases for breast cancer, and more recently,
lymphoma; and a Cell Banking and Purification
Facility for the study of hematological malignancies. The CORP also serves as the major access
point to the University of Miami’s general clinical
research center for clinical oncology research.
The CORP meets on a monthly basis and
invites investigators from other multidisciplinary
research programs to share findings in a group
forum designed to foster translation and application to the clinical arena. Recent CORP initiatives include the testing of a locally developed
antibody to CD30 for treatment of Hodgkin’s
and non-Hodgkin’s lymphomas, testing of novel
genetically engineered lung cancer vaccines in
phase I/II trials, novel radio-sensitizers, identification of new molecular prognostic factors in lymphoma and breast cancer, and the targeting of
non-dividing anaerobic tumor cells using glycolytic inhibitors. The CORP continues to promote
the identification and adaptation of promising
strategies developed by UM/Sylvester basic scientists for clinical application.
Lampidis, Theodore J., Ph.D.
Cell Biology and Anatomy
Benedetto, Pasquale W., M.D.
Medicine
Feun, Lynn G., M.D.
Medicine
Lee, Kelvin P., M.D.
Microbiology and Immunology
Lipshultz, Steven E., M.D.
Pediatrics
Lokeshwar, Balakrishna L., Ph.D.
Urology
Lokeshwar, Vinata B., Ph.D.
Urology
Lossos, Izidore, M.D.
Medicine
Milikowski, Clara, M.D.
Pathology
Raez, Luis E., M.D., F.A.C.P.
Medicine
Rocha Lima, Caio Max S., M.D.
Medicine
Rosenblatt, Joseph D., M.D.
Medicine
Savaraj, Niramol, M.D.
Medicine
Singal, Rakesh, M.D.
Medicine
Slingerland, Joyce M., M.D., Ph.D., F.P.R.C.(C)
Medicine
Soloway, Mark S., M.D.
Urology
34
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
Tang, Shou-Ching, M.D., Ph.D.
Medicine
Tolba, Khaled A., M.D.
Medicine
Vincek, Vladimir, M.D., Ph.D.
Pathology
Wolfson, Aaron H., M.D.
Radiation Oncology
LYNN G. FEUN, M.D.
Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Feun’s research focuses on developing
novel treatment strategies for patients with
melanoma, liver cancer, and brain tumors.
SELECTED PUBLICATIONS
2002
Feun, L, Modiano, M, Lee, K, Mao, J, Marini, A,
Savaraj, N, Plezia, P, Almassian, B, Colacino, E,
Fischer, J, and MacDonald, S. Phase I and pharmacokinetic study of 3-aminopyridine-2carboxaldehyde thiosemicarbazone (3-AP) using a
single intravenous dose schedule. Cancer Chemotherapy and Pharmacology 50:223-29, 2002.
Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG,
Xu, R, Xu, J, and Savaraj, N. Procollagen-like
protein as a molecular target in the treatment of
primary brain tumor. ScientificWorldJournal
2:125-26, 2002.
Feun, LG, Savaraj, N, Hurley, J, and Marini, A.
Phase II trial of Paclitaxel and Dacarbazine with
filgrastim administration in advanced malignant
melanoma. Cancer Investigation 20:357-61,
2002
study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus
interleukin-2 alone in patients with metastatic
melanoma. Journal of Clinical Oncology 20:12533, 2002
2003
Feun, LG, O’Brien, C, Molina, E, Rodriguez, M,
Jeffers, L, Schiff, ER, Marini, A, Savarj, N, and
Ardalan, B. Recombinant leukocyte interferon,
doxorubicin, and 5FUDR in patients with hepatocellular carcinoma-a phase II trial. Journal of
Cancer Research and Clinical Oncology 129:1720, 2003
Prados, MD, Schold, SC JR SC, Fine, HA,
Jaeckle, K, Hochberg, F, Mechtler, L, Fetell, MR,
Phuphanich, S, Feun, L, Janus, TJ, Ford, K, and
Graney, W. A randomized, double-blind, placebo-controlled, phase II study of RMP-7 in
combination with carboplatin administered intravenously for the treatment of recurrent malignant
glioma. Journal of Neuro-Oncology 5:96-110,
2003
Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L,
Donnelly, E, Solomon, J, Sundaram, M, Feun,
LG, and Savaraj, N. Phase II study of vinorelbine
with low dose prednisone in the treatment of
hormone-refractory metastatic prostate cancer.
Oncology Reports 10:885-89, 2003
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, T, Robles, C, Furst, AJ, and Feun, LG.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal of Oncology 23:173-79, 2003
Agarwala, SS, Glaspy, J, O’Day, SJ, Mitchell, M,
Gutheil, J, Whitman, E, Gonzalez, R, Hersh, E,
Feun, LG, Belt, R, Meyskens, F, Hellstrand, K,
Wood, D, Kirkwood, JM, Gehlsen, KR, and
Naredi, P. Results from a randomized phase III
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
35
CLINICAL ONCOLOGY RESEARCH PROGRAM
HIGHLIGHTS/DISCOVERIES
• Collaborated on a phase I trial of arginine
deiminase in melanoma with promising results.
A phase II protocol currently is under development.
• Developed a phase I clinical trial for patients
whose brain tumors expressed a procollagenlike protein, based on Dr. Feun and Niramol
Savaraj, M.D.’s in vitro discovery that this
protein may predict clinical response to vitamin
D therapy. This trial has been approved by the
Institutional Review Board (IRB); the Investigational New Drug (IND) application is under
review by the Food and Drug Administration
(FDA).
AWTAR GANJU-KRISHAN, PH.D.
Professor of Radiation Oncology
DESCRIPTION OF RESEARCH
M
ost of Dr. Krishan’s current research
focuses on:
• Monitoring of nuclear hormone receptor expression in human breast and prostate tumors.
Dr. Krishan has developed flow cytometric
methods for determining estrogen, androgen,
and vitamin D receptor expression in archival
human tumors. These methods recently have
been used to determine expression in human
male and female breast tumors and prostate
tumors.
• Evaluating a novel apoptosis assay with antibodies to ssDNA using flow cytometry; Dr.
Krishan and Oscar Frankfurt, Ph.D., (University of Miami) have been studying the use of a
novel method for discriminating between
apoptotic and the necrotic cells by laser flow
cytometry, which was recently published.
and the American Cancer Society (ACS). This
instrument can measure nuclear volume and
thus discriminate between normal and tumor
cells. Supported by an exploratory grant from
the NIH-NCI, they are currently examining the
potential of this technique for detecting occult
tumor cells in body fluids from cancer patients.
• Studying androgen receptor expression in human prostate tumors; Dr. Krishan and May
Abdel-Wahab, M.D., Ph.D., have used flow
cytometric methods to correlate receptor expression with clinical response in patients on
the Radiation Therapy Oncology Group’s
(RTOG) study of radiation and hormone
therapy in prostate cancer patients.
• Evaluating DNA aneuploidy and S-phase fraction as indicators of response to chemoradiotherapy in patients with invasive cervical
carcinoma; Dr. Krishan, Aaron H. Wolfson,
M.D., and Daniel Estape, M.D., are involved
in this project, which is funded by the RTOG
and seeks to use high-resolution flow cytometry
for the analysis of aneuploidy and cell cycle distribution in human cervical cancer under a
University of Miami IRB-approved protocol.
• Organizing annual Indo-U.S. workshops in
cytomics. These workshops include six to ten
U.S. faculty members along with their Indian
counterparts, who teach the latest methods in
flow cytometry in India. Up to 50 researchers
attend these workshops, and so far, four workshops have been held in research institutes/
universities in Chandigarh, Hyderabad, Jammu,
and Bombay.
• Evaluating tumor cells in body fluids using high
resolution flow cytometry; Dr. Krishan and his
colleagues have recently developed a high resolution flow cytometer with funding from NASA
36
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
SELECTED PUBLICATIONS
2002
Krishan, A. Flow cytometric monitoring of hormone receptor expression in human solid tumors.
Proceedings of SPIE 4622: 211-17, 2002.
Arya, P, Andritsch, IH, and Krishan, A . Androgen receptor expression in archival human breast
tumors. Methods in Cell Science 24:61-64, 2002.
Krishan, A. Flow cytometric monitoring of drug
resistance in human tumor cells. Methods in Cell
Science 24:55-60, 2002.
Thomas, RA, Krishan, A , and Brochu, M. High
resolution flow cytometric analysis of electronic
nuclear volume and DNA content in normal and
abnormal human tissue. Methods in Cell Science
24:11-18, 2002.
Adiga, SK, Andritsch, IH, Rao, RV, and Krishan,
A. Androgen receptor expression and DNA content of paraffin-embedded archival human prostate tumors. Cytometry 50:25-30, 2002.
2003
Frankfurt, OS and Krishan, A. Apoptosis-based
drug screening and detection of selective toxicity
to cancer cells. Anticancer Drugs 14:555-61,
2003.
Frankfurt, OS and Krishan, A . Microplate
screening for apoptosis with antibody to singlestranded DNA distinguishes anticancer drugs
from toxic chemicals. Journal of Biomolecular
Screening 8:185-90, 2003.
Frankfurt, OS and Krishan, A . Apoptosis enzyme-linked immunosorbent assay distinguishes
anticancer drugs from toxic chemicals and predicts drug synergism. Chemico-biological Interactions 145:89-99, 2003.
Krishan, A. Flow cytometric monitoring of drug
resistance in human tumor cells. Methods in Cell
Science 24:55-60, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Abdel-Wahab, M, Krishan, A, Milikowski, C,
Wahab, AA, Walker, G, and Markoe, A. Androgen receptor antigen density and S-phase fraction
in prostate cancer: a pilot study. Prostate Cancer
and Prostatic Disease 6:294-300, 2003.
HIGHLIGHTS/DISCOVERIES
• Developed Krishan’s propidium iodide/hypotonic citrate method for rapid determination of
cellular DNA content and cell cycle traverse.
This method is universally used for rapid cell
cycle analysis by flow cytometry.
• Developed flow cytometric assays for drug
transport and efflux. This rapid method is now
universally used as a functional assay for drug
resistance.
• Developed flow cytometric methods for rapid
determination of nuclear hormone receptor expression in human archival tumors.
• Developed the NASA/ACS flow cytometer,
which now is sold by NPE Systems Inc., as a
commercial unit for rapid determination of
cellular volume and DNA content.
SHELDON GREER, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
D
r. Greer’s laboratory has developed a drug
that selectively radiosensitizes human tumors. The drug is 5-chloro-2'-deoxycytidine
(cytochlor). When it is coadministered with
tetrahydrouridine (H4U), an inhibitor of its preliminary systemic deamination before it reaches
the tumor site, it has been shown to be efficacious versus seven rodent tumors and seven human tumors in nude mice. For example, with a
rodent mammary adenocarcinoma, 80 percent
cures were obtained with weight loss no greater
than that obtained with radiation alone. This was
confirmed by an independent blind study. Similar response was obtained with human tumors,
37
CLINICAL ONCOLOGY RESEARCH PROGRAM
which included two prostatic tumors, three head
and neck tumors, a glioblastoma, a lung tumor,
and a breast tumor.
Cytochlor has resulted in a three-fold dose
increase effect, meaning that a dose of 70 Gy is
equivalent to a dose of 210 Gy to the tumor
without damage to underlying tissue. The success
of the radiosensitizer can be understood in view
of several biochemical studies that show: 1) 99
percent of the cells of a human prostate tumor
and a head and neck tumor incorporated the
radiosensitizer into DNA, 2) 40 percent of thymine was replaced by 5-chlorouracil in DNA of
tumor cells, 3) all tumors obtained from patients
with head and neck tumors had elevated levels
over that of normal tissue of one of the two enzymes, which anabolize cytochlor to become a
radiosensitizer, and 50 percent of patients had
elevations of both enzymes (averaging greater
than 10-fold), 4) 5-chlorouracil derived from
cytochlor is not removed from DNA as is 5iodoruacil (the first generation radiosensitizer), 5)
5-CldUMP derived from cytochlor inhibits
thymidylate synthetase as effectively as
FdUMP—this prevents the formation of TTP,
the competitor to the incorporation of CldUTP,
and 6) CldUTP activates dendritic cell (DC)
kinase, the enzyme responsible for the first step
in the anabolism of cytochlor.
Studies commissioned by the NCI have
shown that cytochlor did not display any clinical
signs of toxicity to primates when given the drug
five days per week for three weeks. No toxicity
was seen in mice and dogs where it was shown
that H4U extended the half life and increased the
selectivity of cytochlor. The drug is awaiting IND
approval by the FDA and will be tested in a phase
I clinical trial at UM/Sylvester in patients with
squamous cell carcinoma (SCCA) of the oropharynx and oral cavity.
Dr. Greer also has discovered an approach to
tumors that arise or are successful as a result of
gene silencing. These include tumors due to the
silencing of genes, encoding tumor suppressor
genes, repair enzymes, migration suppressor glycoproteins such as cadherin, estrogen receptors,
38
enzymes protecting cells, oxidative damage, antiangiogenesis factors, and factors that prevent the
tumors from being controlled by the patient’s
immune system. The drug, called zebularine, can
be administered orally and is non-toxic. The NCI
has ordered the development of this drug after
studies in nude mice showed its effectiveness.
The drug also has the potential to be utilized in
patients with abnormal globin gene expression
(hemoglobinopathies) and abnormalities in the
immune system.
SELECTED PUBLICATIONS
2003
Cheng, JC, Matsen, CB, Gonzales, FA, Ye, W,
Greer, S, Marquez, VE, Jones, PA, and Selker,
EU. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. Journal of
the National Cancer Institute March 5; 95:399409, 2003.
HIGHLIGHTS/DISCOVERIES
• Developed and tested cytochlor, in collaboration with the NCI, which is now under review
by the FDA for clinical application and testing.
• Developed zebularine in cooperative studies
including the University of Oregon, the University of Southern California, the NIH, and the
University of Miami. Zebularine is approved for
further development by the NIH.
• Developed an approach for chemotherapy or
radiation therapy based on the enzymatic profile of human tumors and adjacent normal tissue with respect to four enzymes involved in
nucleic acid metabolism. The study requires a
small amount of biopsy material. The approach
is novel in that it involves several (nine) antimetabolites including cytochlor and zebularine,
which have never been used in humans. The
novel approach also involves gene therapy combined with radiation therapy, allowing greater
selectivity than gene therapy combined with
chemotherapy because of the very nature of
external beam radiation therapy.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
LEONIDAS G. KONIARIS, M.D., F.A.C.S.
Associate Professor of Surgery
DESCRIPTION OF RESEARCH
D
r. Koniaris’ research concentrates on the
mechanism of growth control and deregulation in vivo in the gastrointestinal (GI) tract and
breast. In particular, he has focused on the role of
two secreted factors—interleukin-6 (IL-6) and
macrophage inflammatory cytokine-1 (MIC-1).
IL-6 is a pro-inflammatory cytokine essential
in normal liver homeostasis. Investigators in the
laboratory have recently demonstrated that IL
functions as a growth factor for hepatocytes
through an apparent direct mechanism that does
not involve activation of cMET or epidermal
growth factor (EGF). Subsequent work has demonstrated that this mitogenic response is associated with profound anti-apoptotic activity. Other
work from the laboratory has examined how the
IL-6 response affects insulin signaling and contributes to the hepatocellular dysfunction seen in
chronic liver disease. In addition, they are examining the effects of IL-6 on hepatocellular carcinoma with collaborators at the University of
North Carolina.
MIC-1 is a divergent member of the transforming growth factor-beta (TGF-β) superfamily
of growth and differentiation factors. MIC-1
strongly has been implicated in the pathogenesis
of both colorectal and prostate cancers and may
have a potent anti-tumor function. The laboratory has examined the expression of MIC-1 and
found it to be an immediate early response to a
variety of organ injuries and exposures to carcinogens. They have generated MIC-1 null mice and
are examining their propensity to the development of liver, colorectal, breast, and prostate
cancers.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SELECTED PUBLICATIONS
2002
Barreiro, CJ, Lillemoe, KD, Koniaris, LG , Sohn,
TA, Yeo, CJ, Coleman, J, Fishman, EK, and
Cameron, JL. Diagnostic laparoscopy for
periampullary and pancreatic cancer: what is the
true benefit? Journal of Gastrointestinal Surgery
6:75-81, 2002.
Kovach, SJ, Hendrickson, RJ, Cappadona, CR,
Schmidt, CM, Groen, K, Koniaris, LG , and
Sitzmann, JV. Cryoablation of unresectable pancreatic cancer. Surgery 131:463-64, 2002.
Sayeed, S, Koniaris, LG , and Papadakos, PJ. Image of the month. Acute respiratory distress syndrome. Archives of Surgery 137:491-92, 2002.
Abt, PL, Halaby, I, Schoeniger, LO, and
Koniaris, LG . Intrahepatic gas. Journal of the
American College of Surgeons 195:129, 2002.
Cirillo, RL Jr. and Koniaris, LG . Detecting blunt
pancreatic injuries. Journal of Gastrointestinal
Surgery 6:587-98, 2002.
Hendrickson, RJ, Koniaris, LG , Kovach, SJ, and
Johnson, JA. Gamma probe-confirmed
laparoscopic accessory splenectomy. Surgical Endoscopy 16:1364, 2002.
Hendrickson, RJ, Koniaris, LG , Schoeniger, LO,
Strang, J, Killackey, MA, and Peacock, JL. Small
bowel obstruction due to a paracolonic retroperitoneal hernia. American Journal of Surgery
68:756-58, 2002.
Sayeed, S, Koniaris, LG , Kovach, SJ, and
Hirokawa, T. Torsion of a wandering spleen. Surgery 132:535-36, 2002.
Ognibene. SJ, Koniaris. LG , Pegoli, W Jr., and
Drugas, GT. Intraoperative colonic lavage in a
premature infant: a case report. Journal of Pediatric Surgery 37:1645-47, 2002.
39
CLINICAL ONCOLOGY RESEARCH PROGRAM
Price, JA, Kovach, SJ, Johnson, T, Koniaris, LG ,
Cahill, PA, Sitzmann, JV, and McKillop, IH. Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of
hepatocellular carcinoma. Hepatology 36:108997, 2002.
Hendrickson, RJ, Koniaris, LG , Jiang, S,
Waldman, D, Massey, HT, and Sitzmann, JV.
Purposeful delay in the repair of a traumatic left
common carotid pseudoaneurysm in a bovine
aortic arch presenting as a widened mediastinum.
Journal of Trauma 53:1166-69, 2002.
Sitzmann, JV and Koniaris, LG . Intra-arterial
hepatic catheterization and pump placement.
Operative Techniques in General Surgery 4:99110, 2002
Zimmers, TA, Davies, MV, Koniaris, LG ,
Haynes, P, Tomkinson, KN, McPherron, AC,
Wolfman, NM, and Lee SJ. Cachexia induced
by systemic myostatin administration in mice.
Science 296:1486-88, 2002.
2003
Koniaris, LG . Induction of MIC-1/growth differentiation factor-15 following bile duct injury.
Journal of Gastrointestinal Surgery 7:901-5,
2003.
Koniaris, LG , Seibel, JA, Geschwind, JF, and
Sitzmann, JV. Can ethanol therapies injure the
bile ducts? Hepato-gastroenterology 50:69-72,
2003.
Hendrickson, RJ, Diaz, AA, Salloum, R, and
Koniaris, LG . Benign rectal ulcer: an underground cause of inpatient lower gastrointestinal
bleeding. Surgical Endoscopy17:1759-65, 2003.
Koniaris, LG , Schoeniger, LO, Kovach, S, and
Sitzmann, JV. The quick, no-twist, no-kink portal confluence reconstruction. Journal of the
American College of Surgeons 196:490-94, 2003.
Schoeniger, LO, Bankey, P, Drugas, GT, and
Koniaris, LG . Optimal closure of the complex
abdomen. Archives of Surgery 138:458, 2003.
40
Koniaris. LG , Drugas. G, Katzman. PJ, and
Salloum, R. Management of gastrointestinal lymphoma. Journal of the American College of Surgeons 197:127-41, 2003.
Koniaris, LG , Wilson, S, Drugas, G, and
Simmons, W. Capnographic monitoring of ventilatory status during moderate (conscious) sedation. Surgical Endoscopy 17:1340, 2003.
Koniaris, LG , McKillop, IH, Schwartz, SI, and
Zimmers, TA. Liver regeneration. Journal of the
American College of Surgeons 197:634-59, 2003.
Zimmers, TA, McKillop, IH, Pierce, RH, Yoo,
JY, and Koniaris, LG . Massive liver growth in
mice induced by systemic interleukin 6 administration. Hepatology 38:326-34, 2003.
Senn, JJ, Klover, PJ, Nowak, IA, Zimmers, TA,
Koniaris, LG , Furlanetto, RW, and Mooney, RA.
Suppressor of cytokine signaling-3 (SOCS-3), a
potential mediator of interleukin-6-dependent
insulin resistance in hepatocytes. Journal of Biological Chemistry 278:13740-46, 2003.
Klover, PJ, Zimmers, TA, Koniaris, LG , and
Mooney, RA. Chronic exposure to interleukin-6
causes hepatic insulin resistance in mice. Diabetes
52:2784-89, 2003.
THEODORE J. LAMPIDIS, PH.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
D
r. Lampidis’ research has evolved from his
preliminary work on the physiology and
pharmacology of cultured cardiac cells. A video/
electronic-computerized system was developed to
monitor cardiac cell function in vitro. Using pulsating myocardial cells as a model, he focused on
why the widely used anti-tumor agent, Adriamycin,
affected the hearts of patients treated with this
drug. This initial idea led Dr. Lampidis to study
drug selectivity between certain types of tumor
and normal cells and the chemical requirements
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
of anti-cancer drugs for reduced cardiotoxicity
and increased tumoricidal potency.
Dr. Lampidis’ efforts then turned toward
understanding the mechanisms of drug resistance
to mitochondrial agents such as rhodamine 123
and the structure/function requirements of various chemotherapeutic agents for recognition by
p-glycoprotein (Pgp)-mediated multiple drug
resistance (MDR). Molecular and immunochemical probes of MDR and other cellular
resistance mechanisms (i.e., multi-drug resistance-related protein), were developed to detect
and study these phenomena. He and his colleagues found that chemical charge and lipophilicity play critical roles in determining
whether anticancer drugs are recognized by tumor cells expressing these MDR mechanisms.
As an outcome of their studies on mitochondrial agents, these researchers realized that tumor
cells treated with the uncoupling agent, rhodamine
123, were strikingly similar to the poorly oxygenated cancer cells located at the inner core of solid
tumors. In both conditions, the cells rely exclusively on anaerobic metabolism for survival.
Moreover, cells in the center of a tumor divide
more slowly than outer-growing aerobic cells and
consequently are more resistant to standard chemotherapeutic agents, which target the more
rapidly dividing cells. Thus, by the nature of their
slow growth, these tumor cells exhibit a form of
MDR, which contributes significantly to chemotherapy failures in the treatment of solid tumors.
Anaerobiosis, however, also provides a natural window of selectivity for agents that interfere
with glycolysis. This concept forms the basis for
Dr. Lampidis’ current initiative of exploiting the
natural selectivity that inhibitors of glycolysis
should have for hypoxic cells that are slowly
growing at the inner core of solid tumors. His
background and work on mitochondrial localizing drugs and MDR uniquely position him to
stimulate new initiatives in this promising area of
research.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
A long-term goal for Dr. Lampidis is the addition of the appropriate glycolytic inhibitors
(which are presently being designed and synthesized) to current clinical protocols, which may
significantly improve the success rate of cancer
chemotherapy. Moreover, studying how tumor
cells react to combinations of oxidative phosphorylation and glycolytic inhibitors could lead to
the design of future novel approaches to more
successfully treat cancer.
SELECTED PUBLICATIONS
2002
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .
Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:174551, 2002.
2003
Savaraj N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal of Oncology 23:173-79, 2003.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and
Lampidis, TJ . Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
HIGHLIGHTS/DISCOVERIES
• In osteosarcoma, wild type (wt) cells treated
with agents that inhibit mitochondrial oxidative
phosphorylation (OXPHOS) by interacting
with complexes I, III, and V of the electron
transport chain in different ways—rhodamine
123 (Rho-123), rotenone, oligomycin, and antimycin A—all of the agents were found to hypersensitize wt cells to the glycolytic inhibitors
2-deoxyglucose (2-DG) and oxamate.
41
CLINICAL ONCOLOGY RESEARCH PROGRAM
• In ρ0 cells that have lost their mitochondrial
DNA and therefore cannot undergo OXPHOS,
cells were found to be ten and 4.9 times more
sensitive to 2-DG and oxamate, respectively,
than wt cells.
• Lactic acid levels, which are a measure of
anaerobic metabolism, were found to be greater
than three times higher in ρ0 than in wt cells.
Moreover, when wt cells were treated with rho
123, lactic acid amounts increased as a function
of increasing rho 123 doses. Under similar rho
123 treatment, ρ0 cells did not increase their
lactic acid levels. These data confirm these different cell models are similarly sensitive to glycolytic inhibitors due to their dependence on
anaerobic metabolism.
• These results suggest that inner core tumor cells
are more dependent on glycolysis than outer
growing aerobic cells, which provides a window
of selectivity that can be exploited therapeutically. Thus, glycolytic inhibitors could be used
to specifically target the hypoxic slow-growing
cells of solid tumors and thereby increase the
efficacy of current chemotherapeutic and irradiation protocols designed to kill rapidly-dividing cells. Moreover, glycolytic inhibitors could
be particularly useful in combination with antiangiogenic and anti-hypoxic inducible factor
(HIF) agents, which a priori, should make tumors more anaerobic.
• Recently, Dr. Lampidis has provided proof of
principle in two animal models of human cancer (non-small cell lung and osteosarcoma) that
the addition of the glycolytic inhibitor 2-DG
(which targets the slowly growing hypoxic cells
of a tumor), increases the efficacy of standard
chemotherapeutic agents (which target the rapidly growing aerobic cells) in reducing tumor
size and prolonging survival. In collaboration
with Threshold Pharmaceuticals, the NCI, and
UM/Sylvester, they have received FDA approval
and are now nearing the first human trials testing his strategy.
42
KELVIN P. LEE, M.D.
Associate Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
R
esearch in Dr. Lee’s laboratory focuses on
the cells and molecules that play central roles
in initiating the adaptive immune response.
Understanding these interactions is essential for
developing effective immune-based therapies
against cancer. At the cellular level, they are
specifically studying the dendritic cells (DC),
which are thought to be the most important professional antigen presenting cell (APC). Because
DC monitor the local environment for immunologic “danger” signals and control what antigens
are presented to T cells to activate them, they are
positioned to regulate the initiation of immune
responses. Their work has examined how DC
arise from hematopoietic progenitors and their
intracellular/genetic characteristics. Dr. Lee and
his colleagues have previously reported that activation of the protein kinase C (PKC) intracellular
signal transduction pathway in human hematopoietic CD34+ stem cells causes direct differentiation to a pure population of DC. Thus, PKC
signaling specifically triggers the DC differentiation “program” in these cells. Additionally, specific isoforms of PKC appear to regulate specific
aspects of DC differentiation. Ongoing studies
are seeking to completely characterize the components of the PKC signaling pathway and what
genetic events are triggered by this signal.
From a translational standpoint, researchers
in Dr. Lee’s laboratory have found that in addition to normal cells, PKC activation can drive
DC differentiation in acute and chronic myeloid
leukemic blasts. Because these “leukemic” DC
retain the ability to activate T cells and are endogenously loaded with leukemia antigens, they
potentially can be used as “cellular” anti-leukemia
vaccines by re-infusion back into patients. This
work aims to bring this approach to clinical trials.
In addition to the DC studies, a clinical trial
(headed by Dr. Lee) and basic laboratory research
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
currently are looking at novel agents against
multiple myeloma (MM). The NCI-sponsored
phase I/II clinical trial is examining arsenic trioxide + ascorbic acid in the treatment of refractory/
relapsed MM. Initial results demonstrate that this
combination is effective against myeloma that is
resistant to standard chemotherapy (including
thalidomide) with acceptable toxicity. The laboratory component of these studies seeks to understand how arsenic kills myeloma, how ascorbic
acid potentiates that killing, how myeloma cells
become resistant to arsenic, and which host
(i.e., patient) factors may help the myeloma
survive in the bone marrow.
SELECTED PUBLICATIONS
2002
Gray Parkin, K, Stephan, RP, Apilado, RG, LillElghanian, DA, Lee, KP, Saha, B, and Witte, PL.
Expression of CD28 by bone marrow stromal
cells and its involvement in B lymphopoiesis.
Journal of Immunology 169:2292-302, 2002.
Baumgartner, R, Durant, P, van Gessel, Y,
Chattopadhyay, S, Beswick, RL, Tadaki, DK,
Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence for the requirement of T cell costimulation
in the pathogenesis of natural Pneumocystis
carinii pulmonary infection. Microbial Pathogenesis 33:193-201, 2002.
Strbo, N, Yamazaki, K, Lee, KP, Rujkavina, D
and Podack, ER. Heat shock fusion protein
gp96-Ig mediates strong CD8 CTL expansion
in vivo. American Journal of Reproductive Immunology 48:220-25, 2002.
2003
Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and
Harlan, DM. Porcine CD80: cloning, characterization, and evidence for its role in direct human
T-cell activation. Xenotransplantation 10: 25258, 2003.
Lindner. I, Kharfan-Dabaja, M, Ayala. E,
Kolonias, D, Cejas, P, and Lee, KP. Induced differentiation of chronic myelogenous leukemia to
dendritic cells down-regulates BCR-ABL gene
expression. Journal of Immunology 171:1780-91,
2003.
McCafferty-Grad, J, Bahlis, NJ, Krett, N, Reis, I,
Lee, KP, and Boise, LH. Arsenic trioxide utilizes
caspase dependent and caspase independent
death pathways in myeloma cells. Molecular Cancer Therapeutics 2:1155-64, 2003.
HIGHLIGHTS/DISCOVERIES
• Direct activation of PKC causes normal human
hematopoietic CD34+ stem cells to differentiate
into DC.
• PKC activation causes many myeloid leukemias
to differentiate into immunologically functional
“leukemic” DC. These cells have potential utility as “cellular” anti-leukemia vaccines.
• Specific intracellular signaling pathways downstream of PKC activation control specific aspects of DC differentiation.
• Arsenic trioxide + ascorbic acid is an effective
combination in the treatment of refractory/relapsed myeloma.
Bahlis, NJ, McCafferty-Grad, J, JordanMcMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,
Eckman, J, Goodman, M, Fernandez, HF, Boise,
LH, and Lee, KP. Feasibility and correlates of
arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for
the treatment of relapsed/refractory multiple myeloma. Clinical Cancer Research 8:3658-68,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
43
CLINICAL ONCOLOGY RESEARCH PROGRAM
STEVEN E. LIPSHULTZ, M.D.
Professor and Chairman of Pediatrics
DESCRIPTION OF RESEARCH
D
r. Lipshultz’s research focuses on the prevention of cardiomyopathy and heart failure
in children and young adults. He developed
the National Heart, Lung, and Blood Institute
(NHLBI)-sponsored Pediatric Cardiomyopathy
Registry (PCMR) to better understand genetic
and metabolic cardiomyopathies; the NHLBI
P2C2 HIV study to better understand infectious
and inflammatory cardiomyopathies; and the
NCI Dana-Farber Cancer Institute childhood
leukemia and NCI Children’s Oncology Group
childhood cancer survivor cohorts to better understand toxic cardiomyopathies from
anthracycline chemotherapy and mediastinal irradiation. Further understanding of clinical phenotypes, human syndrome delineation,
epidemiology, and the natural history of these
pediatric diseases has resulted from these cohorts.
SELECTED PUBLICATIONS
2002
Lipshultz, SE , Lipsitz, SR, Sallan, SE, Simbre,
VC 2nd, Shaikh, SL, Mone, SM, Gelber, RD,
and Colan, SD. Long-term enalapril therapy for
left ventricular dysfunction in doxorubicintreated survivors of childhood cancer. Journal of
Clinical Oncology 20:4517-22, 2002.
Harmon, WG, Dadlani, GH, Fisher, SD, and
Lipshultz, SE . Myocardial and pericardial disease
in HIV. Current Treatment Options in Cardiovascular Medicine 4:497-509, 2002.
Lipshultz, SE , Giantris, AL, Lipsitz, SR, Kimball,
Dalton V, Asselin, BL, Barr, RD, Clavell, LA,
Hurwitz, CA, Moghrabi, A, Samson, Y, Schorin,
MA, Gelber, RD, Sallan, SE, and Colan, SD.
Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 9101 Acute Lymphoblastic Leukemia protocol.
Journal of Clinical Oncology 20:1677-82, 2002.
44
2003
Zareba, KM and Lipshultz, SE . Cardiovascular
complications in patients with HIV infection.
Current Infectious Disease Reports 5:513-20,
2003.
Constine, LS, Hinkle, AS, French, CA,
Kozlowski, AM, Proukou, C, Lipsitz, SR, Miller,
TL, Vermilion, RP, Rifai, N, and Lipshultz, SE .
Radiation-associated risk factors for premature
cardiovascular disease in childhood cancer survivors include accelerated atherosclerosis. International Journal of Radiation Oncology Biology
Physics 57(2 Supplement):S199-200, 2003.
Adams, MJ, Lipshultz, SE , Schwartz, C, Fajardo,
LF, Coen, V, and Constine, LS. Radiation-associated cardiovascular disease: manifestations and
management. Seminars in Radiation Oncology
13:346-56, 2003.
Lipshultz, SE , Fisher, SD, Lai, WW, and Miller,
TL. Cardiovascular risk factors, monitoring, and
therapy for HIV-infected patients. AIDS 17
Supplement 1:S96-122, 2003.
Fisher, SD, Bowles, NE, Towbin, JA, and
Lipshultz, SE . Mediators in HIV-associated cardiovascular disease: a focus on cytokines and
genes. AIDS 17 Supplement 1:S29-35, 2003.
Lipshultz, SE , Somers, MJ, Lipsitz, SR, Colan,
SD, Jabs, K, and Rifai, N. Serum cardiac troponin and subclinical cardiac status in pediatric
chronic renal failure. Pediatrics 112:79-86, 2003.
Al-Attar, I, Orav, EJ, Exil, V, Vlach, SA, and
Lipshultz, SE . Predictors of cardiac morbidity
and related mortality in children with acquired
immunodeficiency syndrome. Journal of the
American College of Cardiology 41(9):1598-605,
2003.
Benun, J, Fisher, SD, Orav, EJ, Schwartz, ML,
Exil, V, Messere, C, and Lipshultz, SE . Cardiac
management by pediatricians versus pediatric cardiologists in an inpatient academic center. American Heart Journal 145:424-9, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
Dadlani, GH, Harmon, WG, Simbre II, VC,
Tisma-Dupanovic, S, and Lipshultz, SE .
Cardiomyocyte injury to transplant: pediatric
management. Current Opinion in Cardiology
18:91-7 (Review), 2003.
Adams, MJ, Hardenbergh, PH, Constine, LS,
and Lipshultz, SE . Radiation-associated cardiovascular disease. Critical Reviews in Oncology/
Hematology 45:55-75 (Review), 2003.
BALAKRISHNA L. LOKESHWAR, PH.D.
Associate Professor of Urology
DESCRIPTION OF RESEARCH
D
r. Lokeshwar’s research focuses on the
mechanism of prostate cancer metastasis and
its control by novel chemotherapeutic drugs. For
the last several years, Dr. Lokeshwar’s laboratory
has focused on extracellular matrix degradation
and tumor metastasis. His laboratory has studied
the regulation of a class of basement membrane
matrix degrading enzymes called the matrix
metalloproteinases (MMPs) in prostate cancer.
Using cancer cell cultures established from
human prostate tumor tissues obtained after
prostatectomy, they showed that an imbalance
exists between the levels of MMPs (overproduction) and their natural inhibitors (underproduction) in invasive prostate cancer cells. Based on
this finding, they developed a hypothesis that a
novel approach to control metastatic cancer is
to correct the imbalance either by inhibition of
secretion of MMPs or by increasing the extracellular levels of their endogenous inhibitor.
Since several small synthetic inhibitors of
MMPs exist, they tested the usefulness of the inhibitors using the criteria of oral bioavailability,
systemic toxicity, and ability to target bone metastasis. In their search for a suitable inhibitor,
Dr. Lokeshwar’s laboratory tested a series of synthetic tetracycline analogues, which were shown
to possess a strong anti-collagenase activity with
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
little or no antibiotic activity. Researchers tested
eight different chemically modified tetracyclines
(CMTs) and found one of them, 6-deoxy, 6demethyl, 4-dedimethylamino tetracycline
(CMT-3, COL-3, now termed MetastatR by
CollaGenix Pharmaceuticals, Newtown, Pennsylvania), to be the most promising. Oral dosing
with this analogue to rats and mice-bearing metastatic prostate tumors reduced tumor growth and
metastasis, with no measurable systemic toxicity.
Furthermore, prophylactic dosing of animals with
the drug significantly reduced the incidence of
tumor at the site of tumor cell injection. Their
demonstration of a highly antimetastatic and antitumor activity of CMT-3 in a rat prostate tumor model led to its phase I clinical trial by the
Developmental Therapeutics Program of the NCI
(NCI-DTP). In the recently concluded human
clinical phase I trial of CMT-3, the NCI-DTP
recommended CMT-3 for phase II and phase III
in patients with soft tissue sarcoma and advanced
metastatic tumors. The University of Miami and
the State University of New York at Stony Brook
have jointly obtained a use patent on this drug.
This finding also has generated a wide interest in
the use of CMT-3 among many investigators
within and outside the University of Miami, including a new patent issued to the University for
the treatment of corneal ulceration in patients
with meibomian gland disease, also called ocular
rosacea. Dr. Lokeshwar’s current research focuses
on identifying novel plant products that have
been used as folk medicine and identifying novel
combination therapies for advanced hormonerefractive prostate cancer.
In a related development, COL-3 is undergoing a phase III clinical trial against HIVinduced Karposi’s sarcoma. Twenty centers
nationwide are engaged in this trial, headed by
Dr. Bruce DeZube of New England Deaconess
Hospital, Boston.
45
CLINICAL ONCOLOGY RESEARCH PROGRAM
SELECTED PUBLICATIONS
2002
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, M, and Pflugfelder, SC.
Experimentally induced dry eye produces ocular
surface inflammation and epithelial disease. Advances in Experimental Medicine and Biology
506:647-55, 2002.
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern,ME, and Pflugfelder, SC.
A mouse model of keratoconjunctivitis sicca. Investigative Ophthalmology & Visual Science
43:632-38, 2002.
Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block,
NL, and Golub, LM. Inhibition of cell proliferation, invasion, tumor growth and metastasis by
an oral non-antimicrobial tetracycline analog
(COL-3) in a metastatic prostate cancer model.
International Journal of Cancer 98:297-309,
2002.
Whitlatch, LW, Young, MV, Schwartz, GG,
Flanagan, JN, Burnstein, KL, Lokeshwar, BL ,
Rich, ES, Holick, MF, and Chen, TC. 25Hydroxyvitamin D-1alpha-hydroxylase activity is
diminished in human prostate cancer cells and is
enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40,
2002.
2003
Chen, TC, Holick, MF, Lokeshwar, BL ,
Burnstein, KL, and Schwartz, GG. Evaluation of
vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research
164:273-88, 2003.
Dandekar, DS, Lokeshwar, VB, CevallosArellano, E, Soloway, MS, and Lokeshwar, BL .
An orally active Amazonian plant extract (BIRM)
inhibits prostate cancer growth and metastasis.
Cancer Chemotherapy and Pharmacology 52:5966, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that an imbalance exists between
the levels of MMPs (overproduction) and their
natural inhibitors (underproduction) in invasive
prostate cancer cells.
• Identified a novel, chemically modified nonantimicrobial tetracycline (CMT-3) as an effective anti-metastatic drug with potential to treat
prostate cancer metastatic to bone. The NCI
has completed the phase I trial of this drug and
is awaiting further trials. Other novel agents are
being tested in Dr. Lokeshwar’s laboratory, not
only for controlling cancer, but also other
chronic diseases such as chronic ocular surface
inflammation. Dr. Lokeshwar’s research has
brought in one patent to the University of
Miami jointly with the State University of
New York at Stony Brook. Meanwhile, two
patents are pending on the new application of
his research findings.
• Identified a potential application of CMT to
treat the meibomian gland dysfunction that
leads to the ocular rosacea. This was done in
collaboration with Stephen C. Pflugfelder,
M.D., Baylor College of Medicine, Houston,
Texas.
Li de, Q, Shang, TY, Kim, HS, Solomon, A,
Lokeshwar, BL , and Pflugfelder, SC. Regulated
expression of collagenases MMP-1, -8, and -13
and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells. Investigative Ophthalmology & Visual Science 44:2928-36, 2003.
46
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
VINATA B. LOKESHWAR, PH.D.
Associate Professor of Urology
DESCRIPTION OF RESEARCH
D
r. Lokeshwar’s research focuses on understanding the mechanism of cancer progression and tumor angiogenesis. Recent advances in
cancer research have elucidated that the components of extracellular matrix (ECM) and ECMdegrading enzymes play a crucial role in
regulating both the metastatic progression of localized tumors and tumor angiogenesis. Using
bladder and prostate cancer model systems, she
and her colleagues are trying to understand how
ECM affects tumor metastasis and angiogenesis.
Work in Dr. Lokeshwar’s laboratory demonstrates that an ECM component, hyaluronic acid
(HA, which is a glycosaminoglycan), and its degrading enzyme, hyaluronidase (HAase), are
closely associated with the biology of cancers of
the bladder and prostate. They observed that elevated urinary HA and HAase levels are diagnostic indicators of bladder cancer and its grade,
respectively. This finding has led to the development of a simple, noninvasive, highly sensitive,
and specific urine test (HA-HAase test; 90 percent accuracy) for detecting bladder cancer and
monitoring its recurrence.
Dr. Lokeshwar’s research on prostate cancer
showed that immunohistochemical localization
of both HA and HAase in prostate cancer tissues
is greater than 85 percent accurate in predicting
prognosis for prostate cancer patients and is
better than CD44v6 and microvessel density.
Furthermore, both HAase and the HA-HAase
combination are independent predictors of
prognosis. Thus, use of these markers in biopsy
specimens may help clinicians to make individualized treatment decisions and improve patients’
prognosis.
In their efforts to understand the function of
tumor-derived HAase, the researchers purified
and cloned the first tumor-derived HAase. They
have demonstrated that this tumor-derived
HAase degrades tumor-associated HA into small
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
angiogenic fragments, which then interact with a
HA receptor, RHAMM, on endothelial cells. The
HA fragments and RHAMM interaction on the
cell surface induces signaling events, resulting in
the stimulation of endothelial cell functions such
as proliferation through the mitogen-activated
protein kinase (MAPK). Endothelial cell proliferation is of key importance in tumor angiogenesis. Their recent work, using an antisense cDNA
transfection strategy, demonstrates that tumorderived HAase is necessary for tumor growth and
muscle invasion of bladder tumors. This is an
important finding since 60 percent of bladder
cancer patients with muscle invasive disease die
within five years.
Currently, Dr. Lokeshwar’s research efforts
focus on the following areas. First, researchers are
comparing the efficacy of the HA-HAase test
with other FDA-approved bladder tumor markers
for monitoring bladder cancer recurrence. Second, they are testing the potential of HAase and
HA-HAase to predict prognostic potential using
prostate biopsy specimens. Thirdly, they are
investigating the functions of HAase and HAsynthase enzymes in bladder and prostate cancer
growth and progression.
SELECTED PUBLICATIONS
2002
Lokeshwar, VB and Soloway, MS. Re: Urine
based markers of urological malignancy. Journal
of Urology 167:1406-07, 2002.
Lokeshwar, VB , Schroeder, GL, Selzer, MG,
Hautmann, SH, Posey, JT, Duncan, RC, Watson,
R, Rose, L, Markowitz, S, and Soloway, MS.
Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic
acid-hyaluronidase and BTA-Stat tests. Cancer
95:61-72, 2002.
Ekici, S and Lokeshwar, VB . Mesane tumoru
belirleyicileri ve HA-HAase testi. Uroloji Bulteni
13:133-40, 2002.
47
CLINICAL ONCOLOGY RESEARCH PROGRAM
Lokeshwar, VB , Schroeder, GL, Carey, RI,
Soloway, MS, and Iida, N. Regulation of hyaluronidase activity by alternative mRNA splicing.
Journal of Biological Chemistry 277:33654-63,
2002.
2003
Dandekar, DS, Lokeshwar, VB , CevallosArellano, E, Soloway, MS, and Lokeshwar, BL.
An orally active Amazonian plant extract (BIRM)
inhibits prostate cancer growth and metastasis.
Cancer Chemotherapy and Pharmacology 52:5966, 2003.
Simon, MA, Lokeshwar, VB , and Soloway, MS.
Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB . Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45,
2003.
Posey, JT, Soloway, MS, Ekici, S, Sofer, M,
Civantos, F, Duncan, RD, and Lokeshwar, VB.
Evaluation of the prognostic potential of hyaluronidase activity by alternative mRNA splicing.
Journal of Biological Chemistry 277:33654-63,
2002.
HIGHLIGHTS/DISCOVERIES
• Developed the HA-HAase urine test, a noninvasive test that is about 90 percent accurate
in detecting bladder cancer and monitoring its
recurrence.
• Established that HA and HAase are greater than
85 percent accurate prognostic indicators for
prostate cancer.
• Demonstrated the function of tumor-derived
HAase in bladder tumor growth and muscle
invasion.
48
IZIDORE LOSSOS, M.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
B
y examining gene expression profiles in diffuse large B-cell lymphomas (DLBCL) and
applying a pattern recognition algorithm-termed
hierarchical clustering, Dr. Lossos’ laboratory
identified at least two molecularly distinct forms
of the disease. These were defined by specific
gene expression signatures: germinal center (GC)
B cell-like DLBCL characterized by expression of
genes normally expressed in GC B cells, and having a significantly better overall survival than the
activated B cell (ABC)-like DLBCL characterized
by expression of genes normally induced during
in vitro activation of B cells. Discovery of new
DLBCL tumor categories with distinct outcomes
by gene expression data suggested that
lymphomagenesis mechanisms involved in the
establishment or progression of these tumors may
be distinct. Indeed, researchers in this laboratory
and others have demonstrated that: 1) the
t(14;18)(q32;q21) translocation involving the
bcl-2 gene and the amplification of the c-rel locus
on chromosome 2p are detected exclusively in
GCB-like DLBCL; 2) the mutational machinery
introducing somatic mutations into Ig genes is
active in all GCB-like DLBCL but not in the majority of ABC-like DLBCL tumors, and 3) the
ABC-like DLBCL cell lines demonstrate high
expression of NF-κB target genes and have constitutive activity of I-κB kinase complex (IKK)
that is not observed in the GCB-like DLBCL cell
lines. Inhibition of IKK by dominant negative
forms of IκKβ was cytotoxic to ABC-like but not
to GCB-like DLBCL cell lines. The latter study
demonstrated that NF-κB pathway is a potential
new therapeutic target in ABC-like DLBCL.
However, specific pathways active in GCB-like
DLBCL have not yet been characterized.
Analysis of the relative prognostic contribution of the individual genes comprising the expression signatures defining these two DLBCL
subgroups demonstrated that expression of only
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
some of these genes significantly correlates with
DLBCL survival. An expressed sequence tag (EST)
that the laboratory named human germinal
center-associated lymphoma (HGAL) (UniGene
cluster 49614 -Clone 814622,GI:2210537) was
identified as a best predictor of DLBCL survival.
The predictive power of HGAL was International
Prognostic Indicator (IPI) independent, as demonstrated by multivariate analysis including components of the IPI. Furthermore, the prognostic
power of HGAL expression in predicting survival
was also shown when its expression was considered as a continuous variable demonstrating
direct correlation between higher levels of its
expression and longer survival. Higher HGAL
expression in ABC-like DLBCL still predicted
better overall survival. There was no difference in
the complete response rates between patients with
high and low HGAL expression, thus suggesting
that high HGAL expression was associated with
either better response to salvage treatment or
lower relapse rates due to more complete tumor
cell eradication or effective immunological
surveillance.
The laboratory has cloned the full-length
cDNA of this EST from both sorted GC lymphocytes and from the Ramos cell line and
termed the gene human germinal center-associated lymphoma (HGAL) (GenBank accession
number AF521911). HGAL is located on chromosome 3q13. Comparison of the genomic sequence to the cDNA sequence revealed that
HGAL spans 11kb. Recognition of a Kozak sequence and search for the longest open reading
frame (ORF) led to the identification of a putative ORF extending from exon 1 to exon 6 and
encoding a 178 amino acid protein, with 51 percent identity to the murine M17 protein that is
expressed in GC lymphocytes. The HGAL gene
product had a hydrophilic profile with no predicted
transmembrane domain and lacked a nuclear localization sequence. HGAL contains a modified
immunoreceptor tyrosine-based activation motif
termed ITAM (D/EX7D/EX2YX2LX7YX2L) that
plays a role in signal transduction in B and T
lymphocytes. HGAL is not expressed in nonUM/Sylvester Comprehensive Cancer Center Scientific Report 2004
lymphoid tissues but is expressed at high levels
only in GC lymphocytes, at intermediate levels in
memory B cells, and at relatively low levels in
peripheral blood B cells. In tumors, its expression
is high in follicular lymphoma tumors, low in
chronic lymphocytic leukemia cells, and heterogeneous in DLBCL specimens. Thus, HGAL expression may correlate with specific stages of
B-cell differentiation, especially the GC stage.
The function of HGAL in normal lymphocytes and the reason its expression in DLBCL
correlates with better DLBCL outcome, are
not known. Whether the improved survival of
patients with high HGAL-content tumors is
attributed to specific function of this gene or
is a marker of important biologic characteristic
of the tumor is unknown. Researchers in Dr.
Lossos’ laboratory are currently investigating
these questions.
SELECTED PUBLICATIONS
2002
Lossos, IS , Or, R, Ginzburg, V, Christensen,
TG, Mashriki, Y, and Breuer, R. Cyclosporin
A upmodulates bleomycin-induced pulmonary
fibrosis in BALB/c mice. Respiration 69:344-49,
2002.
Auffermann-Gretzinger, S, Lossos, IS , Vayntrub,
TA, Leong, W, Grumet, FC, Blume, KG,
Stockerl-Goldstein, KE, Levy, R, and Shizuru,
JA. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant
recipients. Blood 99:1442-48, 2002.
Bokstein, F, Lossos, A, Lossos, IS , and Siegal, T.
Central nervous system relapse of systemic nonHodgkin’s lymphoma: results of treatment based
on high-dose methotrexate combination chemotherapy. Leukemia & Lymphoma 43:587-93,
2002.
49
CLINICAL ONCOLOGY RESEARCH PROGRAM
Huang, JZ, Sanger, WG, Greiner, TC, Staudt,
LM, Weisenburger, DD, Pickering, DL, Lynch,
JC, Armitage, JO, Warnke, RA, Alizadeh, AA,
Lossos, IS , Levy, R, and Chan, WC. The
t(14;18) defines a unique subset of diffuse large
B-cell lymphoma with a germinal center B-cell
gene expression profile. Blood 99:2285-90, 2002.
Lossos, IS , Thorstenson, YR, Wayne, TL, Oefner,
PJ, Levy, R, and Chu, G. Mutation of the ATM
gene is not involved in the pathogenesis of either
follicle center lymphoma or its transformation to
higher-grade lymphoma. Leukemia & Lymphoma 43:1079-85, 2002.
Lossos, IS , Alizadeh, AA, Diehn, M, Warnke, R,
Thorstenson, Y, Oefner, PJ, Brown, PO,
Botstein, D, and Levy, R. Transformation of follicular lymphoma to diffuse large-cell lymphoma:
Alternative patterns with increased or decreased
expression of c-myc and its regulated genes. Proceedings of the National Academy of Sciences
USA 99:8886-91, 2002.
Lossos, IS , Warnke, R, and Levy, R. BCL-6
mRNA expression in higher grade transformation
of follicle center lymphoma: correlation with somatic mutations in the 5' regulatory region of the
BCL-6 gene. Leukemia 16:1857-62, 2002.
Lossos, IS , Natkunam, Y, Levy, R, and Lopez,
CD. Apoptosis stimulating protein of p53
(ASPP2) expression differs in diffuse large B-cell
and follicular center lymphoma: correlation with
clinical outcome. Leukemia & Lymphoma
43:2309-17, 2002.
2003
Lossos, IS , Alizadeh, AA, Rajapaksa, R,
Tibshirani, R, and Levy, R. HGAL is a novel
interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma.
Blood 101:433-40, 2003.
Martinez-Climent, JA, Alizadeh, AA, Segraves, R,
Blesa, D, Rubio-Moscardo, F, Albertson, DG,
Garcia-Conde, J, Dyer, MJ, Levy, R, Pinkel, D,
and Lossos, IS . Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy
number and gene expression alterations. Blood
101:3109-17, 2003.
Akasaka, T, Lossos, IS , and Levy, R. BCL6 gene
translocation in follicular lymphoma: a harbinger
of eventual transformation to diffuse aggressive
lymphoma. Blood 102:1443-48, 2003.
Lossos, IS and Levy, R. Diffuse large B-cell lymphoma: insights gained from gene expression profiling. International Journal of Hematology
77:321-29, 2003.
Lossos, IS and Levy, R. Higher grade transformation of follicular lymphoma: phenotypic tumor
progression associated with diverse genetic lesions. Seminars in Cancer Biology 13:191-202,
2003.
Lossos, IS , Akasaka, T, Martinez-Climent, JA,
Siebert, R, and Levy, R. The BCL6 gene in B-cell
lymphomas with 3q27 translocations is expressed
mainly from the rearranged allele irrespective of
the partner gene. Leukemia 17:1390-97, 2003.
Do, B, Lossos, IS , Thorstenson, Y, Oefner, PJ,
and Levy, R. Analysis of FAS (CD95) gene mutations in higher-grade transformation of follicle
center lymphoma. Leukemia & Lymphoma
44:1317-23, 2003
Lossos, IS , Akasaka, T, and Levy, R. Multiple
BCL6 translocation partners in individual cases
of gastric lymphoma. Blood 102:1931-32, 2003.
Lossos, IS , Czerwinski, DK, Wechser, MA, and
Levy, R. Optimization of quantitative real-time
RT-PCR parameters for the study of lymphoid
malignancies. Leukemia 17:789-95, 2003.
50
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
CLARA MILIKOWSKI, M.D.
Associate Professor of Pathology
DESCRIPTION OF RESEARCH
S
ince 1993, the Cooperative Breast Cancer
Tissue Resource (CBCTR) has provided
breast cancer tissue to researchers for the study of
clinical markers of tumor prognosis and the
evaluation of promising diagnostic tests based on
these markers. It is a centrally administered repository of archival breast cancer tissues with associated clinical and outcome data to meet this
need, and it is comprised of four sites in the
United States—the University of Miami, Fox
Chase Cancer Center, Kaiser-Permanente (Portland, Oregon), and Washington University (St.
Louis, Missouri). These four institutions are geographically dispersed, offer significantly different
clinical resources to the CBCTR, and have gathered their breast cancer cases from widely different clinical settings, which together parallel SEER
data for breast cancer.
Each site identified, segregated, and cataloged the specimens for the CBCTR locally. Selected clinical and outcome data obtained from
its local hospital tumor registry are associated
with each case. The combined clinical and outcome data from all four sites, stored centrally by
Information Management Services (IMS), in addition to the tissue specimens stored at each site,
constitute the “virtual tissue resource” of the
CBCTR. IMS has used this material to prepare a
searchable database for the CBCTR online, at
http://www-cbctr.ims.nci.nih.gov/. Here, investigators can search the CBCTR material to determine if the specimens are adequate for use in
their research. If investigators feel the resource
meets their needs, instructions for application for
these tissues are available on the same web site.
The CBCTR currently has a “progression
array,” which was designed by an NCI statistician
who calculated the type and number of specimens that would be required to produce an array
whose statistical power had already been calculated. Each of the sites has contributed to this
[tissue micro-] array.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SELECTED PUBLICATIONS
2002
Regev, A, Berho, M, Jeffers, LJ, Milikowski, C ,
Molina, EG, Pyrsopoulos, NT, Feng, ZZ, Reddy,
KR, and Schiff, ER. Sampling error and
intraobserver variation in liver biopsy in patients
with chronic HCV infection. American Journal
of Gastroenterology 97:2614-18, 2002.
2003
Abdel-Wahab, M, Krishan, A, Milikowski, C ,
Abdel-Wahab, A., Walker, G, and Markoe, A.
Androgen receptor antigen density and S-phase
fraction in prostate cancer: a pilot study. Prostate
Cancer and Prostatic Diseases 6:294-300, 2003.
Fishman, JE, Milikowski, C , Ramsinghani, R,
Velasquez, MV, and Aviram, G. US-guided coreneedle biopsy of the breast: how many specimens
are necessary? Radiology 226:779-82, 2003.
Pasquale, M and Milikowski, C . Three millimeter apocrine adenoma in a man: Case report and
review of the literature. Archives of Pathology &
Laboratory Medicine 127:1498-500, 2003.
LUIS E. RAEZ, M.D., F.A.C.P.
Assistant Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Raez’s research focuses on translational
research in the areas of lung cancer, head
and neck cancer, and the development of clinical
trials with novel compounds for these diseases.
Dr. Raez is the principal investigator in two
phase-I trials that are developing allogeneic tumor cancer vaccines for lung cancer patients
(both of them engineered at the University of
Miami by Eckhard R. Podack, M.D., Ph.D.).
Now that the first trial with the co-stimulatory
molecule B7.1 (CD 80) has been successfully
completed, he has developed a phase II clinical
trial with the same vaccine to vaccinate patients
with minimal disease with the goal to prevent
relapse. Patients treated in the first phase I clini51
CLINICAL ONCOLOGY RESEARCH PROGRAM
cal trial with the B7.1 vaccine were incurable and
had an expected survival of less than six months.
Due to the therapy, however, 30 percent of the
patients achieved disease stabilization or response
and at least three patients now have survived for
more than two years, with a median survival of
18 months for the whole group. Dr. Raez will
begin the phase I trial with the allogeneic tumor
vaccine gp-96 for patients with lung cancer soon
after FDA approval. This vaccine is more immunogenic than the B7.1 used before. In mice, it
has been shown to have a stronger immune response. Due to his gp-96 vaccine project and the
success of the B7.1 vaccine, Dr. Raez was granted
a “Research Career Development Award” in 2002
by the American Society of Clinical Oncology
(ASCO) with funds to support his research for
three years.
Dr. Raez and his colleagues recently received
Cancer Therapy Evaluation Program (CTEP)
approval for a phase I clinical trial with a new
drug called cytochlor (NSC 371331), a potent
radiation sensitizer, which was discovered by
Sheldon Greer, Ph.D., at the University of Miami. Dr. Raez and Dr. Greer will treat patients
with radiation therapy with the goal to improve
response and prevent relapse. Dr. Raez also was
awarded the 2002-2003 Stanley J. Glaser Foundation Biomedical Research Award and funding
for the cytochlor project. Additionally, CTEP has
approved the project and will provide funding
and drug production for its development.
Dr. Raez also works with Theodore J.
Lampidis, Ph.D., in developing the first phase I
trial in humans with the combination of 2-DG
with chemotherapy. 2-DG has a novel mechanism of action focused in the destruction of slowgrowing cells in the core of the tumors where
conventional chemotherapy and radiation have
not worked, which already has been proven by
Dr. Lampidis’ research. Dr. Raez also has been
trying to find the prognostic role of c-Kit, Bag-1,
and CEACAM-1 in lung cancer, trying to correlate it with clinical responses and survival.
52
Dr. Raez also has initiated several important
clinical trials with new compounds for lung and
head and neck cancers with Cpt-11, oxaliplatin,
capecitabine, and Velcade, among others.
SELECTED PUBLICATIONS
2003
Santos, ES, Raez, LE, Salvatierra, J,
Morgensztern, D, Shanmugan, N, and Neff, GW.
Primary hepatic non-Hodgkin’s lymphomas: a
case report and review of the literature. American
Journal of Gastroenterology (Review) 98:278993, 2003.
Raez LE, Cassileth, PA, Schlesselman, JJ,
Padmanabhan, S, Fisher, EZ, Baldie, PA, Sridhar,
K, and Podack, ER. Induction of CD8 T-cell-Ifngamma response and positive clinical outcome
after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung
carcinoma. Cancer Gene Therapy 10:850-58,
2003.
Santos, ES, Raez, LE, Kharfan-Dabaja, MA,
Angulo, J, Restrepo, A, and Byrnes, JJ. Survival
of renal allograft following de novo hemolytic
uremic syndrome after kidney transplantation.
Transplantation Proceedings 35:1370-74, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
CAIO MAX S. ROCHA LIMA, M.D.
Associate Professor of Medicine
Rocha Lima, CM and Centeno, B. Update on
pancreatic cancer. Current Opinion in Oncology
14:424-30, 2002.
DESCRIPTION OF RESEARCH
Rocha Lima, CM and Joppert, MG.
Topoisomerase I-based nonplatinum combinations in non-small-cell lung cancer. Oncology
(Huntington) 16:25-31, 2002.
D
r. Rocha Lima’s research focuses on developing novel treatments in patients with cancer
(mainly lung cancer and gastrointestinal malignancies).
Researchers in his laboratory work to identify prognostic factors in patients with cancer.
They also are cooperating in the development of
molecular finger-printing for gastrointestinal cancer patients. They are studying 33,000 genes in
pancreatic cancer and colorectal cancer as an attempt to identify different gene expression patterns (tumor phenotype) and their correlation
with overall survival, benefit to different types of
treatment, and tumor aggressiveness. The investigators also are working to identify chromosomes
alleles related to drug metabolism from buffy coat
(leucocytes) and correlating with chemotherapy
toxicity.
SELECTED PUBLICATIONS
2002
Rocha Lima, CM , Herndon, JE 2nd, Kosty, M,
Clamon, G, and Green, MR. Therapy choices
among older patients with lung carcinoma: an
evaluation of two trials of the Cancer and Leukemia Group B. Cancer 94:181-87, 2002.
Rocha Lima, CM , Savarese, D, Bruckner, H,
Dudek, A, Eckardt, J, Hainsworth, J, Yunus, F,
Lester, E, Miller, W, Saville, W, Elfring, GL,
Locker, PK, Compton, LD, Miller, LL, and
Green, MR. Irinotecan plus gemcitabine induces
both radiographic and CA 19-9 tumor marker
responses in patients with previously untreated
advanced pancreatic cancer. Journal of Clinical
Oncology 20:1182-91, 2002.
Freitas, JR and Rocha Lima, CM . Therapy of
advanced non-small-cell lung cancer with
irinotecan and gemcitabine in combination.
Clinical Lung Cancer 4 (Supplement 1): S26-90,
2002.
2003
Coutinho, AK and Rocha Lima, CM . Metastatic
colorectal cancer: systemic treatment in the new
millennium. Cancer Control 10:224-38, 2003.
Rocha Lima, CM and Chiappori, A. Treatment
of relapsed small-cell lung cancer—a focus on the
evolving role of topotecan. Lung Cancer 40:22936, 2003.
Bhargava, P, Jani, CR, O’Donnel, JL, Stuart, KE,
and Rocha Lima, CM . Gemcitabine and
irinotecan in locally advanced or metastatic
biliary cancer. Oncology 17: 23-26, 2003.
Chiappori, AA and Rocha Lima, CM . New
agents in the treatment of small-cell lung cancer:
focus on gemcitabine. Clinical Lung Cancer 4
(Supplement 2): S56-63, 2003.
Simon, GR, Ruckdeschel, JC, Williams, C, Cantor, A, Chiappori, A, Rocha Lima, CM , Antonia
S, Haura, E, Wagner, H, Robinson, L, Sommers,
E, Alberts, M, and Bepler, G. Gefitinib (ZD1839)
in previously treated advanced non-small-cell
lung cancer: experience from a single institution.
Cancer Control 10:388-95, 2003.
Rocha Lima, CM , Leong, SS, Sherman, CA,
Perkel, JA, Putman, T, Safa, AR, and Green, MR.
Irinotecan and gemcitabine in patients with solid
tumors: phase I trial. Oncology (Huntington)
16:19-24, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
53
CLINICAL ONCOLOGY RESEARCH PROGRAM
HIGHLIGHTS/DISCOVERIES
Novel treatments with the following agents were
designed and tested clinically by Dr. Rocha Lima:
• IrinoGem (gemcitabine and irinotecan in combination) for pancreatic cancer and lung cancer
(both small and non-small cell lung cancer).
• DocGem in lung cancer.
• ETopoTax in small cell lung cancer.
His clinical efforts with the agent IrinoGem
resulted in establishing it as a new clinical treatment option for pancreatic cancer.
JOSEPH D. ROSENBLATT, M.D.
Professor of Medicine and
Division Chief of Hematology-Oncology
DESCRIPTION OF RESEARCH
D
r. Rosenblatt’s research focuses on the development of novel immune therapy and gene
therapy strategies for cancer. Current research has
focused on the potential role of recruitment of
immune effector cells, using the local elaboration
of both constitutive and inflammatory chemokines,
such as secondary lymphoid chemokine (SLC),
DC-CK1 and/or RANTES respectively, on the
development of an anti-tumor response. Chemokine
delivery has been investigated alone, or in combination with, expression of the costimulatory ligands
CD80 (B7.1) or CD40L. Several delivery strategies
have been investigated including the use of retroviral
vectors, and/or the use of herpes simplex virus (HSV)
amplicon vectors in several murine tumor models.
Preliminary results suggest that the recruitment
of naïve T cells using SLC is a particularly effective means of enhancing the anti-tumor immune
response, particularly when combined with CD40Linduced co-stimulation. This strategy is being
formally investigated using the OT-1 transgenic
mouse model, which has a constitutively expressed
T-cell receptor with defined anti-ovalbumin specificity and the murine tumors expressing the target
ovalbumin antigen, for effects on tumor-induced
tolerance and the development of systemic immunity.
54
In a separate effort, the utility of HSV-derived helper virus-free amplicons is being tested
for efficacy in augmenting the immunogenicity
and antigen-presenting capability of fresh chronic
lymphocytic leukemia cells (CLL). Both CD40L
and CD80, and/or the tumor necrosis factor (TNF)
ligand family member LIGHT have been targeted
to fresh CLL cells using the helper free HSV
amplicons. Results suggest the augmented ability
of such CLL cells to present antigen in an allogeneic mixed-lymphocyte-tumor cell reaction, and/
or to serve as stimulatory cells for the derivation
of autologous cytolytic T cells in vitro without
deleterious effects on MHC-I expression is seen
with HSV helper virus-containing preparations.
A novel means of immune effector molecule
delivery, which combines the antigen binding
capabilities and localization characteristics of antibodies with the local delivery of a co-stimulatory
molecule, anti-angiogenic peptide, or a chemokine, also is under investigation. Antibody fusion
proteins targeting the human breast and ovarian
cancer her2/neu antigen, linked to the extracellular domains of the B7.1 and/or 41BB-L
costimulatory ligands, have been synthesized and
their in vitro ability to bind to cognate antigenic
targets and to deliver a local co-stimulatory signal
has been documented. Additional fusions currently being developed in the laboratory include
fusion of the anti-angiogenic peptide endostatin
to anti-her2/neu antibody sequences, as well as
fusion of the inflammatory chemokine RANTES.
Selective targeting of immune effector cells using
both local chemokine vector administration or
antibody-fusion protein administration is being
evaluated further.
A novel antibody-fusion that targets delivery
of endostatin to the site of her2/neu-expressing
tumors has also been synthesized in collaboration
with Seung-Uon Shin, M.D., and shows excellent
efficacy in preclinical models. This fusion appears
to substantially improve the results obtained with
either antibody or endostatin alone.
Currently, Dr. Rosenblatt’s laboratory is
studying efficacy using a novel B-cell deficient
mouse model, which allows testing of antibody
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
fusion protein targeting to xenogeneic (e.g., CEA,
her2/neu) antigens, while preserving T-cell
immune-effector functions. The B-cell deficient
model also has demonstrated T-cell responses to
tumor and may be better than those seen in the
immunocompetent mouse. The laboratory is
currently investigating the reasons for altered
responses in the absence of B cells, and the possibility of applying this approach to clinically using
antibody depletion of B cells with rituximab.
Dr. Rosenblatt and his colleagues also have
collaborated with the laboratory of Vicente
Planelles, Ph.D., at the University of Utah, on
developing several new approaches to HIV-1 gene
therapy. These include the use of mutated tRNALYS3
primers, which can anneal to the sequences other
than primer-binding sequences on the HIV-1
genome, or tRNALYS3 mutated in adenosine residue A58, which prevents normal methylation of
the adenosine residue and disrupts proper termination of the nascent reverse transcript, thereby
inhibiting completion of HIV-1 reverse transcription in model systems. Other investigations have
centered on the effects of defective HIV-1 derived
vectors on HIV-1 spread in culture. Recent experiments have demonstrated that efficient trafficking of defective HIV-1 vectors is observed
in vitro following superinfection with wild type
HIV-1 and that such trafficking results in a
marked inhibition of wild type viral spread.
SELECTED PUBLICATIONS
2002
Lancet, JE, Rosenblatt, JD , and Karp, JE.
Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in
high-risk leukemias. Seminars in Hematology
39:31-35, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented antitumor activity. Cancer Research 62:6545-51,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Rosenblatt, JD , Shin, SU, Nechustan, H, Yi,
KH, and Tolba, K. Potential role of chemokines
in immune therapy of cancer. Israel Medical Association Journal 4:1054-59, 2002.
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD .
HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic
lymphocytic leukemia. Molecular Therapy 6:45563, 2002.
Andela, VB, Rosenblatt, JD , Schwarz, EM,
Puzas, EJ, O’Keefe, RJ, and Rosier, RN. Synergism of aminobisphosphonates and farnesyl
transferase inhibitors on tumor metastasis. Clinical Orthopaedics 397:228-39, 2002.
2003
Khorana, AA, Rosenblatt, JD , Sahasrabudhe,
DM, Evans, T, Ladrigan, M, Marquis, D, Rosell,
K, Whiteside, T, Phillippe, S, Acres, B, Slos, P,
Squiban, P, Ross, M, and Kendra, K. A phase I
trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients
with malignant melanoma. Cancer Gene Therapy
10:251-9, 2003.
Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ,
O’Keefe, RJ, Rosenblatt, JD , and Rosier, RN.
The mevalonate synthesis pathway as a therapeutic target in cancer. (Review) Clinical Orthopaedics 415 (Supplement):S59-66, 2003.
Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A,
Lu, C, McNair, C, Abboud, CN, and Rosenblatt,
JD. Effects of the farnesyl transferase inhibitor
R115777 on normal and leukemic hematopoiesis. Leukemia 17:1806-12, 2003.
Rosenblatt, JD and Harrington, WJ Jr. Leukemia
and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation
21:323-24, 2003.
55
CLINICAL ONCOLOGY RESEARCH PROGRAM
HIGHLIGHTS/DISCOVERIES
• Developed novel antibody-chemokine and antibody-costimulatory ligand fusion proteins with
dual function and preserved targeting capabilities.
• Developed a novel strategy for gene therapy of
HIV-1 using mutations introduced into the
tRNALYS3 primer.
• Demonstrated the potential role for HSV
amplicon vectors in gene therapy of malignancy, particularly CLL.
• Demonstrated the use of trafficking and inhibition by defective HIV-1 as a novel approach to
HIV-1 gene therapy.
• Demonstrated the utility of combining
chemokine delivery with costimulatory ligands
in augmenting mouse response to tumors.
NIRAMOL SAVARAJ, M.D.
Adjunct Professor of Medicine
DESCRIPTION OF RESEARCH
Molecular Mechanism of Drug Resistance in
Small Cell Lung Cancer
Small cell lung cancer (SCLC) usually responds
to chemotherapy, but relapse is inevitable. Although several new chemotherapeutic agents have
shown activity in SCLC, salvage therapy is still
poor. Research in Dr. Savaraj’s laboratory focuses
on identifying the mechanisms of drug resistance
in SCLC and developing approaches to overcome
them.
Since the combination of VP-16 and
cisplatin is the most commonly used regimen in
treating SCLC, the laboratory has studied the
mechanism(s) of resistance of these two agents.
They have established two pairs of cisplatin resistant sublines (SR-2 and BC), one VP-16 resistant
subline (BV), one MRP1 (SCLCA), and one Pgp (SCLCR) resistant subline from two parental
56
lines (SCLC1 and SCLCB). These cell lines were
used to study the mechanism(s) of resistance in
SCLC. Using cDNA subtraction and microarray,
the laboratory has found that both cisplatin resistant cell lines overexpressed three families of
cDNAs, the MMP family, DNA damage and repair proteins, and proteins involved in translation. The specific genes that were consistently
elevated were elongation factor and ribosomal
protein. Since rapamycin or its analog CCI-779
can inhibit translation of the mRNA encoding
elongation factor, they have investigated whether
these analogs could reverse cisplatin drug resistance. Dr. Savaraj and her colleagues found that
all cell lines were sensitive to rapamycin and
CCI-779 with the ID50 ranged from 0.05-0.1µg/
ml. Furthermore, at 0.01µg/ml both drugs could
also restore cisplatin sensitivity, and could completely restore VP-16 sensitivity in BV cell line.
Neither rapamycin nor CCI-779 is able to reverse
P-gp1 or MRP1 resistance.
SELECTED PUBLICATIONS
2002
Feun, LG, Modiano, M, Lee, K, Mao, J, Marini,
A, Savaraj, N , Plezia, P, Almassian, B, Colacino,
E, Fischer, J, and MacDonald, S. Phase I and
pharmacokinetic study of 3-aminopyridine-2carboxaldehyde thiosemicarbazone (3-AP) using a
single intravenous dose schedule. Cancer Chemotherapy and Pharmacology 50:223-29, 2002.
Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG,
Xu, R, Xu, J, and Savaraj, N . Procollagen-like
protein as a molecular target in the treatment of
primary brain tumor. ScientificWorldJournal.
2:125-26, 2002.
Feun, LG, Savaraj, N , Hurley, J, and Marini, A.
Phase II trial of Paclitaxel and Dacarbazine with
filgrastim administration in advanced malignant
melanoma. Cancer Investigation 20:357-61,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ.
Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:174551, 2002.
2003
Feun, LG, O’Brien, C, Molina, E, Rodriguez, M,
Jeffers, L, Schiff, ER, Marini, A, Savaraj, N , and
Ardalan, B. Recombinant leukocyte interferon,
doxorubicin, and 5FUDR in patients with hepatocellular carcinoma-A phase II trial. Journal of
Cancer Research and Clinical Oncology 129:1720, 2003.
Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L,
Donnelly, E, Solomon, J, Sundaram, M, Feun, L,
and Savaraj, N . Phase II study of vinorelbine
with low dose prednisone in the treatment of
hormone-refractory metastatic prostate cancer.
Oncology Report 10:885-89, 2003.
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ, Robles, C, Furst, AJ, and Feun,
LG. Overexpression of mutated MRP4 in
cisplatin resistant small cell lung cancer cell line:
Collateral sensitivity to azidothymidine. International Journal of Oncology 23:173-9, 2003.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N , and
Lampidis, TJ. Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
RAKESH SINGAL, M.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Singal’s research focuses on the mechanisms that inactivate certain tumor-suppressor genes in prostate cancer. A common mode of
such inactivation involves a modification (methylation) in DNA. By understanding how genes are
silenced, treatments can be developed to activate
them and thereby prevent the development and/
or progression of prostate cancer. Researchers in
Dr. Singal’s laboratory also are studying methylation of selected genes as a diagnostic and prognostic marker in prostate cancer.
The present screening techniques for prostate
cancer are very inefficient, and two out of three
patients undergo prostate biopsy to detect cancer
unnecessarily. Cancer patients often have a small
amount of DNA circulating in their serum,
thought to be released from the cancer cells.
Dr. Singal’s laboratory has shown that certain
methylated genes are present at a substantially
higher percentage in prostate cancer tissue compared to benign prostatic conditions. Researchers
are investigating if these methylated genes can
be detected in serum DNA in patients with prostate cancer. If so, this test can be used as a part
of prostate cancer screening, saving unnecessary
prostate biopsies.
DNA methylation plays a role during development by regulating gene expression. Another
project in Dr. Singal’s laboratory focuses on understanding the role of methylation in regulating
the expression of genes responsible for hemoglobin synthesis. Understanding the contribution of
methylation to globin gene expression and the
mechanisms involved will lead to the development of safe and effective therapies for globin
gene disorders like thalassemia and sickle cell
anemia.
57
CLINICAL ONCOLOGY RESEARCH PROGRAM
SELECTED PUBLICATIONS
2002
Singal, R, vanWert, JM, and Ferdinand, L Jr.
Methylation of alpha-type embryonic globin gene
alpha pi represses transcription in primary erythroid cells. Blood 100:4217-22, 2002.
Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and
Ginder, GD. Methylation of promoter proximal
transcribed sequences of an embryonic globin
gene inhibits transcription in primary erythroid
cells and promotes formation of a cell type-specific methyl cytosine binding complex. Journal of
Biological Chemistry 277:1897-1905, 2002.
Noss, KR, Singal, R, and Grimes, SR. Methylation state of the prostate specific membrane antigen (PSMA) CpG island in prostate cancer cell
lines. Anticancer Research 22:1505-11, 2002.
2003
Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal,
R, and Gill, S. Gynecomastia attributable to human chorionic gonadotropin-secreting giant cell
carcinoma of lung. Endocrinology Practices
9:233-35, 2003.
JOYCE M. SLINGERLAND, M.D., PH.D.,
F.P.R.C.(C)
Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Slingerland’s research investigates how
cancers escape negative growth controls. Following her discovery of a key inhibitor of cell
cycle progression, p27, Dr. Slingerland and her
colleagues went on to demonstrate that p27 levels
are reduced in up to 60 percent of common human cancers (breast, prostate, lung, ovarian, and
others), in association with poor patient prognosis. Dr. Slingerland showed that the therapeutic
effect of antiestrogens in breast cancer requires
the cyclin-dependent kinase (cdk) inhibitors p21
and p27 to mediate growth arrest. Oncogenic
58
activation of mitogenic signaling via the mitogenactivated protein kinase (MAPK) pathway deregulates p27 function, causing tamoxifen
resistance in breast cancer. She provided key insights demonstrating the role of cell cycle inhibitors p15 and p27 as mediators of G1 arrest by
transforming growth factor-beta (TGF-β) and
demonstrated that cancer cells lose responsiveness
to this growth inhibitory cytokine through loss or
deregulation of p27. In a recent publication, her
laboratory demonstrated that checkpoint loss
during cancer progression makes p27 an essential
mediator of arrest. They also showed that functional inactivation of p27 in human cancers can
either occur through accelerated p27 degradation
or through altered p27 phosphorylation leading
to p27 mislocalization. The laboratory recently
showed that activation of mitogenic signaling via
the receptor tyrosine kinases and the phosphoinositol 3’ kinase pathway alters p27 phosphorylation and function and the protein accumulates
in the cytoplasm away from its targets in the
nucleus. This work links oncogene activation
with loss or inactivation of the cell cycle inhibitor, p27, elucidating a major mechanism of loss
of growth control in cancer progression.
Dr. Slingerland’s laboratory also is investigating the cause of aggressive estrogen receptor negative (ER-) breast cancers. Her group has found
that oncogenic receptor tyrosine kinase and cSrc
activation may not only activate mitogenic signaling leading to aggressive proliferation, but also
lead to loss of detectable ER protein in ER negative (ER-) breast cancers. One third of newly diagnosed breast cancers are ER- and have a poor
prognosis. Investigation of the mechanisms underlying the loss of ER expression showed that all
of 70 primary ER- breast cancers expressed ER
mRNA. Src or proteasome inhibition increased
ER levels, and Src transfection stimulated both
ligand activated ER transcriptional activity and
ER proteolysis. Cotransfection of Her2 and Src
reduced ER levels further. ER- primary breast
cancers and cell lines showed increased Src activity compared to ER+ cancers and cell lines, and
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
the ER protein half-life was reduced in ERbreast cancer lines. These data support a model
in which Her2 and cSrc cooperate with liganded
ER to promote both ER dependent transcription
and transcription linked ER proteolysis.
SELECTED PUBLICATIONS
2002
Donovan, JC, Rothenstein, JM, and Slingerland,
JM. Non-malignant and tumor-derived cells differ in their requirement for p27Kip1 in transforming growth factor-beta-mediated G1 arrest.
Journal of Biological Chemistry 277:41686-92,
2002.
Lian, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R,
Connor, MK, Han, K, Lee, JH, Ciarallo, S,
Catzavelos, C, Beniston R, Franssen, E, and
Slingerland, JM . PKB/Akt phosphorylates p27,
impairs nuclear import of p27 and opposes p27mediated G1 arrest. Nature Medicine 8:1153-60,
2002.
Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH,
Kotchetkov, R, Sandhu, C, Milic, A, and
Slingerland, JM . Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth
factor beta-mediated G(1) arrest. Molecular and
Cellular Biology 22:2993-3002, 2002.
2003
Connor, MK, Kotchetkov, R, Cariou, S, Resch,
A, Lupetti, R, Beniston, RG, Melchior, F,
Hengst, L, and Slingerland, JM . CRM1/Ranmediated nuclear export of p27(Kip1) involves a
nuclear export signal and links p27 export and
proteolysis. Molecular Biology of the Cell
14:201-13, 2003.
Liang, J and Slingerland, JM . Multiple Roles of
the PI3K/PKB (Akt) Pathway in cell cycle progression. Cell Cycle 2:339-45, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
MARK S. SOLOWAY, M.D.
Professor and Chairman of Urology
DESCRIPTION OF RESEARCH
M
uch of the work in the University of
Miami’s department of Urology is devoted
to better understanding the role of surgery in
treating prostate, bladder, and kidney cancers.
The department has established a rather unique
database of more than 1,300 men who have had
radical prostatectomy performed by one surgeon
and their pathology has been read by one pathologist. Through the efforts of devoted researchers, they have reported on the relationship
between a number of clinical and pathologic risk
factors, e.g., positive surgical margin location,
seminal vesicle invasion, and risk of relapse. This
is critical when counseling patients regarding diagnosis, follow-up schedule and, most importantly, the need and type of additional treatment.
Researchers in Dr. Soloway’s laboratory have
introduced the concept of local anesthesia for
prostate biopsies. This has the potential to benefit
more than 500,000 men annually in the United
States who undergo this otherwise rather painful
procedure. More than 13 randomized studies
confirm the researchers’ observation of the benefit of a periprostatic nerve block prior to ultrasound guided prostate biopsies.
In an effort to minimize the morbidity of
radical retropubic prostatectomy, Dr. Soloway has
taken steps to enhance recovery without sacrificing cancer control. To this end, he has reported
his results with nerve sparing, the omission of a
pelvic drain, and the use of a cell saver to obviate
the need for an allogeneic transfusion.
In collaboration with Gaetano Ciancio,
M.D., professor of Surgery and Urology, they
have carefully detailed their surgical approach to
large kidney tumors. They have adapted techniques developed for liver transplantation to reduce the morbidity and mortality related to
surgery of large renal tumors, many of which involve extension into the vena cava.
59
CLINICAL ONCOLOGY RESEARCH PROGRAM
Lastly, Dr. Soloway’s interest in bladder cancer continues. He has published the first article
detailing the growth pattern of low-grade bladder
tumors. Using a cohort of patients with lowgrade Ta tumors who were observed by periodic
endoscopy, they were able to emphasize the safety
of carefully monitoring such tumors to obviate
the morbidity and cost of frequent outpatient
surgery.
SELECTED PUBLICATIONS
2002
Lokeshwar, VB and Soloway, MS . Re: Urine
based markers of urological malignancy. Journal
of Urology 167:1406-07, 2002.
Lokeshwar, VB, Schroeder, GL, Selzer, MG,
Hautmann, SH, Posey, JT, Duncan, RC, Watson,
R, Rose, L, Markowitz, S, and Soloway, MS .
Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic
acid-hyaluronidase and BTA-Stat tests. Cancer
95:61-72, 2002.
Lokeshwar, VB, Schroeder, GL, Carey, RI,
Soloway, MS , and Iida, N. Regulation of hyaluronidase activity by alternative mRNA splicing.
Journal of Biological Chemistry 277:33654-63,
2002.
2003
Simon, MA, Lokeshwar, VB, and Soloway, MS .
Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003.
Posey, JT, Soloway, MS , Ekici, S, Sofer, M,
Civantos, F, Duncan, RC, and Lokeshwar, VB.
Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Research 63:2638-44, 2003.
60
SHOU-CHING TANG, M.D., PH.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
B
AG-1 is a recently identified anti-apoptotic
protein that binds to Bcl-2, hepatocyte, and
platelet-derived growth factor receptors, enhancing their inhibition of apoptosis. It also binds to
heat shock proteins, RAF-1 serine/threonine kinase, and hormone receptors and modulates their
functions. Researchers in Dr. Tang’s laboratory
detected the presence of one new BAG-1 isoform,
p29. They showed that the four BAG-1 isoforms
are localized differentially in subcellular compartments and in various tissues, suggesting that they
perform different functions. They recently demonstrated that each BAG-1 isoform has a differing ability to inhibit apoptosis induced by various
apoptosis-inducing agents. On the other hand,
antisense against BAG-1 sensitized cells to
apoptosis was induced by various chemotherapeutic agents. More significantly, these researchers observed the overexpression of BAG-1 in the
majority of breast and lung cancer patients and
its prognostic value. In addition, they observed
the coexpression of BAG-1 with Bcl-2, p53, and
estrogen receptor/progesterone receptor (ER/PR)
in breast cancer tissues. They have isolated the
BAG-1 promoter region and noted its up-regulation by the mutant p53. The laboratory also has
raised monoclonal antibodies against individual
BAG-1 isoforms, allowing for clinical correlation
of BAG-1 expression and disease course. Current
research at the basic molecular biology level involves the study of BAG-1 expression control and
its interaction with other cellular proteins, including Bcl-2, ER/PR, and hsp to explore how
BAG-1 inhibits apoptosis. At the clinical research
level, research involves the development of BAG1 Mab and antisense in the prognosis and prediction to treatment response in a variety of solid
tumors.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
SELECTED PUBLICATIONS
HIGHLIGHTS/DISCOVERIES
2002
• Cloned mouse and human BAG-1 genes and its
promoter.
Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X,
Pater, A, and Liepins, A. The alkaloid sanguinarine is effective against multi-drug resistance in
human cervical cells via bimodal cell death. Biochemical Pharmacology 63:1415-21, 2002.
Ding, Z, Green, AG, Yang, X, Chernenko, G,
Tang, S-C, and Pater, A. Retinoic acid inhibits
telomerase activity and downregulates expression
but does not affect splicing of hTERT: correlation with cell growth rate inhibition in an in vitro
cervical carcinogenesis/multidrug-resistance
model. Experimental Cell Research 272:185-91,
2002.
Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X,
Chernenko, G, Pater, A, and Liepins, A. The alkaloid sanguirine is effective against multidrug
resistance in human cervical cells via bimodal cell
death. Biochemical Pharmacology 63:1415-21,
2002.
Tang, S-C. BAG-1, an anti-apoptotic tumor
marker. (Invited Review) IUBMB Life 53:99105, 2002.
Chen, J, Chernenko, G, Xiong, J and Tang, S-C.
Distinct BAG-1 isoforms have different antiapoptotic functions in BAG-1-transfected C33A
human cervical carcinoma cell line. Oncogene
21:7050-59, 2002.
2003
Tang, S-C. Differential anti-apoptotic function
of BAG-1 isoforms in human malignancy. Recent
Research and Development in Biophysics and
Biochemistry 3:427-44, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Discovered the mechanism by which four BAG1 isoforms are generated.
• Discovered the possible prognostic value of
BAG-1 in breast and lung cancer.
• Generated BAG-1-isoform-specific Mab’s
(patent pending).
• Generated BAG-1 antisense cDNA and siRNA.
• Discovered BAG-1’s involvement in chemotherapy resistance.
• Developed Eastern Cooperative Oncology
Group (ECOG) protocol using BAG-1 as predictive marker in the treatment of NSCLC.
KHALED A. TOLBA, M.D.
Assistant Professor of Medicine
DESCRIPTION OF RESEARCH
D
uring the past five years, Dr. Tolba has been
developing immunotherapeutic strategies for
B-cell hematologic malignancies, with particular
interest in chronic lymphocytic leukemia (CLL).
CLL is the most common leukemia in the Western hemisphere. As a relatively slow-progressing
tumor with readily accessible tumor cells, it offers
an opportunity to develop and test immunotherapeutic interventions. A number of profound
immunologic deficiencies affecting both the B
and T-cell responses, however, have posed a challenge to immune therapy of CLL.
The laboratory has co-developed and
adapted the use of herpes simplex virus (HSV)
amplicons for gene transduction of CLL cells.
Using CD40L as an effector molecule, they have
shown robust induction of co-stimulatory molecules on transduced and bystander cells and in
roughly one-third of tested patients demonstrated
the capacity to generate cytotoxic T lymphocytes
(CTL) activity. This capacity to elicit autologous
CTL response, however, was not universal as
more than half the patients tested failed to mount
61
CLINICAL ONCOLOGY RESEARCH PROGRAM
such a response despite adequate up-regulation
of costimulatory signal on both transduced and
bystander CLL cells. In addition to being a
highly efficient gene transfer vector, herpes simplex virus (HSV)-based amplicons possess the
capacity to engage and activate different elements
of the innate immune system. Currently, the
laboratory is studying various aspects of HSV
amplicon/innate immune interaction and how
this might influence the outcome of an adaptive
anti-tumor immune response.
Immune therapeutic strategies targeting the
innate immune system might offer an alternative
pathway to bypass inherent CD8+ T-cell defects,
and effectively mount a systemic anti-tumor immune response. Dr. Tolba and his colleagues are
currently exploring how HSV amplicon interacts
with the family of toll-like (TL) receptors and
up-regulates NKG2D ligands on target cells.
SELECTED PUBLICATIONS
2002
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD.
Herpes simplex virus (HSV)-amplicon-mediated
delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia.
Molecular Therapy 6:455-63, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented antitumor activity. Cancer Research 62:6545-51,
2002.
Rosenblatt, JD, Shin, SU, Nechustan, H, Yi,
KH, and Tolba, KA. Potential role of
chemokines in immune therapy of cancer. Israel
Medical Association Journal 4:1054-59, 2002.
62
VLADIMIR VINCEK, M.D., PH.D.
Associate Professor of Pathology
DESCRIPTION OF RESEARCH
P
rogress in the understanding of molecular
events involved in the development and progression of human disease is revolutionizing the
way diseases are diagnosed and treated. Physicians
and scientists now are harnessing the power of
molecular techniques to diagnose and prognosticate pathologic disorders. Furthermore, it is now
possible to direct therapeutic agents to specific
products expressed by diseased cells without affecting normal tissues. On the other hand, while
standard histopathologic methods maintain tissue
architecture for morphologic assessment, they do
not preserve macromolecules. The extraction of
nucleic acids from formaldehyde-fixed, paraffinembedded tissue, the most widely available material for clinical studies, is a notoriously unreliable
and irreproducible process. Therefore, macromolecules usually are extracted from fresh or snapfrozen tissue specimens. Fresh or frozen tissue
specimens, however, are of limited value for the
assessment of histomorphology and cannot be
utilized for long-term retrospective studies. Similarly, currently available tissue preservatives that
protect nucleic acids cause considerable damage
to the cell and tissue architecture and render
them unsuitable for histomorphologic evaluation.
Current studies in this laboratory show that
it is feasible to simultaneously protect histomorphology and the integrity of macromolecules in
fixed and processed tissue. The UMFIX reagent,
developed in collaboration with other members
of the Department of Pathology, seems to provide
enormous advantage over the conventional fixation methods in allowing diagnosis, prognostication, and identification of treatment targets in
patient samples.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
CLINICAL ONCOLOGY RESEARCH PROGRAM
SELECTED PUBLICATIONS
2002
Malek, TR, Yu, A, Vincek, V, Scibelli, P, and
Kong, L. CD4 regulatory T cells prevent lethal
autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2.
Immunity 17:167-78, 2002.
Morales, A, Essenfeld, H, Dubane, C, Vincek, V,
and Nadji, M. Continuous-specimen-flow, highthroughput, 1-hour tissue processing. Archives of
Pathology & Laboratory Medicine 126:584-90,
2002.
2003
Vincek, V, Knowles, J, and Nassiri, M. p63
mRNA expression in normal human tissue. Anticancer Research 23:3945-48, 2003.
Vincek, V, Nassiri, M, Knowles, J, Nadji, M, and
Morales, AR. Preservation of tissue RNA in normal saline. Laboratory Investigation 83:137-38,
2003.
Adkins, B, Bu, Y, Vincek, V, and Guevara, P.
The primary responses of murine neonatal lymph
node CD4+ cells are Th2-skewed and are sufficient for the development of Th2-biased memory.
Clinical & Developmental Immunology 10:4351, 2003.
Vincek, V, Nassiri, M, Nadji, M., and Morales,
AR. A novel tissue preservative that protects macromolecules (DNA, RNA, protein) and
histomorphology in clinical samples. Laboratory
Investigation 83:1-9, 2003.
Jacob, SE, Berman, B, Nassiri, M, and Vincek, V.
Topical application of imiquimod 5% cream to
keloids alters expression genes associated with
apoptosis. British Journal of Dermatology 149:14, 2003.
HIGHLIGHTS/DISCOVERIES
• Patent pending for alcohol-based UMFIX preservative that preserves histomorphology and
macromolecules.
Jacob, SE, Nassiri, M, Kerdel, FA, and Vincek, V.
Rapid measurement of multiple cytokines in psoriasis patients and correlation with disease severity. Mediators of Inflammation 12:309-13, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
63
CLINICAL ONCOLOGY RESEARCH PROGRAM
64
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
TUMOR CELL BIOLOGY PROGRAM
PROGRAM LEADER
Kermit L. Carraway, Ph.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF PROGRAM
T
he Tumor Cell Biology Program currently
comprises 28 faculty members in 11 different departments at the University of Miami
School of Medicine. Faculty members are chosen
based on the potential of their research to contribute to important aspects in the understanding
of cancer cell biology. Faculty members must have
peer-reviewed cancer related research funding in
a field aligned with the scientific goals of the program or be newly recruited faculty investigators.
GOALS OF PROGRAM
The overall goal of the Tumor Cell Biology Program is to develop knowledge in the area of cell
biology that can be applied to translational research on neoplastic disease. The focus of the individual studies varies widely, from gene therapy
to the ultrastructural analyses of protein; however, all investigators are involved in cutting-edge
research using the developing methods of molecular biology and cell structural analysis to ask
questions important to tumor cell biology.
The specific aims of the program are to:
1) Understand how genetic information is maintained, transferred, and translated into functional cell proteins, a fundamental issue
throughout the history of cancer research.
2) Determine how tumor cells interact with other
cells and their environment, particularly the
molecular species and associations that favor or
disfavor those interactions. This issue is critically important for understanding metastasis
of tumors, the process that usually determines
mortality of cancer patients.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
3) Determine how signaling pathways and
molecules transmit and integrate information,
which determines cell fate, including cell structure and function. Included in such analyses are
the mechanisms by which the molecular components of signaling and metabolic pathways
are localized in cells to perform their particular
roles.
All of these questions and approaches are important to understanding how tumor cells behave
and determining whether specific tumor cell
behaviors can be exploited in combating cancer.
Developing such translational applications is the
ultimate goal of the Tumor Cell Biology
Program.
PARTICIPANTS
Burnstein, Kerry L., Ph.D.
Molecular and Cellular Pharmacology
Carraway, Kermit L., Ph.D.
Cell Biology and Anatomy
Deutscher, Murray P., Ph.D.
Biochemistry and Molecular Biology
D’Urso, Gennaro, Ph.D.
Molecular and Cellular Pharmacology
Fletcher, Terace M., Ph.D.
Biochemistry and Molecular Biology
Franzmann, Elizabeth J., M.D.
Otolaryngology
Han, Zhiyong, Ph.D.
Biology
Harris, Thomas K., Ph.D.
Biochemistry and Molecular Biology
King, Mary Lou, Ph.D.
Cell Biology and Anatomy
65
TUMOR CELL BIOLOGY PROGRAM
Lampidis, Theodore J., Ph.D.
Cell Biology and Anatomy
Li, Jie, M.D., Ph.D.
Dermatology and Cutaneous Surgery
Liu, Chia-Yang, Ph.D.
Ophthalmology
Lokeshwar, Balakrishna L., Ph.D.
Urology
Lokeshwar, Vinata B., Ph.D.
Urology
Malhotra, Arun, Ph.D.
Biochemistry and Molecular Biology
Mayeda, Akila, Ph.D.
Biochemistry and Molecular Biology
Moraes, Carlos T., Ph.D.
Neurology
Perez, Aymee, Ph.D.
Cell Biology and Anatomy
Salas, Pedro J. I., M.D., Ph.D.
Cell Biology and Anatomy
Shonukan, Oluwatoyin, M.D.
Medicine
Singal, Rakesh, M.D.
Medicine
Slingerland, Joyce M., M.D., Ph.D., F.P.R.C. (C)
Medicine
Verde, Fulvia, Ph.D.
Molecular and Cellular Pharmacology
Weed, Donald T., M.D., F.A.C.S.
Otolaryngology
Welsh, Catherine F., M.D.
Medicine
Werner, Rudolf K., Ph.D.
Biochemistry and Molecular Biology
Wyche, James, Ph.D.
Biology
Zimmers, Teresa A., Ph.D.
Surgery
66
HIGHLIGHTS/DISCOVERIES
• MUC4 expression potentiates the phosphorylation/activation of the ErbB2 and ErbB3 tyrosine kinase receptors induced by neuregulin,
providing a mechanism by which MUC4 may
contribute to tumor progression through
changes in cell signaling pathways (K. Carraway).
• MUC4 in mammary gland is regulated at the
post-transcriptional level by extracellular matrix
(basement membrane) and by transforming
growth factor-beta. Responses to both of these
are known to change during breast cancer progression (K. Carraway).
• MUC4 overexpression increases primary tumor
growth in nude mice, acting as an antiapoptotic agent in the growing tumors and in
cell culture (K. Carraway).
• MUC4 regulates the localization of the receptor
tyrosine kinase ErbB2 in polarized epithelial
cells (K. Carraway).
• Vitamin D inhibits the cell cycle by promoting
nuclear exclusion of cyclin dependent kinase 2,
opening new avenues for prostate cancer
therapy. Regulation of cdk2 localization represents a new regulatory paradigm in G1 to Sphase progression (K. Burnstein).
• Pol ε is required for initiation of DNA replication, suggesting that it provides multiple functions in promoting DNA replication, one of
which is to facilitate assembly of the DNA replication initiation complex (G. D’Urso).
• Discovery of a new endoribonuclease, RNase G
(M. Deutscher).
• Oligoribonuclease is an essential component of
mRNA degradation (M. Deutscher).
• Development of an efficient, cell-free translation system for mammalian cells (M.
Deutscher).
• Discovery of CD44v3-containing isoforms in
head and neck squamous cell tumor tissues and
cell lines (E. Franzmann).
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
• Development of a novel thermodynamically
balanced inside-out method of polymerase
chain reaction (PCR)-based synthesis to generate codon-optimized human kinase genes
(T. Harris).
• VegT, a T-box transcription factor, is essential
for three important steps in development (M.
L. King).
• Glycolytic inhibitors can be used to specifically
target the hypoxic slow-growing cells of solid
tumors and thereby increase the efficacy of current chemotherapeutic and irradiation protocols
designed to kill rapidly dividing cells (T.
Lampidis).
• In osteosarcoma, the addition of the glycolytic
inhibitor 2-Deoxyglucose (2-DG) increases the
efficacy of Adriamycin in reducing tumor size
and prolonging survival (T. Lampidis).
• In non-small cell lung cancer, the addition of 2DG increases the effectiveness of taxol (T.
Lampidis).
• Microvascular endothelial cells produce two
extracellular matrix proteins, laminin-8 and
laminin-10, which play important roles in tumor angiogenesis (J. Li).
• Discovery of an imbalance between the levels of
matrix metalloproteinases (MMPs) (overproduction) and their natural inhibitors (underproduction) in invasive prostate cancer cells (B.
Lokeshwar).
• Identification of a novel chemically modified
non-antimicrobial tetracycline (COL-3) as an
effective anti-metastatic drug with the potential
to treat prostate cancer metastatic to bone;
completion of NCI phase I trial of this drug (B.
Lokeshwar).
• Development of the HA-HAase urine test, a
non-invasive test that is about 90 percent accurate in detecting bladder cancer and monitoring
its recurrence (V. Lokeshwar).
• Development of HA and HAase tests that are
greater than 85 percent accurate prognostic
indicators for prostate cancer (V. Lokeshwar).
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Demonstration of the function of tumor-derived HAase in bladder tumor growth and
muscle invasion (V. Lokeshwar).
• Splicing activator RNPS1 is incorporated in the
early splicing complex, stimulating formation of
the ATP-dependent splicing complex, and subsequently increasing generation of both intermediate and final spliced products (A. Mayeda).
• Cells with defective mitochondrial respiration
can be more resistant to cell death, which might
explain the presence of mtDNA mutations in
some cancers (C. Moraes).
• Mitochondrial defects stimulate the production
of metalloproteases, which in turn promotes
tissue invasion (C. Moraes).
• Up-regulation of ErbB2 ligand Muc4 expression correlates with the overexpression of transcription factor PEA3 and the receptor tyrosine
kinase ErbB2 (A. Perez).
• Observation of the attachment of centrosomes
to intermediate filaments (P. Salas).
• Nerve growth factor (NGF) mediates the invasiveness of melanoma cells in vitro by inducing
the coupling of the intracellular domain of the
p75 neurotrophin receptor with the actin cytoskeleton (O. Shonukan).
• Neurotrophin-induced melanoma invasiveness
is mediated by signals generated through PI-3
kinase (O. Shonukan).
• NGF induces the disruption of cadherin-mediated cell-cell adhesion, thereby permitting melanoma cells to dissociate from the keratinocytes
in the epidermis, and invade the dermis, from
whence they metastasize to distant sites (O.
Shonukan).
• Aberrant p27 in breast cancer cells causes them
to be unable to respond to antiestrogen therapies such as Tamoxifen (J. Slingerland).
• Activation of the Src pathway is linked with
both the lack of detectable estrogen receptor
(ER) and clinically aggressive behavior of breast
cancers (J. Slingerland).
67
TUMOR CELL BIOLOGY PROGRAM
• Discovery of estrogen regulation of the gap
junction protein connexin 43 via an internal
ribosome entry site for translation (R. Werner).
• Discovery of the requirement for Rho family
GTPases for key adhesion-dependent G1
events, including cyclin D1 expression, Rb
phosphorylation, and cyclin A expression (C.
Welsh).
KERRY L. BURNSTEIN, PH.D.
Professor of Molecular and Cellular
Pharmacology
DESCRIPTION OF RESEARCH
D
r. Burnstein’s research focuses on signaling
mechanisms that govern prostate cancer cell
cycle and androgen responsiveness. Vitamin D is
of particular interest, stemming from epidemiological data showing a relationship between vitamin D deficiency and increased risk of prostate
cancer mortality. It has been shown that vitamin
D inhibits the growth of prostate cancer cell lines
and primary cell cultures derived from human
prostate tumors. Researchers in Dr. Burnstein’s
laboratory found that the mechanism underlying
such growth arrest is a vitamin D-induced cellular accumulation in the initial phase of the cell
cycle, G1. They demonstrated that vitamin Dmediated antiproliferative effects are not dependent on androgen/AR. This finding is of clinical
relevance, as a requirement for androgen would
severely limit use of vitamin D in advanced prostate cancer, which is customarily treated by androgen ablation. Furthermore, Dr. Burnstein’s
laboratory showed that vitamin D causes upregulation of specific and potent cell cycle inhibitors, p21 and p27, a finding that has potentially
important therapeutic implications. Her laboratory recently made the novel discovery that vitamin D mediates the nuclear exclusion of cyclin
dependent kinase (cdk)-2, thereby decreasing its
activity and promoting p27 stability. Current efforts are directed at understanding vitamin D
regulation of cdk-2 nucleocytoplasmic trafficking.
68
A finding that emerged from the studies on
vitamin D was that the most highly malignant
prostate cancer cell lines expressed very low levels
of cdk inhibitors. Subsequent studies on human
prostate cancer biopsies confirmed this observation. Because of these findings and the fact that
the genes encoding these inhibitors are rarely mutated, Dr. Burnstein decided to investigate possible intracellular signaling alterations that might
suppress levels of these inhibitory proteins and
contribute to uncontrolled cell proliferation. In
collaboration with Catherine F. Welsh, M.D., she
made the novel observation that Rac1, a Ras-related Rho GTPase (small G protein), exhibits
high activity in the more malignant prostate
cancer cells. Specific inhibition of Rac1 in these
cells results in increased levels of the cdk inhibitor
p21 and decreased proliferation. These findings
are unique in describing a role for Rac1 in the
regulation of p21 and implicate the Rac1 signaling pathway as a therapeutic target. Recently, researchers found that a protein that activates Rac1
also enhances the transcriptional activity
of the androgen receptor (AR). This observation
provides a tantalizing link between two critical
signaling pathways in prostate cancer and suggests a plausible mechanism for AR activity
during progression to androgen independence.
SELECTED PUBLICATIONS
2002
Yang, ES, Maiorino, CA, Roos, BA, Knight, SR,
and Burnstein, KL . Vitamin D-mediated growth
inhibition of an androgen-ablated LNCaP cell
line model of human prostate cancer. Molecular
and Cellular Endocrinology 186:69-79, 2002.
Whitlatch, LW, Young, MV, Schwartz, GG,
Flanagan, JN, Burnstein, KL , Lokeshwar, BL,
Rich, ES, Holick, MF, and Chen, TC. 25Hydroxyvitamin D-1alpha-hydroxylase activity is
diminished in human prostate cancer cells and is
enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
2003
Kizu, R, Okamura, K, Toriba, A, Kakishima, H,
Mizokami, A, Burnstein, KL , and Hayakawa, K.
A role of aryl hydrocarbon receptor in the
antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma
cells. Archives of Toxicology 77:335-43, 2003.
Yang, E and Burnstein, KL . Vitamin D inhibits
G1 to S progression in LNCaP prostate cancer
cells through p27Kip1 stabilization and Cdk2
mislocalization to the cytoplasm. Journal of Biological Chemistry 278:46862-68, 2003.
Chen, TC, Holick, MF, Lokeshwar, BL,
Burnstein, KL , and Schwartz, GG. Evaluation of
vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research
164:273-88, 2003.
Kizu, R, Okamura, K, Toriba, A, Mizokami, A,
Burnstein, KL , Klinge, CM, and Hayakawa, K.
Antiandrogenic activities of diesel exhaust particle
extracts in PC3/AR human prostate carcinoma
cells. Toxicology Sciences 76:299-309, 2003.
HIGHLIGHTS/DISCOVERIES
• Vitamin D inhibits the cell cycle by promoting
nuclear exclusion of cdk-2, which opens up new
avenues for prostate cancer therapy. Further,
regulation of cdk-2 localization represents a
new regulatory paradigm in G1 to S phase
progression.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
KERMIT L. CARRAWAY, PH.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
F
or much of the past decade, Dr. Carraway’s
primary research effort has been to examine
the role of cell surface glycoproteins in mammary
cancer, focusing on a particular glycoprotein
complex (sialomucin complex, MUC4, rat
Muc4) that his laboratory discovered about 20
years ago. This complex has both mucin- and
growth factor-containing subunits. This putative
bi-functionality can potentially contribute to two
of the major attributes of cancer cells, loss of adhesiveness, and autonomous growth. Consistent
with both of those activities, MUC4 has been
implicated in tumor metastasis. The anti-adhesive
function of MUC4 allows it to block tumor cell
killing by lymphokine-activated killer (LAK)
cells, a mechanism that permits the MUC4-overexpressing tumor cells to escape immune surveillance. One of the two growth factor domains of
the transmembrane subunit of MUC4 has been
shown to act as an intramembrane ligand for the
class I tyrosine kinase growth factor receptor
ErbB2/HER2/Neu. Binding of MUC4 as a
ligand to ErbB2 potentiates tyrosine phosphorylation of the receptor and its co-receptor ErbB3,
when the latter is stimulated with its soluble
ligand Neuregulin.
Researchers in Dr. Carraway’s laboratory are
currently investigating the effects of this receptor
modulation on downstream signaling pathways
and cellular functions. Recently, they have found
that induction of MUC4 overexpression in a
melanoma tumor cell model potentiates both primary tumor growth and metastasis when the tumors are injected into nude mice. The former is
correlated with a reduction in apoptosis in the
MUC4-overexpressing animals. One important
question is whether the anti-apoptotic effects of
MUC4 result from its growth factor domains or
other features of its structure. Recent results have
shown that MUC4 can regulate both the phosphorylation and location of ErbB2 in polarized
69
TUMOR CELL BIOLOGY PROGRAM
epithelial cells, providing two mechanisms by
which it can regulate signaling. Since MUC4 has
been implicated in breast cancer progression, it is
of interest to know how it is regulated in the
mammary gland. Investigations of primary mammary epithelial cells indicate a major role for
post-transcriptional regulation. Interactions with
the extracellular matrix regulate MUC4 expression at the translational level, while transforming
growth factor-beta (TGF-β) regulates it at the
post-translational level. Both of these types of
regulation are lost in rat mammary tumor cells,
and both are known to change during human
breast cancer progression. These and other results
suggest that MUC4 acts as a “tumor progressor”
gene rather than a primary oncogene. Thus,
MUC4 might serve as a future target for prognosis and therapies in breast cancer.
SELECTED PUBLICATIONS
2002
Carraway, KL , Perez, A, Idris, N, Jepson, S,
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,
SA, Zhang, J, and Carraway, CA. Muc4/
sialomucin complex, the intramembrane ErbB2
ligand, in cancer and epithelia: to protect and to
survive. Progress in Nucleic Acid Research in Molecular Biology 71:149-85, 2002.
Swan, JS, Arango, ME, Carothers Carraway, CA,
and Carraway, KL . An ErbB2-Muc4 complex in
rat ocular surface epithelia. Current Eye Research
24:397-402, 2002.
Jepson, S, Komatsu, M, Haq, B, Arango, ME,
Huang, D, Carraway, CA, and Carraway, KL .
Muc4/sialomucin complex, the intramembrane
ErbB2 ligand, induces specific phosphorylation
of ErbB2 and enhances expression of p27 (kip),
but does not activate mitogen-activated kinase or
protein kinase B/Akt pathways. Oncogene
21:7524-32, 2002.
Komatsu, M, Arango, ME, and Carraway, KL .
Synthesis and secretion of Muc4/sialomucin
complex: implication of intracellular proteolysis.
Biochemical Journal 368:41-48, 2002.
70
2003
Ramsauer, VP, Carothers Carraway, CA, Salas, PJ,
and Carraway, KL . Muc4/Sialomucin complex,
the intramembrane ErbB2 ligand, translocates
ErbB2 to the apical surface in polarized Epithelial
cells. Journal of Biological Chemistry 278:3014247, 2003.
Carraway, KL , Ramsauer, VP, Haq, B, and
Carothers Carraway, CA. Cell signaling through
membrane mucins. BioEssays 25:66-71, 2003.
Fischer, BM, Cuellar, JG, Diehl, ML, deFreytas,
AM, Zhang, J, Carraway, KL , and Voynow, JA.
Neutrophil elastase increases MUC4 expression
in normal human bronchial epithelial cells.
American Journal of Physiology. Lung Cellular
and Molecular Physiology 284:L671-79, 2003.
Hu, YP, Haq, B, Carraway, KL , Savaraj, N, and
Lampidis, TJ. Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
Soto, P, Price-Schiavi, SA, and Carraway, KL .
SMAD2 and SMAD7 involvement in the posttranslational regulation of Muc4 via the transforming growth factor-beta and interferon-gamma
pathways in rat mammary epithelial cells. Journal
of Biological Chemistry 278:20338-44, 2003.
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,
SA, and Carraway, KL . PEA3 transactivates the
Muc4/sialomucin complex promoter in mammary epithelial and tumor cells. Journal of Biological Chemistry 278(38):36942-52, 2003.
HIGHLIGHTS/DISCOVERIES
• MUC4 expression potentiates the phosphorylation/activation of the ErbB2 and ErbB3 tyrosine kinase receptors induced by neuregulin,
providing a mechanism by which MUC4 may
contribute to tumor progression through
changes in cell signaling pathways.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
• MUC4 in the mammary gland is regulated at
the post-transcriptional level by extracellular
matrix (basement membrane) and by TGF-β.
Responses to both of these are known to change
during breast cancer progression.
• MUC4 regulation in the uterus during pregnancy is at the transcript level, indicating the
complexity of the control of its gene.
• MUC4 overexpression increases primary tumor
growth in nude mice, acting as an antiapoptotic agent in the growing tumors and in
cell culture.
• MUC4 regulates the localization of the receptor
tyrosine kinase ErbB2 in polarized epithelial
cells.
MURRAY P. DEUTSCHER, PH.D.
Professor and Chairman of Biochemistry
and Molecular Biology
DESCRIPTION OF RESEARCH
R
esearchers in Dr. Deutscher’s laboratory
focus on two major areas of research. One
deals with the identification, characterization,
and determination of the physiological role of
RNA processing and degradative enzymes. To
date, eight exoribonucleases and seven endo-ribonucleases have been identified in Escheichia coli.
Many of the enzymes have been purified and
studied for their catalytic properties. Mutations
have been constructed in the genes for each of
these enzymes, and the genes have been cloned
and their sequences identified. Several of these
enzymes have now been shown to participate in
transfer RNA and ribosomal RNA maturation,
and in messenger RNA degradation. The availability of the purified enzymes and of mutants
lacking these RNases is being used to elucidate
complete RNA maturation pathways and to
study the regulation of these processes. In addition, his studies have shown that cells contain
RNA quality control mechanisms for eliminating
defective RNA molecules.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
The second area of investigation deals with
the translation system of mammalian cells. Protein synthesis in mammalian cells proceeds as
much as 100-fold faster than synthesis in isolated
cell-free systems. What is lost in these in vitro
systems is the organization that normally exists in
vivo. They have shown that many of the components of the translation apparatus are associated
with each other, and that protein synthesis is a
“channeled” pathway, i.e., the aminoacyl-tRNA
and peptidyl-tRNA intermediates are directly
transferred from one component of the translation apparatus to the next without dissociation
into the cellular fluid. A permeabilized mammalian cell system has been developed that allows
study of these events in close to an in vivo situation. Studies are in progress to determine the role
of the actin cytoskeleton in maintaining the organization of the translation system and to identify
other factors associated with the translation apparatus that affect its function. Dr. Deutscher’s
laboratory has taken this work further to show
that the whole mammalian cell is highly organized
and that macromolecules don’t diffuse, but move
in motor-driven processes on the cytoskeleton.
SELECTED PUBLICATIONS
2002
Li, Z and Deutscher, MP . RNase E plays an essential role in the maturation of Escherichia coli
tRNA precursors. RNA 8:97-109, 2002.
Li, Z, Reimers, S, Pandit, S, and Deutscher, MP .
RNA quality control: degradation of defective
transfer RNA. EMBO Journal 21:1132-38, 2002.
Cheng, ZF and Deutscher, MP . Purification and
characterization of the Escherichia coli
exoribonuclease RNase R. Comparison with
RNase II. Journal of Biological Chemistry
277:21624-29, 2002.
Zuo, Y and Deutscher, MP . The physiological
role of RNase T can be explained by its unusual
substrate specificity. Journal of Biological Chemistry 277:29654-61, 2002.
71
TUMOR CELL BIOLOGY PROGRAM
Zuo, Y and Deutscher, MP . Mechanism of action
of RNase T. I. Identification of residues required
for catalysis, substrate binding, and dimerization.
Journal of Biological Chemistry 277:50155-59,
2002.
Zuo, Y and Deutscher, MP . Mechanism of action
of RNase T. II. A structural and functional model
of the enzyme. Journal of Biological Chemistry
277:50160-64, 2002.
2003
Nathanson, L, Xia, T, and Deutscher, MP .
Nuclear protein synthesis: a re-evaluation. RNA
9:9-13, 2003.
Cheng, ZF and Deutscher, MP . Quality control of
ribosomal RNA mediated by polynucleotide phosphorylase and RNase R. Proceedings of the National Academy of Sciences of the United States of
America 100:6388-93, 2003.
Deutscher, MP . Degradation of stable RNA in
bacteria. Journal of Biological Chemistry
278:45041-44, 2003.
Hudder, A, Nathanson, L, and Deutscher, MP .
Organization of mammalian cytoplasm. Molecular and Cellular Biology 23:9318-26, 2003.
HIGHLIGHTS/DISCOVERIES
• Discovery of a new endoribonuclease, which
has been called RNase G. This enzyme was
shown to be essential for the maturation of the
5’ terminus of E. coli 16S ribosomal RNA as
part of a two-step process that also requires a
second endoribonuclease, RNase E. Researchers
have also identified RNase T as the enzyme that
matures the 3’ terminus of 23S ribosomal
RNA. Degradation of messenger RNA also was
studied. They found that the enzyme
oligoribonuclease is an essential component of
this process, and that in its absence, small
oligoribonucleotides derived from mRNA accumulate. They also have introduced the concept
of quality control of stable RNA molecules.
72
• Development of an efficient, cell-free translation system that synthesizes protein at about 30
percent of the in vivo rate. This compares with
the one to two percent generally obtained in
other systems. Development of this system depended on stabilization of the actin cytoskeleton during cell disruption. In a second study,
they found that aminoacyl-tRNA synthetases
are present in an active form in mammalian cell
nuclei, and that these enzymes exist as part of a
multi-enzyme complex that is analogous to, but
more stable than, the cytoplasmic complex.
Moreover, Dr. Deutscher’s laboratory has made
the important discovery that mammalian cells
are highly organized and behave like macromolecular assemblies.
GENNARO D’URSO, PH.D.
Assistant Professor of Molecular and
Cellular Pharmacology
DESCRIPTION OF RESEARCH
U
nderstanding the molecular mechanisms that
control the initiation of DNA replication in
eukaryotic cells is Dr. D’Urso’s main research interest. Researchers in his laboratory also are
studying the checkpoint controls that prevent
mitosis in the absence of a complete round of
DNA synthesis or in response to DNA damage.
Using the fission yeast Schizosaccharomyces pombe
as a model system, they have identified genes that
are required for DNA replication initiation. Most
of the laboratory’s work has focused on the characterization of the genes encoding the catalytic
subunit of DNA polymerase epsilon (Pol ε) and
its associated subunits. Cells defective for Pol ε
arrest at the G1/S boundary, indicating that this
enzyme plays a critical role in the initiation step.
Interestingly, the polymerization activity of this
enzyme is not essential for cell viability, suggesting that Pol ε may have other roles, perhaps in
the assembly of the replicative complex, that are
not necessarily dependent on its ability to synthesize DNA. Studies in this laboratory on Pol ε
have led to the discovery of a checkpoint control
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
that is activated in response to defects in DNA
replication initiation. The laboratory currently is
continuing efforts to identify proteins that are
involved in the early steps of DNA synthesis and
how these proteins may be involved in the activation of a checkpoint pathway that prevents premature entry into mitosis.
SELECTED PUBLICATIONS
2003
Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F.
Control of cell polarity in fission yeast by association of Orb6p kinase with the highly conserved
protein methyltransferase Skb1p. Journal of Biological Chemistry 278:25256-63, 2003.
Feng, W, Rodriguez-Menocal, L, Tolun, G, and
D’Urso, G. Schizosacchromyces pombe Dpb2
binds to origin DNA early in S phase and is
required for chromosomal DNA replication.
Molecular Biology of the Cell 14:3427-36, 2003.
Burhans, WC, Weinberger, J, Marchetti, MA,
Ramachandran, L, D’Urso, G, and Huberman, J.
Apoptosis-like yeast cell death in response to
DNA damage and replication defects. Mutation
Research 532:227-43, 2003.
HIGHLIGHTS/DISCOVERIES
• Pol ε is required for initiation of DNA replication. These results were particularly important
because Pol ε had earlier been shown to be nonessential for SV40 viral DNA replication, an
extensively used model system of eukaryotic
DNA replication.
• Loss of the catalytic domains of this enzyme
had no effect on cell viability in yeast.
• These findings and observations led to an understanding of the role of Pol ε in DNA replication, and suggested that Pol ε provides multiple
functions in promoting DNA replication. Recent data from this laboratory suggest that at
least one of these functions is to facilitate assembly of the DNA replication initiation complex.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TERACE M. FLETCHER, PH.D.
Assistant Professor of Biochemistry
and Molecular Biology
DESCRIPTION OF RESEARCH
Dr. Fletcher’s research interests focus on chromatin structure and steroid hormone regulation of
transcription, telomere chromatin structure and
genomic stability, telomerase biochemistry, and
mechanisms of inhibition.
The eukaryotic genome is organized into
complex DNA-protein macromolecular assemblies known as chromatin. Chromatin has both
an architectural and regulatory function in the
nucleus. Dr. Fletcher’s laboratory efforts are concentrated in two processes influenced by chromatin structure: telomere maintenance and
transcription.
Telomere Chromatin Structure
Telomeres, specialized nucleoprotein complexes
at the end of chromosomes, have a crucial role in
genomic stability. Disruption of telomere structure induces cell growth arrest or death. Cancer
cells, unlike most normal somatic cells, maintain
stable telomeres through the activation of the telomere-specific DNA polymerase, telomerase.
Dr. Fletcher is particularly interested in the
structural features of telomere higher-order assemblies and the mechanisms by which different
telomere configurations are formed. Possible influences on telomere structure are telomerase activity, telomere length, association of telomere
binding and DNA repair proteins, and DNA
structure.
To structurally and biochemically characterize telomere chromatin, Dr. Fletcher’s laboratory
is reconstituting model telomeres in vitro. They
use these model telomeres to determine recruitment of telomere binding and DNA repair proteins under certain conditions. They also are
interested in the effects of telomere structure on
functions such as telomerase activity and chromosome end protection.
73
TUMOR CELL BIOLOGY PROGRAM
Finally, researchers in her laboratory are investigating the biochemical and hydrodynamic
properties of telomere higher-order structures.
One hydrodynamic method they will focus on is
a unique agarose gel electrophoresis technique.
This technique allows the investigator to analyze
surface electrical charge density and solution
structure of large macromolecular DNA/protein
assemblies from either purified components or in
complex mixtures. Dr. Fletcher and her colleagues are applying this technique to study the
structure of native telomeres isolated from nuclei.
Chromatin Structure and Transcription
It is well established that the same promoter
sequence in different chromatin contexts has
diverse responses to cellular signals. The biochemical mechanisms by which nucleosomes, the
fundamental units of chromatin, exert their influence are under intense investigation. The role of
chromatin higher-order structures in transcriptional activation, however, is still largely unexplored. A goal of Dr. Fletcher’s research is to
simultaneously analyze the structural characteristics of chromatin and transcriptional activation
under various reaction conditions.
Specifically, her laboratory is interested in
the reciprocal relationship between transcription
factors and their chromatin targets. Research efforts include reconstituting promoters and coding
regions into chromatin in vitro and analyzing
protein binding, chromatin remodeling, and
transcriptional activation. Dr. Fletcher and her
colleagues also are characterizing the solution
structure of these chromatin fibers, both reconstituted in vitro and isolated from cells.
74
SELECTED PUBLICATIONS
2002
Fletcher, TM , Xiao, N, Mautino, G, Baumann,
CT, Wolford, R, Warren, BS, and Hager, GL.
ATP-dependent mobilization of the glucocorticoid receptor during chromatin remodeling. Molecular and Cellular Biology 22:3255-63, 2002.
Lu, H, Pise-Masison, CA, Fletcher, TM , Schiltz,
RL, Nagaich, AK, Radonovich, M, Hager, G,
Cole, PA, and Brady, JN. Acetylation of nucleosomal histones by p300 facilitates transcription
from tax-responsive human T-cell leukemia virus
type 1 chromatin template. Molecular and Cellular Biology 22:4450-62, 2002.
Keeton, EK, Fletcher, TM, Baumann, CT,
Hager, GL, and Smith, CL. Glucocorticoid receptor domain requirements for chromatin remodeling and transcriptional activation of the
mouse mammary tumor virus promoter in different nucleoprotein contexts. Journal of Biological
Chemistry 277:28247-55, 2002.
2003
Georgel, PT, Fletcher, TM , Hager, GL, and
Hansen, JC. Formation of higher-order secondary and tertiary chromatin structures by genomic
mouse mammary tumor virus promoters. Genes
& Development 17:1617-29, 2003.
Fletcher, TM . Telomere higher-order structure
and genomic instability. IUBMB Life 55:443-49,
2003.
HIGHLIGHTS/DISCOVERIES
• Obtained patent for methods and compositions
for modulation and inhibition of telomerase.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
ELIZABETH J. FRANZMANN, M.D.
Assistant Professor of Otolaryngology
DESCRIPTION OF RESEARCH
D
r. Franzmann is interested in the molecular
mechanisms of head and neck squamous cell
cancer (HNSCC) progression. Despite rigorous
therapy using various combinations of surgery,
radiation, and chemotherapy, successful treatment of head and neck cancer only occurs 50
percent of the time. Because of the complexity of
the head and neck, current therapy often results
in facial disfigurement, speech and swallowing
problems, and substantial health care costs.
Screening and staging methods for HNSCC also
are deficient.
To better understand the molecular mechanisms that lead to HNSCC, Dr. Franzmann’s
laboratory is investigating the CD44 family of
alternatively spliced isoforms. Some CD44
isoforms are found normally in cells. Other
isoforms termed CD44 variant (CD44v) isoforms
are found in tumor tissues and are associated with
poor prognosis. There is particular interest in the
CD44v3-containing isoforms since these
isoforms contain a growth factor binding site.
Preliminary work suggests that CD44v3-containing isoforms are differentially expressed in
HNSCC tumors and normal tissue and may be
involved in tumor cell growth. Using reverse
transcriptase-polymerase chain reaction (RTPCR), southern blot, cloning, and sequencing,
the laboratory is defining CD44v3-containing
isoform expression in head and neck tumor and
normal tissues. The laboratory will perform immunohistochemical staining to characterize
CD44v3 expression at the protein level. Transfection studies will be used to investigate the mechanisms by which these isoforms alter HNSCC cell
behavior. In addition to identifying HNSCC in
the early stage when treatment is much more effective, Dr. Franzmann’s laboratory is evaluating
whether a salivary CD44 ELISA test is a useful
screening tool for HNSCC.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SELECTED PUBLICATIONS
2003
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45, 2003.
HIGHLIGHTS/DISCOVERIES
• CD44v3-containing isoforms are found in
HNSCC tumor tissues and cell lines using RTPCR. CD44v3 and CD44v3-10 have been
cloned and sequenced from HNSCC cell lines.
• In a preliminary study including 26 patients
with HNSCC and ten normal controls, CD44
levels were significantly higher in HNSCC patient saliva compared to normal volunteer saliva.
ZHIYONG HAN, PH.D.
Assistant Professor of Biology
DESCRIPTION OF RESEARCH
D
r. Han’s research seeks to understand how
anti-cancer drugs induce apoptosis of cancer
cells. His recent work focuses on how the natural
product camptothecin (CPT) and its semi-synthetic derivatives such as CPT-11, 9-amino-CPT
(9AC), and 9-nitro-CPT (9NC) induce apoptosis
of human colon cancer cells.
CPT and its derivatives are considered important anti-cancer drugs. Many aspects of the
mechanism by which these drugs exert their
death effect on cancer cells, however, remain
largely unknown. In recent years, Dr. Han and
his colleagues have used a cell model of human
colon cancer to demonstrate that treatment with
low doses of CPT induces senescence in the presence of a protein called p21, but apoptosis in the
absence of p21. Therefore, p21 is a key determinant of the outcome of colon cancer cells treated
with CPT drugs at doses that are relevant to
clinical application. CPT treatment of colon cancer cells with p21 should result in disease stabili75
TUMOR CELL BIOLOGY PROGRAM
zation, whereas CPT treatment of p21-deficient
colon cancer cells should result in rapid apoptosis
and disease regression.
It is well established that p21 inhibits cyclindependent kinases (cdks) and several other factors
including proliferating cell nuclear antigen. Dr.
Han and his colleagues hypothesize that inhibition of cdks by p21 is essential to inhibit
apoptosis and induce senescence. In this context,
they propose that the protein, named E2F1, is
essential for apoptosis of colon cancer cells
treated with CPT. According to this hypothesis,
inhibition of cdks should result in activation of
another protein, named retinoblastoma (Rb),
which in turn, inhibits E2F1 and consequentially
E2F1-dependent apoptosis. They also hypothesize that the ability of p21 to induce senescence
requires a protein called STAT1. To test their hypothesis, they are currently using techniques to
selectively alter the status of a cdk, E2F1, Rb, and
STAT1 in human colon cancer cells. Subsequently, Dr. Han’s laboratory will investigate the
role of each protein in the process of apoptosis
and senescence in the colon cancer cells after
CPT treatment.
The information obtained from these investigations will provide better insight into the molecular pathways activated in colon cancer cells
after CPT treatment and eventually lead to specific experimental designs to completely understand how CPTs affect colon cancer.
SELECTED PUBLICATIONS
2002
Han, Z, Wei, W, Dunaway, S, Darnowski, JW,
Calabresi, P, Sedivy, J, Hendrickson, EA, Balan,
KV, Pantazis, P, and Wyche, JH. Role of p21 in
apoptosis and senescence of human colon cancer
cells treated with camptothecin. Journal of Biological Chemistry 277(19):17154-60, 2002.
2003
Hu, X, Han, Z, Wyche, JH, and Hendrickson,
EA. Helix 6 of tBid is necessary but not sufficient
for mitochondrial binding activity. Apoptosis
8:277-89, 2003.
76
Pantazis, P, Han, Z, Balan, K, Wang, Y,
and Wyche, JH. Camptothecin and 9nitrocamptothecin (9NC) and anti-cancer,
anti-HIV, and cell-differentiation agents.
Development of resistance, enhancement of
9NC-induced activities and combination treatments in cell and animal models. Anticancer
Research 23:3623-38, 2003.
Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche,
JH, Han, Z, and Pantazis, P. Differential susceptibility to 9-nitrocamptothecin (9-NC)-induced
apoptosis in clones derived from a human ovarian
cancer cell line: possible implications in the treatment of ovarian cancer patients with 9-NC. Anticancer Drugs 14:427-36, 2003.
THOMAS K. HARRIS, PH.D.
Assistant Professor of Biochemistry
and Molecular Biology
DESCRIPTION OF RESEARCH
D
r. Harris’ research seeks to understand the
structure and mechanism of both
phosphoinositide-dependent protein kinase
(PDK1) and protein kinase B (PKB/Akt), which
are important in maintaining the growth, survival, and proliferation of numerous types of cancer cells. PDK1 and PKB/Akt are pivotal
signaling enzymes and are activated by growthfactor binding events to receptor tyrosine kinases,
which activate phosphatidylinositol 3-kinase (PI3K)
and result in generation of the membrane-bound
second messenger phosphatidylinositol 3,4,5triphosphate. Activation of PDK1 and PKB/Akt
is facilitated by recruitment of each of these
proto-oncogenic enzymes to the membranebound second messenger, which binds the
pleckstrin homology (PH) domain present in
each of these kinases. The specific goals are to
1) determine the structural bases of specificity
for membrane targeting mediated by the PH
domains of human PDK1 and PKB/Akt, and
2) determine how binding of the PH domains to
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
the membrane-bound second messenger leads to
the catalytic activation of their respective kinase
domains.
A combination of high-resolution heteronuclear multidimensional nuclear magnetic resonance (NMR) methods, nuclear Overhauser
effects, and nuclear relaxation rates will be used
to determine the effects that Ins(1,3,4,5)P4 binding has on the solution structures and dynamics
of the bacterially expressed recombinant 15N- and
13
C-isotopically labeled PH domain constructs of
both human PDK1 and PKB/Akt. In addition,
the recombinant 15N-isotopically labeled PH domain constructs of both PDK1 and PKB/Akt will
be spliced with their corresponding bacterially
expressed recombinant unlabeled kinase domains
to determine the effects that Ins(1,3,4,5)P4 binding to the PH domain has on the conformations,
dynamics, and position of the PH domain with
respect to the corresponding kinase domain.
Finally, the modes of activation of PDK1
and PKB/Akt will be elucidated by measuring the
effects of Ins(1,3,4,5)P4 binding to the PH domains on the equilibrium and activation free energies associated with binding of nucleotide,
metal, or protein substrates, conformational
changes, and covalent catalysis. Such structural
and mechanistic understanding will be useful in
the rational design of potent and selective inhibitors by “linking” the free energies of binding of
substrate analogs with analogs of the inositol polar head group of the phospholipid second messenger.
SELECTED PUBLICATIONS
2002
Harris, TK and Turner, GJ. Structural basis of
perturbed pKa values of catalytic groups in enzyme active sites. IUBMB Life 53:85-98, 2002.
2003
Harris, TK . PDK1 and PKB/Akt: ideal targets
for development of new strategies to structurebased drug design. IUBMB Life 55:117-26,
2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Gao, X, Yo, P, Keith, A, Ragan, TJ, and Harris,
TK. Thermodynamically balanced inside-out
(TBIO) PCR-based gene synthesis: a novel
method of primer design for high-fidelity assembly of longer gene sequences. Nucleic Acids Research 31:e143, 2003.
HIGHLIGHTS/DISCOVERIES
• Designed and synthesized codon-optimized
genes and gene constructs for PDK1 and PKB/
Akt in order to optimize production of 15Nand 13C-isotopically labeled human PDK1 and
PKB/Akt necessary for NMR structural and
dynamical studies, which facilitate high-level
protein production in bacteria. Researchers developed a novel thermodynamically balanced
inside-out (TBIO) method of polymerase chain
reaction (PCR)-based synthesis to generate the
codon-optimized human kinase genes.
• Filed a U.S. Patent and Trademark Office provisional patent application for the TBIO method
on August 28, 2003.
MARY LOU KING, PH.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
D
r. King is trying to understand how spatial
patterning and cell fate is determined in the
early Xenopus embryo. Researchers in her laboratory and others in the field have shown that the
first step in patterning the embryo appears to be
the localization of specific mRNAs to the vegetal
cortex during oogenesis. These maternal mRNAs
are subsequently inherited by a subset of cells in
the embryo. Evidence indicates that the proteins
encoded by localized mRNAs influence gene expression in a region-specific manner, leading to
cellular diversification. They are actively pursuing
the mechanism through which the spatial distribution of mRNAs is established and maintained.
Dr. King’s laboratory has isolated seven localized mRNAs from Xenopus oocytes. Remarkably,
three RNAs, Xcat-2 (related to nanos), Xdazl (in
77
TUMOR CELL BIOLOGY PROGRAM
DAZ family), and DeadSouth (in vasa family), are
localized to germ plasm and are related to germ
cell components in Drosophila and humans. All
three of these RNAs encode RNA-binding proteins. The laboratory is interested in identifying
the downstream targets of these germ cell components and their function in development. Most
recently they have shown that interfering with
Xdazl function eliminates or depletes primordial
germ cells (PGCs) because these fail to migrate
out of the endoderm. Another mRNA, VegT, encodes a T-box transcription factor. Dr. King and
her colleagues have shown that maternal VegT is
required for germ layer (endoderm, mesoderm,
ectoderm) formation during gastrulation and specifically for endoderm identity. Experimental approaches used in these studies include the creation
of dominant negatives, antisense oligos, over-expression, ectopic expression, frog transgenics,
transgenics, reverse transcription-polymerase
chain reaction (RT-PCR), immunocytochemistry,
and in situ hybridization. A new gene, Xcat4, appears
to control the cell cycle in early development, as
over-expression of part of this protein completely
blocks G1/S transition.
Dr. King and her colleagues also have found
that VegT and the germ plasm mRNAs localize by
at least two different mechanisms and at different
times during oogenesis. They have determined
the RNA signal required for proper localization
of Xcat-2 and VegT and are currently working on
isolating the proteins that bind these localization
signals. Their long-term goal is to characterize all
seven genes as to their role in development as well
as to characterize the transport systems involved
in their localization.
SELECTED PUBLICATIONS
2002
Kloc, M, Dougherty, MT, Bilinski, S, Chan, AP,
Brey, E, King, ML, Patrick, CW Jr., and Etkin,
LD. Three-dimensional ultrastructural analysis of
RNA distribution within germinal granules of
Xenopus. Developmental Biology 241:79-93,
2002.
78
Bubunenko, M, Kress, TL, Vempati, UD,
Mowry, KL, and King, ML. A consensus RNA
signal that directs germ layer determinants to the
vegetal cortex of Xenopus oocytes. Developmental
Biology 248:82-92, 2002.
2003
Zhou, Y, Zhang, J, and King, ML. Xenopus
ARH couples lipoprotein receptors with the AP-2
complex in oocytes and embryos and is required
for vitellogenesis. Journal of Biological Chemistry
278:44584-92, 2003.
Bruce, AE, Howley, C, Zhou, Y, Vickers, SL, Silver, LM, King, ML, and Ho, RK. The maternally
expressed zebrafish T-box gene eomesodermin
regulates organizer formation. Development
130:5503-17, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated for the first time that a germ
plasm component is required for PGC specification in a vertebrate. PGC migration out of
the endoderm is a critical step in PGC differentiation and Xdazl is clearly involved. Dr. King
and her colleagues want to learn more about
this pathway and its requirements. They have
shown that in Xenopus, germ plasm RNAs are
under translational control and that most of
them encode RNA binding proteins.
• Observed that a single maternally expressed
gene, VegT, appears to control the patterning of
the Xenopus blastula. The laboratory’s studies on
maternal VegT, a T-box transcription factor,
have shown that it is essential for three important steps in development. VegT is required for
endoderm specification, the production, activation, or delivery of the mesoderm inducer, and
for maintaining the boundary between endoderm and mesoderm. Their results strongly suggest that the major mesoderm-inducing signal is
a post-transcriptional event in Xenopus.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
THEODORE J. LAMPIDIS, PH.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
D
r. Lampidis’ research has evolved from his
preliminary work on the physiology and
pharmacology of cultured cardiac cells. A video/
electronic-computerized system was developed to
monitor cardiac cell function in vitro. Using pulsating myocardial cells as a model, he focused on
why the widely used anti-tumor agent, Adriamycin, affected the hearts of patients treated with
this drug. This initial idea led Dr. Lampidis to
study drug selectivity between certain types of
tumor and normal cells and the chemical requirements of anti-cancer drugs for reduced cardiotoxicity and increased tumoricidal potency.
Dr. Lampidis’ efforts then turned toward
understanding the mechanisms of drug resistance
to mitochondrial agents such as rhodamine 123
and the structure/function requirements of various chemotherapeutic agents for recognition by
p-glycoprotein-mediated multiple drug resistance
(MDR). Molecular and immunochemical probes
of MDR and other cellular resistance mechanisms (i.e., multi-drug resistance-related protein
(MRP)), were developed in his laboratory to
detect and study these phenomena. He and his
colleagues found that chemical charge and
lipophilicity play critical roles in determining
whether anti-cancer drugs are recognized by tumor cells expressing these MDR mechanisms.
As an outcome of their studies on mitochondrial agents, the researchers realized that tumor
cells treated with the uncoupling agent, rhodamine
123, were strikingly similar to the poorly oxygenated cancer cells located at the inner core of solid
tumors. In both conditions, the cells rely exclusively on anaerobic metabolism for survival.
Moreover, cells in the center of a tumor divide
more slowly than outer-growing aerobic cells and
consequently are more resistant to standard chemotherapeutic agents, which target the more rapidly dividing cells. Thus, by the nature of their
slow growth, these tumor cells exhibit a form of
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
MDR, which contributes significantly to chemotherapy failures in the treatment of solid tumors.
Anaerobiosis, however, also provides a natural window of selectivity for agents that interfere
with glycolysis. This concept forms the basis for
Dr. Lampidis’ current initiative to exploit the
natural selectivity that inhibitors of glycolysis
should have for hypoxic cells that are slowly
growing at the inner core of solid tumors. His
background and work on mitochondrial localizing drugs and MDR uniquely position him to
stimulate new initiatives in his laboratory in this
promising area of research.
A long-term goal for Dr. Lampidis is the addition of the appropriate glycolytic inhibitors
(which are presently being designed and synthesized) to current clinical protocols, which may
significantly improve the success rate of cancer
chemotherapy. Moreover, studying how tumor
cells react to combinations of oxidative phosphorylation and glycolytic inhibitors could lead to
the design of future novel approaches to more
successfully treat cancer.
SELECTED PUBLICATIONS
2002
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .
Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:174551, 2002.
2003
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal of Oncology 23:173-9, 2003.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and
Lampidis, TJ . Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
79
TUMOR CELL BIOLOGY PROGRAM
HIGHLIGHTS/DISCOVERIES
• In osteosarcoma wild type (wt) cells treated
with agents that inhibit mitochondrial oxidative
phosphorylation (OXPHOS) by interacting
with complexes I, III, and V of the electron
transport chain in different ways—rhodamine
123 (Rho-123), rotenone, oligomycin, and antimycin A—all of the agents were found to hypersensitize wt cells to the glycolytic inhibitors
2-deoxyglucose (2-DG) and oxamate.
of a tumor), increases the efficacy of standard
chemotherapeutic agents (which target the rapidly growing aerobic cells) in reducing tumor
size and prolonging survival. In collaboration
with Threshold Pharmaceuticals, the NCI, and
UM/Sylvester, they have received FDA approval
and are now nearing the first human trials testing his strategy.
• In ρ0 cells that have lost their mitochondrial
DNA and therefore cannot undergo OXPHOS,
cells were found to be ten and 4.9 times more
sensitive to 2-DG and oxamate, respectively,
than wt cells.
JIE LI, M.D., PH.D.
Assistant Professor of Dermatology
and Cutaneous Surgery
• Lactic acid levels, which are a measure of
anaerobic metabolism, were found to be greater
than 3 times higher in ρ0 than in wt cells.
Moreover, when wt cells were treated with Rho123, lactic acid amounts increased as a function
of increasing Rho-123 doses. Under similar
Rho-123 treatment, ρ0 cells did not increase
their lactic aid levels. These data confirm these
different cell models are similarly sensitive to
glycolytic inhibitors due to their dependence on
anaerobic metabolism.
A
• These results suggest that inner core tumor cells
are more dependent on glycolysis than outer
growing aerobic cells, which provides a window
of selectivity that can be exploited for therapeutic gain. Thus, glycolytic inhibitors could be
used to specifically target the hypoxic slowgrowing cells of solid tumors and thereby increase the efficacy of current chemotherapeutic
and irradiation protocols designed to kill rapidly dividing cells. Moreover, glycolytic inhibitors could be particularly useful in combination
with anti-angiogenic and anti-hypoxic inducible factor (HIF) agents, which a priori, should
make tumors more anaerobic.
• Recently, Dr. Lampidis has provided proof of
principle in two animal models of human cancer (non-small cell lung and osteosarcoma ) that
the addition of the glycolytic inhibitor 2-DG
(which targets the slowly growing hypoxic cells
80
DESCRIPTION OF RESEARCH
mong the unanswered critical questions in
cancer research is the mechanism for new
blood vessel formation during tumor development, a process called tumor angiogenesis, which
is important for both tumor growth and metastasis. Angiogenesis is dependent on the production
and organization of the basement membrane
zone, a structure underlying endothelial cells in
blood vessels. Dr. Li’s current research focuses on
the role of extracellular matrix laminins of major
basement membrane components in tumor angiogenesis, invasion, and metastasis. The longterm goal of the study is to determine their
potential in tumor diagnosis/prognosis and
therapy.
Dr. Li’s laboratory uses cellular and molecular biological approaches to study the function of
laminins in the two most common and malignant human skin cancers: melanomas and squamous cell carcinomas (SCC). She and her
colleagues have found that microvascular endothelial cells produce two laminins, laminin-8 and
laminin-10. The laboratory has shown that
laminin-8 has strong effects on human endothelial cell attachment, migration, and capillary tubule formation. Importantly, they have identified
a high expression of laminin-10 in human melanomas while there is no expression of laminin-10
in benign nevi. Significantly higher expression of
laminin-10 also was detected in the basement
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
membranes of invasive SCC-masses and newly
formed tumor vasculature. Strikingly, the studies
demonstrated an incremental expression pattern
as tumors progress from pre-malignant skin lesions of actinic keratosis to malignant SCC. The
studies revealed a clear correlation between the
expression level of laminin-10 and tumor invasiveness, which indicates that laminin-10 plays
important roles in tumor angiogenesis and
invasion.
Dr. Li anticipates that her laboratory’s research will provide evidence that these two
laminins play important roles in one or more key
steps of tumor angiogenesis, including endothelial cell attachment, migration, basement membrane assembly, and microvascular blood vessel
formation. She and her colleagues expect to establish the roles of laminins in cancer cell migration, invasion, and metastasis. These studies are
expected to have profound implications for the
development of novel therapies designed to target
these extracellular matrix components and alter
the angiogenesis and progression of cancers.
SELECTED PUBLICATIONS
2002
Calautti, E, Grossi, M, Mammucari, C, Aoyama,
Y, Pirro, M, Ono, Y, Li, J, and Dotto, GP. Fyn
tyrosine kinase is a downstream mediator of Rho/
PRK2 function in keratinocyte cell-cell adhesion.
Journal of Cell Biology 156:137-48, 2002.
2003
Vincek, V, Knowles, J, Li, J, and Nassiri, M. Expression of p63 mRNA isoforms in normal human tissue. Anticancer Research, 23:3945-48,
2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that microvascular endothelial
cells produce two extracellular matrix laminin
proteins of laminin-8 and laminin-10, and that
these two laminins play important roles in tumor angiogenesis. Angiogenesis is critical to
tumor growth and metastasis and the aggressive
behavior of malignant tumors is regulated by
signals from their extracellular matrix environment.
• Demonstrated that laminin-8 has strong effects
on endothelial cell attachment, migration, and
capillary tubule formation.
• Identified the high expression of laminin-10
in human malignant melanomas. Significantly
higher expression of laminin-10 also was
detected in the basement membranes of invasive SCC mass and newly formed tumor blood
vessels.
• Demonstrated an incremental expression pattern as tumors progress from pre-malignant
skin lesions of actinic keratosis to malignant
SCC. These studies revealed a clear correlation
between the expression level of laminin-10 and
SCC invasiveness and indicate that laminin-10
plays important roles in tumor angiogenesis and
invasion.
Li, J, Zhang, YP and Kirsner, RS. Angiogenesis in
wound repair: angiogenic growth factors and the
extracellular matrix. Microscopy Research and
Technique 60:107-14, 2003.
Li, J, Tzu, J, Chen, Y, Zhang, YP, Nguyen, NT,
Gao, J, Bradley, M, Keene, DR, Oro, AE, Miner,
JH, and Marinkovich, MP. Laminin-10 is crucial
for hair morphogenesis. EMBO Journal
22(10):2400-10, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
81
TUMOR CELL BIOLOGY PROGRAM
CHIA-YANG LIU, PH.D.
Assistant Professor of Ophthalmology
DESCRIPTION OF RESEARCH
D
r. Liu’s research focuses on the roles of a
membrane/soluble glycoprotein complex
(Muc4/sialomucin complex, SMC), which is a
major contributing mucin at the ocular surface
and in the ocular tear film. Two specific aims
were designed to examine the biological function
of Muc4/SMC in vivo. The first aim is to generate Muc4/SMC knockout (KO) mice to examine
its loss-of-function. Dr. Liu’s rationale is that
Muc4/SMC is composed of two subunits derived
from a single gene: an O-glycosylated mucin subunit ASGP-1, which has been implicated in antiadhesion phenomena at epithelial cell surfaces,
and a transmembrane subunit ASGP-2, which is
N-glycosylated, has two epidermal growth factorlike (EGF-like) domains, and has been implicated
in ErbB2cellular signaling. Immunohistochemical
analyses have shown that Muc4/SMC is expressed
only in the cell layers of the superficial half of the
corneal and conjunctival epithelia. These results
have led the group to hypothesize that Muc4/
SMC acts as an intrinsic differentiation and survival factor regulating the behavior of the cells in
those epithelia through its effects on ErbB2.
Muc4/SMC KO mice will be created via gene
targeting. This KO mouse strain can be used to
examine the biological function of Muc4/SMC
and can be used as an animal model to investigate
the pathogenesis of ocular surface disease such as
dry eye.
Dr. Liu’s second aim is to generate K14Muc4 transgenic mice to investigate Muc4/SMC
gain-of-function. His rationale is that a matured
corneal epithelium contains three types of cells
organized in five to six layers, which include basal
cells (one layer), supra-basal cells (two layers),
and superficial cells (two to three layers). These
three types of cells are phenotypically distinct in
terms of their proliferative activity and differentiative status. The basal cells are relatively
proliferative, whereas the superficial cells are
82
post-mitotic and become terminally differentiated. Since Muc4/SMC is expressed only in the
cell layers of the superficial half of the corneal
and conjunctival epithelia and Muc4/SMC can
induce cellular signaling through ErbB2 receptor,
it is hypothesized that Muc4/SMC-ErbB2 signaling may play an important role in regulating
corneal epithelial differentiation, apoptosis, and
desquamation. To test this hypothesis, an epithelial basal cell-specific promoter (K14 keratin
promoter) will be used to drive Muc4/SMC expression in the K14-Muc4 transgenic (Tg) mice.
It is anticipated that in the K14-Muc4 Tg, Muc4/
SMC will be aberrantly over-expressed in basal
corneal epithelium, which in turn will affect the
corneal epithelium homeostasis. The K14-Muc4
Tg will allow Dr. Liu and his colleagues to investigate the corneal epithelial cell biology. These
combined studies should help to provide them
with a more complete picture of the functions
of Muc4/SMC at the ocular surface as well as
insights into the roles of this mucin in ocular
surface diseases and aberrations.
SELECTED PUBLICATIONS
2002
Saika, S, Ohnishi, Y, Ooshima, A, Liu, CY, and
Kao, WW. Epithelial repair roles of extracellular
matrix. Cornea (2 Suppl 1): S23-S29, 2002.
Wang, IJ, Carlson, EC, Liu, CY, Kao, CW, Hu,
FR, and Kao, WW. Cis-regulatory elements of
the mouse Krt1.12 gene. Molecular Vision 8: 94101, 2002.
Austin, BA, Coulon, C, Liu, CY, Kao, WW, and
Rada, JA. Altered collagen fibril formation in the
sclera of lumican-deficient mice. Investigative
Ophthalmology & Visual Science 43:1695-1701,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
Paradis, H, Liu, CY, Saika, S, Muhamad, A,
Doetschman, T, Good, W, Nayak, R, Laver, N,
Kao, C, Kao, WW, and Gendron, R. Tubedown1 in remodeling of the developing vitreal vasculature in vivo and regulation of capillary outgrowth
in vitro. Developmental Biology 249:140-55,
2002.
Espana, EM, Kawakita, T, Romano, A,
DiPascuale, M, Smiddy, R, Liu, CY, and
Tseng, SC. Stromal niche controls the plasticity
of limbal and corneal epithelial differentiation in
a rabbit model of recombined tissue. Investigative
Ophthalmology & Visual Science 44: 5130-35,
2003.
Nikitin, AY, Liu, CY, Flesken-Nikitin, A, Chen,
CF, Chen, PL, and Lee, WH. Cell lineagespecific effects associated with multiple deficiencies of tumor susceptibility genes in Msh2-/-Rb+/mice. Cancer Research 62: 5134-38, 2002.
Espana, EM, He, H, Kawakita, T, Di Pascuale,
MA, Raju, VK, Liu, CY, and Tseng, SC. Human
keratocytes cultured on amniotic membrane
stroma preserve morphology and express
keratocan. Investigative Ophthalmology &
Visual Science 44: 5136-41, 2003.
2003
Carlson, EC, Mamiya K, Liu, CY, Gendron, RL,
Birk, DE, Funderburgh, JL, and Kao, WW. Role
of 41Cys in the N-terminal domain of lumican in
ex vivo collagen fibrillogenesis by cultured corneal
stromal cells. Biochemical Journal 369:461-68,
2003.
Kao, WW and Liu, CY. The use of transgenic
and knockout mice in the investigation of ocular
surface cell biology. The Ocular Surface 1:5-19,
2003.
Saika, S, Miyamoto, T, Tanaka, S, Tanaka, T,
Ishida, I, Ohnishi, Y, Ooshima, A, Ishiwata, T,
Asano, G, Chikama, T, Shiraishi, A, Liu, CY,
Kao, CW, and Kao, WW. Response of lens epithelial cells to injury: role of lumican in epithelial-mesenchymal transition. Investigative
Ophthalmology & Visual Science 44:2094-102,
2003.
Liu, CY, Birk, DE, Hassell, JR, Kane, B, and
Kao, WW. Keratocan-deficient mice display alterations in corneal structure. Journal of Biological
Chemistry 278:21672-677, 2003.
Carlson, EC, Wang, IJ, Liu, CY, Brannan, P,
Kao, CW, and Kao, WW. Altered KSPG
expression by keratocytes following corneal
injury. Molecular Vision 9:615-23, 2003.
Meek, KM, Quantock, AJ, Boote, C, Liu, CY,
and Kao, WW. An X-ray diffraction investigation
of corneal structure in keratocan-deficient mice.
Matrix Biology 22:467-75, 2003.
HIGHLIGHTS/DISCOVERIES
• Identified one targeted clone (#194) that was
microinjected into the foster female mice by the
gene targeting core facility at the University of
Miami. Six chimeric founders have been obtained. The laboratory is in the process of
breeding these chimeric mice with wt mouse to
generate heterozygote mutant mice.
• Plan to generate a Tg mouse model to study a
mucin gene function on maintenance of epithelial tissues including mammary gland, ocular
surface, and reproductive tract among others.
Zhang, L, Wang, W, Hayashi, Y, Jester, JV, Birk,
DE, Gao, M, Liu, CY, Kao, WW, Karin, M, and
Xia, Y. A role for MEK kinase 1 in TGF-beta/
activin-induced epithelium movement and embryonic eyelid closure. EMBO Journal 22: 444354, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
83
TUMOR CELL BIOLOGY PROGRAM
BALAKRISHNA L. LOKESHWAR, PH.D.
Associate Professor of Urology
DESCRIPTION OF RESEARCH
D
r. Lokeshwar’s research focuses on the
mechanism of prostate cancer metastasis
and its control by novel chemotherapeutic drugs.
For the last several years, Dr. Lokeshwar’s laboratory has focused on the extracellular matrix degradation and tumor metastasis. His laboratory
has studied the regulation of a class of basement
membrane matrix degrading enzymes called the
matrix metalloproteinases (MMPs) in prostate
cancer. Using cancer cell cultures established
from human prostate tumor tissues obtained after
prostatectomy, they showed that an imbalance
exists between the levels of MMPs (overproduction) and their natural inhibitors (underproduction) in invasive prostate cancer cells. Based on
this finding, they developed a hypothesis that a
novel approach to control metastatic cancer is
to correct the imbalance either by inhibition
of secretion of MMPs or by increasing the extracellular levels of their endogenous inhibitor.
Since several small synthetic inhibitors of
MMPs exist, they tested the usefulness of the inhibitors using the criteria of oral bioavailability,
systemic toxicity, and the ability to target bone
metastasis. In their search for a suitable inhibitor,
Dr. Lokeshwar’s laboratory tested a series of synthetic tetracycline analogues, which were shown
to possess a strong anti-collagenase activity with
little or no antibiotic activity. Researchers tested
eight different chemically modified tetracyclines
(CMTs) and found one of them, 6-deoxy, 6demethyl, 4-dedimethylamino tetracycline
(CMT-3, COL-3, now termed MetastatR by
CollaGenix Pharmaceuticals, Newtown, Pennsylvania), to be the most promising. Oral dosing
with this analogue to rats and mice-bearing metastatic prostate tumors reduced tumor growth and
metastasis, with no measurable systemic toxicity.
Furthermore, prophylactic dosing of the animals
with the drug significantly reduced the incidence
of tumor at the site of tumor cell injection. Their
84
demonstration of highly antimetastatic and antitumor activity of CMT-3 in a rat prostate tumor
model led to its phase I clinical trial by the Developmental Therapeutics Division of the National Cancer Institute (NCI-DTP). In a recently
concluded first human clinical phase I trial of
COL-3, the NCI-DTP recommended COL-3 for
phase II and phase III in patients with soft tissue
sarcoma and advanced metastatic tumors. The
University of Miami and the State University of
New York at Stony Brook have jointly obtained a
use patent on this drug. This finding also has
generated wide interest in the use of COL-3
among many investigators within and outside the
University of Miami; a new patent was issued to
the University for the treatment of corneal ulceration in patients with meibomian gland disease,
also called ocular rosacea. Dr. Lokeshwar’s current
research focuses on identifying novel plant products that have been used as folk medicine and on
identifying novel combination therapies for advanced hormone-refractive prostate cancer.
Dr. Lokeshwar’s research for this study also
was funded by two consecutive grants from the
Department of Defense Congressionally Directed
Medical Program on Prostate Cancer. In its summary report to the U.S. Congress, his research was
highlighted as one of the most significant outcomes of the CDMRP Prostate Cancer Program.
SELECTED PUBLICATIONS
2002
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, M, and Pflugfelder, SC.
Experimentally induced dry eye produces ocular
surface inflammation and epithelial disease. Advances in Experimental Medicine and Biology
506(Pt A):647-55, 2002.
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, ME, and Pflugfelder, SC.
A mouse model of keratoconjunctivitis sicca. Investigative Ophthalmology & Visual Science
43:632-38, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block,
NL, and Golub, LM. Inhibition of cell proliferation, invasion, tumor growth and metastasis by
an oral non-antimicrobial tetracycline analog
(COL-3) in a metastatic prostate cancer model.
International Journal of Cancer 98:297-309,
2002.
Whitlatch, LW, Young, MV, Schwartz, GG,
Flanagan, JN, Burnstein, KL, Lokeshwar, BL ,
Rich, ES, Holick, MF, and Chen, TC. 25Hydroxyvitamin D-1alpha-hydroxylase activity is
diminished in human prostate cancer cells and is
enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40,
2002.
NCI has completed the phase I trial of this
drug and is awaiting further trials. Other novel
agents are being tested in Dr. Lokeshwar’s laboratory, not only for controlling cancer, but also
other chronic diseases such as chronic ocular
surface inflammation. Dr. Lokeshwar’s research
has brought in one patent to the University of
Miami jointly with the State University of New
York at Stony Brook. Meanwhile, two patents
are pending on the new application of his
research findings.
2003
• Identified a potential application of CMTs to
treat the meibomian gland dysfunction that
leads to the ocular rosacea. This was done in
collaboration with Stephen C. Pfulgfelder,
M.D., Baylor College of Medicine, Houston,
Texas.
Chen, TC, Holick, MF, Lokeshwar, BL ,
Burnstein, KL, and Schwartz, GG. Evaluation of
vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research
164:273-88, 2003.
VINATA B. LOKESHWAR, PH.D.
Associate Professor of Urology
Li, de Q, Shang, TY, Kim, HS, Solomon, A,
Lokeshwar, BL , and Pflugfelder, SC. Regulated
expression of collagenases MMP-1, -8, and -13
and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells. Investigative Ophthalmology & Visual Science 44:2928-36, 2003.
Dandekar, DS, Lokeshwar, VB, CevallosArellano, E, Soloway, MS, and Lokeshwar, BL .
An orally active Amazonian plant extract (BIRM)
inhibits prostate cancer growth and metastasis.
Cancer Chemotherapy and Pharmacology
52(1):59-66, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that an imbalance exists between
the levels of MMPs (overproduction) and their
natural inhibitors (underproduction) in invasive
prostate cancer cells.
• Identified a novel, chemically modified nonantimicrobial tetracycline (COL-3) as an effective anti-metastatic drug with the potential to
treat prostate cancer metastatic to bone. The
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
DESCRIPTION OF RESEARCH
D
r. Lokeshwar’s research focuses on understanding the mechanism of cancer progression and tumor angiogenesis. Recent advances
in cancer research have elucidated that the components of extracellular matrix (ECM) and
ECM-degrading enzymes play a crucial role in
regulating both the metastatic progression of
localized tumors and tumor angiogenesis. Using
bladder and prostate cancer model systems, her
laboratory is trying to understand how ECM
affects tumor metastasis and angiogenesis.
Work in Dr. Lokeshwar’s laboratory demonstrates that an ECM component, hyaluronic acid
(HA, which is a glycosaminoglycan), and its degrading enzyme, hyaluronidase (HAase), are
closely associated with the biology of cancers of
the bladder and prostate. They observed that elevated urinary HA and HAase levels are diagnostic indicators of bladder cancer and its grade,
respectively. This finding has led to the development of a simple, noninvasive, highly sensitive,
85
TUMOR CELL BIOLOGY PROGRAM
and specific urine test (HA-HAase test; 90 percent accuracy) for detecting bladder cancer and
monitoring its recurrence.
Dr. Lokeshwar’s research on prostate cancer
showed that immunohistochemical localization of
both HA and HAase in prostate cancer tissues is
greater than 85 percent accurate in predicting
prognoses for prostate cancer patients and are
better than CD44v6 and microvessel density.
Furthermore, both HAase and the HA-HAase
combination are independent predictors of prognosis. Thus, use of these markers in biopsy specimens may help clinicians make individualized
treatment decisions and improve patients’
prognoses.
In their efforts to understand the function of
tumor-derived HAase, Dr. Lokeshwar and her
colleagues purified and cloned the first tumorderived HAase. They have demonstrated that this
tumor-derived HAase degrades tumor-associated
HA into small angiogenic fragments, which then
interact with a HA receptor, RHAMM, on endothelial cells. The HA fragments and RHAMM
interaction on the cell surface induces signaling
events, resulting in the stimulation of endothelial
cell functions, such as proliferation through the
mitogen-activated protein kinase (MAPK) pathway. Endothelial cell proliferation is of key importance in tumor angiogenesis. Their recent
work using anti-sense cDNA transfection strategy
demonstrates that tumor-derived HAase is necessary for tumor growth and muscle invasion of
bladder tumors. This is an important finding
since 60 percent of bladder cancer patients with
muscle invasive disease die within five years.
Currently, Dr. Lokeshwar’s research focuses
on three areas. First, the laboratory is comparing
the efficacy of the HA-HAase test with other
FDA-approved bladder tumor markers for monitoring bladder cancer recurrence. Secondly, they
are testing the potential of HAase and HA-HAase
to predict prognostic potential using prostate
biopsy specimens. Thirdly, they are investigating
the functions of HAase and HA-synthase enzymes in bladder and prostate cancer growth
and progression.
86
SELECTED PUBLICATIONS
2002
Lokeshwar, VB and Soloway, MS. Re: Urine
based markers of urological malignancy. Journal
of Urology 167:1406-07, 2002.
Lokeshwar, VB , Schroeder, GL, Selzer, MG,
Hautmann, SH, Posey, JT, Duncan, RC, Watson,
R, Rose, L, Markowitz, S, and Soloway, MS.
Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic
acid-hyaluronidase and BTA-Stat tests. Cancer
95:61-72, 2002.
Ekici, S and Lokeshwar, VB . Mesane tumoru
belirleyicileri ve HA-Haase testi. Uroloji Bulteni
13:133-40, 2002.
Lokeshwar, VB , Schroeder, GL, Carey, RI,
Soloway, MS, and Iida, N. Regulation of hyaluronidase activity by alternative mRNA splicing.
Journal of Biological Chemistry 277:33654-63,
2002.
2003
Dandekar, DS, Lokeshwar, VB , CevallosArellano, E, Soloway, MS, and Lokeshwar, BL.
An orally active Amazonian plant extract (BIRM)
inhibits prostate cancer growth and metastasis.
Cancer Chemotherapy and Pharmacology 52:5966, 2003.
Simon, MA, Lokeshwar, VB , and Soloway, MS.
Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB . Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45,
2003.
Posey, JT, Soloway, MS, Ekici, S, Sofer, M,
Civantos, F, Duncan, RC, and Lokeshwar, VB .
Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Research 63:2638-44, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
HIGHLIGHTS/DISCOVERIES
• Developed the HA-HAase urine test, a noninvasive test that is about 90 percent accurate in
detecting bladder cancer and monitoring its
recurrence.
• Established that HA and HAase are greater than
85 percent accurate prognostic indicators for
prostate cancer.
• Demonstrated the function of tumor-derived
HAase in bladder tumor growth and muscle
invasion.
ARUN MALHOTRA, PH.D.
Assistant Professor of Biochemistry and
Molecular Biology
DESCRIPTION OF RESEARCH
D
r. Malhotra’s research interests lie in structural biology of macromolecules involved in
a variety of basic cellular functions. Three major
areas of research include bacterial nucleases
involved in RNA maturation and degradation,
enzymes involved in RNA modification, and
molecules involved in axonal guidance and
neuronal development. These macromolecules
are being studied using the tools of X-ray crystallography and molecular biology.
Bacterial Exoribonucleases
Ribonucleases play a central role in vital cellular
RNA processes such as mRNA degradation and
maturation and turnover of stable RNAs. Eight
distinct exoribonucleases have been identified in
E. coli. Of these, three (RNase T, RNase D, and
oligoribonuclease) are members of a larger exonuclease superfamily (named the DEDD exonuclease family, after the four invariant acidic
residues in these proteins) that includes the
proofreading domains of DNA polymerases.
While these proteins share similar sequence
motifs, they are functionally quite different.
RNase T is involved in tRNA turnover and maturation of tRNAs, 23S, and 5S rRNAs. RNase D
also is involved in the maturation of tRNAs and
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
small RNAs, but mainly as a backup enzyme.
RNase D functions as a monomer, while RNase
T and oligoribonuclease exist as dimers.
Oligoribonuclease catalyzes the degradation of
very short RNAs and is the only exoribonuclease
essential for cell viability in E. coli.
This project aims to obtain structures of
these three exoribonucleases and to compare
them to better understand differences in substrate
specificities. The long-term goal of this research is
to understand the structures and mechanisms of
action of all exoribonucleases in a single organism; this study complements a parallel study under way in the laboratory of Murray P. Deutscher,
Ph.D., (University of Miami), to completely
characterize the physiological role of all the
exoribonucleases in E. coli.
Pseudouridine Synthases
One of the most abundant post-transcriptional
modifications seen in RNA is the isomerization
of uridine to pseudouridine (5-ribosyluracil).
While the physiological role of this modification
in cells is not yet well understood, pseudouridines
are often seen in functionally important regions
of structural RNAs such as ribosomal RNAs,
transfer RNAs, and splicing RNAs.
The isomerization of uridines to pseudouridines
is carried out by specialized enzymes called
pseudouridine synthases. These enzymes fall into
five different families; crystallographic studies in
a number of laboratories have shown that three of
these families have very similar structures in spite
of limited sequence homologies. This project
focuses on the structural studies of pseudouridine
synthases from the other two families (RluD from
the RluA family, and the newly discovered TruD
family), in collaboration with the laboratory of E.
James Ofengand, Ph.D., (University of Miami).
Structural Studies of Axonal Guidance
Molecules
Research in this area aims to structurally characterize the interactions between ephrins and their
receptors, a class of molecules involved in axonal
guidance in the developing nervous system. Apart
from axonal guidance, these receptors/ligands
87
TUMOR CELL BIOLOGY PROGRAM
also are involved in cell migration, patterning of
the nervous system, and angiogenesis. Given their
critical roles in neuronal regeneration and angiogenesis, ephrins and their receptors are excellent
targets for therapeutic intervention in a variety of
cancers, injuries, and diseases.
Eph receptors are the largest-known family
of receptor tyrosine kinases, with at least 16
members identified until now. Eph receptors have
an extracellular region that consists of two
fibronectin motifs, a cysteine-rich region, and a
conserved 180 amino acids N-terminal globular
domain. The ligands for Eph receptors are the
ephrins, which have eight members identified so
far. These ligands share conserved core sequences
of approximately 125 amino acids, including four
invariant cysteine residues. Ephrin A1–A5 are
anchored by glycosil-phosphatidil-inositol (GPI)
to cellular membranes, while ephrin B1–B3 receptors have a transmembrane domain and an
intracellular domain, which interacts with a variety of adapter and signaling molecules such as
PDZ-RGS3, GRB4, JNK, and others.
The two classes of ephrins and their receptors,
A and B, are defined by sequence homologies,
mechanism of membrane anchorage, and by preferential binding of the ligands to their receptors.
While within the same class, the ligand-receptor
binding tends to be nonspecific; there is no cross
interaction between the two classes, except Eph
A4, which binds some of the B class ephrins.
Ephrins-Eph interactions also are intriguing because these molecules often display bidirectional
signaling: a forward signal (binding of ephrins to
Eph receptor determines a response in a cell or
axon) and a reverse/downstream signal (binding
of Eph receptor to ephrin causes a change in the
cell or axon to which ephrin molecule is bound).
This research aims to better understand the
structural basis of ephrin/Eph ligand-receptor binding and specificity by crystallographic studies of
the extracellular domains of several of these molecules. Residues identified as being critical for ephrin/
Eph specificity also will be tested functionally using
mutational approaches, in collaboration with the
laboratory of Daniel J. Leibl, Ph.D., at The Miami
Project to Cure Paralysis, University of Miami.
88
SELECTED PUBLICATIONS
2003
Everhart, D, Reiller, E, Mirzoian, A, McIntosh,
JM, Malhotra, A, and Luetje, CW. Identification
of residues that confer a-conotoxin-PnIA sensitivity on the α3 subunit of neuronal nicotinic acetylcholine receptors. Journal of Pharmacology
and Experimental Therapeutics 306: 664-70,
2003.
Del Campo, M, Ofengand, J, and Malhotra, A .
Purification and crystallization of Escherichia coli
pseudouridine synthase RluD. Acta
Crystallographica D, 59:1871-73, 2003.
Del Campo, M, Ofengand, J, and Malhotra, A .
Crystal structure of the catalytic domain of
RluD, the only rRNA pseudouridine synthase
required for normal growth of Escherichia coli.
RNA 10:231-39, 2003.
AKILA MAYEDA, PH.D.
Assistant Professor of Biochemistry
and Molecular Biology
DESCRIPTION OF RESEARCH
T
he human genome project has underscored
the critical importance of alternative premRNA splicing for expressing a full proteome
with its complexity from an unexpectedly small
set of genes, i.e., less than 30,000 by most recent
estimation.
Researchers in Dr. Mayeda’s laboratory are
working to understand the basic mechanisms of
splicing regulation in human genes. Three main
projects are ongoing: 1) to study the function of
the human splicing activator RNPS1, which is
also an important factor to link splicing and the
post-splicing process, e.g., nonsense-mediated
mRNA decay (NMD); 2) to study the function
of human HMGA1a, which is the hypoxia-inducible factor causing aberrant splicing of
Presenilin-2 (PS2) pre-mRNA. PS2 is one of the
genes linked to Alzheimer’s disease (AD); and
3) to study the splicing mechanisms of extremely
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
long introns using the dystrophin (DMD) gene.
Many cases of Duchenne muscular dystrophy
are caused by splicing defects of the DMD gene
transcript.
The high prevalence of clinically relevant
mutations that affect splicing in genetic diseases
and cancer has become increasingly apparent.
The aberrant splicing patterns of many genes are
involved in the establishment or maintenance of
the transformed phenotype or in the progression
to malignancy of cancer cells. Thus, Dr. Mayeda’s
research will advance the basic understanding of
the regulation of pre-mRNA splicing, which will
undoubtedly have a long-term impact on public
human health.
Manabe, T, Katayama, T, Sato, N, Gomi, F,
Hitomi, J, Yanagida, T, Kudo, T, Honda, A,
Mori, Y, Matsuzaki, S, Imaizumi, K, Mayeda, A,
and Tohyama, M. Induced HMGAIa expression
causes aberrant splicing of presenilin-2 premRNA in sporadic Alzheimer’s disease. Cell
Death and Differentiation 10:698–708, 2003.
Amada, N, Tezuka, T, Mayeda, A, Araki, K,
Takei, N, Todokoro, K, and Nawa, H. A novel
rat orthologue and homologue for the Drosophila
crooked neck gene in neural stem cells and their
immediate descendants. Journal of Biochemistry
135:615–623, 2003.
HIGHLIGHTS/DISCOVERIES
SELECTED PUBLICATIONS
2002
Hou, VC, Lersch, R, Gee, SL, Ponthier, JL, Lo,
AJ, Wu, M, Turck, CW, Koury, M, Krainer, AR,
Mayeda, A, and Conboy, JG. Decrease in
hnRNP A/B expression during erythropoiesis
mediates a pre-mRNA splicing switch. EMBO
Journal 21:6195-204, 2002.
2003
Liu, X, Mayeda, A, Tao, M, and Zheng, Z-M.
Exonic splicing enhancer-dependent selection of
bovine papillomavirus type 1 nucleotide 3225 3’
splice site can be rescued in a cell lacking splicing
factor ASF/SF2 through activation of the
phosphatidylinositol 3-kinase/Akt pathway. Journal of Virology 77:2105–15, 2003.
Domsic, JK, Wang, Y, Mayeda, A, Krainer, AR,
and Stoltzfus, CM. HIV-1 hnRNP A/B-dependent exonic splicing silencer ESSV antagonizes
binding of U2AF65 to viral polypyrimidine
tracts. Molecular and Cellular Biology 23:876272, 2003.
Hu, D, Mayeda, A, Trembley, JH, Lahti, JM, and
Kidd, VJ. CDK11 complexes promote premRNA splicing. Journal of Biological Chemistry
278:8623–29, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Demonstrated that splicing activator RNPS1 is
incorporated in the early splicing complex,
stimulates formation of the ATP-dependent
splicing complex, and subsequently increases
generation of both intermediate and final
spliced products.
• Discovered experimental evidence supporting a
novel mechanism, termed ‘nested intron splicing’, i.e., multiple splicing of internal nested
introns preceding the eventual splicing at the
authentic 5’ and 3’ splice sites by using the human DMD gene.
CARLOS T. MORAES, PH.D.
Associate Professor of Neurology
DESCRIPTION OF RESEARCH
A
lthough mitochondrial genetics of yeast and
trypanosomes has been explored extensively
in the last 20 years, the study of human mitochondrial DNA (mtDNA) gained momentum in
1988 with the discovery of diseases associated
with mtDNA mutations. The human mtDNA is
a compact circular genome (16.6 kb) coding for
components of the ATP-producing oxidative
phosphorylation system. Because mtDNA-coded
polypeptides are synthesized in mitochondrialspecific ribosomes, the mtDNA also codes for a
89
TUMOR CELL BIOLOGY PROGRAM
set of rRNAs and tRNAs necessary for intraorganelle translation. The contribution of the
mitochondrial genome to cellular respiration,
though vital, is not sufficient. Dozens of nuclearcoded proteins synthesized in the cytoplasm are
imported into mitochondria and assembled with
mitochondrially synthesized proteins to form a
functional oxidative phosphorylation system.
Recently, defects in mitochondrial function
also have been associated with some forms of
tumors. Mutations in the mtDNA also have
been described in a large number of tumors.
Dr. Moraes currently is studying the potential
role of these mutations in cell signaling and invasion. Mitochondria also are major players in programmed cell death, an important determinant
of tumorigenesis. A number of anti- and proapoptotic factors seem to mediate their functions
in association with mitochondrial membranes.
Dr. Moraes and his colleagues also are exploring
the role of cytochrome c in stimulating apoposis.
Diaz, F, Bayona-Bafaluy, MP, Rana, M, Mora, M,
Hao, H, and Moraes, CT. Human mitochondrial
DNA with large deletions repopulates organelles
faster than full-length genomes under relaxed
copy number control. Nucleic Acids Research
30:4626-33, 2002.
SELECTED PUBLICATIONS
Bayona-Bafaluy, MP, Manfredi, G, and Moraes,
CT. A chemical enucleation method for the
transfer of mitochondrial DNA to rho(o) cells.
Nucleic Acids Research 31:e98, 2003.
2002
Moraes, CT , Srivastava, S, Kirkinezos, I, OcaCossio, J, van Waveren, C, Woischnick, M, and
Diaz, F. Mitochondrial DNA structure and function. International Review of Neurobiology 53:323, 2002.
Moraes, CT. Studying mitochondria of animal
cells. Methods 26:291, 2002.
Woischnik, M and Moraes, CT. Pattern of organization of human mitochondrial pseudogenes in
the nuclear genome. Genome Research 12:88593, 2002.
Lanza, RP, Chung, HY, Yoo, JJ, Wettstein, PJ,
Blackwell, C, Borson, N, Hofmeister, E, Schuch,
G, Soker, S, Moraes, CT , West, MD, and Atala,
A. Generation of histocompatible tissues using
nuclear transplantation. Nature Biotechnology
20:689-96, 2002.
90
2003
Manfredi, G, Kwong, JQ, Oca-Cossio, JA,
Woischnik, M, Gajewski, CD, Martushova, K,
D’Aurelio, M, Friedlich, AL, and Moraes, CT .
BCL-2 improves oxidative phosphorylation and
modulates adenine nucleotide translocation in
mitochondria of cells harboring mutant mtDNA.
Journal of Biological Chemistry 278:5639-45,
2003.
Bacman, SR, Atencio, DP, and Moraes, CT . Decreased mitochondrial tRNALys steady-state levels and aminoacylation are associated with the
pathogenic G8313A mitochondrial DNA mutation. Biochemical Journal 374:131-36, 2003.
HIGHLIGHTS/DISCOVERIES
• Discovered that cells with defective mitochondrial respiration can be more resistant to cell
death. This is a counterintuitive concept since it
was previously thought that the less energy a
cell has, the easier it is to kill it. Programmed
cell death, however, does require a considerable
amount of ATP (energy) to occur. These findings may explain the presence of mtDNA mutations in some cancers.
• Demonstrated that mitochondrial defects
stimulate the production of metalloproteases,
which in turn, promote tissue invasion.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
AYMEE PEREZ, PH.D.
Assistant Professor of
Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
S
ialomucin complex (SMC/Muc4) is a
heterodimeric glycoprotein complex consisting of a mucin subunit ascites sialoglycoprotein-1
(ASGP-1) and a transmembrane subunit (ASGP2), which is aberrantly expressed on the surface of
a variety of tumor cells. Muc4 is transcribed from
a single gene, translated into a large polypeptide
precursor, and further processed to yield the mature ASGP-1/ASGP-2 complex. Muc4 has complex spatial and temporal expression patterns in
the normal rat, suggesting that it has complex
regulatory mechanisms.
Muc4 is expressed in most vulnerable epithelia and is presumed to serve as a protective agent
whose mucin subunit provides a steric block to
the access of noxious agents such as bacteria or
viruses. In many of these epithelia, such as the
airway and cervix/vagina, Muc4 is constitutively
expressed. Two notable exceptions are the mammary gland and uterus. In the uterus, Muc4 is
expressed in the virgin animal, but down-regulated hormonally at the transcript level to repress
Muc4 expression at the time of blastocyst implantation. Regulation in the mammary gland is
even more complex and includes transcriptional
and post-transcriptional levels of regulation.
Dr. Perez has two ongoing projects in her
laboratory. The first project investigates the
mechanisms involved in the transcriptional regulation of Muc4 by prolactin and the transcription
factor PEA3. The second project focuses on the
post-transcriptional regulatory mechanisms involved in repressing Muc4 in the virgin animal,
which are overridden during mid-pregnancy and
tumor progression. Dr. Perez and her colleagues
believe that these regulatory mechanisms provide
a key to understanding the function of Muc4 in
both the normal gland and its tumors.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SELECTED PUBLICATIONS
2002
Carraway, KL, Perez, A, Idris, N, Jepson, S,
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,
SA, Zhang, J, and Carraway, CA. Muc4/
sialomucin complex, the intramembrane ErbB2
ligand, in cancer and epithelia: to protect and to
survive. Progress in Nucleic Acid Research and
Molecular Biology 71:149-85, 2002.
2003
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,
SA, and Carraway, KL. PEA3 transactivates the
Muc4/Sialomucin Complex promoter in mammary epithelial and tumor cells. Journal of Biological Chemistry 278:36942-52, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that up-regulation of the Muc4
gene in the 13762 sublines of the rat mammary
adenocarcinoma correlates with the overexpression of transcription factor PEA3 and the receptor tyrosine kinase ErbB2. PEA3 is capable of
transactivating the Muc4 promoter in a dosedependent manner via direct attachment to a
PEA3 binding site. Ras and MEKK1 kinases
potentiate transcriptional activation of Muc4 by
PEA3. These data suggest that expression of
PEA3 in mammary tumors leads to up-regulation of MUC4 transcription, the gene product
of which may contribute to the metastatic
potential of mammary tumors.
91
TUMOR CELL BIOLOGY PROGRAM
PEDRO J. I. SALAS, M.D., PH.D.
Associate Professor of Cell Biology
and Anatomy
DESCRIPTION OF RESEARCH
C
entrosomes are an essential piece of the mitotic machinery. In polarized epithelial cells,
centrosomes and other non-centrosomal microtubule organizing centers (MTOC) are distributed
in a subapical localization. During mitosis, centrosomes migrate to the lateral domain, from
where they organize the spindle. This orientation
of the spindle is crucial for the maintenance of
epithelial polarity since it determines that the cytokinesis will proceed in a plane perpendicular to
the plane of the epithelial layer. Likewise, the polarization of MTOCs during interphase is essential to the polarization because it ensures that the
minus ends of microtubules will be aligned under
the apical domain.
Dr. Salas’ research has demonstrated that
centrosomes and non-centrosomal MTOCs colocalize with the apical intermediate filament (IF)
cytoskeleton by using high-resolution confocal
microscopy, near-neighbor deconvolution, and
3D image reconstruction. At the electron microscopy level, co-localization indicated that
pericentriolar material containing g-tubulin and
the cytokeratin (CK) 19 intermediate filaments
approach up to 10 nm. Using sonication, homogenization, and immunoprecipitation coupled
with immunoblot, his laboratory also demonstrated that CKs 18 and 19 co-immunoprecipitate with g-tubulin in fragments that cannot
sustain physical trapping. The down-regulation of
CK19 IF using anti-sense oligonucelotides resulted in changes in localization of the centrosomes. The analysis of the sonication
fragments indicated that only a few proteins
other than CKs and g-tubulin are present, so that
two potential candidates identified by yeast twohybrid and MS-MS microsequencing to fulfill
the role of the “glue” attaching centrosomes, are
now under consideration. Interestingly, one of
those proteins is phosphorylated by p34cdc2. Because the IF do not depolymerize during mitosis
92
in epithelial cells, the attachment of centrosomes
to IF must be necessarily broken at the onset of
mitosis. Current laboratory projects include the
isolation and identification of the protein(s) involved in the apical attachment of centrosomes to
IF and their function during mitosis. Theoretically, a manipulation of this mechanism may halt
the cell cycle in actively dividing epithelial cells.
In addition, the relevance of this mechanism during ischemia or ATP depletion also is under
investigation.
SELECTED PUBLICATIONS
2002
Yang, X, Salas, PJ , Pham, TV, Wasserlauf, BJ,
Smets, MJ, Myerburg, RJ, Gelband, H,
Hoffman, BF, and Bassett, AL. Cytoskeletal actin
microfilaments and the transient outward potassium current in hypertrophied rat ventriculocytes.
Journal of Physiology 541:411-21, 2002.
Figueroa, Y, Wald, FA, and Salas, PJ . p34cdc2mediated phosphorylation mobilizes microtubule-organizing centers from the apical
intermediate filament scaffold in CACO-2 epithelial cells. Journal of Biological Chemistry
277:37848-54, 2002.
2003
Ramsauer, VP, Carothers Carraway, CA, Salas,
PJ, and Carraway, KL. MUC4/Sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized
epithelial cells. Journal of Biological Chemistry
278:30142-47, 2003.
Ameen, NA, Marino, C, and Salas, PJ . cAMPdependent exocytosis and vesicle traffic regulate
CFTR and fluid transport in rat jejunum in vivo.
American Journal of Physiology Cell Physiology
284:C429-38, 2003.
Wald, FA, Figueroa, Y, Oriolo, AS, and Salas, PJ .
Membrane repolarization is delayed in proximal
tubules after ischemia-reperfusion: possible role
of microtubule-organizing centers. American
Journal of Physiology Renal Physiology
285:F230-40, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
HIGHLIGHTS/DISCOVERIES
HIGHLIGHTS/DISCOVERIES
• Observed the attachment of centrosomes to IF.
Although the implications of the mechanism of
detachment during mitosis are still to be assessed, this may be relevant for cancer therapy.
• Nerve growth factor (NGF), the prototypic
member of this family of growth factors, mediates the invasiveness of melanoma cells in vitro
by inducing the coupling of the intracellular
domain of the p75 neurotrophin receptor with
the actin cytoskeleton.
OLUWATOYIN SHONUKAN, M.D.
Assistant Professor of Medicine
• Neurotrophin-induced melanoma invasiveness
is mediated by signals generated through PI-3
kinase.
DESCRIPTION OF RESEARCH
• NGF induces the disruption of cadherin-mediated cell-cell adhesion, thereby permitting melanoma cells to dissociate from the keratinocytes
in the epidermis and invade the dermis, from
whence they metastasize to distant sites. Dr.
Shonukan’s ongoing research efforts include
identifying the components of this pathway in
order to identify therapeutic targets.
M
alignant melanoma arises from the melanocytes, cells that originate in the neural
crest. Normal melanocyte development in the
neural crest and subsequent migration of the
melanocyte precursors into the skin require
trophic signals from the neurotrophin family
of growth factors. With terminal differentiation,
melanocytes lose expression of neurotrophin
receptors. Following transformation, however,
melanoma cells aberrantly express the receptors
for the neurotrophins, with more advanced stages
of the disease being more likely to express the
neurotrophin receptors than the earlier stages.
Dr. Shonukan’s research discovered that the
melanoma cells also express several members of
the neurotrophin growth factor family, thus
suggesting that the neurotrophin/neurotrophin
receptor system may be involved in the mediation
of melanoma progression. The focus of her
laboratory’s research is to understand the role
of the neurotrophins and their receptors in the
mediation of tumor progression in malignant
melanoma.
SELECTED PUBLICATIONS
2003
Shonukan, O, Bagayogo, I, McCrea, P, Chao, M,
and Hempstead, B. Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Oncogene
22:3616-23, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
RAKESH SINGAL, M.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Singal’s research focuses on the mechanisms that inactivate certain tumor-suppressor genes in prostate cancer. A common mode of
such inactivation involves a modification (methylation) in DNA. By understanding how genes are
silenced, treatments can be developed to activate
them and thereby prevent the development and/
or progression of prostate cancer. Researchers in
Dr. Singal’s laboratory also are studying methylation of selected genes as a diagnostic and prognostic marker in prostate cancer.
The present screening techniques for prostate
cancer are very inefficient, and two out of three
patients undergo prostate biopsy unnecessarily
to detect cancer. Cancer patients often have a
small amount of DNA circulating in their serum,
thought to be released from the cancer cells. Dr.
Singal’s laboratory has shown that certain methylated genes are present at a substantially higher
percentage in prostate cancer tissue but not in
benign prostatic conditions. Researchers are
93
TUMOR CELL BIOLOGY PROGRAM
investigating if these methylated genes can be
detected in serum DNA in patients with prostate
cancer. If so, this test can be used as a part of
prostate cancer screening, saving unnecessary
prostate biopsies.
DNA methylation plays a role during development by regulating gene expression. Another
project in Dr. Singal’s laboratory focuses on understanding the role of methylation in regulating
the expression of genes responsible for hemoglobin synthesis. Understanding the contribution of
methylation to globin gene expression and the
mechanisms involved will lead to the development
of safe and effective therapies for globin gene disorders like thalassemia and sickle cell anemia.
SELECTED PUBLICATIONS
2002
Singal, R, vanWert, JM, and Ferdinand, L Jr.
Methylation of alpha-type embryonic globin gene
alpha pi represses transcription in primary erythroid cells. Blood 100:4217-22, 2002.
Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and
Ginder, GD. Methylation of promoter proximal
transcribed sequences of an embryonic globin
gene inhibits transcription in primary erythroid
cells and promotes formation of a cell type-specific methyl cytosine binding complex. Journal of
Biological Chemistry 277:1897-1905, 2002.
Noss, KR, Singal, R, and Grimes, SR. Methylation state of the prostate specific membrane antigen (PSMA) CpG island in prostate cancer cell
lines. Anticancer Research 22:1505-11, 2002.
2003
Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal,
R, and Gill, S. Gynecomastia attributable to human chorionic gonadotropin-secreting giant cell
carcinoma of lung. Endocrine Practice 9:233-35,
2003.
94
JOYCE M. SLINGERLAND, M.D., PH.D.,
F.P.R.C. (C)
Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Slingerland’s research investigates how
cancers escape negative growth controls. Following her discovery of a key inhibitor of cell
cycle progression, p27, Dr. Slingerland and her
colleagues went on to demonstrate that p27 levels
are reduced in up to 60 percent of common human cancers (breast, prostate, lung, ovarian, and
others), in association with poor patient prognosis. Dr. Slingerland showed that the therapeutic
effect of antiestrogens in breast cancer requires
the cyclin-dependent kinase (cdk) inhibitors p21
and p27 to mediate growth arrest. Oncogenic
activation of mitogenic signaling via the mitogenactivated protein kinase (MAPK) pathway deregulates p27 function, causing tamoxifen resistance
in breast cancer. She provided key insights demonstrating the role of cell cycle inhibitors p15 and
p27 as mediators of G1 arrest by transforming
growth factor-beta (TGF-β) and demonstrated
that cancer cells lose responsiveness to this
growth inhibitory cytokine through loss or deregulation of p27. In a recent publication, her
laboratory demonstrated that checkpoint loss
during cancer progression makes p27 an essential
mediator of arrest. They also showed that functional inactivation of p27 in human cancers can
either occur through accelerated p27 degradation
or through altered p27 phosphorylation leading to
p27 mislocalization. The laboratory recently
showed that activation of mitogenic signaling
via the receptor tyrosine kinases and the
phosphoinositol 3’ kinase pathway alters p27
phosphorylation and function and the protein
accumulates in the cytoplasm away from its targets in the nucleus. This work links oncogene
activation with loss or inactivation of the cell
cycle inhibitor, p27, elucidating a major mechanism
of loss of growth control in cancer progression.
Dr. Slingerland’s laboratory also is investigating the cause of aggressive estrogen receptor
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
negative (ER-) breast cancers. Her laboratory has
found that oncogenic receptor tyrosine kinase
and cSrc activation may not only activate mitogenic signaling leading to aggressive proliferation, it
may also lead to loss of detectable ER protein in
ER- breast cancers. One-third of newly diagnosed
breast cancers are ER- and have a poor prognosis.
Investigation of mechanisms underlying loss of
ER expression showed that all of 70 primary ERbreast cancers expressed ER mRNA. Src or
proteasome inhibition increased ER levels and
Src transfection stimulated both ligand-activated
ER transcriptional activity and ER proteolysis.
Cotransfection of Her2 and Src reduced ER levels
further. ER- primary breast cancers and cell lines
showed increased Src activity compared to ER+
cancers and cell lines, and the ER protein half-life
was reduced in ER- breast cancer lines. These
data support a model in which Her2 and cSrc
cooperate with liganded ER to promote both ER
dependent transcription and transcription linked
ER proteolysis.
SELECTED PUBLICATIONS
2002
Donovan, JC, Rothenstein, JM, and Slingerland,
JM. Non-malignant and tumor-derived cells differ in their requirement for p27Kip1 in transforming growth factor-beta-mediated G1 arrest.
Journal of Biological Chemistry 277:41686-92,
2002.
Liang, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R,
Connor, MK, Han, K, Lee, JH, Ciarallo, S,
Catzavelos, C, Beniston, R, Franssen, E, and
Slingerland, JM . PKB/Akt phosphorylates p27,
impairs nuclear import of p27 and opposes p27mediated G1 arrest. Nature Medicine 8:1153-60,
2002.
Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH,
Kotchetkov, R, Sandhu, C, Milic, A, and
Slingerland, JM . Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth
factor beta-mediated G(1) arrest. Molecular and
Cellular Biology 22:2993-3002, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
2003
Connor, MK, Kotchetkov, R, Cariou, S, Resch,
A, Lupetti, R, Beniston, RG, Melchior, F,
Hengst, L, and Slingerland, JM . CRM1/Ranmediated nuclear export of p27(Kip1) involves a
nuclear export signal and links p27 export and
proteolysis. Molecular Biology of the Cell
14:201-13, 2003.
Liang, J and Slingerland, JM . Multiple roles of
the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339-45, 2003.
FULVIA VERDE, PH.D.
Assistant Professor of Molecular and
Cellular Pharmacology
DESCRIPTION OF RESEARCH
Control of Cell Morphogenesis
r. Verde’s research seeks to understand the
molecular basis of cell morphogenesis in eukaryotic cells and its coordination to cell proliferation. To this end, Dr. Verde and her colleagues
have investigated the function of Orb6, a conserved protein kinase that is required for maintenance of cell polarity and regulation of the cell
cycle. They have identified six proteins that
physically interact with Orb6 and established
their role in the control of Orb6 function. Five of
these proteins are conserved in human cells.
These factors are involved in Orb6 activity regulation, are implicated in the control of Orb6 intracellular localization, or function as substrate
effectors of Orb6 kinase in the control of cell
morphology and the cell cycle.
Furthermore, Dr. Verde’s laboratory has been
working with Tea1, a microtubule-associated protein, that functions as a marker for cell polarity
and shows similarity to human ERM (ezrin,
radixin, and moesin) proteins. They have identified several proteins that interact with Tea1 by 2hybrid screening. One of these proteins has been
recently shown to be essential for spatial organi-
D
95
TUMOR CELL BIOLOGY PROGRAM
zation of microtubule dynamics. These findings
are important because little is known about the
mechanism of microtubule-dependent cell morphogenesis.
DONALD T. WEED, M.D., F.A.C.S.
Assistant Professor of Otolaryngology
SELECTED PUBLICATIONS
MUC4 (Sialomucin Complex) Expression in
Head and Neck Cancer
ialomucin complex (SMC) is a novel membrane/soluble glycoprotein complex originally identified and isolated from membranes of
ascites sublines of the highly metastatic 13762 rat
mammary adenocarcinoma. Peptide sequence
homology between the gene product of the human mucin MUC4 and rat SMC has recently
been reported. SMC is composed of a mucin subunit ASGP-1 (ascites sialoglycoprotein-1) linked
to the plasma membrane via an N-glycosylated
transmembrane subunit ASGP-2. The transmembrane subunit has two epidermal growth factor
(EGF)-like domains and can act selectively as a
ligand for the receptor tyrosine kinase ErbB2.
The mucin subunit ASGP-1 also has anti-adhesive activity. The human MUC4 has corresponding transmembrane (MUC4-β) and mucin
(MUC4-α) subunits, with similar growth factor
domains and anti-adhesive potential. These characteristics suggest SMC/MUC4 plays a functional
role in normal cells by providing a direct protective barrier at the cell surface to limit absorption
of microbes and other noxious agents to the epithelial surface, while also participating in repair
and cell replacement processes in the epithelia as
a ligand and modulator of signaling via ErbB2.
SMC/MUC4 can participate in cell signaling
pathways via its complex with ErbB2 to mediate
pathways characterized by cell proliferation, or
pathways characterized by cell cycle inhibition
and growth arrest. Disregulation of proliferative
pathways may lead to transformation of the normal epithelia to a neoplastic phenotype by means
of autocrine stimulation of cell growth and proliferation via activation of ErbB2. The antiadhesive
properties of the ASGP-1/MUC4-α component
of the molecules result in reversible disruption of
integrin-mediated cell adhesion to the extracellular matrix, and may be important in the develop-
2003
Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F.
Control of cell polarity in fission yeast by association of Orb6p kinase with the highly conserved
protein methyltransferase Skb1p. Journal of Biological Chemistry 278:25256-63, 2003.
Hou, MC, Wiley, DJ, Verde, F, and McCollum,
D. Mob2p interacts with the protein kinase
Orb6p to promote coordination of cell polarity
with cell cycle progression. Journal of Cellular
Science 116:125-35, 2003.
Kim, H, Yang, P, Catanuto, P, Verde, F, Lai, H,
Du, H, Chang, F, and Marcus, S. The kelch repeat protein, Tea1, is a potential substrate target
of the p21-activated kinase, Shk1, in the fission
yeast, Schizosaccharomyces pombe. Journal of Biological Chemistry 278:30074-82, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that Bot1 may function as a molecular bridge between Tea1, a microtubuleassociated protein required to establish cell
polarity and Orb6, a conserved protein kinase
related to mammalian Rho kinase and myotonic dystrophy kinase. These findings suggest
that one of the effectors of Orb6 kinase is the
formin For3p that functions in the control of
actin cable polymerization. They also offer insight into the hierarchy of events that lead to
polarized cell growth and in the mechanisms of
microtubule-dependent cell polarity control.
96
DESCRIPTION OF RESEARCH
S
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
ment of metastatic potential of the transformed
cell. Alternatively, SMC/MUC4 may be an important mediator of differentiation by its cell
cycle inhibitory functions. MUC4 expression has
been associated with several human malignancies,
including some where MUC4 expression correlates with poor prognosis and others where the
opposite association is seen.
Immunocytochemical analyses have shown
that the oral cavity is one of the earliest sites of
expression of SMC during development of the
rat, and that the molecule is expressed throughout the upper aerodigestive tract and in the salivary glands of the adult animal. This study
postulates that human MUC4 is similarly expressed in the epithelia of the human upper aerodigestive tract and salivary glands, and that the
molecule participates in the normal processes of
cellular protection, repair, and replacement of
these vulnerable tissues. It is further postulated
that alterations in MUC4 expression are relevant
to the cell biology of neoplastic transformation
and subsequent invasion and metastasis of these
cancers. The hypotheses of this study are threefold: 1) MUC4 expression is altered in head and
neck malignancies compared with normal epithelial expression; 2) cellular expression of MUC4
modulates as lesions progress from dysplastic noninvasive lesions to invasive lesions with regional
and distant metastases; 3) characterization of
MUC4 expression in neoplasia will correlate with
tumor behavior such as invasion and metastasis,
and clinical outcomes such as likelihood of recurrence and prognosis.
Preliminary data from immunoblotting studies using fresh frozen operative tissue samples and
immunohistochemical localization studies using
paraffin embedded tissue blocks have identified
MUC4 throughout the normal human upper
aerodigestive tract mucosa, and in major and minor salivary glands. MUC4 is identified in squamous cell carcinomas (SCCA) of the upper
aerodigestive tract, as well as in metastatic cervical lymph nodes. SMC/MUC4 also is identified
in a variety of salivary neoplasms. Alterations in
the normal mucosal MUC4 expression are seen
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
in otherwise histologically normal mucosa adjacent to invasive tumors. MUC4 expression in the
salivary gland tumor mucoepidermoid carcinoma
has been associated with improved prognosis independent of pathologic grade, the strongest
known predictor of clinical behavior in this malignancy. No clear correlation between MUC4
expression and ErbB2 expression was seen by immunohistochemical analysis. On the other hand,
MUC4 expression was noted to be expressed in
the minority (14 percent) of head and neck
SCCA, but a significant association between
MUC4 expression and ErbB2 expression has
been identified. Furthermore, MUC4 expression
is associated with improved survival and decreased risk of recurrence in these tumors as established by immunohistochemical analysis.
These studies suggest that in mucoepidermoid
carcinoma and in head and neck SCCA MUC4
may be functioning as a marker or mediator of
differentiation, with tumors that lose this expression associated with a more aggressive clinical course.
These studies have established MUC4 as a
novel molecular prognostic marker for these
tumors. Mechanistic studies to better define the
functional relationship between MUC4 and
ErbB2 in these tumors are planned.
SELECTED PUBLICATIONS
2003
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45,
2003.
Civantos, FJ, Gomez, C, Duque, C, Pedroso, F,
Goodwin, WJ, Weed, DT, Arnold, D, and
Moffat, F. Sentinel node biopsy in oral cavity
cancer: correlation with PET scan and immunohistochemistry. Head & Neck 25:1-9, 2003.
Foster, PK and Weed, DT. Tongue viability after
bilateral lingual artery ligation and surgery for
recurrent tongue-base cancer. Ear, Nose, &
Throat Journal 82:720-724, 2003.
97
TUMOR CELL BIOLOGY PROGRAM
CATHERINE F. WELSH, M.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Welsh studies the cell cycle progression
through the G1 phase and its regulation by
growth factor receptors and adhesion to the extracellular matrix. Her laboratory is particularly interested in how these signaling pathways
contribute to breast cancer tumorigenesis and
progression. Signals from the plasma membrane
emanating from receptor tyrosine kinases as well
as integrins are each required for G1 progression.
Cell spreading and cytoskeletal integrity as a consequence of integrin engagement also are necessary. Their laboratory studies involve the role of
Rho family GTPases, a subset of the Ras superfamily, in the regulation of adhesion-dependent
cell cycle progression. These proteins have been
shown to play a role in integrin- and growth factor-mediated signaling, and they are potent mediators of cytoskeletal architecture during cell
spreading. They are therefore situated to play a
key role in the regulation of adhesion-dependent
cell cycle progression. Recent research has revealed that Rho GTPases become deregulated in
breast cancer and may contribute to tumorigenesis. Dr. Welsh’s laboratory is currently investigating the contribution of Rho GTPases to
abnormalities in cell cycle proteins that typify
poor prognosis breast cancer.
HIGHLIGHTS/DISCOVERIES
• Rho family GTPases are in fact required for key
adhesion-dependent G1 events, including
cyclin D1 expression, Rb phosphorylation, and
cyclin A expression. In addition, they participate in the activation of the mitogen-activated
kinase, ERK1/2, a key upstream regulator of
cyclin D1 expression. Furthermore, Rho proteins appear to be involved in determining the
timing of cyclin D1 expression within G1
phase.
98
• Hyperactivation of Rho proteins in a subset of
breast cancers underlies abnormalities in cell
cycle regulators that typify poor prognosis
breast cancer. In addition, inactivation of Rho
GTPases normalizes these regulatory molecules
and restores a more orderly progression through
the cell cycle, even in aggressively growing
breast cancer cells. Pathways mediating these
actions include the MEK-ERK pathway. These
findings may have implications for more targeted therapeutic approaches that specifically
inhibit the autonomous proliferation of breast
cancer cells.
RUDOLF K. WERNER, PH.D.
Professor of Biochemistry and
Molecular Biology
DESCRIPTION OF RESEARCH
D
r. Werner’s research focuses on the regulation
of connexin43 expression. He and his colleagues had discovered that the 5’-UTR of
connexin43 mRNA contains a very active internal ribosome entry site (IRES) element that appears to be regulated by estrogen. His laboratory
continues to investigate this regulation in the
myometrium where connexin43 is produced at
parturition in response to estrogen. Dr. Werner’s
research also has demonstrated that in several
other tissues, such as heart and smooth muscle,
connexin43 pre-mRNA is alternatively spliced
producing mRNA with different 5’-UTRs but
identical coding regions. This finding suggests
that the expression of connexin43 is regulated at
the translational level in different tissues.
Dr. Werner and his colleagues discovered
alternatively spliced 5’-UTR-coding exons in five
other connexins. Again, the splicing seems to be
tissue-specific. They currently are investigating
whether some of these novel exons contain IRES
elements.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
Dr. Werner’s laboratory also is pursuing the
investigation of Ini, a novel transcription factor
that is involved in connexin43 gene regulation at
the transcriptional level. Knockout experiments
in Saccharomyces pombe indicated that the yeast
homolog of Ini is an essential protein. It appears
to be involved in the mRNA splicing process.
SELECTED PUBLICATIONS
2003
Oltra, E, Pfeifer, I, and Werner, R. Ini, a small
nuclear protein that enhances the response of the
connexin43 gene to estrogen. Endocrinology
144:3148-58, 2003.
HIGHLIGHTS/DISCOVERIES
• Demonstrated that, in humans, connexin43 is
expressed in the heart and the uterus, as well as
in many other tissues. Because it is an essential
protein (as determined in mice) that affects
early development, it is important to understand the mechanisms of its regulation of expression. In the uterus, connexin43 expression
is inducible by estrogen. This regulation is clinically important because women who suffer
from premature labor also express connexins
prematurely.
JAMES WYCHE, PH.D.
Professor of Biology
DESCRIPTION OF RESEARCH
O
ne of Dr. Wyche’s interests has been to understand how anti-cancer drugs induce
apoptosis (cell deaths) of cancer cells. Recently,
he and his colleagues studied how the natural
product camptothecin (CPT) and its semi-synthetic derivatives such as CPT-11, 9-amino-CPT
(9AC), and 9-nitro-CPT (9NC) induce apoptosis
of human colon cancer cells. Many aspects of the
mechanism by which these drugs exert their
death effect on cancer cells, however, remain
largely unknown. In recent years, Dr. Wyche and
his colleagues have used a cell model of human
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
colon cancer to demonstrate that treatment with
low doses of CPT induces senescence in the presence of a protein call p21. Apoptosis, however,
occurs in the absence of p21. Therefore, p21 is a
key determinant of the outcome of colon cancer
cells treated with CPT drugs at doses that are relevant to clinical application. Thus, CPT treatment of colon cancer cells with p21 should result
in disease stabilization, whereas CPT treatment
of p21-deficient colon cancer cells should result
in rapid apoptosis and disease regression.
It is well established that p21 inhibits cyclindependent kinases (Cdks) and several other factors, including proliferating cell nuclear antigens.
They hypothesize that inhibition of Cdks by p21
is essential to inhibit apoptosis and induce senescence. In this context, Dr. Wyche and his colleagues propose that a protein named E2F1 is
essential for apoptosis of colon cancer cells
treated with CPT. According to this hypothesis,
inhibition of Cdks should result in activation of
another protein, named retinoblastoma (Rb),
which in turn, inhibits E2F1 and consequentially
E2F1-dependant apoptosis. They also hypothesize that the ability of p21 to induce senescence
requires a protein called STAT1. To test their
hypothesis, Dr. Wyche’s laboratory currently is
using techniques to selectively alter the status of
Cdk, E2F1, Rb, and STAT1 genes in human
colon cancer cells. They will then investigate the
role of each protein in the process of apoptosis
and senescence in the colon cancer cells after
CPT treatment.
The information obtained from these investigations will provide a better insight into the
molecular pathways activated in colon cancer
cells after CPT treatment and eventually will lead
to specific experimental designs to completely
understand how CPTs affect colon cancer.
99
TUMOR CELL BIOLOGY PROGRAM
SELECTED PUBLICATIONS
HIGHLIGHTS/DISCOVERIES
2002
• The research activities in Dr. Wyche’s laboratory
focus on the use of natural products that induce
the death of cancer cells. They use several human tumor types, but predominantly colon
cancer cells, and exploit substances that damage
the cells’ genetic material with a specific effect
on killing or controlling the proliferation of
theses cells. Current research has led the team
to focus on key cellular proteins and manipulation of their genes that may eliminate protein
production. They then observe the concomitant
impact on cellular functions such as growth or
death of the target cancer cell.
Han, Z, Wei, W, Dunaway, S, Darnowski, JW,
Calabresi, P, Sedivy, J, Hendrickson, EA, Balan,
KV, Pantazis, P, and Wyche, JH. Role of p21 in
apoptosis and senescence of human colon cancer
cells treated with camptothecin. Journal of Biological Chemistry 277:17154-60, 2002.
Han, Z, Ribbizi, I, Pantazis, P, Wyche, J,
Darnowski, J, and Calabresi, P. The antibacterial
drug taurolidine induces apoptosis by a mitochondrial cytochrome c-dependent mechanism.
Anticancer Research 22:1959-64, 2002.
2003
Hu, X, Han, Z, Wyche, JH, and Hendrickson,
EA. Helix 6 of tBid is necessary but not sufficient
for mitochondrial binding activity. Apoptosis
8:277-89, 2003.
Pantazis, P, Han, Z, Balan, K, Wang, Y, and
Wyche, JH. Camptothecin and 9nitrocamptothecin (9NC) and anti-cancer, antiHIV, and cell-differentiation agents:
Development of resistance, enhancement of
9NC-induced activities, and combination treatments in cell and animal models. Anticancer Research 23:3623-38, 2003.
Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche,
J, Han, Z, and Pantazis, P. Differential susceptibility to 9-nitrocamptothecin (9-NC)-induced
apoptosis in clones derived from a human ovarian
cancer cell line: possible implications in the treatment of ovarian cancer patients with 9-NC. Anticancer Drugs 14:427-36, 2003.
100
TERESA A. ZIMMERS, PH.D.
Assistant Professor of Surgery
DESCRIPTION OF RESEARCH
D
r. Zimmers’ research aims to understand the
mechanisms regulating tissue homeostasis in
order to apply such knowledge to the prevention
and treatment of human disease. Recently, she
has focused on the roles of the transforming
growth factor-beta (TGF-ß) superfamily member—myostatin—in the regulation of skeletal
muscle and fat mass. Myostatin is a highly conserved gene expressed at high levels in skeletal
muscle and at low levels in white fat. Mice and
cattle lacking myostatin function develop skeletal
muscle hypertrophy and hyperplasia. Research
in Dr. Zimmers’ laboratory has shown that
overexpression of myostatin in mice produces
hypoglycemia along with a wasting syndrome
similar to the cachexia that complicates many
chronic diseases such as cancer, AIDS, and organ
failure. Concomitant over-expression of the
myostatin binding proteins, follistatin and
myostatin propeptide, inhibits this wasting, suggesting a means of interfering with endogenous
myostatin signaling in animals and patients.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR CELL BIOLOGY PROGRAM
Dr. Zimmers’ current research focuses on the
following questions:
1) Is dysregulation of the myostatin signaling
pathway involved in the etiology of muscle
wasting due to cancer, AIDS, congestive heart
failure, burn, or sepsis in mouse models and in
humans?
2) How does myostatin regulate muscle and fat
mass in vivo?
3) What are the target genes induced by
myostatin signaling?
4) How does myostatin influence glucose homeostasis?
5) How does myostatin-induced wasting differ
from that induced by cytokines such as
interleukin-6 (IL-6) or tumor necrosis factor
(TNF)?
Dr. Zimmers’ latest data derived from
microarray analysis of RNA from muscle cells
treated in vitro and in vivo with myostatin suggest
that myostatin may regulate skeletal muscle mass
on several levels, including by altering proteolysis,
cell proliferation and apoptosis, and cell energetics/metabolism. Using this approach, she has
identified a number of candidate genes that
might control skeletal muscle regulation in normal development and disease.
A second, long-standing focus of Dr.
Zimmers’ research is the remarkable phenomenon of liver regeneration, a striking manifestation of tissue growth regulation. The laboratory
has examined the roles of several members of the
TGF-ß superfamily in liver regeneration using
gene targeting, transgenesis and overexpression
studies. Using such strategies, they demonstrated
that the TGF-ß family members inhibin-ßC and
–ßE, alone and in combination, and bone morphogenetic protein (BMP)-9 are not essential for
liver regeneration after hepatectomy.
Dr. Zimmers’ current work, done in collaboration with Leonidas G. Koniaris, M.D., focuses
upon the role of the IL-6 signaling pathway in
hepatocyte proliferation. They have shown that
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
administering high levels of IL-6 to mice results
in profound liver growth (with concomitant peripheral cachexia) without activating known
growth factor signaling pathways. These results
suggest that IL-6 may be a hepatocyte mitogen.
Because elevated IL-6 levels also are associated
with human liver disease, however, their current
effort focuses upon identifying the mechanisms
by which IL-6 induces liver growth and facilitate
regeneration when administered acutely, but suppresses the regenerative response and potentially
contributes to progressive liver injury and failure
when present chronically.
Finally, a chance observation that mice
treated with high-dose IL-6 develop increased
intestinal growth (increased gut length, diameter,
and mass) has led to a third project examining
the role of IL-6 in epithelial cell proliferation in
the gut.
Dr. Zimmers’ ultimate goal is to apply what
is learned in the basic science laboratory to solving clinical problems, including the treatment of
patients with muscle wasting disorders, obesity,
diabetes, and liver disease.
SELECTED PUBLICATIONS
2002
Zimmers, TA , Davies, MV, Koniaris, LG,
Haynes, P, Tomkinson, KN, McPherron, AC,
Wolfman, NM, and Lee, S-J. Cachexia induced
by systemic myostatin administration in mice.
Science 296:1486-1488, 2002.
2003
Sean, JJ, Klover, PJ, Nowak, IA, Zimmers, TA ,
Koniaris, LG, Furlanetto, RW, and Mooney, RA.
Suppressor of cytokine signaling-3, a potential
mediator of interleukin-6 dependent insulin resistance in hepatocytes. Journal of Biological Chemistry 278:13740-13746, 2003.
101
TUMOR CELL BIOLOGY PROGRAM
Koniaris, LG, McKillop, IH, Schwartz, SI, and
Zimmers, TA . Liver regeneration. Journal of the
American College of Surgeons 197:634-59, 2003.
Zimmers, TA , McKillop, IH, Pierce, RH, Yoo,
JY, and Koniaris, LG. Massive liver growth in
mice induced by systemic interleukin 6 administration. Hepatology 38:326-34, 2003.
Klover, PJ, Zimmers, TA , Koniaris, LG, and
Mooney, RA. Chronic exposure to interleukin-6
causes hepatic insulin resistance in mice. Diabetes
52:2784-89, 2003.
102
HIGHLIGHTS/DISCOVERIES
• Demonstrated that overexpression of the TGFß family member, myostatin, leads to hypoglycemia and muscle and fat wasting despite
adequate food intake, suggesting a role for the
myostatin pathway in the etiology or treatment
of human wasting diseases such as cancer
cachexia.
• Observed that overexpression of the inflammatory cytokine IL-6 leads to hypoglycemia and
peripheral cachexia, along with increased liver
and bowel growth, suggesting a role for IL-6 in
human wasting syndromes and in treatment or
progression of liver disease, hepatocellular carcinomas, or short gut syndrome.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
TUMOR IMMUNOLOGY PROGRAM
PROGRAM LEADER
Diana M. Lopez, Ph.D.
Professor of Microbiology and Immunology
DESCRIPTION OF PROGRAM
T
he Tumor Immunology Program presently
consists of 15 faculty members from four different departments at the University of Miami
School of Medicine. The program comprises
multiple aspects of basic immunology and a substantial number of studies involving tumor systems and samples obtained from patients. The
program investigates numerous characteristics of
the immune system in relation to the development and treatment of cancer.
Lichtenheld, Mathias G., M.D.
Microbiology and Immunology
Lopez, Diana M., Ph.D.
Microbiology and Immunology
Malek, Thomas R., Ph.D.
Microbiology and Immunology
Podack, Eckhard R., M.D., Ph.D.
Microbiology and Immunology
Riley, Richard L., Ph.D.
Microbiology and Immunology
GOALS OF PROGRAM
Rosenblatt, Joseph D., M.D.
Medicine
1) Elucidate the mechanisms underlying the activities of innate and adaptive immune cells.
Thomas, Giovanna R., M.D.
Otolaryngology
2) Study various aspects of stem cell biology and
bone marrow transplantation.
Tolba, Khaled, M.D.
Medicine
3) Analyze the role of T cells and B cells in the
host defenses against tumors.
Torroella-Kouri, Marta, Ph.D.
Microbiology and Immunology
4) Study the mechanisms of tumor evasion of the
immune system.
Vincek, Vladimir, M.D., Ph.D.
Pathology
5) Devise novel immunotherapeutic protocols.
HIGHLIGHTS
PARTICIPANTS
Adkins, Rebecca D., Ph.D.
Microbiology and Immunology
Blomberg, Bonnie B., Ph.D.
Microbiology and Immunology
Jurecic, Roland, Ph.D.
Microbiology and Immunology
Lee, Kelvin P., M.D.
Microbiology and Immunology
Levy, Robert B., Ph.D.
Microbiology and Immunology
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Recent findings reveal that the primary function of interleukin 2 (IL-2) is the generation of
T regulatory cells and not T-cell proliferation
and sensitization to cell death as previously
thought. (T. Malek)
• During in vitro priming, IL-2 promotes subsequent engraftment and successful adoptive tumor immunotherapy by persistent memory
phenotypic CD8+ T cells. (T. Malek)
• Heatshock fusion vaccines generate CD8
cytotoxic T lymphocytes (CTL) without CD4
help; progress towards novel and efficient tumor-specific vaccines is underway. (E. Podack)
103
TUMOR IMMUNOLOGY PROGRAM
• CD30 is identified as a major negative regulator
of cytotoxic lymphocytes; blocking CD30 signals in vivo may enhance anti-tumor immune
responses. (E. Podack)
• A phase I study testing a vaccine therapy protocol in advanced non-small cell lung carcinoma
showed that the vaccine was safe and stimulated
an immune response. Clinical benefit was seen
in six patients. (E. Podack)
• A role for perforin in lymphocyte homeostasis
revealed that cytotoxicity by perforin is necessary to remove antigen-presenting cells and turn
off T-cell activation. (E. Podack)
• A unique peptide with immunoenhancing
properties has been identified in a secreted form
of human MUC1 and used in vaccination experiments. This peptide inhibits tumor development in the mammary cells transfected with the
secreted MUC1 and also protects against a variety of other tumor types. (D. Lopez)
• Thymuses of mammary tumor bearers are profoundly involuted, and this is not due to a decrease of the thymocytes proliferation. A minor
increase of apoptosis was noted; however, the
major cause of this phenomenon appears to be
an arrest at an early stage of differentiation, possibly brought about by the direct or indirect
effects of tumor derived factors. (D. Lopez and
R. Adkins)
• After allogeneic bone marrow transplant, the
recipient can resist the engraftment of transplanted donor stem cells by using immune responses, which do not involve the two major
pathways of T lymphocyte-mediated killing.
This is a surprising finding and demonstrates
that it is likely that for some transplants, different pathways in the recipient must be blocked
to help the transplanted bone marrow engraft.
(R. Levy)
104
• Lymphocytes, which were added to donor stem
cells before transplant to help or facilitate the
engraftment by these stem cells after transplant,
use different functions for the purposes of: 1)
helping to “seed” the stem cells in the recipient,
and 2) helping to maintain their permanent
presence. (R. Levy)
• Direct activation of protein kinase C (PKC)
causes normal human hematopoietic CD34+
stem cells to differentiate into dendritic cells
(DC). (K. Lee)
• PKC activation causes many myeloid leukemias
to differentiate into immunologically functional
“leukemic” DC. These cells have potential utility as “cellular” anti-leukemia vaccines. (K. Lee)
• Researchers identified two essential enhancers
of the perforin gene and demonstrated that they
are under the control of Stat5 molecules. This
work sheds molecular light on fundamental
principles of effector gene activation in cytotoxic lymphocytes. (M. Lichtenheld)
• Compromised humoral immune response in
aged individuals may be at least partially explained by antibody VH repertoire differences at
the pre-B cell level (before antigen selection).
(B. Blomberg)
• Breast cancer patients show improved immune
response after psychosocial intervention. (B.
Blomberg)
• The molecular deficits, which underlie dysfunctions in lymphocyte activity during old age,
have yet to be well characterized. The finding
that expression of a transcription factor (E47)
and surrogate light chains, both of which are
critical to B-lineage cell development, are decreased in aged B-cell precursors provides a molecular basis for understanding deficient
lymphopoiesis in senescence. (R. Riley)
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
REBECCA D. ADKINS, PH.D.
Associate Professor of Microbiology and
Immunology
DESCRIPTION OF RESEARCH
C
ancer in infants and children differs markedly from that in adults. For example, there
are some solid tumors that occur in children but
never or rarely develop in adults, including neuroblastoma, Wilms tumor, rhabdomyosarcoma,
osteosarcoma, hepatoblastoma, Ewing’s sarcoma,
and retinoblastoma. Moreover, solid tumors as
well as hematologic malignancies, such as acute
lymphoblastic leukemia (ALL) or acute myeloid
leukemia (AML), demonstrate distinct biological
features and responses to treatment in children
and adults. During the last half of the 20th century, great strides were made in improving survival rates of many pediatric cancers. This was
achieved largely by increasing the aggression of
chemotherapy treatments. Because of the high
intensity of current therapy, however, future improvements are unlikely to come from further
increases in chemotherapy intensity. Moreover,
chemotherapy is not ideal for use in children because of adverse side effects that can manifest in
later life. In this light, it appears that the improved survival of pediatric cancer patients is
awaiting the application of new therapeutic regimens.
One relatively new and especially promising
approach for treating cancers in adults is the
application of immunotherapy. A good deal of
attention is being paid to the possibility of
enhancing endogenous anti-tumor responses.
Because of the limitations with current therapies,
the idea of enhancing the anti-tumor responses of
children with cancer is very appealing. At the
present time, however, all hands are tied because
there simply is not enough known about the
neonatal/juvenile immune system to devise the
appropriate immunotherapeutic approaches.
Using a mouse model system, Dr. Adkins has
focused on studying the development of immune
system function in neonatal life. Her laboratory
has made many interesting and important
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
observations that have significantly broadened
the knowledge base of neonatal immunity. First,
Dr. Adkins and her colleagues have shown that,
unlike in adults, responses mediated by T lymphocytes differ in the newborn lymph nodes and
spleen. Second, they have found that neonates
show an abnormal persistence of anti-inflammatory T-cell responses following exposure to model
vaccine antigens. Third, they have demonstrated
definitively that the immature responses of neonatal T lymphocytes are due to inherent properties of this population of cells rather than
immature signals in the neonatal environment.
Lastly, they most recently discovered that the
properties of neonatal T lymphocytes are at least
partly due to an “imprinting” that occurs during
embryonic life. Currently, Dr. Adkins and her
colleagues are beginning to uncover the molecular regulation of the neonatal phenomenon.
These studies will aim at identifying new tools that
can be applied to enhancing neonatal immune
responses. It is becoming increasingly apparent
that murine newborns are immunologically quite
similar to human fetuses and infants. On this
basis, it reasonably can be argued that they stand
to learn a great deal about what is potentially
happening in humans by studying murine models. Thus, the long-term goal of these studies will
be to utilize the information gained here to devise
new strategies for the prevention and treatment
of pediatric cancer.
SELECTED PUBLICATIONS
2002
Muller-Sieburg, CE, Cho, RH, Thoman, M,
Adkins, B, and Sieburg, HB. Deterministic regulation of hematopoietic stem cell self-renewal and
differentiation. Blood 100:1302-9, 2002.
Adkins, B, Bu, Y, and Guevara, P. Murine neonatal CD4+ lymph node cells are highly deficient in
the development of antigen-specific Th1 function
in adoptive adult hosts. Journal of Immunology
169:4998-5004, 2002.
105
TUMOR IMMUNOLOGY PROGRAM
Lopez, DM, Charyulu, V, and Adkins, B. Influence of breast cancer on thymic function in mice.
Journal of Mammary Gland Biology and Neoplasia 7:191-9, 2002.
BONNIE B. BLOMBERG, PH.D.
Professor of Microbiology and Immunology
2003
R
Petito, CK, Adkins, B, McCarthy, M, Roberts, B,
and Khamis, I. CD4+ and CD8+ cells accumulate in the brains of acquired immunodeficiency
syndrome patients with human immunodeficiency virus encephalitis. Journal of
Neurovirology 9:36-44, 2003.
Adkins, B, Williamson, T, Guevara, P, and Bu, Y.
Murine neonatal lymphocytes show rapid early
cell cycle entry and cell division. Journal of Immunology 170:4548-56, 2003.
Auais, A, Adkins, B, Napchan, G, and
Piedimonte, G. Immunomodulatory effects of
sensory nerves during respiratory syncytial virus
infection in rats. American Journal of Physiology—Lung Cellular and Molecular Physiology
285:L105-13, 2003.
Adkins B, Bu Y, Vincek V, and Guevara P. The
primary responses of murine neonatal lymph
node CD4+ cells are Th2-skewed and are sufficient for the development of Th2-biased memory.
Clinical and Developmental Immunology 10:4351, 2003.
Adkins, B. Peripheral CD4+ lymphocytes derived
from fetal versus adult thymic precursors differ
phenotypically and functionally. Journal of Immunology 171:5157, 2003.
106
DESCRIPTION OF RESEARCH
esearch in Dr. Blomberg’s laboratory focuses
on two projects. One of those projects involves basic research on the molecular regulation
of B lymphopoiesis in mice. Generation of B
lymphocytes is important in cancer patients receiving bone marrow as well as in the normal
production of the humoral (antibody) response.
Aged humans and other mammals have a poorer
immune response to pathogens.
In collaboration with Richard L. Riley,
Ph.D., in the department of Microbiology and
Immunology, Dr. Blomberg has shown that aged
mice, those greater than or equal to about 80
percent of their full life span, have a substantial
decrease in the number of precursor B lymphocytes as well as the amount of the precursor B-cell
receptor (preBCR) including the surrogate light
chain (SLC)y5 and VpreB. Their data indicate
that this affects the antibody VH repertoire at the
pre-B cell level, i.e., before antigen selection.
More recent data indicate that the transcription
factor, E2A, is reduced in not only precursor B
cells but also in mature B cells in peripheral lymphoid organs in aging, leading to defects in Ig
class switch and humoral immunity. Current
studies will reveal the molecular and cellular
causes of these defects in the aged humoral immune response and attempt to reverse these defects. These studies are important for cancer for
two reasons: 1) the depressed immune response
seen in aged humans likely contributes to increased susceptibility to cancer, and 2) bone marrow transplantation given to many types of
cancer patients requires generation of mature B
lymphocytes from the precursors in the bone
marrow. Knowledge about the cellular and molecular requirements for B lymphopoiesis in
young and aged individuals should lead to improvements in the humoral immune system of
cancer patients.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
Another project in Dr. Blomberg’s laboratory
involves clinical research with breast cancer patients. In collaboration with Michael H. Antoni,
Ph.D., in the department of Psychiatry and Behavioral Sciences, Charles S. Carver, Ph.D., in the
department of Psychology, Sharlene Weiss, R.N.,
Ph.D., in the department of Medicine, and members of the Cancer Prevention and Control Program at the University of Miami Sylvester
Comprehensive Cancer Center, researchers are
measuring the status of various immune parameters in patients in response to psychosocial intervention (e.g., group therapy, stress reduction).
Preliminary experiments have shown that intervention patients have an improved immune response as seen by the ability of their T cells to
proliferate in response to an antigen-specific receptor stimulus (anti-CD3). Current studies are
measuring T, NK, and lymphokine-activated
killer cells (LAK) cytotoxic function as well as
potential TH1/TH2 differences by cytokine production resulting from T-cell stimulation. These
studies are important to allow optimal immune
response in cancer patients, which will better
detect and destroy residual cancer and allow for
better patient survival.
SELECTED PUBLICATIONS
2002
Jin, Y, Fuller, L, Carreno, M, Esquenazi, V,
Blomberg, BB , Wei, YT, Ciancio, G, Burke, GW
3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional and phenotypic properties of peripheral T
cells anergized by autologous CD3(+) depleted
bone marrow cells. Human Immunology 63:56775, 2002.
Burke, GW, Ciancio, C, Blomberg, BB , Rosen,
A, Suzart, K, Roth, D, Kupin, W, Esquenazi, V,
and Miller, J. Randomized trial of three different
immunosuppressive regimens to prevent chronic
renal allograft rejection. Transplantation Proceedings 34:1610-11, 2002.
Ricordi, C, Tzakis, A, and Miller, J. Human bone
marrow cells retrovirally transduced with the allogeneic class II gene, HLA-DR3beta, down regulate anti-allogeneic responses of autologous
lymphoid cells. Human Immunology 63:S19,
2002.
2003
Mathew, JM, Blomberg, BB, Fuller, L, Burke,
GW, Ciancio, G, Kenyon, N, Ricordi, C, Tzakis,
AG, Esquenazi, V, and Miller, J. A novel microcell-mediated lympholytic assay for the evaluation of regulatory cells in human alloreactive
CTL responses. Journal of Immunological Methods 272:67-80, 2003.
Blomberg, BB , Hussini, S, Fainman, H, Mathew,
JM, Hernandez, A, Carreno, M, Hnatyszyn, HJ,
Garcia-Morales, R, Fuller, L, Rosen, A, Ricordi,
C, Tzakis, A, Miller, J, and Esquenazi, V.
Retroviral transduction of an allogeneic class II
gene into human bone marrow down regulates
allo-immune reactivity. Human Immunology
64:S128, 2003.
Hernandez, A, Lindner, I, Blomberg, BB ,
Hussini, S, Burger, M, Mathew, JM, Carreno, M,
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,
Lee, KP, Miller, J, and Esquenazi, V. Suppression
of allogeneic T-cell proliferation through blocking
of NF-κB in the differentiation process of human
dendritic cells. Human Immunology 64:S128,
2003.
Mathew, JM, Alvarez, S, Vallone, T, Blomberg,
BB, Joshua, M, and Esquenazi, V. A humanSCID-mouse-islet transplant model for the evaluation of the regulatory activity of donor bone
marrow cells. Human Immunology 64:S7, 2003.
Van Der Put, E, Sherwood, EM, Blomberg, BB ,
and Riley, RL. Aged mice exhibit distinct B cell
precursor phenotypes differing in activation, proliferation, and apoptosis. Experimental Gerontology 38:1137-47, 2003.
Blomberg, BB , Mathew, J, Fainman, H, Hussini,
S, Carreno, M, Hnatyszyn, H, Garcia-Morales,
R, Fuller, L, Vallone, T, Rosen, A, Esquenazi, V,
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
107
TUMOR IMMUNOLOGY PROGRAM
Frasca, D, Nguyen, D, Van Der Put, E, Riley,
RL, and Blomberg, BB . The age-related decrease
in E47 DNA-binding does not depend on increased Id Inhibitory proteins in bone marrowderived B cell precursors. Frontiers in Bioscience
8:A110-16, 2003.
Frasca D, Nguyen D, Riley RL, and Blomberg,
BB. Effects of aging on proliferation and E47
transcription factor activity induced by different
stimuli in murine splenic B cells. Mechanisms of
Ageing and Development 124:361-69, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Frasca, D, Van der Put, E, Riley, RL, and
Blomberg, BB . Reduced Ig class switch in aged
mice correlates with decreased E47 and activation-induced cytidine deaminase. Journal of Immunology 172:2155-62, 2003.
HIGHLIGHTS/DISCOVERIES
• Compromised humoral immune response in
aged individuals may be at least partially explained by antibody VH repertoire differences at
the pre-B cell level (before antigen selection).
• Decreased transcription factor E2A is important
for decreased Ig class switch and optimal humoral immunity.
• Demonstrated improved immune response is
shown by breast cancer patients after psychosocial intervention.
ROLAND JURECIC, PH.D.
Assistant Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
T
he lifelong maintenance and regenerative capacity of the blood cell-forming (hematopoietic) system depend on self-renewal, lineage commitment, and differentiation of hematopoietic
stem cells (HSC) and progenitors. HSC hold tremendous promise for the development of stem
cell transplantation and cell and gene therapy
protocols for treatment of various diseases. Research in Dr. Jurecic’s laboratory focuses on: 1)
elucidation of genetic mechanisms that regulate
self-renewal, lineage commitment, and differentiation of HSC, 2) identification and functional
genetic analysis of novel genes that are involved
in the leukemogenesis, and 3) developmental
plasticity of HSC.
Molecular Genetics of Stem Cell Self-Renewal
and Maintenance
Self-renewal of stem cells in diverse species and
tissues suggests that evolutionarily conserved
mechanisms regulate this common feature. Dr.
Jurecic’s laboratory is studying the role of the evolutionarily conserved Pumilio family of RNAbinding proteins in self-renewal and maintenance
of mammalian hematopoietic and neural stem
cells. Gain of function experiments have shown
that: 1) overexpression of mouse Pum genes leads
to increased maintenance and suppression of
multilineage differentiation of HSC and
multipotent progenitors, and 2) Pum genes support maintenance and self-renewal of multipotent
hematopoietic cells through regulation of the
SCF/c-kit signaling pathway.
Molecular Genetics of Hematopoietic Stem Cell
Differentiation
The developmental cascade from HSC to mature
blood cells, defined by a series of commitment
steps that gradually restrict the developmental
potential of intermediate progenitor cells, is regu-
108
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
lated by an intricate network of genes. Through a
comprehensive gene expression analysis during
stem cell differentiation, Dr. Jurecic and his colleagues have identified a novel evolutionarily conserved RING finger protein FLRF (Rnf41).
During blood cell development, FLRF (fetal liver
ring finger) acts as an E3 ubiquitin ligase and affects proliferation and differentiation of HSC and
multipotent progenitors by regulating cytokine
receptor levels through ligand independent degradation. By regulating steady-state levels of
cytokine receptors, FLRF could be maintaining
optimal signaling for a proper cellular response
(proliferation, lineage commitment, differentiation) of HSC and progenitors, while preventing
oversignaling that could lead to leukemogenesis.
SELECTED PUBLICATIONS
Developmental Biology and Plasticity of
Hematopoietic Stem Cells
HSC may have the capacity to develop into cells
of unrelated tissue(s). This discovery could have
important implications for designing new stem
cell transplantation and cell therapy protocols for
treatment of various diseases. The aim of this
project is to analyze whether HSC possess the
potential for differentiation into cell types other
than that of blood lineages. To study the full developmental potential of HSC, Dr. Jurecic’s laboratory has developed a new in utero stem cell
transplantation assay, named blastocyst engraftment assay (BEA). BEA is based on microinjection of purified HSC into mouse preimplantation
embryos (blastocysts), similar to embryonic stem
(ES) cell technology. Using BEA, they have demonstrated that microinjected transgenic HSC successfully engraft fetal hematopoietic tissues (yolk
sac, fetal liver). They also obtained preliminary
evidence that mouse adult HSC have the capacity
to develop into fetal central nervous system
(CNS) and heart muscle cells. If adult HSC can
indeed develop into functional cells from unrelated tissues, this would permit the possibility of
using autologous HSC to treat disorders affecting
various tissues.
Spassov, DS and Jurecic, R. Mouse Pum1 and
Pum2 genes, members of the Pumilio family of
RNA-binding proteins, show differential expression in fetal and adult hematopoietic stem cells
and progenitors small star, filled. Blood Cells,
Molecules and Diseases 30:55-69, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
2002
Chen, AJ, Zhou, G, Juan, T, Colicos, SM, Cannon, JP, Cabriera-Hansen, M, Meyer, CF, Jurecic,
R, Copeland, NG, Gilbert, DJ, Jenkins, NA,
Fletcher, F, Tan, TH, and Belmont, JW. The dual
specificity JKAP specifically activates the c-Jun
N-terminal kinase pathway. Journal of Biological
Chemistry 277:36592-601, 2002.
Spassov, DS and Jurecic, R. Cloning and comparative sequence analysis of PUM1 and PUM2
genes, human members of the Pumilio family of
RNA-binding proteins. Gene 299:195-204,
2002.
2003
Komatsu, M, Mammolenti, M, Jones, M,
Jurecic, R, Sayers, TJ, and Levy, RB. Antigenprimed CD8+ T cells can mediate resistance, preventing allogeneic marrow engraftment in the
simultaneous absence of perforin-, CD95L-,
TNFR1-, and TRAIL-dependent killing. Blood
101:3991-99, 2003.
Spassov, DS and Jurecic, R. The PUF family of
RNA-binding proteins: does evolutionarily
conserved structure equal conserved function?
IUBMB Life 55: 359-66, 2003.
Liang, H, Chen, Q, Coles, AH, Anderson, SJ,
Pihan, G, Bradley, A, Gerstein, R, Jurecic, R, and
Jones, SN. Wnt5a inhibits B cell proliferation
and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4:349-60, 2003.
109
TUMOR IMMUNOLOGY PROGRAM
HIGHLIGHTS/DISCOVERIES
• Discovered Pum genes as an evolutionarily conserved intrinsic mechanism that supports the
self-renewal of HSC and multipotent progenitors by regulating the SCF/c-kit signaling pathway.
• Discovered a new E3 ubiquitin ligase that affects proliferation and differentiation of HSC
and multipotent progenitors by regulating
steady-state cytokine receptor levels through
ligand independent degradation, and that may
be involved in etiology of hematological malignancies.
• Found that the Wnt5a gene negatively regulates
B-cell proliferation, and that inactivation of
Wnt5a leads to development of myeloid leukemias and B-cell lymphomas. Discovery of the
deletion of the WNT5a gene and/or loss of
WNT5a expression in human primary leukemias, demonstrating for the first time that the
WNT5a gene functions as a tumor suppressor
(in collaboration with Stephen Jones, Ph.D.,
University of Massachusetts Medical School).
KELVIN P. LEE, M.D.
Associate Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
R
esearch in Dr. Lee’s laboratory focuses on
the cells and the molecules that play central
roles in initiating the adaptive immune response.
Understanding these interactions is essential for
developing effective immune-based therapies
against cancer. At the cellular level, they are specifically studying the dendritic cells (DC), which
are thought to be the most important professional antigen presenting cell (APC). Because
DC monitor the local environment for immunologic “danger” signals and control what antigens
are presented to T cells to activate them, they are
positioned to regulate the initiation of immune
110
responses. Their work has examined how DC
arise from hematopoietic progenitors and their
intracellular/genetic characteristics. They previously have reported that activation of the protein
kinase C (PKC) intracellular signal transduction
pathway in human hematopoietic CD34+ stem
cells causes direct differentiation to a pure population of DC. Thus, PKC signaling specifically
triggers the DC differentiation “program” in
these cells. Additionally, specific isoforms of PKC
appear to regulate specific aspects of DC differentiation. Ongoing studies are seeking to completely characterize the components of the PKC
signaling pathway and what genetic events are
triggered by this signal.
From a translational standpoint, researchers
in Dr. Lee’s laboratory have found that in
addition to normal cells, PKC activation can
drive DC differentiation in acute and chronic
myeloid leukemic blasts. Because these “leukemic” DC retain the ability to activate T cells and
are endogenously loaded with leukemia antigens,
they can potentially be used as “cellular” antileukemia vaccines by re-infusion back into patients. This work aims to bring this approach to
clinical trials.
In addition to the DC studies, a clinical trial
(headed by Dr. Lee) and basic laboratory research
currently are looking at novel agents against multiple myeloma (MM). The NCI-sponsored phase
I/II clinical trial is examining arsenic trioxide +
ascorbic acid in the treatment of refractory/relapsed MM. Initial results demonstrate that this
combination is effective against myeloma that is
resistant to standard chemotherapy (including
thalidomide) with acceptable toxicity. The laboratory component of these studies seeks to understand how arsenic kills myeloma, how ascorbic
acid potentiates that killing, how myeloma cells
become resistant to arsenic, and which host (i.e.,
patient) factors may actually help the myeloma
survive in the bone marrow.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
SELECTED PUBLICATIONS
2002
Strbo, N, Yamazaki, K, Lee, KP, Rukavina, D,
and Podack, ER. Heat shock fusion protein
gp96-Ig mediates strong CD8 CTL expansion in
vivo. American Journal of Reproductive Immunology 48:220-25, 2002.
Bahlis, NJ, McCafferty-Grad, J, JordanMcMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,
Eckman, J, Goodman, M, Fernandez, HF, Boise,
LH, and Lee, KP. Feasibility and correlates of
arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for
the treatment of relapsed/refractory multiple myeloma. Clinical Cancer Research 8:3658-68,
2002.
Gray, Parkin K, Stephan, RP, Apilado, RG, LillElghanian, DA, Lee, KP, Saha, B, and Witte, PL.
Expression of CD28 by bone marrow stromal
cells and its involvement in B lymphopoiesis.
Journal of Immunology 169:2292-302, 2002.
Baumgartner, R, Durant, P, van Gessel, Y,
Chattopadhyay, S, Beswick, RL, Tadaki, DK,
Lasbury, M, Lee, CH, Perrin, P, and Lee, KP. Evidence for the requirement of T cell costimulation
in the pathogenesis of natural Pneumocystis
carinii pulmonary infection. Microbial Pathogenesis 33:193-201, 2002.
McCafferty-Grad, J, Bahlis, NJ, Krett, N,
Aguilar, TM, Reis, I, Lee, KP, and Boise, LH.
Arsenic trioxide utilizes caspase-dependent and
caspase-independent death pathways in myeloma
cells. Molecular Cancer Therapeutics 2:1155-64,
2003.
Hernandez, A, Lindner, I, Blomberg, BB,
Hussini, S, Burger, M, Mathew, JM, Carreno, M,
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,
Lee, KP, Miller, J, and Esquenazi, V. Suppression
of allogeneic T cell proliferation through blocking of NF-KB in the differentiation process of
human dendritic cells. Human Immunology
64:S128, 2003.
HIGHLIGHTS/DISCOVERIES
• Direct activation of PKC causes normal human
hematopoietic CD34+ stem cells to differentiate
into DC.
• PKC activation causes many myeloid leukemias
to differentiate into immunologically functional
“leukemic” DC. These cells have potential utility as “cellular” anti-leukemia vaccines.
• Specific intracellular signaling pathways downstream of PKC activation control specific aspects of DC differentiation.
• Arsenic trioxide + ascorbic acid is an effective
combination in the treatment of refractory/relapsed myeloma.
2003
Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and
Harlan, DM. Porcine CD80: cloning, characterization, and evidence for its role in direct human
T-cell activation. Xenotransplantation 10:252-58,
2003.
Lindner, I, Kharfan-Dabaja, MA, Ayala, E,
Kolonias, D, Carlson, LM, Beazer-Barclay, Y,
Scherf, U, Hnatyszyn, JH, and Lee, KP. Induced
dendritic cell differentiation of chronic myeloid
leukemia blasts is associated with down-regulation of BCR-ABL. Journal of Immunology
171:1780-91, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
111
TUMOR IMMUNOLOGY PROGRAM
ROBERT B. LEVY, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
R
esearchers in Dr. Levy’s laboratory study the
immunological responses following allogeneic bone marrow transplantation (BMT), which
determine the success or failure of the hematopoietic graft. The primary objective of these studies is to define how different effector molecules
produced by transplanted donor T cells and by
barrier cells in the recipient regulate the development of graft versus host disease (GVHD) and
control hematopoietic engraftment, respectively.
The work concerning GVHD has focused
on elucidating the role of donor-mediated cytotoxicity against recipient cells following the transplant. Their findings have demonstrated that
differing pathways of cytotoxicity play different
roles in the GVHD process. Granule dependent
cytotoxicity dependent on perforin function is
important in the development and onset of the
disease. Cytotoxicity mediated by CD95L (FasL)
is an important pathway in the pathogenesis
occurring in the liver during GVHD and also can
contribute to cutaneous GVHD. Most interestingly, even when both of these molecular pathways are absent in donor T cells (i.e., when they
are “doubly cytotoxic deficient”), they remain
capable of inducing many GVHD symptoms and
death in recipients. Dr. Levy and his colleagues
have recently found that highly purified populations of CD8+ or CD4+ T cells lacking these killing functions also induce lethal GVHD posttransplant.
Researchers in this laboratory also investigate
the process of engraftment following BMT. These
studies examine the presence of defined donor
progenitor cell populations (lineage committed
and more primitive multi-lineage stem cells) and
peripheral chimerism in recipients post-transplant. They are interested in understanding the
mechanisms used by: 1) donor lymphoid cells for
their facilitation and support of progenitor cells
and engraftment after transplant, and 2) barrier
cells in the host, which inhibit progenitor cells
112
and engraftment. Their recent findings have surprisingly demonstrated that total body irradiated
BMT recipients lacking both perforin- and
CD95L-dependent mechanisms maintain strong
barrier function. Thus, efforts directed at diminishing the host’s ability to affect cytotoxicity
through these pathways are unlikely to facilitate
the engraftment process. Transplant of progenitor
cells with defined cytokine receptor deficiencies
will be used to further investigate the molecules
involved. Recent studies also have documented
that during the first month following BMT, there
are two defined stages of engraftment, i.e., an
early period when progenitor cells from the donor are present in the recipient followed by a later
period during which time such cells may be
eliminated. These findings show that cytotoxic
function via perforin and FasL is not necessary to
establish early progenitor presence but is required
for the establishment of long-term chimerism in
the recipient.
SELECTED PUBLICATIONS
2002
Jiang, Z, Adams, GB, Hanash, AM, Scadden,
DT, and Levy, RB. The contribution of cytotoxic
and noncytotoxic function by donor T-cells that
support engraftment after allogeneic bone marrow transplantation. Biology of Blood and Marrow Transplantation 8:588-96, 2002.
Chill, JH, Nivasch, R, Levy, RB, Albeck, S,
Schreiber, G, and Anglister, J. The human interferon receptor: NMR-based modeling, mapping
of the IFN-alpha 2 binding site, and observed
ligand-induced tightening. Biochemistry
41:3575-85, 2002.
Levy, RB and Aoki, C. Alpha7 nicotinic acetylcholine receptors occur at postsynaptic densities
of AMPA receptor-positive and -negative excitatory synapses in rat sensory cortex. The Journal of
Neuroscience 22:5001-15, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
2003
Yu, A, Zhou, J, Marten, N, Bergmann, CC,
Mammolenti, M, Levy, RB, and Malek, TR. Efficient induction of primary and secondary T celldependent immune responses in vivo in the
absence of functional IL-2 and IL-15 receptors.
Journal of Immunology 170:236-42, 2003.
HIGHLIGHTS/DISCOVERIES
• After allogeneic BMT, the recipient can resist
the engraftment of transplanted donor stem
cells by using immune responses, which do not
involve the two major pathways of T lymphocyte-mediated killing. This is a surprising finding and demonstrates that it is likely that for
some transplants, different pathways in the recipient must be blocked to help the transplanted bone marrow engraft.
• Lymphocytes that are added to donor stem cells
before transplant to help or facilitate the engraftment by these stem cells after transplant,
use different functions for the purposes of: 1)
helping to “seed” the stem cells in the recipient,
and 2) helping to maintain their permanent
presence.
MATHIAS G. LICHTENHELD, M.D.
Associate Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
C
ytotoxic lymphocytes defeat tumors and virus infections. Their prevailing mechanism
to kill the diseased targets requires a unique organelle—the cytotoxic granule. Perforin,
granzyme A, and granzyme B constitute the
prototypic killer molecules of the granule, which
collaborate to induce the target to commit suicide. Researchers in Dr. Lichtenheld’s laboratory
investigate which genes and transcriptional
mechanisms promote the identity and function
of cytotoxic lymphocytes through their endowment with cytotoxic granules. Recently, his labo-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
ratory has shown that the activation and differentiation of cytotoxic lymphocytes involves the Stat
signaling pathway and epigenetic controls of the
perforin gene. Interestingly, distal regulatory elements rather than proximal promoter elements
are involved, suggesting long-range changes of
the chromatin structure, which are under investigation along with the further characterization of
the far-distal enhanceosomes that may comprise a
locus control-like region. To study the hierarchy
of nuclear events induced during the differentiation process, these researchers are characterizing
transcription factors differentially expressed in
cDNA subtractions and nuclear proteins differentially present in proteomic analyses of 2D gels.
The functional analysis of the respective genes is
undertaken in transgenic mice and a unique
model cell line for the maturation process of cytotoxic lymphocytes in which cytokine receptor
signals determine the maturation process of cytotoxic lymphocytes but not their growth and survival.
Frequently, dysregulation of signaling pathways is an essential component of hematopoietic
malignancies. A particular example is multiple
myeloma (MM), an incurable B-cell malignancy.
The goal of a new project is to develop preclinical
therapies defined at the molecular level. To that
end, Dr. Lichtenheld’s laboratory has shown that
the farnesyl transferase inhibitor R115777,
known to inhibit Ras signaling, kills MM cell
lines despite Ras prenylation, implying participation of Ras-independent mechanism(s). This
mechanism requires activation of caspase-9. The
molecular components of this pathway and their
characterization are under investigation.
SELECTED PUBLICATIONS
2002
Zhou, J, Zhang, J, Lichtenheld, MG, and Meadows, GG. A role for NF-kappa B activation in
perforin expression of NK cells upon IL-2 receptor signaling. Journal of Immunology 169:131925, 2002.
113
TUMOR IMMUNOLOGY PROGRAM
2003
Lu, Q, Wu, A, Ray, D, Deng, C, Attwood, J,
Hanash, S, Pipkin, M, Lichtenheld, MG, and
Richardson, B. DNA methylation and chromatin
structure regulate T-cell perforin gene expression.
Journal of Immunology 170:5124-32, 2003.
Beaupre, D, Grad, J, Bahlis, N, Boise, L, and
Lichtenheld, MG. Farnesyl transferase inhibitors
sensitize to death receptor signals and induce
apoptosis of multiple myeloma cells. Leukemia &
Lymphoma 44:2123-34, 2003.
HIGHLIGHTS/DISCOVERIES
• Successfully cloned mouse and human perforin
genes, including the functional identification of
the complete transcriptional territory.
• Identified Stat5 as a central player in lymphocyte-mediated cytotoxicity.
• Developed a novel method to detect regulatory
domains in up to 100,000 bp restriction fragments.
• Demonstrated Ras-independent, caspases 9dependent cell death of MM by farnesylation
inhibitors.
DIANA M. LOPEZ, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
M
atrix metalloproteinase-9 (MMP-9), a matrixdegrading enzyme, is crucial in tumor
invasion and metastasis and is implicated in
leukocyte extravasation. Dr. Lopez and her colleagues have demonstrated that during growth of
the D1-7, 12-dimethylbenzanthracene-3 mammary tumor in BALB/c mice, there is progressive
up-regulation of MMP-9 in splenic T cells at
both the transcriptional and translational levels.
Their previous work has identified several factors
produced by this tumor, including PGE2, granulocyte macrophage-colony stimulating factor
(GM-CSF), and phosphatidyl serine; however,
114
none of these agents induces increased production of MMP-9 by normal splenic T cells.
Although not produced by the tumor, tumor necrosis factor-alpha (TNF-α), and interleukin-6
(IL-6) are up-regulated in both macrophages and
B cells in tumor-bearing mice. Exposure of normal T cells to these two cytokines, however, also
fails to up-regulate MMP-9 production. Vascular
endothelial growth factor (VEGF) is produced by
many tumors, and it was determined that the
mammary tumors used in studies express high
levels of this angiogenic growth factor. Importantly, splenic T cells from tumor bearers constitutively produce increased amounts of VEGF,
and treatment of normal T cells with VEGF results in up-regulated MMP-9 production. Of
crucial importance is their finding that tumorinfiltrating T cells also produce high levels of
VEGF and MMP-9. Studies indicate that VEGF
can act directly on T lymphocytes and that elevated VEGF levels may contribute to the aberrant MMP-9 secretion by mammary tumor
bearers’ T cells.
Development of mammary tumors results in
profound down-regulation of macrophage
functions. Dr. Lopez and her colleagues have
previously described that peritoneal elicited macrophages (PEMs) from mice-bearing large mammary tumors have profoundly depressed
production of IL-12 and nitric oxide (NO).
Analysis of the molecular events occurring during
these down-regulations has revealed that the
mRNA expression of both IL-12p40 and the inducible nitric oxide synthase (iNOS) appears to
be diminished. An analysis of transcription factors that might be involved in such phenomena
was undertaken, using electromobility shift assay
(EMSA). The major transcription factors reported to be involved in the synthesis of IL12p40 are NFκB, C/EBP, ets (PU.1), and AP-1.
In the case of iNOS, NFκB is the major transcription factor reported to be involved. Recent
evidence using transfection experiments with
dominant negative mutants suggest that C/EBP
and ATF-2 also may be involved in the regulation
of the iNOS promoter. Comparative studies by
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
EMSA, using probes specific for the IL-12p40
and iNOS murine promoters, revealed that in
macrophages from tumor-bearing mice, the binding activities of NFκB and C/EBP are downregulated in both promoters. Their results suggest
that in macrophages from tumor hosts, the
NFκB and C/EBP might be functionally impaired. These two transcription factors are crucial
for appropriate innate immunity functions. Pertinent studies are ongoing in Dr. Lopez’s laboratory
to determine if these deficiencies in the presence
of the tumor environment could be due to insufficient amounts, inadequate levels of phosphorylation, or impaired translocation of these
transcription factors.
Implantation of DA-3 mammary tumor
cells into BALB/c mice results in tumor growth,
metastatic lesions, and death. These cells were
transfected with genes encoding for either
the transmembrane (DA-3/TM) or secreted
(DA-3/sec) form of human mucin 1 (MUC1).
Although the gene for the secreted form lacks the
transmembrane and cytoplasmic domains, the 5’
sequences of these mucins are identical. However,
the gene for the secreted mucin isoform ends
with a sequence encoding for a unique 11 amino
acid peptide. The DA-3/TM cells or DA-3 cells
transfected with the neomycin vector only (DA3/neo) have the same in vivo growth characteristics as the parent cell line. In contrast, DA-3/sec
cells implanted in nude mice resulted in tumor
development verifying the tumorigenic potential
of these cells. Pre-exposure of BALB/c mice to
DA-3/sec cells afforded protection against challenge with DA-3/TM or DA-3/neo mammary
tumors and the unrelated tumors K7, an osteosarcoma, and RENCA, a renal cell carcinoma.
Partial protection against subsequent tumor
challenges was also achieved by substituting
the 11 amino acid peptide found only in the
secreted mucin-1 isoform, as it also retarded the
growth of Lewis lung carcinoma cells in C57
BL/6 mice. These findings reveal that a unique
peptide present in the secreted MUC1 has
immunoenhancing properties and may be a
potential agent for use in immunotherapy.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SELECTED PUBLICATIONS
2002
Sun, QL, Charyulu, V, Lobo, D, and Lopez,
DM. Role of thymic stromal cell dysfunction in
the thymic involution of mammary tumor-bearing mice. Anticancer Research 22:91-6, 2002.
Lopez, DM, Charyulu, V, and Adkins, B. Influence of breast cancer on thymic function in mice.
Journal of Mammary Gland Biology and Neoplasia 7:191-99, 2002.
2003
Torroella-Kouri, M, Keith, JC, Ivanova, M, and
Lopez, DM. IL-11-induced reduction of C/EBP
transcription factor binding may contribute to
the IL-12 downregulation in tumor-bearing mice.
International Journal of Oncology 22:439-48,
2003.
Owen, JL, Iragavarapu-Charyulu, V, GunjaSmith, Z, Herbert, LM, Grosso, JF, and Lopez,
DM. Up-regulation of matrix metalloproteinase9 in T lymphocytes of mammary tumor bearers:
role of vascular endothelial growth factor. Journal
of Immunology 171(8):4340-51, 2003.
Torroella-Kouri, M and Lopez, D. Mammary
tumor derived TGF-β impairs crucial innate immune responses in tumor hosts. Journal of Immunology and Immunopathology 5:31-38, 2003.
HIGHLIGHTS/DISCOVERIES
• The thymus is crucial for the development of
T lymphocytes involved in cell-mediated immunity to tumors. The thymuses of mammary
tumor bearers are profoundly involuted and
their studies have shown that this is not due to
a decrease of the thymocytes proliferation. A
minor increase of apoptosis was noted; however,
the major cause of this phenomenon appears to
be an arrest at an early stage of differentiation
possibly brought about by the direct or indirect
effects of tumor derived factors.
• A unique peptide with immunoenhancing
properties has been identified in a secreted form
of human MUC1 and used in vaccination ex115
TUMOR IMMUNOLOGY PROGRAM
periments. This peptide inhibits tumor development not only in the mammary cells transfected
with the secreted MUC1, but also provides protection against a variety of other tumor types.
• The very important molecule MMP-9 has been
shown to be overproduced by T lymphocytes from
tumor bearing mice due in part to the overexpression of vascular endothelial growth factor.
The intriguing possibility that this molecule
may be helping tumor spread is being evaluated.
THOMAS R. MALEK, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
T
he development of lymphocytes and the
regulation of the immune response are critically controlled by cytokines that mediate their
function by binding to specific multi-subunit cell
surface receptors. Recent evidence by others has
established that the genetically inherited X-linked
severe combined immunodeficiency disease
(SCID) is the result of mutations in the γc cytokine
receptor subunit that is a shared component of
the receptors for interleukin-2 (IL-2), IL-4, IL-7,
IL-9, and IL-15. This genetic defect prevents the
function of these five cytokines, resulting in a
severe blockade in T-lymphocyte development
and a greatly impaired immune system. These
cytokines and receptors are also important regulators of the peripheral immune compartment.
A long-term goal of Dr. Malek’s laboratory
is to understand the role of cytokine receptors,
especially the IL-2 receptor, in the regulation of
the immune system. A current research emphasis
is to establish the molecular basis by which the γc
subunit contributes to binding multiple cytokines
as a component of five cytokine receptors and to
determine the mechanism by which γc utilizing
cytokines control T-cell development and function. Another major aim of his laboratory is to
study the interaction of tumor-specific T cells
with its cognate tumor to define the mechanisms
responsible for failed anti-tumor immunity and
116
to develop new strategies to more effectively engage the immune system to reject tumors.
Related to these goals, progress has been
made in the following areas: 1) distinct functional regions of the extracytoplasmic domain of
γc have been defined and demonstrate that IL-2
and IL-7 utilize largely overlapping sites within
γc; 2) a cytoplasmic subdomain of γc was identified that is critical for rapid IL-2-induced receptor-mediated endocytosis, which occurs by a
novel proteasome dependent pathway; 3) IL-7
and IL-15 were found to be the essential gc-dependent cytokines important for thymic-dependent T-cell development, while IL-2, IL-7, and
IL-15 are required for the full production of
intraepithelial T lymphocytes, a second anatomical site of T-cell development; 4) separate cytoplasmic domains of the IL-7Rα chain controlled
distinct activities during T-cell development,
while normal IL-7R-dependent thymic development requires the integrated activity of all these
domains; 5) a novel and unexpected role for IL-2
in thymic development was uncovered that is essential to prevent autoimmunity and is related to
the production of T regulatory cells; and 6) one
important reason for failed anti-tumor immunity
is that tumor-specific T cells are ignorant of the
growing tumor. Memory T cells, however, were
shown not to be ignorant and induced effective
anti-tumor immune responses. Importantly, a
dendritic cell (DC)-based vaccine potently functioned to induce tumor immunity, which sometimes may lead to the rejection of the tumor.
SELECTED PUBLICATIONS
2002
Olosz, F and Malek, TR . Structural basis for
binding multiple ligands by the common
cytokine receptor gamma-chain. Journal of Biological Chemistry 277:12047-52, 2002.
Demirci, G, Gao, W, Zheng, XX, Malek, TR,
Strom, TB, and Li, XC. On CD28/CD40 ligand
costimulation, common gamma-chain signals,
and the alloimmune response. Journal of Immunology 168:4382-90, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
Malek, TR , Yu, A, Vincek, V, Scibelli, P, and
Kong, L. CD4 regulatory T cells prevent lethal
autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2.
Immunity 17:167-78, 2002.
Malek, TR . T helper cells, IL-2 and the generation of cytotoxic T-cell responses. Trends in Immunology 23:465-67, 2002.
2003
Molano, RD, Pileggi, A, Berney, T, Poggioli, R,
Zahr, E, Oliver, R, Malek, TR , Ricordi, C, and
Inverardi, L. Long-term islet allograft survival in
nonobese diabetic mice treated with tacrolimus,
rapamycin, and anti-interleukin-2 antibody.
Transplantation 75:1812-19, 2003.
Bathe, OF, Dalyot-Herman, N, and Malek, TR.
Therapeutic limitations in tumor-specific CD8+
memory T cell engraftment. BMC Cancer 3:21,
2003.
HIGHLIGHTS/DISCOVERIES
• Established that the essential non-redundant
function of IL-2 is the development of
CD4+CD25+ T regulatory cells.
ECKHARD R. PODACK, M.D., PH.D.
Professor and Chairman of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
Induction of Immunity by Heat Shock
Protein gp96-Ig
Heat shock protein gp96 is a natural adjuvant
and a peptide chaperone binding to antigen
presenting cells (APC) inducing APC activation,
maturation, and channeling gp96-associated
peptides into the class I major histocompatibility
complex (MHC) presentation pathway for
priming CD8 cytotoxic T lymphocyte (CTL)
responses. Gp96 is unique in that it provides
antigenicity and peptide-specificity through its
peptide chaperone function and adjuvanticity
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
through its ability to bind to scavenging receptors
and toll-like receptors (TLRs) and to activate
APC. Realizing the potential of gp96 as a vaccine,
Dr. Podack’s laboratory had previously created a
gp96-Ig fusion protein that is secreted from tumor cells upon transfection. In murine studies,
tumor secreted gp96-Ig induced specific CD8
cytotoxic T lymphocyte (CTL) expansion and,
when used as vaccine, mediated tumor rejection
and long lasting tumor immunity by CD8 cells
with the help of natural killer (NK) cells. Murine
preclinical data suggest that human tumor cells
secreting gp96-Ig will be a powerful, therapeutic
CD8 CTL vaccine, because gp96-Ig provides
both the adjuvant effect and the specific peptides
for dendritic cell (DC) activation and presentation.
Tumor secreted gp96-Ig recruits and activates DC and NK cells, and causes CD8 CTL
expansion. The molecular determinants of the
three-way cell interaction are studied by Dr.
Podack and his colleagues. The potential of gp96Ig to break immune tolerance to tumors is also
under investigation.
Death Receptor and its Ligand TL1a Mediate
TH2 Switch and Contribute to Asthma
The biological function of death receptor 3
(DR3, TNFR-SF12) is not known. DR3transgenes expressed on T cells were used to determine the physiological function of DR3, a
member of the tumor necrosis factor (TNF)receptor family expressing an intracellular death
domain. The full-length form of DR3, a dominant negative form of DR3 (DR3-DN) lacking
the intracellular death domain and an alternatively spliced form of DR3 (DR3-∆5, 6) lacking
exon 5 and 6 encoding the fourth extracellular
cysteine rich domain, was analyzed by Dr.
Podack’s laboratory. Transgenic expression of
DR3 on T cells mediated TH2 polarization of
cytokine and antibody production upon T-cell
activation and antigen exposure. In addition,
DR3 partially inhibited T-cell receptor (TCR)
driven proliferation of CD4 and CD8 cells and
reduced total T cell numbers in lymphoid organs
without inducing apoptosis. CD8 cells were more
117
TUMOR IMMUNOLOGY PROGRAM
affected by DR3 than CD4 cells. They concluded
that DR3 signals may be important in effector
responses to pathogens by shaping the ensuing
polarization toward TH2 or toward a mixed
TH1/TH2 response.
DR3 transgenic mice were highly susceptible
to antigen-induced airway hyper-reactivity in an
asthma model in mice and produced increased
quantities of interleukin-13 (IL-13) and eosinophils in the lung upon antigen exposure by inhalation. Transgenic mice expressing a dominant
negative form of DR3 showed increased resistance to airway hyper reactivity when compared
to wild type mice. Similarly, a blocking antiTL1a antibody was able to ameliorate asthma in
wild type mice, indicating that DR3 and TL1a
are involved in the pathogenesis of asthma.
CD30—Governor of T Cells?
CD30-L knock-out mice, when challenged with
tumor secreted gp9-Ig, exhibit severely diminished CD8 CTL expansion. When used as allogeneic bone marrow graft recipients, collaboration
with the laboratory of Robert B. Levy, Ph.D.,
showed that CD30-L knock-out exhibit diminished graft versus host disease in a MHC II mismatch. CD30 is highly expressed on CD45-RO
memory cells and serves as a T-cell costimulator
and as a regulator of trafficking molecules and of
pro- and anti-apoptotic molecules. CD30 signals
lead to IL-13 and Ifn-g production. Researchers
in Dr. Podack’s laboratory are studying the function of CD30 and its ligand in tumor rejection
following vaccination.
Immunotherapy for Advanced Non-Small Cell
Lung Carcinoma
To determine whether CD8-mediated immune
responses could be elicited in stage IIIB/IV nonsmall cell lung carcinoma (NSCLC) patients, 19
subjects were immunized several times with allogeneic NSCLC cells transfected with CD80
(B7.1) and HLA-A1 or A2. Patients enrolled
were matched or unmatched at the HLA A1 or
A2 locus and their immune response compared.
Immunization significantly increased the fre118
quencies of interferon-γ secreting CD8 T cells in
all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of
matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did
not react to K562. Clinically, 6 of 19 patients
responded to immunization with stable disease or
partial tumor regression. The study demonstrates
that CD8 Ifn-γ responses against non-immunogenic or immunosuppressive tumors can be
evoked by cellular vaccines even at advanced
stages of disease. The positive clinical outcome
suggests that non-immunogenic tumors may be
highly susceptible to immune effector cells generated by immunization. Further trials with curative intent are warranted.
Macrophage-Perforin, a New Member of the
Perforin/C9 Family of Proteins
Searching the genomic database with perforin as
query sequence, Dr. Podack and colleagues found
two novel members of the perforin family. Structure analysis suggests that the novel members
have a typical pore-forming domain but that the
proteins themselves are membrane anchored. Expressed sequence tags (EST) analysis suggests that
one new perforin member is expressed in trophoblast cells, while the second member is expressed
in macrophages. The laboratory has cloned the
macrophage-perforin (MΦ-Pf) and fused a gfp
tag to it for ease of detection. Expression of MΦPf-gfp in NIH 3T3 cells and in 293T cells results
in fluorescence in the nucleus and in the cytoplasm. Fluorescent cells, however, subsequently
round up and die, and after several days no fluorescence is detected. The data suggest that expression of MΦ-Pf leads to cell death, putatively by
ectopic expression of a pore former. The data further suggest that MΦ-perforin and trophoblastperforin have essential lytic functions that need to
be carefully regulated for expression. Dr. Podack’s
laboratory team is in the process of deleting MΦPf and trophoblast-Pf in order to discover their
physiological function.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
SELECTED PUBLICATIONS
2002
Metkar, SS, Wang, B, Aguilar-Santelises, M, Raja,
SM, Uhlin-Hansen, L, Podack, ER, Trapani, JA,
and Froelich, CJ. Cytotoxic cell granule-mediated
apoptosis: perforin delivers granzyme B-serglycin
complexes into target cells without plasma membrane pore formation. Immunity 16:417-28,
2002.
Kawasaki, C, Ohshima, K, Muta, H, Muta, K,
Deyev, V, Podack, ER, and Kikuchi, M. Prognostic value of Bcl 10 rearrangement in diffuse large
B-cell lymphoma. Leukemia & Lymphoma
43:823-26, 2002.
Merger, M, Viney, JL, Borojevic, R, SteeleNorwood, D, Zhou, P, Clark, DA, Riddell, R,
Maric, R, Podack, ER, and Croitoru, K. Defining the roles of perforin, Fas/FasL, and tumour
necrosis factor alpha in T cell induced mucosal
damage in the mouse intestine. Gut 51:155-63,
2002.
Harlin, H, Podack, ER, Boothby, M, and Alegre,
ML. TCR-independent CD30 signaling selectively induces IL-13 production via a TNF receptor-associated factor/p38 mitogen-activated
protein kinase-dependent mechanism. Journal of
Immunology 169:2451-59, 2002.
Nam, SY, Cho, KS, Heo, YM, Ha, JC, Kim, YH,
Keun Yi, H, Han Hwang, P, Kim, HM, and
Podack, ER. Regulation of lymphocyte clustering
by CD30-mediated ICAM-1 up-regulation. Cellular Immunology 219:38-47, 2002.
Laskarin, G, Tokmadzic, VS, Strbo, N, Bogovic,
T, Szekeres-Bartho, J, Randic, L, Podack, ER,
and Rukavina, D. Progesterone induced blocking
factor (PIBF) mediates progesterone induced suppression of decidual lymphocyte cytotoxicity.
American Journal of Reproductive Immunology
48:201-9, 2002.
Par, G, Rukavina, D, Podack, ER, Horanyi, M,
Szekeres-Bartho, J, Hegedus, G, Paal, M,
Szereday, L, Mozsik, G, and Par, A. Decrease in
CD3-negative-CD8dim(+) and Vdelta2/
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Vgamma9 TcR+ peripheral blood lymphocyte
counts, low perforin expression and the impairment of natural killer cell activity is associated
with chronic hepatitis C virus infection. Journal
of Hepatology 37:514, 2002.
Strbo, N, Yamazaki, K, Lee, K, Rukavina, D, and
Podack, ER. Heat shock fusion protein gp96-Ig
mediates strong CD8 CTL expansion in vivo.
American Journal of Reproductive Immunology
48:220-25, 2002.
Tokmadzic, VS, Tsuji, Y, Bogovic, T, Laskarin, G,
Cupurdija, K, Strbo, N, Koyama, K, Okamura,
H, Podack, ER, and Rukavina, D. IL-18 is
present at the maternal-fetal interface and enhances cytotoxic activity of decidual lymphocytes.
American Journal of Reproductive Immunology
48:191-200, 2002.
Podack, ER, Strbo, N, Sotosec, V, and Muta, H.
CD30-governor of memory T cells? Annals of the
New York Academy of Sciences 975:101-13,
2002.
2003
Dai, J, Liu, B, Caudill, MM, Zheng, H, Qiao, Y,
Podack, ER, and Li, Z. Cell surface expression of
heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of
tumor-specific T cell memory. Cancer Immunity
3:1, 2003.
Dix, RD, Podack, ER, and Cousins, SW. Loss of
the perforin cytotoxic pathway predisposes mice
to experimental cytomegalovirus retinitis. Journal
of Virology 77:3402-8, 2003.
Strbo, N, Oizumi, S, Sotosek-Tokmadzic, V, and
Podack, ER. Perforin is required for innate and
adaptive immunity induced by heat shock protein gp96. Immunity 18:381-90, 2003.
Gulan, G, Ravlic-Gulan, J, Strbo, N, Sotosek, V,
Nemec, B, Matovinovic, D, Rubinic, D, Podack,
ER, and Rukavina, D. Systemic and local expression of perforin in lymphocyte subsets in acute
and chronic rheumatoid arthritis. Journal of
Rheumatology 30:660-70, 2003.
119
TUMOR IMMUNOLOGY PROGRAM
Dix, RD, Podack, ER, and Cousins, SW. Murine
cytomegalovirus retinitis during retrovirus-induced immunodeficiency (MAIDS) in mice:
interleukin-2 immunotherapy correlates with increased intraocular levels of perforin mRNA. Antiviral Research 59:111-19, 2003.
Raez, L, Cassileth, PA, Schlesselman, JJ,
Padmanabhan, S, Fisher, EZ, Baldie, PA,
Sridhar, K, and Podack, ER. Induction of CD8
T-cell-Ifn-γ response and positive clinical outcome after immunization with gene-modified
allogeneic tumor cells in advanced non-small-cell
lung carcinoma. Cancer Gene Therapy 10:85058, 2003.
HIGHLIGHTS/DISCOVERIES
cell transition, a developmental step that requires
both function of the pre-B cell receptor complex
and responses to the growth and survival cytokine
interleukin-7 (IL-7). Expression of a critical component of the pre-B cell receptor, the surrogate
light chain, is reduced in aged mice, and IL-7
responsiveness is diminished. This predisposes the
B-cell precursors in aged mice to apoptotic cell
death. These functions, and others important to
B-cell development, are governed, in part, via the
transcriptional regulator E2A. E2A expression
also is compromised in old age; this appears to
involve enhanced degradation of E2A proteins.
As a consequence of the B-cell developmental
deficits in old age, the repertoire of antibody
specificities is skewed and the capacity to develop
effective immune responses is hindered.
• Completed successful lung tumor vaccine trial.
• Discovered that MΦ-perforin, a new member
of the perforin family, promises interesting discoveries.
• Discovered that death receptor 3 does not kill,
but produces, IL-13, which is immunosuppressive and mediates asthma.
• Realized potential of heat shock proteins to
enter the clinical field of immunotherapy.
RICHARD L. RILEY, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
Altered B Cell Development in Senescence
Senescent mice show diminished B lymphopoiesis when compared to young mice and typically
exhibit decreased numbers of pre-B cells and
newly formed B cells within the bone marrow.
Researchers in Dr. Riley’s laboratory have focused
upon elucidating the mechanisms responsible for
the altered B lymphopoiesis in old age and the
ramifications for antibody repertoire and humoral immunity. In particular, he and his colleagues have found that B lymphopoiesis in old
age is partially interrupted at the pro-B to pre-B
120
SELECTED PUBLICATIONS
2002
Riley, RL, Knowles, J, and King, AM. Levels of
E2A protein expression in B cell precursors are
stage-dependent and inhibited by stem cell factor
(c-kit ligand). Experimental Hematology
30:1412-18, 2002.
2003
Van Der Put, E, Sherwood, EM, Blomberg, BB,
and Riley, RL. Aged mice exhibit distinct B cell
precursor phenotypes differing in activation, proliferation and apoptosis. Experimental Gerontology 38:1137-47, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Sherwood, EM, Xu, W, and Riley, RL. B cell precursors in senescent mice exhibit decreased recruitment into proliferative compartments and
altered expression of Bcl-2 family members.
Mechanisms of Ageing and Development
124:147-53, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Effects of aging on proliferation and E47
transcription factor activity induced by different
stimuli in murine splenic B cells. Mechanisms of
Ageing and Development 124:361-69, 2003.
JOSEPH D. ROSENBLATT, M.D.
Professor of Medicine and
Division Chief of Hematology-Oncology
Frasca, D, Nguyen, D, Van Der Put, E, Riley,
RL, and Blomberg, BB. The age-related decrease
in E47 DNA-binding does not depend on increased Id Inhibitory proteins in bone marrowderived B cell precursors. Frontiers in Bioscience
8:A110-6, 2003.
D
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Wilson, EL, Sherwood, EM, King, AM, and
Riley, RL. A phenotypically distinct subset of
bone marrow immature B cells exhibits partial
activation, increased survival, and preferential
expression of VhS107. European Journal of Immunology 33:3398, 2003.
HIGHLIGHTS/DISCOVERIES
• Molecular deficits, which underlie dysfunctions
in lymphocyte activity during old age, have yet
to be well characterized. These findings, that
expression of a transcription factor (E2A) and
surrogate light chains, both of which are critical
to B-lineage cell development, are decreased in
aged B-cell precursors, provide a molecular basis
for understanding deficient lymphopoiesis in
senescence.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
DESCRIPTION OF RESEARCH
r. Rosenblatt’s research focuses on the development of novel immune therapy and gene
therapy strategies for cancer. Current research has
focused on the potential role of recruitment of
immune effector cells, using the local elaboration
of both constitutive and inflammatory chemokines, such as secondary lymphoid chemokine
(SLC), DC-CK1, and/or RANTES respectively,
on the development of an anti-tumor response.
Chemokine delivery has been investigated alone,
or in combination with, expression of the costimulatory ligands CD80 (B7.1) or CD40L.
Several delivery strategies have been investigated
including the use of retroviral vectors, and/or the
use of herpes simplex virus (HSV) amplicon vectors in several murine tumor models. Preliminary
results suggest that the recruitment of naïve T
cells using SLC is a particularly effective means of
enhancing the anti-tumor immune response, particularly when combined with CD40L-induced
co-stimulation. This strategy is being formally
investigated using the OT-1 transgenic mouse
model, which has a constitutively expressed T-cell
receptor with defined anti-ovalbumin specificity
and the murine tumors expressing the target ovalbumin antigen, for effects on tumor-induced tolerance and the development of systemic
immunity.
In a separate effort, the utility of HSV-derived helper virus-free amplicons is being tested
for efficacy in augmenting the immunogenicity
and antigen-presenting capability of fresh chronic
lymphocytic leukemia cells (CLL). Both CD40L,
CD80, and/or the tumor necrosis factor (TNF)
ligand family member LIGHT, have been targeted to fresh CLL cells using the helper free
HSV amplicons. Results suggest the augmented
ability of such CLL cells to present antigen in an
allogeneic mixed-lymphocyte-tumor cell reaction
and/or to serve as stimulatory cells for the deriva121
TUMOR IMMUNOLOGY PROGRAM
tion of autologous cytolytic T cells in vitro without deleterious effects on major histocompatibility complex (MHC)-I expression seen with HSV
helper virus-containing preparations.
A novel means of immune effector molecule
delivery, which combines the antigen binding
capabilities and localization characteristics of antibodies with the local delivery of a co-stimulatory molecule, anti-angiogenic peptide, or a
chemokine, also is under investigation. Antibody
fusion proteins targeting the human breast and
ovarian cancer her2/neu antigen, linked to the
extracellular domains of the B7.1 and/or 41BB-L
costimulatory ligands, have been synthesized and
the in vitro ability to bind to cognate antigenic
targets and to deliver a local costimulatory signal
documented. Additional fusions currently being
developed in the laboratory include fusion of the
anti-angiogenic peptide endostatin to anti-her2/
neu antibody sequences, as well as fusion of the
inflammatory chemokine RANTES. Selective
targeting of immune effector cells using both local chemokine vector administration or antibodyfusion protein administration is being evaluated
further.
A novel antibody-fusion that targets delivery
of endostatin to the site of her2/neu expressing
tumors also has been synthesized in collaboration
with Seung-Uon Shin, M.D., and shows excellent
efficacy in preclinical models. This fusion appears
to substantially improve the results obtained with
either antibody or endostatin alone.
Currently, Dr. Rosenblatt’s laboratory is
studying efficacy using a novel B-cell deficient
mouse model, which allows testing of antibody
fusion protein targeting to xenogeneic (e.g., CEA,
her2/neu) antigens, while preserving T-cell immune
effector functions. The B cell-deficient model
also has demonstrated that T-cell responses to
tumor may be better than those seen in the immunocompetent mouse. The laboratory currently
is investigating the reasons for altered responses
in the absence of B cells and the possibility of
applying this approach to the human setting using antibody depletion of B cells with rituximab.
Dr. Rosenblatt and his colleagues also have
collaborated with the laboratory of Vicente
122
Planelles, Ph.D., at the University of Utah, on
the development of several new approaches to
HIV-1 gene therapy. These include the use of
mutated tRNALYS3 primers, which can anneal to
the sequences other than primer–binding sequences on the HIV-1 genome, or tRNALYS3 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 HIV1 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.
SELECTED PUBLICATIONS
2002
Lancet, JE, Rosenblatt, JD , and Karp, JE.
Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in
high-risk leukemias. Seminars in Hematology
39:31-35, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented antitumor activity. Cancer Research 62:6545-51,
2002.
Rosenblatt, JD , Shin, SU, Nechustan, H, Yi,
KH, and Tolba, K. Potential role of chemokines
in immune therapy of cancer. Israel Medical Association Journal 4:1054-59, 2002.
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD .
HSV amplicon mediated-delivery of LIGHT enhances the antigen-presenting capacity of chronic
lymphocytic leukemia. Molecular Therapy 6:45563, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
Andela, VB, Rosenblatt, JD , Schwarz, EM, Puzas,
EJ, O’Keefe, RJ, and Rosier, RN. Synergism of
aminobisphosphonates and farnesyl transferase
inhibitors on tumor metastasis. Clinical Orthopaedics and Related Research 397:228-39, 2002.
• Demonstrated the utility of combining
chemokine delivery with costimulating ligands
in augmenting mouse response to tumors.
2003
GIOVANNA R. THOMAS, M.D.
Assistant Professor of Otolaryngology
Khorana, AA, Rosenblatt, JD , Sahasrabudhe,
DM, Evans, T, Ladrigan, M, Marquis, D, Rosell,
K, Whiteside, T, Phillippe, S, Acres, B, Slos, P,
Squiban, P, Ross, M, and Kendra, K. A phase I
trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients
with malignant melanoma. Cancer Gene Therapy
10:251-9, 2003.
Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ,
O’Keefe, RJ, Rosenblatt, JD , and Rosier, RN.
The mevalonate synthesis pathway as a therapeutic target in cancer. (Review) Clinical Orthopaedics 415 (Supplement): S59-66, 2003.
Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A,
Lu, C, McNair, C, Abboud, CN, and Rosenblatt
JD. Effects of the farnesyl transferase inhibitor
R115777 on normal and leukemic hematopoiesis. Leukemia 17:1806-12, 2003.
Rosenblatt, JD and Harrington, WJ Jr. Leukemia
and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation
21:323-24, 2003.
HIGHLIGHTS/DISCOVERIES
• Developed novel antibody-chemokine and antibody co-stimulatory ligand fusion proteins with
dual function and preserved targeting capabilities.
• Developed a novel strategy for gene therapy of
HIV-1 using mutations introduced into
tRNALYS3 primers.
• Demonstrated the potential role for HSV
amplicon vectors in gene therapy of malignancy, particularly CLL.
• Demonstrated trafficking and inhibition by
defective HIV-1 as a novel approach to HIV-1
gene therapy.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
DESCRIPTION OF RESEARCH
H
ead and neck squamous cell carcinoma
(HNSCC) of the upper aerodigestive tract is
a devastating disease that impacts human communication and survival. Lack of effective immune responses is important in the progression
of HNSCC and is a prognostic marker for poor
clinical response and decreased survival. The
long-range goal of Dr. Thomas’ research is to develop novel therapeutic modalities to improve
anti-tumor immunity in patients with HNSCC
who continue to have disappointingly low survival rates despite aggressive treatments. The
CD80/CD28 co-stimulation pathway is critical
for T-cell activation and proliferation. It has been
well documented in the literature that engagement of CD80 on antigen-presenting cells by its
receptor CD28 on T cells leads to multiple effects
on immune responses in addition to increasing
the synthesis of autocrine growth factors such as
interleukin-2 (IL-2). To date, however, not much is
known regarding the role of CD80 co-stimulatory
molecules in generating anti-tumor immune responses against tumors formed from epithelial cells.
Dr. Thomas’ objective is to determine the
role and regulation of the CD80 co-stimulatory
molecule during tumor progression of HNSCC.
Her laboratory has previously characterized the
expression of CD80 in different murine HNSCC
clones derived naturally following tumor progression in the absence of T cell-mediated immunity
in severe combined immune deficient (SCID)
mice. Exciting features observed during their
study were that HNSCC that did not express
CD80 grew as progressors, while those that expressed CD80 were regressors when grown in immune competent animals. Preliminary data show
123
TUMOR IMMUNOLOGY PROGRAM
CD80-mediated T-cell dependent anti-tumor
immunity and the generation of protective immunity in animals are resistant to rechallenge. In
addition, they found that constitutive expression
of one or more of the cytokines IL-1α, IL-6, and
GM-CSF is associated with down-modulation of
CD80 co-stimulatory molecule expression in oral
HNSCC cells. The HNSCC cell lines that exhibit a combination of constitutive cytokine expression and low CD80 expression also exhibit
increased tumorigenic potential in immune-competent mice, as previously reported. Reduction of
CD80 co-stimulatory molecule expression by
pro-inflammatory cytokines IL-1α, IL-6, and
GM-CSF has not been previously described. This
decrease in CD80 expression during malignant
progression of HNSCC may result in dysfunctional anti-tumor immunity, thereby promoting
malignant growth.
Studies are under way to determine the regulatory mechanisms of cytokine-induced downregulation of CD80 expression and to determine
the prognostic significance of its expression on
tumor specimens from patients with HNSCC.
Once the role and regulation of CD80 in
HNSCC are understood, CD80 expression can
be up-regulated pharmacologically in new and
innovative approaches to increase anti-tumor immune responses for the prevention and treatment
of HNSCC.
SELECTED PUBLICATIONS
2002
Thomas, GR , Regalado, JJ, and McClinton, M.
A rare case of mucoepidermoid carcinoma of the
nasal cavity. Ear, Nose, and Throat Journal
81:519-22, 2002.
2003
Pandey, M, Chandramohan, K, Thomas, G ,
Mathew, A, Sebastian, P, Somanathan, T,
Abraham, EK, Rajan, B, and Krishnan Nair, M.
Soft tissue sarcoma of the head and neck region
in adults. International Journal of Oral and Maxillofacial Surgery 32:43-48, 2003.
124
KHALED TOLBA, M.D.
Assistant Professor of Medicine
DESCRIPTION OF RESEARCH
D
uring the past five years, Dr. Tolba has been
developing immunotherapeutic strategies for
B-cell hematologic malignancies, with particular
interest in chronic lymphocytic leukemia (CLL).
CLL is the most common leukemia in the Western hemisphere. As a relatively slow-progressing
tumor with readily accessible tumor cells, it offers
an opportunity to develop and test immunotherapeutic interventions. A number of profound
immunologic deficiencies affecting both the Band T-cell responses, however, have posed a challenge to immune therapy of CLL.
The laboratory has co-developed and
adapted the use of herpes simplex virus (HSV)
amplicons for gene transduction of CLL cells.
Using CD40L as an effector molecule, they have
shown robust induction of co-stimulatory molecules on transduced and bystander cells
and in roughly one-third of tested patients
demonstrated the capacity to generate cytotoxic
T lymphocyte (CTL) activity. This capacity to
elicit autologous CTL response, however, was not
universal as more than half the patients tested
failed to mount such a response in spite of adequate up-regulation of co-stimulatory signal on
both transduced and bystander CLL cells. In addition to being a highly efficient gene transfer vector, herpes simplex virus (HSV)-based amplicons
possess the capacity to engage and activate different
elements of the innate immune system. Currently,
the laboratory is studying various aspects of HSV
amplicon/innate immune interaction and their
influence on the outcome of an adaptive antitumor immune response.
Immune therapeutic strategies targeting the
innate immune system might offer an alternative
pathway to bypass inherent CD8+ T-cell defects
and effectively mount a systemic anti-tumor immune response. Dr. Tolba and his colleagues are
exploring how HSV amplicon interacts with the
family of toll-like (TL) receptors and up-regulates
NKG2D ligands on target cells.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
SELECTED PUBLICATIONS
2002
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD.
Herpes simplex virus (HSV)-amplicon-mediated
delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia.
Molecular Therapy 6:455-63, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented antitumor activity. Cancer Research 62:6545-51,
2002.
Rosenblatt, JD, Shin, SU, Nechustan, H, Yi,
KH, and Tolba, K. Potential role of chemokines
in immune therapy of cancer. Israel Medical
Association Journal 4:1054-59, 2002.
MARTA TORROELLA-KOURI, PH.D.
Assistant Professor of Microbiology
and Immunology
DESCRIPTION OF RESEARCH
W
hen tumor cells initially emerge in a
healthy organism, they are recognized by
the immune system. This recognition leads to an
incipient defense reaction and elimination of the
initial tumor cell population. For unknown reasons, however, some tumors progress, infiltrate,
and eventually metastasize and kill the host. Before this occurs, a progressive decline in the immune response of the host is observed. Today,
researchers know that the tumor is directly responsible for this immunodepression observed in
tumor-bearing organisms.
The study of the interplay between a tumor
and its host, in terms of the mechanisms displayed by the tumor that eventually control and
diminish the otherwise healthy immune response
of the host organism, is the center of Dr.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Torroella-Kouri’s research. She is particularly interested in the role of the innate immune response in cancer. Researchers in her laboratory
work with a mouse mammary tumor model in
which they observe a profound decrease in the
immune response of tumor-bearing animals. Specifically, and among many other events, a deregulation in the production of cytokines, important
mediators in cell-to-cell communication, is observed. One of them, the critical cytokine
interleukin-12 (IL-12), produced by macrophages
and dendritic cells (DC), is seriously decreased in
the diseased animals. IL-12 has not only been
shown to play a central role in the communication between the innate and induced immune
responses, but also recently has been the center of
much clinical interest due to its recognized antitumor properties.
The laboratory has shown that several mammary tumor-derived factors appear to be responsible for the decreased production of IL-12 in the
tumor host. Their present research focuses particularly in elucidating the mechanisms through
which the tumor-derived phospholipid phosphatidylserine, as well as the cytokine IL-6, overproduced in tumor-bearing animals, are able to
impair IL-12 expression in tumor animals. The
understanding of the molecular mechanisms governing the expression of the critical cytokine IL12 in the context of the interaction between a
tumor and the immune system is essential in efforts aimed at designing therapeutic strategies to
treat malignant disorders. Given its many roles,
direct applications of IL-12 or modulation of IL12 levels will remain an important aspect of research for the treatment of cancer. The
laboratory’s tumor system, which like in the human situation presents a severe impairment of IL12 production, is an excellent model in which to
design future translational research.
125
TUMOR IMMUNOLOGY PROGRAM
SELECTED PUBLICATIONS
2003
Torroella-Kouri, M and Lopez, D. Mammary
tumor derived TGF-β impairs crucial innate immune responses in tumor hosts. Journal of Immunology and Immunopathology 5:31-38, 2003.
Torroella-Kouri, M , Keith, JC, Ivanova, M, and
Lopez, DM. IL-11-induced reduction of C/EBP
transcription factor binding may contribute to
the IL-12 down-regulation in tumor-bearing
mice. International Journal of Oncology 22:43948, 2003.
HIGHLIGHTS/DISCOVERIES
• Focused on the tumor-induced mechanisms
that explain the impaired expression of IL-12 in
the macrophages of the mice bearing the D1DMBA-3 mammary tumor.
• Demonstrated that indeed there is a decreased
IL-12 production in elicited peritoneal macrophages from tumor-bearing mice, both at the
level of the protein (ELISA) as well as at the
level of the gene (RT-PCR and Northern blot).
They have shown that the expression of gene
p40 is profoundly decreased, although gene p35
has a slightly diminished expression as well in
macrophages of tumor bearers (IL-12 is a
heterodimer comprised of two independently
regulated genes, p40 and p35).
• Demonstrated that in message stability experiments there is no difference in the mRNA stability of the p40 message between normal and
tumor-bearing animals, meaning that the regulation of the deficiency seems not to be posttranscriptional.
• Electromobility shift assays (EMSAs) with
nuclear extracts of macrophages from normal
and tumor animals have shown that of several
transcription factors that appear to be relevant
in the transcription of the p40 gene, there is a
diminished binding activity of NFκB and
C/EBP transcription factors to their sites in the
126
p40 promoter of tumor-bearing animals. It is
known that there are several factors produced
by the D1-DMBA-3 tumor that are able to
down-regulate IL-12. Among these,
phopsphatidylserine and prostaglandin E2,
which are produced by this tumor, have been
shown to down-regulate IL-12 in macrophages
of normal mice pretreated with these factors.
• Demonstrated that this mammary tumor produces the anti-inflammatory and metastasispromoting cytokine IL-11, and that IL-11
decreases IL-12 production as well, by diminishing the expression of p40 gene (RT-PCR).
Researchers in her laboratory also have demonstrated that IL-11 decreases the binding activity
of the C/EBP transcription factor, but not that
of NFκB to the p40 promoter in tumor bearing
animals.
• Demonstrated that the immunosuppressor
cytokine transforming growth factor-beta
(TGF-β) also is produced by the D1-DMBA-3
tumor, as well as by macrophages and T cells
from these tumor-bearing animals. TGF-β also
is known to down-regulate IL-12. On the other
hand, macrophages and B cells from tumorbearing animals overproduce the cytokines IL-6
and tumor necrosis factor-alpha (TNF-α).
TNF-α is known to down-regulate IL-12, and
her laboratory has been able to demonstrate
that IL-6 decreases the production of this
cytokine as well. Therefore, there are different
tumor-associated factors that could be playing a
role in the impairment of IL-12 production in
the laboratory’s tumor model. Some of their
mechanisms have been worked out.
• Observed that two of these molecules, the phospholipid PS and the cytokine IL-6 are novel
modulators of this important cytokine. Dr.
Torroella-Kouri plans to focus her laboratory’s
immediate research efforts on the elucidation
of the molecular mechanisms by which these
molecules down-regulate the expression of the
IL-12 genes.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
TUMOR IMMUNOLOGY PROGRAM
• Currently studying the expression of IL-12
receptor in the T cells from tumor bearers, in
order to determine if the decreased levels of
IFN-gamma observed in T cells from tumor
bearers might also be explained in part because
of a low level of expression of this receptor, in
addition to low levels of IL-12. IL-12 is known
to stimulate the production of interferongamma (IFN-γ) in naïve T cells.
VLADIMIR VINCEK, M.D., PH.D.
Associate Professor of Pathology
DESCRIPTION OF RESEARCH
P
rogress in the understanding of molecular
events involved in the development and progression of human disease is revolutionizing the
way diseases are diagnosed and treated. Physicians
and scientists now are harnessing the power of
molecular techniques to diagnose and prognosticate pathologic disorders. Furthermore, it is now
possible to direct therapeutic agents to specific
products expressed by diseased cells without affecting normal tissues. On the other hand, while
standard histopathologic methods maintain tissue
architecture for morphologic assessment, they do
not preserve macromolecules. The extraction of
nucleic acids from formaldehyde-fixed, paraffinembedded tissue, the most widely available material for clinical studies, is a notoriously unreliable
and irreproducible process. Therefore, macromolecules usually are extracted from fresh or snapfrozen tissue specimens. Fresh or frozen tissue
specimens, however, have limited value for the
assessment of histomorphology and cannot be
utilized for long-term retrospective studies. Similarly, currently available tissue preservatives that
protect nucleic acids cause considerable damage
to the cell and tissue architecture and render
them unsuitable for histomorphologic evaluation.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Current studies in this laboratory show that
it is feasible to simultaneously protect histomorphology and the integrity of macromolecules
in fixed and processed tissue. The UMFIX
reagent, developed in collaboration with other
members of the Department of Pathology, seems
to provide enormous advantage over the conventional fixation methods in allowing diagnosis,
prognostication, and identification of treatment
targets in patient samples.
SELECTED PUBLICATIONS
2002
Malek, TR, Yu, A, Vincek, V, Scibelli, P, and
Kong, L. CD4 regulatory T cells prevent lethal
autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2.
Immunity 17:167-78, 2002.
Morales, A, Essenfeld, H, Dubane, C, Vincek, V,
and Nadji, M. Continuous-specimen flow, highthroughput, 1-hour tissue processing. Archives of
Pathology & Laboratory Medicine 126:584-90,
2002.
2003
Vincek, V, Knowles, J, and Nassiri, M. p63
mRNA expression in normal human tissue. Anticancer Research 23:3945-48, 2003.
Jacob, SE, Nassiri, M, Kerdel, FA, and Vincek, V.
Rapid measurement of multiple cytokines in psoriasis patients and correlation with disease severity. Mediators of Inflammation 12:309-13, 2003.
Adkins, B, Bu, Y, Vincek, V, and Guevara, P. The
primary responses of murine neonatal lymph
node CD4+ cells are Th2-skewed and are sufficient for the development of Th2-biased memory.
Clinical & Developmental Immunology 10:4351, 2003.
Vincek, V, Nassiri, M, Nadji, M, and Morales,
AR. A novel tissue preservative that protects macromolecules (DNA, RNA, protein) and histomorphology in clinical samples. Laboratory
Investigation 83:1-9, 2003.
127
TUMOR IMMUNOLOGY PROGRAM
Jacob, SE, Berman, B, Nassiri, M, and Vincek, V.
Topical application of imiquimod 5% cream to
keloids alters expression genes associated with
apoptosis. The British Journal of Dermatology
149:1-4, 2003.
128
HIGHLIGHTS/DISCOVERIES
• Applied for a patent for an alcohol-based
UMfix preservative that preserves histomorphology and macromolecules; the patent
currently is pending.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
VIRAL ONCOLOGY PROGRAM
PROGRAM LEADERS
William J. Harrington, Jr., M.D.
Professor of Medicine
Glen N. Barber, Ph.D.
Professor of Microbiology and Immunology
DESCRIPTION OF PROGRAM
T
he Viral Oncology Program currently consists
of faculty members from five different departments at the University of Miami School of
Medicine. The principal objective of this program
is to promote clinical and basic investigation of
oncogenic viruses. The investigators were recruited on the basis of productive track records in
their respective disciplines and a commitment to
innovative and complementary research.
Each investigator studies a particular aspect
of cancer biology and therapy such as apoptosis,
DNA replication and repair, mechanisms of
cytokines, interferons and oncolytic viruses,
membrane transport, and experimental therapeutics. This has resulted in the formation of an integrated, collaborative effort where each member
provides an important, yet distinct, contribution.
The program also is committed to the development of physician-scientists and basic researchers
in the field of viral oncology.
Bench research conducted by members of
this program has translated into novel clinical
trials. A forum for such experimental trials exists
through the NIH-sponsored AIDS Malignancy
Consortium (AMC), and the University of
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Miami Sylvester Comprehensive Cancer Center is
a fully funded independent member. National
trials for AIDS-related central nervous system
lymphoma, AMC 019, originated at the University
of Miami School of Medicine. The program is
developing pre-clinical models for cancer therapy
by utilizing oncolytic viruses as targeted anti-cancer
and immuno-therapeutic agents. Program members also are investigating the basic mechanisms
of lympho-magenesis by focusing on cytokine
dependence (IL-6), pro- and anti-apoptotic gene
expression, viral interactions with transcription
factors, and the effect of viruses on nuclear membrane transport.
There is a concerted effort to extend pathogenesis-based studies and therapeutic trials of viral
malignancies to developing nations such as Zambia and Brazil. These efforts are funded through
Fogarty grants and the NCI. A principal goal is to
establish the University of Miami as a preeminent
center for international studies of viral oncology.
UM/Sylvester, with its diverse patient base
and large numbers of cases of HIV gamma
herpesvirus and human T-lymphotropic virus
type I (HTLV-I) associated tumors, is the ideal
site for the study of viral oncology.
129
VIRAL ONCOLOGY PROGRAM
GOALS OF PROGRAM
HIGHLIGHTS
1) Investigate the regulation of programmed cell
death, membrane transport, interferons,
cytokines, and viral and cellular gene expression in cancers that arise in immunocompromised patients.
Basic/Translational Research
• Glen N. Barber, Ph.D., and his colleagues study
the mechanisms of host defense against viral
and malignant disease. Their research focuses
on elucidating the mechanisms of interferons
including their role in regulating apoptosis.
These researchers recently have demonstrated
that vesicular stomatitis virus (VSV), an essentially nonpathogenic negative-stranded RNA
virus, can selectively induce the cytolysis of numerous transformed human cell lines in vitro.
The ability of these viruses to selectively kill
tumor cells and not normal cells was dependent
on the protein kinase R/interferon (PKR/IFN)
pathway being defective in susceptible cells.
They have now demonstrated in vivo that tumors defective in p53 function or transformed
with myc or activated ras also are susceptible to
viral cytolysis, and that the mechanism of viral
oncolytic activity involves the induction of multiple caspase-dependent apoptotic pathways.
Furthermore, VSV caused significant inhibition
of tumor growth when administered intravenously in immunocompetent hosts. Their findings suggest that VSV could be used as a
potential oncolytic agent against a wide variety
of malignant diseases associated with a diversity
of genetic defects. Extensions of this work now
include engineering VSV to express proteins
from viruses associated with cancer such as
hepatitis C (HCV) and human papilloma virus
(HPV) for vaccine and therapeutic purposes.
For example, chimeric VSV containing HCV
structural proteins is being examined as a therapeutic or preventative vaccine.
2) Devise novel therapeutic strategies for therapy
of viral malignancies.
3) Train investigators in the field of viral oncology and extend our basic and clinical studies
to developing nations with a high incidence of
viral-induced malignancies.
PARTICIPANTS
Barber, Glen N., Ph.D.
Microbiology and Immunology
Boehmer, Paul E., Ph.D.
Biochemistry and Molecular Biology
Boise, Lawrence H., Ph.D.
Microbiology and Immunology
Byrne, Jr., Gerald E., M.D
Pathology
Fontoura, Beatriz M.A., Ph.D.
Molecular and Cellular Pharmacology
Harhaj, Edward W., Ph.D.
Microbiology and Immunology
Harrington, Jr., William J., M.D.
Medicine
Mian, Abdul M., Ph.D.
Medicine
So, Antero G., M.D., Ph.D.
Medicine
• William J. Harrington, Jr., M.D., investigates
the use of antiviral agents in viral-induced malignancies. He has found that antiviral thymidine analogues such as azidothymidine (AZT)
and IFN α induce marked apoptosis in EpsteinBarr virus (EBV) and human herpes virus type
8 (HHV-8)-associated primary effusion lymphomas (PELs). This therapy was very effective
in eradicating AIDS-related brain lymphoma
and formed the basis for a nationwide clinical
130
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
trial. His data demonstrate that IFN α potently
induces the death receptor ligand TRAIL. AZT
is phosphorylated by the herpes virus thymidine
kinase and acts by blocking NF-κB (p50, p65)
translocation into the nucleus allowing for an
unopposed death signal. AZT also down-regulates the expression of anti-viral, anti-apoptotic
proteins such as vFLIP. A similar mechanism
has been shown to occur in other viral-induced
tumors such as post-transplant lymphoma
(EBV). Dr. Harrington and his colleagues have
initiated a new clinical trial for HHV-8-associated lymphomas that utilizes parenteral AZT
and IFN α (these tumors virtually are always
fatal). The first patient enrolled has remained in
complete remission for more than two years.
AZT-mediated blockade of NF-κB is a potentially exciting novel strategy that combines both
anti-HIV and EBV activity. The target malignancy (and one of the most common worldwide) for this type of approach is endemic
Burkitt’s lymphoma. Current studies focus on
understanding the specificity of this therapy for
herpes virus-associated lymphomas, the development of more potent antiviral antilymphoma
thymidine analogues, and the extension of this
approach to other gamma herpes and lymphomas that occur in the immunocompromised
patients (post-transplant, hereditary immunodeficiencies). This work is done in collaboration
with Abdul M. Mian, Ph.D., and Ram Agarwal,
Ph.D. Dr. Harrington also recently received a
NCI-funded career award (K24), which will
enable him to focus on the above described
laboratory and clinical studies.
• Antero G. So, M.D., Ph.D., and Kathleen M.
Downey, Ph.D., recently have identified a novel
protein, polymerase delta interacting protein
(PDIP1). This protein interacts with the small
subunit (p50) of DNA polymerase delta (the
primary polymerase responsible for cell growth
and differentiation) and the proliferating cell
nuclear antigen (PCNA). PDIP1 colocalizes
with pol delta and PCNA at replication foci in
the nuclei of S-phase cells and stimulates its
activity (in the presence of PCNA). The expresUM/Sylvester Comprehensive Cancer Center Scientific Report 2004
sion of PDIP1 can be induced by the cytokines
tumor necrosis factor alpha (TNF-α) and IL-6.
PDIP1 is a distal target of IL-6. There is increasing evidence suggesting that the cytokine
IL-6 plays an important role in the pathogenesis
of certain types of AIDS-related lymphomas.
Recent studies strongly have implicated a critical role for IL-6 in EBV-dependent lymphoproliferative disease. It also has been reported
that the development of AIDS-associated
Burkitt’s/small non-cleaved cell lymphoma is
preceded by elevated serum levels of IL-6. In
addition, cell lines derived from HHV-8-associated AIDS primary effusion lymphomas constitutively secrete high levels of both IL-6 and the
HHV-8 IL-6 homologue (vIL-6). Consistent
with these findings is the observation that the
inhibition of NF-κB (by AZT or other inhibitors) down-regulates cytokine IL-6 and induces
apoptosis in Karposi’s sarcoma-associated herpes
virus (KSHV) infected cells.
• Researchers in Lawrence H. Boise, Ph.D.’s laboratory investigate factors that regulate the pathways associated with death receptor-induced
apoptosis. Previous studies have indicated that
cells can utilize one of two pathways to propagate death signals resulting from the ligation of
the TNF receptor as well as from CD95 (Fas/
Apo-1). Cells referred to as type I cells can activate a caspase cascade that does not require release of factors from the mitochondria.
Expression of anti-apoptotic proteins Bcl-2 or
Bcl-xL is incapable of inhibiting death receptor
signaling in type I cells. In contrast, death receptor signaling in type II cells requires release
of mitochondrial factors and is inhibited by
Bcl-2/xL expression. Dr. Boise has demonstrated
that cells can utilize both type I and type II signals and that Bcl-2/xL can affect type I death
receptor signaling when used in concert with
inhibitors of signaling caspases. Interestingly, γherpes viruses associated with Karposi’s sarcoma
and PELs encode both a Bcl-2 homologue as
well as an inhibitor of CD95 signaling (vFlip).
While it has been previously suggested that viruses express these molecules to block distinct
131
VIRAL ONCOLOGY PROGRAM
death pathways, based on his results it is hypothesized that vBcl-2 and vFlip may work in
concert to block complex death receptor signaling. Researchers currently are testing this hypothesis through the introduction of these
genes into TNF-α-sensitive cell lines as well as
inhibiting expression of virally expressed genes
in PEL cell lines. This work is being carried out
primarily by M.D./Ph.D. student Esther
Obeng. Ms. Obeng has received a Howard
Hughes Medical Institute Fellowship to support
her research. This work is the basis of collaboration with William J. Harrington, Jr., M.D., on
his studies to determine the mechanisms of
anti-viral induced apoptosis in AIDS-related
lymphomas that appear to be death receptor
mediated.
• Beatriz M.A. Fontoura, Ph.D.’s laboratory
works on the signal-mediated nuclear import
and export of molecules that occurs through
nuclear pore complexes (NPC). These are
highly regulated pathways that control nuclear
entry and exit of molecules such as transcription factors, RNAs, kinases, and viral particles.
NPCs are composed of proteins termed
nucleoporins or Nups, which have a role in the
structure of the NPC and also in regulating
translocation of molecules through the NPC.
Nups are targets of viral proteins and disruption
of Nup function is involved in cancer. Dr.
Fontoura has identified and characterized two
major Nups—Nup98 and Nup96—which are
key controllers of nuclear entry and exit of proteins and RNAs. The Nup98-Nup96 pathway
is highly regulated by specific signaling pathways, is a target of viral proteins, and is involved in tumorigenesis. The goal of the
investigators working in this laboratory is to
understand the molecular mechanisms of the
nuclear transport machinery and how they are
regulated by different signaling pathways and
viruses. The discovery of novel mechanisms or
factors of this pathway are important for controlling cell growth and also may serve as therapeutic targets.
132
• Edward W. Harhaj, Ph.D.’s laboratory studies
viral-induced malignancy by the human T-cell
leukemia virus type I (HTLV-I). HTLV-I is associated with several diseases including adult Tcell leukemia (ATL) and a neurological disorder
known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLC-I
encodes a trans-activating protein, Tax, which
has pleiotropic functions and is highly oncogenic. Tax activates cellular signaling pathways
and transcription factors, such as NF-κB, resulting in global changes in gene expression.
NF-κB is a family of dimeric DNA-binding
proteins that regulates the expression of genes
that control a variety of cellular functions such
as activation, differentiation, survival, and effector function. A major effort of Dr. Harhaj’s
laboratory is to elucidate the mechanisms utilized by Tax to activate the NF-κB signaling
pathway. Toward this end, researchers are identifying cellular proteins that interact with Tax
and are examining the role of these proteins in
Tax-medicated NF-κB activation and cellular
transformation.
An example of how the laboratories interact is
demonstrated in the illustration on page 133.
Each group addresses a distinct area relevant to
viral lymphomagenesis.
Training and International Effort
The laboratories of Dr. Harrington and Charles
Wood, Ph.D., (University of Nebraska) have a
long-standing relationship in AIDS-associated
malignancies and currently collaborate on two
R01-funded research projects and two Fogarty
International Training Programs. These research
projects center around the molecular epidemiology of the transmission of HHV-8 and EBV and
the role these viruses play in the induction of malignancies. The objectives of these projects are: 1)
determine the factors associated with transmission of HHV-8 in Zambia and its relationship on
progression to AIDS, 2) develop an NCI-sponsored research repository in Brazil and Africa,
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
VIRAL LYMPHOMA
3) initiate clinical trials for AIDS-related malignancies in Brazil, and 4) study the molecular
tumor pathogenesis of viral lymphomas in Africa
and Brazil.
Researchers in the Viral Oncology Program
recently collaborated with Dr. Carlos Brites (Brazil) and successfully obtained funding through
Fogarty to establish a viral oncology training program in Salvador, Brazil. Such studies are critical
to understanding and developing rational therapy
for malignancies in immunocompromised patients. The program recently was funded through
the NCI for a study of inhibition of NF-κB and
disruption of latency in high-grade primary lymphomas derived from Brazilian patients. Juan
Carlos Ramos, M.D., (University of Miami) received a supplemental NCI grant linked to the
AMC parent grant for a molecular study of PELs.
In collaboration with the Federal University of
Bahia in Brazil, a five-year training grant for
AIDS/oncology was submitted. Bahia is a unique
area that principally is populated by descendants
of West Africa and is endemic for HTLV-I. The
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
majority of non-Hodgkin’s lymphomas are associated with EBV or HTLV-I. Therefore, this presents an outstanding opportunity for clinical and
basic investigation of these illnesses.
Zambia is a central African nation located in
the “AIDS and tumor belt.” In order to support
their research activities in Zambia, the University
of Nebraska at Lincoln, under Dr. Wood, and the
University of Miami under Dr. Harrington and
Charles D. Mitchell, M.D., have developed a successful training and research collaboration with
the University of Zambia School of Medicine and
the University Teaching Hospital, under the auspices of the Zambian Ministry of Health. This
program, funded through the Fogarty International Post-Doctoral Training Program in HIV/
AIDS, has provided instruction to Zambian
health care personnel in clinical, epidemiological,
and basic science research methodology at both
the Universities of Miami and Nebraska.
133
VIRAL ONCOLOGY PROGRAM
GLEN N. BARBER, PH.D.
Professor of Microbiology and Immunology
DESCRIPTION OF RESEARCH
D
r. Barber’s research focuses on understanding
the mechanisms of innate immunity to viral
infection and malignant disease. Specifically, one
area of research in his laboratory aims to understand the mechanisms by which the interferons
(IFNs) mediate their anti-viral and anti-proliferative effects. One key IFN-inducible gene is the
dsRNA-dependent protein kinase PKR, which is
activated upon virus infection and limits viral
replication by inhibiting host cell protein translation. Researchers recently have shown that mice
lacking PKR are very sensitive to lethal infection
by vesicular stomatitis virus (VSV) and influenza
virus, underscoring the importance of this
molecule in host defense. They additionally have
shown that PKR and IFN can contribute towards
the induction of apoptosis in a virally infected
cell. The laboratory currently is identifying new
IFN-induced genes and examining their importance in cellular growth control and immunity.
In addition to examining the mechanisms of
innate immunity to viral infection, researchers in
Dr. Barber’s laboratory are interested in studying
how viruses such as hepatitis C (HCV) and
human herpes virus type-8 (HHV-8) contribute
towards oncogenesis. Such viruses are known to
subvert key checkpoints of host-cell growth control. Understanding the mechanisms involved in
these processes could lead to an improvement of
current therapies as well as the identification of
new therapeutic targets and of malignant disease
involving these viruses.
SELECTED PUBLICATIONS
2002
Fernandez, M, Porosnicu, M, Markovic, D, and
Barber, GN. Genetically engineered vesicular stomatitis virus in gene therapy: application for
treatment of malignant disease. Journal of Virology 76:895-904, 2002.
Pataer, A, Vorburger, SA, Barber, GN, Chada, S,
Mhashilkar, AM, Zou-Yang, H, Stewart, AL,
Balachandran, S, Roth, JA, Hunt, KK, and
Swisher, SG. Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7)
induces apoptosis of lung cancer cells via upregulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Research
62:2239-43, 2002.
Grandvaux, N, Servant, MJ, tenOever, B, Sen,
GC, Balachandran, S, Barber, GN, Lin, R, and
Hiscott, J. Transcriptional profiling of interferon
regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated
genes. Journal of Virology 76:5532-9, 2002.
Vorburger, SA, Pataer, A, Yoshida, K, Barber,
GN, Xia, W, Chiao, P, Ellis, LM, Hung, MC,
Swisher, SG, and Hunt, KK. Role for the doublestranded RNA activated protein kinase PKR in
E2F-1-induced apoptosis. Oncogene 21:627888, 2002.
Ezelle, HJ, Markovic D, and Barber, GN. Generation of hepatitis C virus-like particles by use of
a recombinant vesicular stomatitis virus vector.
Journal of Virology 76:12325-34, 2002.
2003
Ogilvie, VC, Wilson, BJ, Nicol, SM, Morrice,
NA, Saunders, LR, Barber, GN, and Fuller-Pace,
FV. The highly related DEAD box RNA helicases
p68 and p72 exist as heterodimers in cells.
Nucleic Acids Research 31:1470-80, 2003.
Saunders, LR and Barber, GN. The dsRNA
binding protein family: critical roles, diverse cellular functions. The FASEB Journal 17:961-83,
2003.
134
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
Obuchi, M, Fernandez, M, and Barber, GN. Development of recombinant vesicular stomatitis
viruses that exploit defects in host defense to augment specific oncolytic activity. Journal of Virology 77:8843-56, 2003.
PAUL E. BOEHMER, PH. D.
Associate Professor of Biochemistry and
Molecular Biology
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ Jr.
Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through
azidothymidine-mediated inhibition of NFkappa B. Blood 101:2321-7, 2003.
R
Balachandran, S and Barber, GN. Defective
translational control facilitates vesicular stomatitis
virus oncolysis. Cancer Cell 5:51-65, 2003.
Poroniscu, M, Mian, A, and Barber, GN. The
oncolytic effect of recombinant vesicular stomatitis virus is enhanced by expression of the fusion
cytosine deaminase/uracil phosphoribosyltransferease
suicide gene. Cancer Research 63:8366-76, 2003.
HIGHLIGHTS/DISCOVERIES
• Discovered that IFN-inducible protein kinase
PKR is a critical mediator of innate immunity
to a number of viruses, since mice lacking this
kinase are very susceptible to lethal infection by
several viruses at doses that are innocuous to
wild type mice.
• Discovered that VSV has potent oncolytic (antitumor) properties. Dr. Barber’s laboratory has
shown that VSV replicates to high levels in tumorigenic, but not normal cells, and has identified defects in IFN signaling and translational
control in tumorigenic cells as possible reasons
for this uncontrolled replication.
• Developed recombinant VSV that expresses
other virus proteins, such as from HCV and
HPV (implicated in tumorigenesis), as possible
vaccines for these viruses.
• Constructed VSV variants expressing suicide
cassettes and immunomodulatory genes in an
effort to increase the potency and specificity of
VSV oncolysis.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
DESCRIPTION OF RESEARCH
esearchers in Dr. Boehmer’s laboratory are
studying molecular mechanisms of replication and recombination in herpes simplex virus
type-1 (HSV-1). HSV-1 serves as an excellent
system in which to study DNA transactions.
Hence, like eukaryotic chromosomes, the HSV-1
genome contains multiple origins of replication.
Replication of the HSV-1 genome is mediated by
the concerted action of several virus-encoded proteins that are thought to assemble into a
multiprotein complex. Several host-encoded factors have also been implicated in viral DNA replication. Furthermore, replication of the HSV-1
genome is known to be closely associated with
homologous recombination, which may function
in the initiation of DNA replication and in maintaining genome stability. Moreover, the virusencoded enzymes also provide a system in which
to investigate the interaction of DNA replication
enzymes with DNA damage.
HSV-1 also is the prototypic herpes virus
and therefore serves as a model to understand the
mechanism of replication of this class of virus. In
this regard, HSV-1 is one of eight human herpes
viruses that are known to cause diverse diseases
ranging from cold sores and chicken pox to mononucleosis and even cancer. The high incidence of
herpes viruses in the human population and the
increased susceptibility of immunocompromised
individuals to these viruses make them a very important public health problem. HSV-1 in particular is the cause of oro-labial lesions as well as
more serious encephalitis and corneal blindness.
Most recently, Dr. Boehmer’s laboratory has
proposed to examine how the virus initiates replication at an origin, the role recombination plays
during initiation and at later times during the
replicative cycle, how leading and lagging strand
DNA synthesis are coordinated at the viral replication fork, and finally, the mechanism whereby
135
VIRAL ONCOLOGY PROGRAM
the viral DNA polymerase can promote translesion
DNA synthesis. Collectively, the proposed studies
will provide novel insight into the replication of
this medically important and biologically fascinating virus. They also will serve to increase the
overall knowledge of fundamental mechanisms in
DNA replication and recombination.
SELECTED PUBLICATIONS
2002
Tanguy Le Gac, N and Boehmer, PE . Activation
of the herpes simplex virus type-1 origin-binding
protein (UL9) by heat shock proteins. Journal of
Biological Chemistry 277:5660-6, 2002.
Nimonkar, AV and Boehmer, PE . In vitro strand
exchange promoted by the herpes simplex virus
type-1 single strand DNA-binding protein
(ICP8) and DNA helicase-primase. Journal of
Biological Chemistry 277:15182-9, 2002.
Villani, G, Tanguy Le Gac, N, Wasungu, L,
Burnouf, D, Fuchs, RP, and Boehmer, PE . Effect
of manganese on in vitro replication of damaged
DNA catalyzed by the herpes simplex virus type1 DNA polymerase. Nucleic Acids Research
30:3323-32, 2002.
2003
Boehmer, PE and Nimonkar, AV. Herpes virus
replication. IUBMB Life 55:13-22, 2003.
Nimonkar, AV and Boehmer, PE . The herpes
simplex virus type-1 single-strand DNA-binding
protein (ICP8) promotes strand invasion. Journal
of Biological Chemistry 278:9678-82, 2003.
Nimonkar, AV and Boehmer, PE . On the mechanism of strand assimilation by the herpes simplex
virus type-1 single-strand DNA-binding protein
(ICP8). Nucleic Acids Research 31:5275-81,
2003.
Nimonkar, AV and Boehmer, PE . Reconstitution
of recombination-dependent DNA synthesis in
herpes simplex virus 1. Proceedings of the National Academy of Sciences USA 100:10201-6,
2003.
136
Boehmer, PE and Villani, G. Herpes simplex virus type-1: a model for genome transactions.
Progress in Nucleic Acid Research and Molecular
Biology 75:139-171, 2003.
HIGHLIGHTS/DISCOVERIES
• Discovered that recombination reactions were
promoted by the HSV single-strand DNA
binding protein.
• Reconstituted recombination-dependent DNA
synthesis in a eukaryotic viral system.
• Discovered that cellular heat shock proteins
participate in the initiation of viral origin-specific replication.
• Discovered translesion synthesis by a model
eukaryotic replicative DNA polymerase.
LAWRENCE H. BOISE, PH.D.
Associate Professor of Microbiology and
Immunology
DESCRIPTION OF RESEARCH
Regulation of Programmed Cell Death
rogrammed cell death, or apoptosis, is a process utilized by multicellular organisms to
eliminate unnecessary or damaged cells without
inducing an inflammatory response. The ability
of inducing a cellular suicide is required for normal development and maintenance of cell number in multicellular organisms since loss of
control of this process can lead to cancer, autoimmune disease, or neurodegenerative disorders in
mice and humans. While the genetic studies in
the nematode suggest that members of the Bcl-2
family should function upstream of caspases, this
result could be the consequence of two biochemical explanations—either Bcl-2 blocks caspase activation or Bcl-2 blocks the consequence of
protease activation.
In studies performed on a pro-B cell line,
Dr. Boise and his colleagues have found
cooperativity between overexpression of Bcl-2
family members and inhibition of caspases in the
P
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
prevention of tumor necrosis factor (TNF)induced cell death. Together these data suggest
that the cell death pathway in mammalian cells is
not likely to be a simple linear pathway as has
been suggested by C. elegans genetics. They are
currently using biochemical and genetic tools to
dissect this pathway and to determine the interplay between the Bcl-2 family and the caspase
family. Additionally, from these studies researchers have determined that many of the changes
that occur to mitochondria during apoptosis are
caspase dependent. These include loss of the mitochondrial membrane potential. His laboratory
has determined that mitochondria must be inactivated during apoptosis to prevent excessive production of reactive oxygen species. They are
currently examining the mechanisms by which
caspases regulate mitochondrial function.
As a product of the laboratory’s studies of
bcl-x expression in drug resistant tumors, they
became interested in the study of arsenic trioxide
as a potential therapeutic agent in the treatment
of multiple myeloma. Dr. Boise and his colleagues
are studying the mechanism by which this agent
can kill chemo refractory myeloma cells as well
as determine the mechanisms of acquired arsenic
resistance in myeloma cell lines. These studies
have led to a new clinical trial initiated at
UM/Sylvester. They also will gather corollary
scientific information from patients on this trial.
SELECTED PUBLICATIONS
2002
Anderson, KC, Boise, LH, Louie, R, and
Waxman, S. Arsenic trioxide in multiple myeloma: rationale and future directions. Cancer
Journal 8:12-25, 2002.
Bahlis, NJ, McCafferty-Grad, J, JordanMcMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,
Eckman, J, Goodman, M, Fernandez, HF, Boise,
LH, and Lee, KP. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the
treatment of relapsed/refractory multiple myeloma. Clinical Cancer Research 8:3658-68,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
2003
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ Jr.
Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through
azidothymidine-mediated inhibition of NFkappa B. Blood 101:2321-7, 2003.
McCafferty Grad, J, Bahlis, N, Aguilar, T, Kratt,
N, Lee, KP, and Boise, LH. Arsenic trioxide utilizes caspase dependent and caspase independent
death pathways in multiple myeloma cells. Molecular Cancer Therapeutics 2:1155-64, 2003.
Beaupre, DM, McCafferty Grad, J, Bahlis, NJ,
Boise, LH, and Lichtenheld, MG. Farnesyl transferase inhibitors sensitize to death receptor signals
and induce apoptosis in multiple myeloma cells.
Leukemia & Lymphoma 44:2123-34, 2003.
BEATRIZ M.A. FONTOURA, PH.D.
Assistant Professor of Molecular and
Cellular Pharmacology
DESCRIPTION OF RESEARCH
S
ignal-mediated nuclear import and export of
molecules occurs through nuclear pore complexes (NPC). These are highly regulated pathways that control nuclear entry and exit of
molecules such as transcription factors, RNAs,
kinases, and viral particles. In general, to be imported or exported from the nucleus, molecules:
1) bind to transport receptors, 2) are transported
through NPC present in the nuclear envelope,
and 3) translocate from NPC to intranuclear or
cytoplasmic target sites. Although progress has
been made regarding the composition and
mechanisms of the nuclear transport machinery,
less is known about the function and regulation
of major constituents of NPC. NPC are composed of proteins termed nucleoporins or Nups,
which have a role in the structure of NPC and
also in regulating translocation of molecules
through NPC. Nups also are target of viral
137
VIRAL ONCOLOGY PROGRAM
proteins and disruption of Nup function is involved in cancer.
Researchers in Dr. Fontoura’s laboratory have
identified and characterized two major Nups,
Nup98 and Nup96, which are key controllers of
nuclear entry and exit of proteins and RNAs. The
Nup98 and Nup96-mediated pathway(s) is
highly regulated by specific signaling pathways
such as interferon (IFN) pathways, is a target of
viral proteins, and is involved in tumorigenesis.
Her laboratory currently is characterizing novel
constituents of this pathway and studying their
regulation by signaling pathways, viruses, and
during mitosis. The researchers’ goal is to understand the molecular mechanisms of the nuclear
transport machinery and how they are regulated
by different signaling pathways and viruses. Thus,
Dr. Fontoura’s research proposes innovative findings on Nup function and regulation, which are
important to advance the nuclear transport field
and essential for understanding the role of Nups
in cancer and in IFN-mediated processes, such as
anti-viral response, innate immunity, and cell
proliferation.
HIGHLIGHTS/DISCOVERIES
SELECTED PUBLICATIONS
D
2002
Enninga, J, Levy, DE, Blobel, G, and Fontoura,
BM. Role of nucleoporin induction in releasing
an mRNA nuclear export block. Science
295:1523-5, 2002.
Comment on the Science publication by
Enninga, J, Levy, DE, Blobel, G, and Fontoura,
BM. Nature Cell Biology 4:E55, 2002.
2003
Yin, X, Fontoura, BM , Morimoto, T, and
Carroll, RB. Cytoplasmic complex of p53 and
eEF2. Journal of Cellular Physiology 196:474-82,
2003.
Enninga, J, Levay, A, and Fontoura, BM. Sec13
shuttles between the nucleus and the cytoplasm
and stably interacts with Nup96 at the nuclear
pore complex. Molecular and Cellular Biology
23:7271-7284, 2003.
138
• Discovered in 2002 that two major NPC proteins that Dr. Fontoura’s laboratory had previously identified, Nup98 and Nup96, can
regulate antiviral response by controlling
nuclear export of mRNA. These findings were
published in Science and a comment was published in Nature Cell Biology. This pathway is
involved in tumorigenesis.
• Discovered in 2003 another constituent of the
Nup98-Nup96 pathway(s), Sec13, which also is
a component of the endoplasmic reticulum.
The findings were recently published in Molecular and Cellular Biology. Sec13 may be involved
in a crosstalk between the NPC and the endoplasmic reticulum.
EDWARD W. HARHAJ, PH. D.
Assistant Professor of Microbiology and
Immunology
DESCRIPTION OF RESEARCH
r. Harhaj’s research interests focus on the
mechanisms of viral-induced malignancy by
the human T-cell leukemia virus type I (HTLVI). HTLV-I is linked to the genesis of both adult
T-cell leukemia (ATL) and a neurological disorder known as HTLV-I-associated myelopathy/
tropical spastic paraparesis (HAM/TSP). Although it is unclear why HTLV-I infection proceeds to either ATL, HAM/TSP, or an
asymptomatic state, there are likely cellular, viral,
and environmental determinants that influence
disease progression. The host immune response
to HTLV-I appears to be an important cellular
determinant of HTLV-I-associated disease.
Whereas ATL patients are commonly immunosuppressed, asymptomatics and particularly
HAM/TSP patients mount vigorous immune
responses to HTLV-I. One of the goals of the
laboratory is to define the molecular mechanisms
that account for dysregulated host immune responses to HTLV-I. Understanding how HTLV-I
influences the host immune response may proUM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
vide targets for therapeutic intervention to control infection and decrease proviral load.
HTLV-I encodes a trans-activating protein,
Tax, which is responsible for the oncogenic properties of HTLV-I. Tax activates numerous cellular
signaling cascades, including NF-κB and CREB/
ATF, resulting in global changes in gene expression. Tax regulates the expression of a multitude
of cellular genes that control T-cell activation,
proliferation and apoptosis. Another goal of Dr.
Harhaj’s laboratory is to delineate the mechanisms utilized by Tax to activate cellular signaling
pathways, such as NF-κB, which are essential for
Tax-mediated immortalization of T cells. Toward
this end, identification of cellular proteins that
interact with Tax may shed light on strategies
used by Tax to constitutively activate NF-κB and
mediate T-cell oncogenesis.
SELECTED PUBLICATIONS
2003
Barmak, K, Harhaj, EW, and Wigdahl, B. Mediators of central nervous system damage during
the progression of HTLV-I-associated myelopathy/tropical spastic paraparesis. Journal of
NeuroVirology 9:522-9, 2003.
Barmak, K, Harhaj, EW Grant, C, Alefantis, T,
and Wigdahl, B. Human T cell leukemia virus
type I-induced disease: pathways to cancer and
neurodegeneration. Virology 308:1-12, 2003.
Alefantis, T, Barmak, K, Harhaj, EW, Grant, C,
and Wigdahl, B. Characterization of a nuclear
export signal within the human T cell leukemia
virus type I transactivator protein Tax. Journal of
Biological Chemistry 278:21814-22, 2003.
WILLIAM J. HARRINGTON, JR., M.D.
Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. Harrington's laboratory efforts center on
understanding the mechanisms of antiviralmediated apoptosis of viral-mediated malignancies.
His team found that interferon (IFN) potently
induces death receptor ligands in certain unique
viral-mediated lymphomas. This had led to a
novel therapeutic approach for these deadly tumors. Epstein-Barr virus (EBV)-related Burkitts
(BL) and primary central nervous system (CNS)
lymphoma, human herpes virus-type 8 (HHV-8)associated primary effusion lymphoma (PEL),
and human T lymphotropic virus-type I (HTLVI)-associated adult T-cell leukemia (ATL) are all
refractory to conventional chemotherapy yet remarkably sensitive to antiviral therapy. Clinical
trials have been designed and implemented that
exploit this phenomenon. Their AIDS-related
brain lymphoma study is now a national trial and
is run through the NCI cooperative group, the
Aids Malignancy Consortium (AMC).
The three principal projects currently underway
include:
• Mapping the apoptotic pathways induced in
viral-associated lymphomas. Their work has
demonstrated that IFNα induced the soluble
death receptor ligand TRAIL, which when
combined with AZT, indicates a FADD-dependent suicide program in gamma herpes virus
lymphomas. Signal transduction deficits in
IFNα and pathways in resistant tumors also are
being studied.
• Studying the signaling components involved in
constitutive activation of NF-κB in all forms of
viral-mediated non-Hodgkin's lymphoma
(NHL). Their data demonstrate specific activation pathways that may serve as targets for future therapeutic agents.
• Elucidating the mechanism whereby AZT
inhibits NF-κB in EBV+ endemic BL. New
data demonstrate that this mechanism is highly
specific and occurs through interruption of
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
139
VIRAL ONCOLOGY PROGRAM
lymphotoxin beta-mediated activation of
NF-kB. AZT appears to be a targeted form of
therapy particularly active in type 1 latency BL
cells. Dr. Harrington recently has received NCI
funding to study this mechanism in primary
endemic BL cells from patients seen at the National Cancer Institute of Brazil (INCA). This
also will be translated to a clinical trial for refractory EBV+ B1. They have received a major
commitment from GlaxoSmithKline to provide
parenteral AZT. This will be used as part of a
protocol to treat patients at the INCA.
SELECTED PUBLICATIONS
2002
Tulpule, A, Groopman, J, Saville, MW,
Harrington, WJ Jr , Friedman-Kien, A, Espina,
BM, Garces, C, Mantelle, L, Mettinger, K,
Scadden, DT, and Gill, PS. Multicenter trial of
low-dose paclitaxel in patients with advanced
AIDS-related Kaposi sarcoma. Cancer 95:14754, 2002.
2003
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ Jr .
Potentiation of TRAIL-induced apoptosis in
primary effusion lymphoma through
azidothymidine-mediated inhibition of NFkappa B. Blood 101:2321-7, 2003.
ANTERO G. SO, M.D., PH.D.
Professor of Medicine
DESCRIPTION OF RESEARCH
D
r. So and Kathleen M. Downey, Ph.D., are
studying the molecular mechanism by which
normal cells regulate proliferation during the cell
cycle and how this is altered in cancer cells. The
major focus of these studies is DNA polymerase
delta, the principal mammalian DNA polymerase
required for replication of chromosomal DNA
and involved in several major DNA repair pathways. DNA polymerase delta was the first eukaryotic DNA polymerase found to have an intrinsic
proofreading 3’ to 5’ exonuclease activity and
therefore capable of editing errors made during
DNA synthesis. The importance of this proofreading activity in DNA replication was recently
shown by a report that inactivation of the exonuclease activity of DNA polymerase delta in mice
resulted in a recessive mutator phenotype characterized by a high incidence of epithelial (carcinoma) and mesenchymal (lymphomas and
sarcomas) cancers. Current research emphasizes
the elucidation of the molecular mechanism of
regulation of DNA polymerase delta activity by
its processivity factor, the proliferating cell
nuclear antigen (PCNA), and the identification
of new proteins that regulate DNA polymerase
delta activity.
Rosenblatt, J and Harrington, WJ Jr . Leukemia
and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation
21:323-4, 2003.
Schultz, DR and Harrington, WJ Jr . Apoptosis:
programmed cell death at a molecular level.
Seminars in Arthritis and Rheumatism 32:34569, 2003.
140
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
VIRAL ONCOLOGY PROGRAM
SELECTED PUBLICATIONS
HIGHLIGHTS/DISCOVERIES
2002
• Demonstrated a direct interaction between the
small subunit of human DNA polymerase delta
(p50) and PCNA, a marker for cell proliferation, by reciprocal co-immunoprecipitation of
the two proteins using antibodies against either
p50 or PCNA, suggesting that this interaction
is primarily responsible for processive DNA
synthesis by DNA polymerase delta. Researchers in Dr. So’s laboratory have now confirmed
that this interaction readily occurs in cells. This
is important because the interaction of DNA
polymerase delta with PCNA is at the core of
replication machinery (replisome) function and
crucial to our understanding of how DNA replication is coordinated with DNA repair and
cell cycle progression.
Carastro, LM, Tan, CK, Selg, M, Jack, HM, So,
AG, and Downey, KM. Identification of delta
helicase as the bovine homolog of HUPF1: demonstration of an interaction with the third subunit of DNA polymerase delta. Nucleic Acids
Research 30:2232-43, 2002.
Meyer, PR, Matsuura, SE, Tolun, AA, Pfeifer, I,
So, AG, Mellors, JW, and Scott, WA. Effects of
specific zidovudine resistance mutations and substrate structure on nucleotide-dependent primer
unblocking by human immunodeficiency virus
type 1 reverse transcriptase. Antimicrobial Agents
and Chemotherapy 46:1540-5, 2002.
Lu, X, Tan, CK, Zhou, JQ, You, M, Carastro,
LM, Downey, KM, and So, AG. Direct interaction of proliferating cell nuclear antigen with the
small subunit of DNA polymerase delta. Journal
of Biological Chemistry 277:24340-5, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
• Identified a novel 36-kDa protein, designated
polymerase delta interacting protein 1 (PDIP1)
that physically and functionally interacts with
both PCNA and the 50-kDa subunit of DNA
polymerase delta, both in vitro and in vivo.
Researchers further have shown the expression
of this protein is induced by tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). These
cytokines are essential for growth and proliferation of many cell types and implicated in the
tumorigenesis of a number of cancers, including
AIDS-related non-Hodgkin’s lymphoma and
multiple myeloma. Thus, PDIP1 is a potential
target for the development of novel therapeutic
agents for the treatment of these tumors.
141
VIRAL ONCOLOGY PROGRAM
142
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SHARED RESOURCES
SHARED RESOURCES
ANALYTI CAL I MAG I NG CORE
MANAGER
SERVICES
Alberto Pugliese, M.D.
Associate Professor of Medicine
This core provides the following services:
CO-MANAGER
Beata R. Frydel, Ph.D.
Associate Scientist of Neurosurgery
PURPOSE
M
any research endeavors rely on state-of-theart imaging and molecular histology techniques requiring the use of complex and costly
equipment not practical for the individual investigator to acquire and maintain. The Analytical
Imaging Core is a campus-wide resource spearheaded by the Diabetes Research Institute and
UM/Sylvester, with seed support from the dean
of the University of Miami School of Medicine.
The Juvenile Diabetes Research Foundation
awarded additional support for a five-year period
in December 2003. The core’s main goals are to:
• Provide access to sophisticated, modern instrumentation for imaging and molecular analysis
of tissue and cellular specimens to investigators.
• Provide expertise, guidance, and training to
core users and help them optimize protocols for
their applications that can be shared with other
investigators.
1) Confocal Microscopy: Confocal microscopy offers many advantages over standard fluorescent
microscopy including increased sensitivity,
resolution, and the ability to image relatively
thick, fluorescently labeled biological specimens in two or three dimensions. Confocal
microscopy creates an “optical section” of the
cells or tissues being imaged and an increase in
effective resolution due to a large increase in
signal-to-noise ratio. As a result, outstanding
images can be collected from cells and tissue
sections that would otherwise yield little or no
information.
The workhorse instrument for confocal microscopy is the Zeiss LSM-510, which can detect up to five channels and four fluorescent
channels simultaneously—from UV to far red,
plus a separate detector for transmitted light.
The outstanding beam control afforded by the
Zeiss LSM-510 makes it an ideal instrument
for other advanced fluorescent applications
such as fluorescence resonance energy transfer
(FRET), fluorescence recovery after photo
bleaching (FRAP), or ratio-imaging for
fluorescence quantitation. The core also is
equipped with an Atto Instruments spinning
disk confocal microscope (CARV), a confocal
instrument particularly suited for live cell
analysis, and video-rate (30 frames per second)
imaging.
2) Standard Epifluorescence Microscopy: The core
also is equipped with a Leica DMIRB inverted
microscope capable of performing triple fluorescence, phase contrast, and light microscopy, etc.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
143
SHARED RESOURCES
3) Laser Scanning Cytometer (LSC): The LSC allows “flow cytometer-like” fluorescent imaging
and quantitation of tissue sections on a microscope slide. The LSC records the position and
time of measurement for each cell analyzed so
that multiple biochemical, immunological,
and morphological measurements can be made
on each cell. Possible applications for the LSC
include: detection and quantitation of
apoptosis (TUNEL, annexin); in situ hybridization (FISH); and the study of cell adhesion,
cell cycle, and DNA content, etc.
4) MetaMorph Imaging System (MIS): This imaging system consists of hardware and software
that enables the capture and analysis of microscopy and digital images obtained using the
instruments described above.
144
5) Laser Capture Dissection Microscope (LCM):
The LCM can dissect portions of tissues (or
even single cells) from cell smears and fixed
and frozen tissue sections, obtaining essentially
pure samples of a desired cell population (5001,000 cells per hour). The dissected cells can
then be used to extract RNA, DNA, or proteins for further studies. LCM offers unprecedented access to specific cells for defining
their pattern of gene expression, in combination with powerful techniques such as gene
array and real-time PCR. This technology is
particularly powerful in the study of human
diseases and several cancer applications, where
only small amounts of tissue may be available
for study.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SHARED RESOURCES
B I O S TAT I S T I C S
MANAGER
James J. Schlesselman, Ph.D.
Professor of Epidemiology and Public Health
PURPOSE
T
he division of Biostatistics provides statistical
expertise in the study, design, and analysis
of data for UM/Sylvester members. Statisticians
collaborate on developing protocols for clinical
trials, work together on research proposals for
laboratory-based investigations, and conduct epidemiological studies. They also perform statistical
analyses, interpret results, and author or coauthor papers for publication. Biostatistics is
committed to applying statistical and computational methods to improve the way in which
clinical trials and translational research are conducted within UM/Sylvester and to developing
statistical methodology that aids cancer research.
SERVICES
Biostatistics provides cancer center members with
the following services:
1) Collaboration: Biostatistics seeks to establish
enduring collaborations with UM/Sylvester
investigators to advance the cancer center’s
programmatic research. Such collaborations
develop statisticians’ knowledge of specific areas of cancer-related investigation and ensure
that statistical considerations are adequately
incorporated throughout the course of ongoing research programs. Priority is given to collaborative work, not consulting.
times a preliminary step to collaborative research where Biostatistics plays a significant
role.
3) Study Design: Biostatistics formulates study
objectives and endpoints in terms that are appropriate for statistical analysis, recommends
alternative study designs, determines the
sample size needed to address study objectives
at an appropriate level of significance and
power, and develops and writes plans for statistical analyses.
4) Data Analysis: After study data have been collected, biostatisticians provide graphical and
tabular reports of the results as well as substantive interpretation of the findings.
5) Clinical Trial Applications: Biostatisticians contribute to the design and statistical analysis of
investigator-initiated phase I and phase II cancer clinical trials; clinical epidemiology studies;
novel diagnostic tests; clinical investigations of
cancer therapies; basic science studies of cancer
mechanisms; and translational studies of immunologic therapies, chemotherapy-modifying
agents, and radio-sensitizing drugs.
2) Consulting: In contrast to collaborations,
which involve long-term collegial relationships
in planning studies or analyzing data, statistical consulting generally entails statistical advice or analysis with little involvement in the
studies themselves and no co-authorship of
publications. Consulting, however, is some-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
145
SHARED RESOURCES
C E L L P U R I F I C AT I O N A N D B A N K I N G F A C I L I T Y
MANAGER
SERVICES
Kelvin P. Lee, M.D.
Associate Professor of Microbiology and
Immunology
Specifically, the services of this facility are to:
PURPOSE
F
or many UM/Sylvester researchers, the transition from small animal to human studies is
prevented by their inability to obtain primary
human cells, whether normal or malignant. The
overall goal of this facility is to generate purified
primary human cells for the cancer research community at the University of Miami.
146
1) Provide purified normal primary human hematopoietic cells (T cells, B cells, monocytes,
and CD34+ stem cells) for cancer-related
research.
2) Bank and provide primary leukemia, lymphoma, and myeloma cell isolates to investigators working with these malignancies.
3) Provide centralized hematopoietic cell isolation, banking, inventory, and database capability for cancer-related clinical trials that are
collecting cell samples for research.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SHARED RESOURCES
CLINICAL RESEARCH SERVICES RESOURCE
CLINICAL DIRECTOR
SERVICES
Joseph A. Lucci, III., M.D.
Associate Professor of Obstetrics and
Gynecology
1) Regulatory Office: This office handles all activities involving activation of clinical trials, which
include preparing and presenting documents
to both the Protocol Review Committee
and the University of Miami Internal Review
Board, writing informed consents, and distributing active protocols throughout the clinical
areas on the medical campus.
ASSISTANT DIRECTOR
James D. Hanlon, Jr., R.N.
Manager
T
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.
• Evaluate clinical trial protocol design, scientific
merit, and patient care-related issues through
the UM/Sylvester Protocol Review Committee.
3) Budget Office: This office controls the budget
for the Clinical Research Services Resource’s
personal and office expenditures and negotiates contracts with clinical trial sponsors.
PURPOSE
he Clinical Research Services Resource
provides UM/Sylvester investigators with
broad-based support for their clinical research
activities to:
• Provide support services for screening, evaluating, recruiting, tracking, protecting, and maintaining patients on clinical protocols.
• Assist investigators with protocol development
by providing consultation in protocol design,
access to other needed resources, and assistance
with reporting requirements and other federal
regulations.
• Assure compliance with guidelines for investigational drug use and toxicity reporting and
maintain quality data management.
4) Quality Assurance: This office monitors the
quality of data management and conducts case
auditing to ensure compliance with FDA requirements. It also interacts with the Data
Safety and Monitoring Board.
5) Research Pharmacy: The research pharmacy is
responsible for investigational drug accountability and inventory, as well as providing drug
information for medical, nursing, and pharmacy staff.
• Develop a data safety and monitoring board to
monitor institutional clinical trials.
• Support national cooperative group activities
and interact with UM/Sylvester affiliates.
• Develop, operate, and maintain a computerized
protocol data management system.
• Budget clinical trial expenditures and negotiate
contracts with clinical trial sponsors.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
147
SHARED RESOURCES
DNA CORE FACILITY
MANAGER
SERVICES
Rudolf K. Werner, Ph.D.
Professor of Biochemistry and Molecular
Biology
This facility provides cancer center investigators
with the following services:
PURPOSE
T
he purpose of the DNA Core Facility is to
make DNA sequencing services available to
UM/Sylvester members in support of their peerreviewed funded research.
1) DNA Sequencing: The investigator provides
purified DNA for analysis and receives a sequence within three to five days. The sequence
data are about 98 percent accurate. Some investigators perform their own sequencing reactions and provide the completed reaction
mixture for analysis on the instrument.
To achieve more uniform DNA quality, the
facility also offers, for a small surcharge, DNA
purification from a single bacterial colony
containing the plasmid to be sequenced.
In addition to the sequence analysis of doublestranded DNA, the facility also provides
sequencing of polymerase chain reaction
(PCR) products. These results are usually
superior to those obtained from cloning DNA.
2) Order Coordination: The facility coordinates
orders for the synthesis of oligonucleotides
from commercial sources.
148
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SHARED RESOURCES
FLOW CYTOMETRY RESOURCE
MANAGER
SERVICES
Richard L. Riley, Ph.D.
Professor of Microbiology and Immunology
This resource provides the following services to
cancer center members:
PURPOSE
T
he Flow Cytometry Resource provides
UM/Sylvester investigators, in support of
their peer-reviewed funded research, with sophisticated methods for analysis and preparative
sorting of normal and tumor cells, and trains
investigators in the use of flow cytometry for
their research.
1) Laser-excited flow cytometry for analysis of
cell surface antigens expressed in complex cell
mixtures; up to four different fluorescent
parameters and two light-scatter parameters
(forward and side scatter) can be analyzed
simultaneously.
2) Laser-excited cell sorting (six parameters) for
isolation of selected cell populations from
heterogeneous mixtures.
3) DNA content/cell cycle analysis via both
visibly excited dyes (propidium iodide) and
UV-excited dyes (Hoescht dyes) with pulse
processing or doublet discrimination.
4) High-efficiency sorting and sorting of large
particles via the MacroSort system.
5) Intracellular calcium ratio measurements.
6) Applications for limiting dilution or cloning
experiments via the automatic cell deposition
unit (ACDU).
7) Training in the use of the FACScan and LSR
analytical flow cytometers, computer programs
for data analysis, and data storage; consultation in the procedures for cell preparation,
staining, fixation, data analysis, and preparative sorting also are provided.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
149
SHARED RESOURCES
GENE KNOCKOUT AND TRANSGENE FACILITY
MANAGER
SERVICES
Thomas R. Malek, Ph.D.
Professor and Vice Chair of Microbiology
and Immunology
This facility provides the following services to
cancer center members:
PURPOSE
1) Set up breeding of donor and recipient mice
and subsequently check plugs to confirm
mating.
T
2) Perform vasectomies of male mice for the
recipient colony.
he Gene Knockout and Transgene Facility
produces transgenic and knockout mice and
trains investigators to apply this technology to
their research. The major goal of the facility is to
provide this technological capability to peer-reviewed funded cancer researchers at UM/
Sylvester.
3) Collect fertilized eggs or blastocysts.
4) Sort and culture eggs.
5) Prepare microinjection needles.
6) Microinject eggs with DNA or blastocysts
with cells.
7) Inject donor and recipient mice with
hormones.
8) Perform microsurgery to re-implant eggs or
blastocysts.
9) Culture and transfer embryonic stem cells for
microinjection into blastocysts.
10) Generate gene-targeting constructs rapidly
by using an arrayed library.
11) Provide investigators with tissue biopsies to
screen for transmission of transgene.
12) Advise investigators in the production of
transgenic and gene knockout constructs.
13) Advise investigators in culturing and gene
targeting in embryonic stem cells.
150
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SHARED RESOURCES
HISTOLOGY RESEARCH LAB CORE
MANAGER
SERVICES
Carol K. Petito, M.D.
Professor of Pathology
The facility currently provides the following services:
PURPOSE
1) Processing of fixed material into paraffin
blocks.
T
2) Tissue sectioning for routine hematoxylineosin stains and other stains.
he UM/Sylvester Histology Research Lab
Core provides histology services to cancer
center members in support of their peer-reviewed
funded research and of their preliminary studies
completed to prepare for grant submission.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
3) Tissue sectioning for immunohistochemistry.
4) Professional consulting for methodology and
for histological interpretation.
151
SHARED RESOURCES
I N F O R M AT I C S
ASSOCIATE DIRECTOR
Dido Franceschi, M.D.
Associate Professor of Surgery
PURPOSE
T
he Division of Informatics at UM/Sylvester
facilitates the integration of information to
support patient care, research, education, and
administration. The division is composed of
two subdivisions: Systems Development and
Support and Network Management and Personal
Computing.
SERVICES
Systems Development and Support
The Systems Development team conducts
technical research and development to meet
UM/Sylvester’s short- and long-term requirements. It also delivers software solutions in
the areas of research, administration, and web
development. The team’s primary objective is
to increase productivity and efficiency in various
areas of the cancer center by providing:
1) Systems analysis and design services.
2) Database development, administration, and
support.
3) Programming of quality computer applications.
4) Development of Intranet web sites that provide employees with organized, readily accessible information in a central repository and
secured web-based applications.
5) Project management and implementation,
which includes technical and user documentation and user training.
6) Expedited document processing via electronic
forms that are accessible through the web.
The group provides infrastructure support with
web-enabled database systems as follows:
Systems Development team for the management
of clinical trials and the protocol approval process;
tracking of patient accrual data; collection of research personnel time and generation of invoices
for protocol billing; management of investigatorinitiated clinical trial patient data; administration
of web accessible protocols and related documents; secure dissemination of reports to investigators; and management of patient tissue banks
including a web interface that allows investigators
to search the tissue bank and request specimens
according to their investigational interests.
Administration: A centralized database system has
been developed that unifies information from the
various administrative divisions and facilitates the
management and sharing of information. The
database and related applications provide functionality for the management of UM/Sylvester’s
members as well as profiles of their research interests and involvement, investigator’s published
materials, grants, and research funded projects,
shared resource facilities, and human resources.
Network Management and Personal
Computing
The Network Management team provides infrastructure support for cancer center connectivity,
central computing hardware, and firewall security.
The network group has four major functions:
1) Integrate information systems and communications for the research, administrative, and
clinical areas of the cancer center.
2) Support the operation of a center-wide
Intranet with defined security.
3) Support connectivity to campus networks
including access to wide-area networks.
4) Assist with hardware and software installation
and support.
5) Provide system backup, disaster recovery, and
high availability.
Research: The essential support needed by
UM/Sylvester investigators is provided by the
152
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
SHARED RESOURCES
M O L E C U L A R A N A LY S I S C O R E
MANAGER
Roland Jurecic, Ph.D.
Assistant Professor of Microbiology and
Immunology
PURPOSE
T
he Molecular Analysis Core provides UM/Sylvester members with: 1) capillary-based DNA
sequencing of plasmids and polymerase chain
reaction (PCR) fragments, 2) shotgun sequencing
of large cDNA and genomic DNA inserts
(transgenic and knockout/targeting vectors), 3)
basic DNA fragment analysis, and 4) real time
quantitative PCR and reverse transcriptase-PCR
(RT-PCR) using LightCycler technology.
3) Basic DNA fragment analysis. Detection of
isoforms, alternative transcripts, and DNA rearrangements, etc.
4) Automated heterozygote detection.
Quantitative Real Time PCR Techniques Using
the Roche LightCycler
1) Real time quantitative PCR and RT-PCR.
2) Full melt curve analysis of amplified products.
3) Design and testing of fluorogenic probes for
rapid and sensitive detection of gene targets.
4) Genotyping of transgenic and knockout
mouse models.
SERVICES
This facility provides UM/Sylvester investigators,
in support of their peer-reviewed research, with
the following services:
Genetic Analysis using the Beckman CEQ 2000
Genetic Analyzer
1) Capillary-based DNA sequencing of plasmids
and PCR fragments (800 base pairs in 90 minutes), using standard (T3, T7, Sp6, M13, etc.)
or custom-designed primers.
2) Shotgun sequencing of large cDNA and genomic
DNA inserts (transgenic and knockout/targeting vectors) using transposon technology for
fast and easy insertion of sequencing primer
binding sites and kanamycin resistance markers into target DNA in vitro. Selection of different clones with transposon integrated only
into the genomic insert (not the plasmid
backbone) by digest restriction and size difference. Based on the insert size, 20 to 40 different clones are subjected to automated sequencing
and assembled into contigs using sequence utility software.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
153
SHARED RESOURCES
P O P U L AT I O N R E S E A R C H C O R E
(Developing Shared Resource)
DIRECTOR
Recruitment
Michael H. Antoni, Ph.D.
Professor of Psychology
1) Help UM/Sylvester investigators develop and
assess recruitment and retention plans for
funded projects.
MANAGER
Dorothy F. Parker, M.H.S.
2) Increase awareness of population research
studies open for accrual.
PURPOSE
3) Serve as liaison with local health care providers
and community organizations.
T
he purpose of the Population Research Core
will be to provide services to support population-based cancer prevention and control research
at UM/Sylvester and to help increase the diversity
of study participants to represent the racial, ethnic, and socioeconomic composition of South
Florida’s diverse and unique community.
The Population Research Core evolved from
the Florida Comprehensive Cancer Control Initiative (FCCCI), a project funded by the Centers
for Disease Control that established regional cancer control collaboratives throughout Florida.
UM/Sylvester continues to support the Southeast
Florida Regional Cancer Control Collaborative, a
group of more than 40 organizations that are a
potential source of recruitment for populationbased studies. FCCCI’s staff of three also supports the Population Research Core. They have
experience in cancer control research, data analysis, and community outreach.
4) Develop agreements and procedures for recruitment of participants in cancer control
studies.
5) Pretest and/or conduct focus groups with target populations to develop appropriate recruitment tools and strategies (e.g., brochures,
flyers, and advertisements).
Data and Measurement
1) Provide aggregate local, regional, and national
cancer and demographic data.
2) Help develop or identify appropriate questionnaires and survey tools.
3) Arrange for translation of materials (e.g., into
Spanish and Haitian Creole).
4) Provide assistance with data collection tools
and database design.
Education
SERVICES
The Population Research Core will offer services
in three areas: recruitment, data and measurement, and education. Additionally, in an effort to
better meet the needs of UM/Sylvester investigators, the core is conducting a faculty survey to
determine what is needed to facilitate research
and recruitment.
154
1) Assess needs of investigators for understanding
issues related to population science.
2) Provide workshops and training on issues such
as: community outreach and campus-community research concerns, cultural and socioeconomic factors that affect recruitment
strategies, study design, the informed consent
process, and participation in studies.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
P U B L I C AT I O N S 2 0 0 2 - 2 0 0 3
Muller-Sieburg, CE, Cho, RH, Thoman, M,
Adkins, B, and Sieburg, HB. Deterministic regulation of hematopoietic stem cell self-renewal and
differentiation. Blood 100:1302-9, 2002.
Adkins, B, Bu, Y, and Guevara, P. Murine neonatal CD4+ lymph node cells are highly deficient in
the development of antigen-specific Th1 function
in adoptive adult hosts. Journal of Immunology
169:4998-5004, 2002.
Lopez, DM, Charyulu, V, and Adkins, B. Influence of breast cancer on thymic function in mice.
Journal of Mammary Gland Biology and Neoplasia 7:191-9, 2002.
Petito, CK, Adkins, B, McCarthy, M, Roberts, B,
and Khamis, I. CD4+ and CD8+ cells accumulate in the brains of acquired immunodeficiency
syndrome patients with human immunodeficiency virus encephalitis. Journal of
Neurovirology 9:36-44, 2003.
Adkins, B, Williamson, T, Guevara, P, and Bu, Y.
Murine neonatal lymphocytes show rapid early
cell cycle entry and cell division. Journal of Immunology 170:4548-56, 2003.
Auais, A, Adkins, B, Napchan, G, and
Piedimonte, G. Immunomodulatory effects of
sensory nerves during respiratory syncytial virus
infection in rats. American Journal of PhysiologyLung Cellular and Molecular Physiology
285:L105-13, 2003.
Adkins, B, Bu, Y, Vincek, V, and Guevara, P.
The primary responses of murine neonatal lymph
node CD4+ cells are Th2-skewed and are sufficient for the development of Th2-biased memory.
Clinical & Developmental Immunology 10:4351, 2003.
Adkins, B. Peripheral CD4+ lymphocytes derived
from fetal versus adult thymic precursors differ
phenotypically and functionally. Journal of Immunology 171:5157, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress
management and immune system reconstitution
in symptomatic HIV-infected gay men over
time: effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American
Journal of Psychiatry 159:143-45, 2002.
Knippels, HM, Goodkin, K, Weiss, JJ, Wilkie,
FL, and Antoni, MH. The importance of cognitive self-report in early HIV-1 infection: validation of a cognitive functional status subscale.
AIDS 16:259-67, 2002.
Culver, JL, Arena, PL, Antoni, MH, and Carver,
CS. Coping and distress among women under
treatment for early stage breast cancer: comparing
African Americans, Hispanics and non-Hispanic
Whites. Psycho-oncology 11:495-504, 2002.
Cruess, S, Antoni, MH, Hayes, A, Penedo, F,
Ironson, G, Fletcher, MA, Lutgendorf, S, and
Schneiderman, N. Changes in mood and depressive symptoms and related change processes during cognitive behavioral stress management in
HIV-infected men. Cognitive Therapy and
Research 26:373-392, 2002.
Kumar, M, Kumar, AM, Waldrop, D, Antoni,
MH, Schneiderman, N, and Eisdorfer, C.
The HPA axis in HIV-1 infection. Journal of
Acquired Immune Deficiency Syndromes 31
Supplement 2:S89-93, 2002.
Antoni, MH. Stress management and
psychoneuroimmunology in HIV infection.
CNS Spectrums 8:40-51, 2003.
Perna, FM, Antoni, MH, Baum, A, Gordon, P,
and Schneiderman, N. Cognitive behavioral
stress management effects on injury and illness
among competitive athletes: a randomized
clinical trial. Annals of Behavioral Medicine
25:66-73, 2003.
155
P UBLIC ATIONS 200 2-200 3
Antoni, MH. Psychoneuroendocrinology and
psychoneuroimmunology of cancer: Plausible
mechanisms worth pursuing? Brain, Behavior,
and Immunity (1 Supplement):S84-91, 2003.
Antoni, MH and Pitts, M. Journal of Psychosomatic Research, Special Issue. Journal of Psychosomatic Research 54:179-83, 2003.
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates the
association between psychological distress and
immune status among HIV-positive men and
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-89,
2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Petronis, VM, Carver, CS, Antoni, MH, and
Weiss, S. Investment in body image and psychosocial well-being among women treated for early
stage breast cancer: partial replication and extension. Psychology & Health 18:1-13, 2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life
stress and cervical squamous intraepithelial lesions in women with human papillomavirus and
human immunodeficiency virus. Psychosomatic
Medicine 65:427-34, 2003.
Weiss, JL, Mulder, CL, Antoni, MH, De
Vroome, EM, Garssen, B, and Goodkin, K. Effects of a supportive-expressive group intervention on long-term psychosocial adjustment in
HIV-infected gay men. Psychotherapy and Psychosomatics 72:132-40, 2003.
156
McGregor, BA, Antoni, MH, Boyers, A, Alferi,
SM, Blomberg, BB, and Carver, CS. Cognitive
behavioral stress management increases benefit
finding and immune function among women
with early stage breast cancer. Journal of Psychosomatic Research 54:1- 8, 2003.
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,
and Schneiderman, N. Psychological distress is
associated with decreased memory helper T-cell
and B-cell counts in pre-AIDS HIV seropositive
men and women but only in those with low viral
load. Psychosomatic Medicine 65:627-35, 2003.
O’Cleirigh, C, Ironson, G, Antoni, MH,
Fletcher, MA, McGuffey, L, Balbin, E,
Schneiderman, N, and Solomon, G. Emotional
expression and depth processing of trauma and
their relation to long-term survival in patients
with HIV/AIDS. Journal of Psychosomatic Research 54:225-35, 2003.
Robbins, M, Szapocznik, J, Tejeda, M, Samuels,
D, Ironson, G, and Antoni, MH. The protective
role of the family and social support network in
a sample of HIV+ African American women:
results of a pilot study. Journal of Black Psychology 29:17-37, 2003.
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,
Schneiderman, N, Brondolo, E, Tobin, J, and
Weiss, S. Cognitive-behavioral interventions improve quality of life in women with AIDS. Journal of Psychosomatic Research 54: 253-261,
2003.
Lechner, SC, Zakowski, SG, Antoni, MH,
Greenhawt, M, Block, K, and Block, P. Do
sociodemographic and disease-related factors influence benefit-finding in cancer patients?
Psycho-oncology 12: 491-499, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-2, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni,
MH, Malow, R, Costa, P, and Schneiderman, N.
Personality, quality of life and HAART adherence
among men and women living with HIV/AIDS.
Journal of Psychosomatic Research 54:271-8,
2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological distress among symptomatic HIV+ men who have
sex with men. Annals of Behavioral Medicine
25:203-13, 2003.
Lemanek, KL, Brown, RT, Armstrong, FD,
Hood, C, Pegelow, CH, and Woods, G. Dysfunctional eating patterns and symptoms of pica in
children and adolescents with sickle cell disease.
Clinical Pediatrics 41:493-500, 2002.
Perrin, E and the Committee on Psychosocial
Aspects of Child and Family Health, American
Academy of Pediatrics. (Armstrong, FD, coauthor), Technical report: co-parent or secondparent adoption by same-sex parents. Pediatrics
109:341-344, 2002.
Thompson, RJ, Jr, Armstrong, FD, Link, CL,
Pegelow, CH, Moser, F, and Wang, W. A prospective study of the relationship over time of behavior problems, intellectual functioning, and family
functioning in children with sickle cell disease: a
report from the Cooperative Study of Sickle Cell
Disease. Journal of Pediatric Psychology 28:5965, 2003.
Fernandez, M, Porosnicu, M, Markovic, D, and
Barber, GN. Genetically engineered vesicular stomatitis virus in gene therapy: application for
treatment of malignant disease. Journal of Virology 76:895-904, 2002.
Pataer, A, Vorburger, SA, Barber, GN, Chada, S,
Mhashilkar, AM, Zou-Yang, H, Stewart, AL,
Balachandran, S, Roth, JA, Hunt, KK, and
Swisher, SG. Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7)
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
induces apoptosis of lung cancer cells via upregulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Research
62:2239-43, 2002.
Grandvaux, N, Servant, MJ, tenOever, B, Sen,
GC, Balachandran, S, Barber, GN, Lin, R, and
Hiscott, J. Transcriptional profiling of interferon
regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated
genes. Journal of Virology 76:5532-9, 2002.
Vorburger, SA, Pataer, A, Yoshida, K, Barber,
GN, Xia, W, Chiao, P, Ellis, LM, Hung, MC,
Swisher, SG, and Hunt, KK. Role for the doublestranded RNA activated protein kinase PKR in
E2F-1-induced apoptosis. Oncogene 21:627888, 2002.
Ezelle, HJ, Markovic, D, and Barber, GN. Generation of hepatitis C virus-like particles by use of
a recombinant vesicular stomatitis virus vector.
Journal of Virology 76:12325-34, 2002.
Ogilvie, VC, Wilson, BJ, Nicol, SM, Morrice,
NA, Saunders, LR, Barber, GN, and Fuller-Pac,
FV. The highly related DEAD box RNA helicases
p68 and p72 exist as heterodimers in cells.
Nucleic Acids Research 31:1470-80, 2003.
Saunders, LR and Barber, GN. The dsRNA
binding protein family: critical roles, diverse cellular functions. FASEB Journal 17:961-83, 2003.
Obuchi, M, Fernandez, M, and Barber, GN. Development of recombinant vesicular stomatitis
viruses that exploit defects in host defense to augment specific oncolytic activity. Journal of Virology 77:8843-56, 2003.
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ, Jr.
Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through
azidothymidine-mediated inhibition of NFkappa B. Blood 101:2321-7, 2003.
157
P UBLIC ATIONS 200 2-200 3
Balachandran, S and Barber, GN. Defective
translational control facilitates vesicular stomatitis
virus oncolysis. Cancer Cell 5:51-65, 2003.
Poroniscu, M, Mian, A, and Barber, GN . The oncolytic effect of recombinant vesicular stomatitis
virus is enhanced by expression of the fusion cytosine
deaminase/uracil phosphoribosyltransferease suicide gene. Cancer Research 63:8366-76, 2003.
Jin, Y, Fuller, L, Carreno, M, Esquenazi, V,
Blomberg, BB , Wei, YT, Ciancio, G, Burke,
GW 3rd, Tzakis, A, Ricordi, C, and Miller, J. Functional and phenotypic properties of peripheral T
cells anergized by autologous CD3(+) depleted
bone marrow cells. Human Immunology 63:56775, 2002.
Burke, GW, Ciancio, C, Blomberg, BB , Rosen,
A, Suzart, K, Roth, D, Kupin, W, Esquenazi, V,
and Miller, J. Randomized trial of three different
immunosuppressive regimens to prevent chronic
renal allograft rejection. Transplantation Proceedings 34:1610-11, 2002
Blomberg, BB , Mathew, J, Fainman, H, Hussini,
S, Carreno, M, Hnatyszyn, H, Garcia-Morale, R,
Fuller, L, Vallone, T, Rosen, A, Esquenazi, V, Ricordi,
C, Tzakis, A, and Miller, J. Human bone marrow
cells retrovirally transduced with the allogeneic
class II gene, HLA-DR3beta, down regulate antiallogeneic responses of autologous lymphoid
cells. Human Immunology 63:S19, 2002.
Mathew, JM, Blomberg, BB , Fuller, L, Burke,
GW, Ciancio, G, Kenyon, N, Ricordi, C, Tzakis,
AG, Esquenazi, V, and Miller, J. A novel microcell-mediated lympholytic assay for the evaluation of regulatory cells in human alloreactive
CTL responses. Journal of Immunological Methods 272:67-80, 2003.
Blomberg, BB , Hussini, S, Fainman, H, Mathew,
JM, Hernandez, A, Carreno, M, Hnatyszyn, HJ,
Garcia-Morales, R, Fuller, L, Rosen, A, Ricordi,
C, Tzakis, A, Miller, J, and Esquenazi, V.
Retroviral transduction of an allogeneic class
II gene into human bone marrow down regulates
allo-immune reactivity. Human Immunology
64:S128, 2003.
158
Hernandez, A, Lindner, I, Blomberg, BB , Hussini,
S, Burger, M, Mathew, JM, Carreno, M, GarciaMorales, R, Fuller, L, Jin, Y, Rosen, A, Lee, KP,
Miller, J, and Esquenazi, V. Suppression of allogeneic T-cell proliferation through blocking of
NF-κB in the differentiation process of human dendritic cells. Human Immunology 64:S128, 2003.
Mathew, JM, Alvarez, S, Vallone, T, Blomberg,
BB, Joshua, M, and Esquenazi, V. A humanSCID-mouse-islet transplant model for the evaluation of the regulatory activity of donor bone
marrow cells. Human Immunology 64:S7, 2003.
Van Der Put, E, Sherwood, EM, Blomberg, BB ,
and Riley, RL. Aged mice exhibit distinct B cell
precursor phenotypes differing in activation, proliferation, and apoptosis. Expermental Gerontology 38:1137-47, 2003.
Frasca, D, Nguyen, D, Van Der Put, E, Riley,
RL, and Blomberg, BB . The age-related decrease
in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrowderived B cell precursors. Frontiers in Bioscience
8:A110-16, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Effects of aging on proliferation and E47
transcription factor activity induced by different
stimuli in murine splenic B cells. Mechanisms of
Ageing and Development 124:361-69, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Frasca, D, Van der Put, E, Riley, RL, and
Blomberg, BB . Reduced Ig class switch in aged
mice correlates with decreased E47 and activation-induced cytidine deaminase. Journal of Immunology 172:2155-62, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
McGregor, BA, Antoni, MH, Boyers, A, Alferi,
SM, Blomberg, BB , and Carver, CS. Cognitive
behavioral stress management increases benefit
finding and immune function among women
with early stage breast cancer. Journal of Psychosomatic Research 54:1-8, 2003.
Tanguy, Le Gac N and Boehmer, PE . Activation
of the herpes simplex virus type-1 origin-binding
protein (UL9) by heat shock proteins. Journal of
Biological Chemistry 277:5660-6, 2002.
Nimonkar, AV and Boehmer, PE . In vitro strand
exchange promoted by the herpes simplex virus
type-1 single strand DNA-binding protein
(ICP8) and DNA helicase-primase. Journal of
Biological Chemistry 277:15182-9, 2002.
Villani, G, Tanguy Le Gac, N, Wasungu, L,
Burnouf, D, Fuchs, RP, and Boehmer, PE . Effect
of manganese on in vitro replication of damaged
DNA catalyzed by the herpes simplex virus type1 DNA polymerase. Nucleic Acids Research
30:3323-32, 2002.
Boehmer, PE and Nimonkar, AV. Herpes virus
replication. IUBMB Life 55:13-22, 2003.
Nimonkar, AV and Boehmer PE . The herpes
simplex virus type-1 single-strand DNA-binding
protein (ICP8) promotes strand invasion. Journal
of Biological Chemistry 278:9678-82, 2003.
Nimonkar, AV and Boehmer, PE . On the mechanism of strand assimilation by the herpes simplex
virus type-1 single-strand DNA-binding protein
(ICP8). Nucleic Acids Research 31:5275-81, 2003.
Nimonkar, AV and Boehmer PE . Reconstitution
of recombination-dependent DNA synthesis in
herpes simplex virus 1. Proceedings of the National
Academy of Sciences USA 100:10201-6, 2003.
Boehmer, PE and Villani, G. Herpes simplex virus type-1: a model for genome transactions.
Progress in Nucleic Acid Research and Molecular
Biology 75:139-171, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Anderson, KC, Boise, LH, Louie, R, and Waxman,
S. Arsenic trioxide in multiple myeloma: rationale and future directions. Cancer Journal 8:1225, 2002.
Bahlis, NJ, McCafferty-Grad, J, Jordan-McMurry,
I, Neil, J, Reis, I, Kharfan-Dabaja, M, Eckman, J,
Goodman, M, Fernandez, HF, Boise, LH , and
Lee, KP. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment
of relapsed/refractory multiple myeloma. Clinical
Cancer Research 8:3658-68, 2002.
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ, Jr.
Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidinemediated inhibition of NF-kappa B. Blood
101:2321-7, 2003.
McCafferty Grad, J, Bahlis, N, Aguilar, T, Kratt,
N, Lee, KP, and Boise, LH. Arsenic trioxide utilizes caspase dependent and caspase independent
death pathways in multiple myeloma cells.
Molecular Cancer Therapeutics 2:1155-64, 2003.
Beaupre, DM, McCafferty Grad, J, Bahlis, NJ,
Boise, LH, and Lichtenheld, MG. Farnesyl transferase inhibitors sensitize to death receptor signals
and induce apoptosis in multiple myeloma cells.
Leukemia & Lymphoma 44:2123-34, 2003.
Yang, ES, Maiorino, CA, Roos, BA, Knight, SR,
and Burnstein, KL . Vitamin D-mediated growth
inhibition of an androgen-ablated LNCaP cell
line model of human prostate cancer. Molecular
and Cellular Endocrinology 186:69-79, 2002.
Whitlatch, LW, Young, MV, Schwartz, GG,
Flanagan, JN, Burnstein, KL , Lokeshwar, BL,
Rich, ES, Holick, MF, and Chen, TC. 25Hydroxyvitamin D-1alpha-hydroxylase activity is
diminished in human prostate cancer cells and is
enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40, 2002.
159
P UBLIC ATIONS 200 2-200 3
Kizu, R, Okamura, K, Toriba, A, Kakishima, H,
Mizokami, A, Burnstein, KL , and Hayakawa, K.
A role of aryl hydrocarbon receptor in the
antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma
cells. Archives of Toxicology 77:335-43, 2003.
Ramsauer, VP, Carothers Carraway, CA, Salas, PJ,
and Carraway, KL . Muc4/Sialomucin complex,
the intramembrane ErbB2 ligand, translocates
ErbB2 to the apical surface in polarized Epithelial
cells. Journal of Biological Chemistry 278:3014247, 2003.
Yang, E and Burnstein, KL . Vitamin D inhibits
G1 to S progression in LNCaP prostate cancer
cells through p27Kip1 stabilization and Cdk2
mislocalization to the cytoplasm. Journal of Biological Chemistry 278:46862-68, 2003.
Carraway, KL , Ramsauer, VP, Haq, B, and
Carothers Carraway, CA. Cell signaling through
membrane mucins. BioEssays 25:66-71, 2003.
Chen, TC, Holick, MF, Lokeshwar, BL,
Burnstein, KL , and Schwartz, GG. Evaluation of
vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research
164:273-88, 2003.
Kizu, R, Okamura, K, Toriba, A, Mizokami, A,
Burnstein, KL , Klinge, CM, and Hayakawa, K.
Antiandrogenic activities of diesel exhaust particle
extracts in PC3/AR human prostate carcinoma
cells. Toxicological Science 76:299-309, 2003.
Carraway, KL , Perez, A, Idris, N, Jepson, S,
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,
SA, Zhang, J, and Carraway, CA. Muc4/
sialomucin complex, the intramembrane ErbB2
ligand, in cancer and epithelia: to protect and to
survive. Progress in Nucleic Acid Research and
Molecular Biology 71:149-85, 2002.
Swan, JS, Arango, ME, Carothers Carraway, CA,
and Carraway, KL . An ErbB2-Muc4 complex in
rat ocular surface epithelia. Current Eye Research
24:397-402, 2002.
Jepson, S, Komatsu, M, Haq, B, Arango, ME,
Huang, D, Carraway, CA, and Carraway, KL .
Muc4/sialomucin complex, the intramembrane
ErbB2 ligand, induces specific phosphorylation
of ErbB2 and enhances expression of p27(kip),
but does not activate mitogen-activated kinase or
protein kinase. Oncogene 21:7524-32, 2002.
Komatsu, M, Arango, ME, and Carraway, KL .
Synthesis and secretion of Muc4/sialomucin
complex: implication of intracellular proteolysis.
Biochemical Journal 368:41-48, 2002.
160
Fischer, BM, Cuellar, JG, Diehl, ML, deFreytas,
AM, Zhang, J, Carraway, KL , and Voynow, JA.
Neutrophil elastase increases MUC4 expression
in normal human bronchial epithelial cells.
American Journal of Physiology-Lung Cellular
Molecular Physiology 284:L671-79, 2003.
Hu, YP, Haq, B, Carraway, KL , Savaraj, N, and
Lampidis, TJ. Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Pharmacology, Biochemistry, and Behavior
65:1419-25, 2003.
Soto, P, Price-Schiavi, SA, and Carraway, KL .
SMAD2 and SMAD7 Involvement in the posttranslational regulation of Muc4 via the transforming growth factor-beta and interferongamma pathways in rat mammary epithelial cells.
Journal of Biological Chemistry 278:20338-44,
2003.
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,
SA, and Carraway, KL . PEA3 transactivates the
Muc4/Sialomucin Complex promoter in mammary epithelial and tumor cells. Journal of Biological Chemistry 278(38):36942-52, 2003.
Perczek, RE, Burke, MA, Carver, CS, Krongrad,
A, and Terris, MK. Facing a prostate cancer diagnosis: who is at risk for increased distress? Cancer
94:2923-29, 2002.
Culver, JL, Arena, PL, Antoni, MH, and Carver,
CS. Coping and distress among women under
treatment for early stage breast cancer: Comparing
African Americans, Hispanics, and non-Hispanic
Whites. Psycho-oncology 11:495-504, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life
stress and cervical squamous intraepithelial lesions in women with human papillomavirus and
human immunodeficiency virus. Psychosomatic
Medicine 65:427-34, 2003.
McGregor, BA, Antoni, MH, Boyers, A, Alferi,
SM, Blomberg, BB, and Carver, CS. Cognitive
behavioral stress management increases benefit
finding and immune function among women
with early stage breast cancer. Journal of Psychosomatic Research 54:1–8, 2003.
Carver, CS, Lehman, JM, and Michael, HA. Dispositional pessimism predicts illness-related disruption of social and recreational activities among
breast cancer patients. Journal of Personality and
Social Psychology 84:813-21, 2003.
Petronis, VM, Carver, CS, Antoni, MH, and
Weiss, S. Investment in body image and psychosocial well-being among women treated for early
stage breast cancer: Partial replication and extension. Psychology & Health 18: 1-13, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-2, 2003.
Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F.
Control of cell polarity in fission yeast by association of Orb6p kinase with the highly conserved
protein methyltransferase Skb1p. Journal of Biological Chemistry 278:25256-63, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Feng, W, Rodriguez-Menocal, L, Tolun, G, and
D’Urso, G. Schizosacchromyces pombe Dpb2
binds to origin DNA early in S phase and is required for chromosomal DNA replication. Molecular Biology of the Cell 14:3427-36, 2003.
Burhans, WC, Weinberger, J, Marchetti, MA,
Ramachandran, L, D’Urso, G, and Huberman, J.
Apoptosis-like yeast cell death in response to
DNA damage and replication defects. Mutation
Research 532:227-43, 2003.
Li, Z and Deutscher, MP . RNase E plays an essential role in the maturation of Escherichia coli
tRNA precursors. RNA 8:97-109, 2002.
Li, Z, Reimers, S, Pandit, S, and Deutscher, MP .
RNA quality control: degradation of defective
transfer RNA. EMBO Journal 21:1132-38, 2002.
Cheng, ZF and Deutscher, MP . Purification
and characterization of the Escherichia coli
exoribonuclease RNase R. Comparison with
RNase II. Journal of Biological Chemistry
277:21624-29, 2002.
Zuo, Y and Deutscher, MP . The physiological
role of RNase T can be explained by its unusual
substrate specificity. Journal of Biological
Chemistry 277:29654-61, 2002.
Zuo, Y and Deutscher, MP . Mechanism of action
of RNase T. I. Identification of residues required
for catalysis, substrate binding, and dimerization.
Journal of Biological Chemistry 277:50155-59,
2002.
Zuo, Y and Deutscher, MP . Mechanism of action
of RNase T. II. A structural and functional model
of the enzyme. Journal of Biological Chemistry
277:50160-64, 2002.
Nathanson, L, Xia, T, and Deutscher, MP .
Nuclear protein synthesis: a re-evaluation. RNA
9:9-13, 2003.
Cheng, ZF and Deutscher, MP . Quality control
of ribosomal RNA mediated by polynucleotide
phosphorylase and RNase R. Proceedings of the
National Academy of Sciences USA 100:638893, 2003.
161
P UBLIC ATIONS 200 2-200 3
Deutscher, MP . Degradation of stable RNA in
bacteria. Journal of Biological Chemistry
278:45041-44, 2003.
Hudder, A, Nathanson, L, and Deutscher, MP .
Organization of mammalian cytoplasm. Molecular and Cellular Biology 23:9318-26, 2003.
Feun, LG, Modiano, M, Lee, K, Mao, J, Marini,
A, Savaraj, N, Plezia, P, Almassian, B, Colacino,
E, Fischer, J, and MacDonald, S. Phase I and
pharmacokinetic study of 3-aminopyridine-2carboxaldehyde thiosemicarbazone (3-AP) using a
single intravenous dose schedule. Cancer Chemotherapy and Pharmacology 50:223-29, 2002.
Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG,
Xu, R, Xu, J, and Savaraj, N. Procollagen-like
protein as a molecular target in the treatment of
primary brain tumor. ScientificWorld Journal
2:125-26, 2002.
Feun, LG, Savaraj, N, Hurley, J, and Marini, A.
Phase II trial of Paclitaxel and Dacarbazine with
filgrastim administration in advanced malignant
melanoma. Cancer Investigation 20:357-61,
2002.
Agarwala, SS, Glaspy, J, O’Day, SJ, Mitchell, M,
Gutheil, J, Whitman, E, Gonzalez, R, Hersh, E,
Feun, LG, Belt, R, Meyskens, F, Hellstrand, K,
Wood, D, Kirkwood, JM, Gehlsen, KR, and
Naredi, P. Results from a randomized phase III
study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus
interleukin-2 alone in patients with metastatic
melanoma. Journal of Clinical Oncology 20:12533, 2002.
Feun, LG, O’Brien, C, Molina, E, Rodriguez, M,
Jeffers, L, Schiff, ER, Marini, A, Savaraj, N, and
Ardalan, B. Recombinant leukocyte interferon,
doxorubicin, and 5FUDR in patients with hepatocellular carcinoma-A phase II trial. Journal of
Cancer Research and Clinical Oncology 129:1720, 2003.
162
Prados, MD, Schold SC Jr., Fine, HA, Jaeckle, K,
Hochberg, F, Mechtler, L, Fetell, MR,
Phuphanich, S, Feun, LG, Janus, TJ, Ford, K,
and Graney, W. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in
combination with carboplatin administered intravenously for the treatment of recurrent malignant
glioma. Neuro-oncology 5:96-110, 2003.
Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L,
Donnelly, E, Solomon, J, Sundaram, M, Feun,
LG, and Savaraj, N. Phase II study of vinorelbine
with low dose prednisone in the treatment of
hormone-refractory metastatic prostate cancer.
Oncology Reports 10:885-89, 2003
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, T, Robles, C, Furst, AJ, and Feun, LG.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal of Clinical Oncology 23:173-79, 2003
Dewailly, E, Furgal, C, Knap, A, Galvin, J,
Baden, D, Bowen, B, Depledge, M, Dugua, L,
Fleming, LE, Ford, T, Moser, F, Owen, R, Suk,
WA, and Unluata, U. Indicators of ocean and
human health. Cancer Journal of Public Health
93: S34-8, 2002.
Grant, P, Skinner, HG, Fleming, LE, and Bean,
JA. Influence of structured encounter forms on
documentation by community pediatricians.
Southern Medical Journal 95:1026-31, 2002.
Knap, A, Dewailly, E, Furgal, C, Galvin, J,
Baden, D, Bowen, RE, Depledge, M, Duguay, L,
Fleming, LE, Ford, T, Moser, F, Owen, R, Suk,
WA, and Unluata, U. Indicators of ocean health
and human health: developing a research and
monitoring framework. Environmental Health
Perspectives 110:839-45, 2002.
Zhou, O, Shimoda, H, Gao, B, Oh, S, Fleming,
LE, and Yue, G. Materials science of carbon
nanotubes: fabrication, integration, and properties of macroscopic structures of carbon
nanotubes. Accounts of Chemical Research
35:1045-53, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, Voti, L, and Peace,
S. Cancer trends among Hispanic men in South
Florida, 1981-1998. Cancer 94:1183-90, 2002.
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, and Peace, S. Cancer among Hispanic women in South Florida: an
18-year assessment: a report from the Florida
Cancer Data System. Cancer 95:1752-58, 2002.
Oberstein, EM, Fleming, LE, Gomez-Marin, O,
and Glassberg, MK. Pulmonary
lymphangioleiomyomatosis (LAM): examining
oral contraceptive pills and the onset of disease.
Journal of Women’s Health (Larchmt) 12:81-5,
2003.
Entzel, PP, Fleming, LE, Trepka, MJ, and
Squicciarini, D. The health status of newly
arrived refugee children in Miami-Dade County,
Florida. American Journal of Public Health
93:286-8, 2003.
Fleming, LE, Gomez-Marin, O, Zheng, D, Ma,
F, and Lee, D. National Health Interview Survey
mortality among U.S. farmers and pesticide applicators. American Journal of Industrial Medicine 43:227-33, 2003.
Varela, JE, Gomez-Marin, O, Fleming, LE, and
Cohn, SM. The risk of death for Jehovah’s Witnesses after major trauma. Journal of Trauma
54:967-72, 2003.
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American
Journal of Psychiatry 159:143-45, 2002.
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates the
association between psychological distress and
immune status among HIV-positive men and
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-89,
2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,
NG, Fletcher, MA , Antoni, MH, LeBlanc, WG,
and Schneiderman, N. Psychological distress is
associated with decreased memory helper T-cell
and B-cell counts in pre-AIDS HIV seropositive
men and women but only in those with low viral
load. Psychosomatic Medicine 65:627-35, 2003.
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,
MA, McGuffey, L, Balbin, E, Schneiderman, N,
and Solomon, G. Emotional expression and
depth processing of trauma and their relation to
long-term survival in patients with HIV/AIDS.
Journal of Psychosomatic Research 54:225-35,
2003.
Fletcher, TM , Xiao, N, Mautino, G, Baumann,
CT, Wolford, R, Warren, BS, and Hager, GL.
ATP-dependent mobilization of the glucocorticoid receptor during chromatin remodeling. Molecular and Cellular Biology 22:3255-63, 2002.
Lu, H, Pise-Masison, CA, Fletcher, TM , Schiltz,
RL, Nagaich, AK, Radonovich, M, Hager, G,
Cole, PA, and Brady, JN. Acetylation of nucleosomal histones by p300 facilitates transcription
from tax-responsive human T-cell leukemia virus
type 1 chromatin template. Molecular and Cellular Biology 22:4450-62, 2002.
Keeton, EK, Fletcher, TM, Baumann, CT,
Hager, GL, and Smith, CL. Glucocorticoid receptor domain requirements for chromatin remodeling and transcriptional activation of the
mouse mammary tumor virus promoter in different nucleoprotein contexts. Journal of Biological
Chemistry 277:28247-55, 2002.
163
P UBLIC ATIONS 200 2-200 3
Georgel, PT, Fletcher, TM , Hager, GL, and
Hansen, JC. Formation of higher-order secondary and tertiary chromatin structures by genomic
mouse mammary tumor virus promoters. Genes
& Development 17:1617-29, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45, 2003.
Fletcher, TM . Telomere higher-order structure
and genomic instability. IUBMB Life 55:443-49,
2003.
Cheng, JC, Matsen, CB, Gonzales, FA, Ye, W,
Greer, S, Marquez, VE, Jones, PA, Selker, EU.
Inhibition of DNA methylation and reactivation
of silenced genes by zebularine. Journal of the
National Cancer Institute March 5;95:399-409,
2003.
Enninga, J, Levy, DE, Blobel, G, and Fontoura,
BM. Role of nucleoporin induction in releasing
an mRNA nuclear export block. Science
295:1523-5, 2002.
Comment on the Science publication by
Enninga, J, Levy, DE, Blobel, G, and Fontoura,
BM. Nature Cell Biology 4:E55, 2002.
Yin, X, Fontoura, BM , Morimoto, T, and Carroll,
RB. Cytoplasmic complex of p53 and eEF2.
Journal of Cellular Physiology 196:474-82, 2003.
Enninga, J, Levay, A, and Fontoura, BM. Sec13
shuttles between the nucleus and the cytoplasm
and stably interacts with Nup96 at the nuclear
pore complex. Molecular and Cellular Biology
23:7271-7284, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45, 2003.
Green, RM, DeVries, KO, Bernstein, J,
Goodman, KW, Kaufmann, R, Kiessling, AA,
Levin, SR, Moss, SL, and Tauer, CA. Overseeing
research on therapeutic cloning: A private ethics
board responds to its critics. Hastings Center
Report 32:27-33, 2002
Markovitz, BP and Goodman, KW. Case reports on
the web redux: confidentiality still in jeopardy. Proceedings from the AMIA Symposium 926, 2003.
Civantos, FJ, Gomez, C, Duque, C, Pedroso, F,
Goodwin, WJ, Weed, DT, Arnold, D, and
Moffat, F. Sentinel node biopsy in oral cavity
cancer: correlation with PET scan and immunohistochemistry. Head & Neck 25:1-9, 2003.
164
Han, Z, Wei, W, Dunaway, S, Darnowski, JW,
Calabresi, P, Sedivy, J, Hendrickson, EA, Balan,
KV, Pantazis, P, and Wyche, JH. Role of p21 in
apoptosis and senescence of human colon cancer
cells treated with camptothecin. Journal of Biological Chemistry 277(19):17154-60, 2002.
Hu, X, Han, Z, Wyche, JH, and Hendrickson,
EA. Helix 6 of tBid is necessary but not sufficient
for mitochondrial binding activity. Apoptosis
8:277-89, 2003.
Pantazis, P, Han, Z, Balan, K, Wang, Y, and
Wyche, JH. Camptothecin and 9 nitrocamptothecin
(9NC) and anti-cancer, anti-HIV, and cell-differentiation agents. Development of resistance,
enhancement of 9NC-induced activities, and
combination treatments in cell and animal
models. Anticancer Research 23:3623-38, 2003.
Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche,
JH, Han, Z, and Pantazis, P. Differential susceptibility to 9-nitrocamptothecin (9-NC)-induced
apoptosis in clones derived from a human ovarian
cancer cell line: possible implications in the treatment of ovarian cancer patients with 9-NC. Anticancer Drugs 14:427-36, 2003.
Barmak, K, Harhaj, E, and Wigdahl, B. Mediators of central nervous system damage during the
progression of HTLV-I-associated myelopathy/
tropical spastic paraparesis. Journal of
Neurovirology 9:522-9, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Barmak, K, Harhaj, E, Grant, C, Alefantis, T,
and Wigdahl, B. Human T cell leukemia virus
type I-induced disease: pathways to cancer and
neurodegeneration. Virology 308:1-12, 2003.
Alefantis, T, Barmak, K, Harhaj, EW, Grant, C,
and Wigdahl, B. Characterization of a nuclear
export signal within the human T cell leukemia
virus type I transactivator protein Tax. Journal of
Biological Chemistry 278:21814-22, 2003.
Tulpule, A, Groopman, J, Saville, MW,
Harrington, W, Jr , Friedman-Kien, A, Espina,
BM, Garces, C, Mantelle, L, Mettinger, K,
Scadden, DT, and Gill, PS. Multicenter trial of
low-dose paclitaxel in patients with advanced
AIDS-related Kaposi sarcoma. Cancer 95:14754, 2002.
Ghosh, SK, Wood, C, Boise, LH, Mian, AM,
Deyev, VV, Feuer, G, Toomey, NL, Shank, NC,
Cabral, L, Barber, GN, and Harrington, WJ, Jr .
Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidinemediated inhibition of NF-kappa B. Blood
101:2321-7, 2003.
Rosenblatt, J and Harrington, WJ, Jr . Leukemia
and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation
21:323-4, 2003.
Schultz, DR and Harrington, WJ, Jr . Apoptosis:
programmed cell death at a molecular level.
Seminars in Arthritis and Rheumatism. 32:34569, 2003.
Harris, TK and Turner, GJ. Structural basis of
perturbed pKa values of catalytic groups in enzyme active sites. IUBMB Life 53:85-98, 2002.
Harris, TK . PDK1 and PKB/Akt: ideal targets
for development of new strategies to structure-based
drug design. IUBMB Life 55:117-26, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Gao, X, Yo, P, Keith, A, Ragan, TJ, and Harris,
TK. Thermodynamically balanced inside-out
(TBIO) PCR-based gene synthesis: a novel
method of primer design for high-fidelity assembly of longer gene sequences. Nucleic Acids
Research 31:e143, 2003.
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress
management and immune system reconstitution
in symptomatic HIV-infected gay men over
time: effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American
Journal of Psychiatry 159:143-5, 2002.
Ironson, G, Freund, B, Strauss, JL, and Williams,
J. Comparison of two treatments for traumatic
stress: a community-based study of EMDR and
prolonged exposure. Journal of Clinical Psychology 58:113-28, 2002.
Ironson, G, Solomon, GF, Balbin, EG, O’Cleirigh,
C, George, A, Kumar, M, Larson, D, and Woods,
TE. The Ironson-Woods Spirituality/Religiousness Index is associated with long survival, health
behaviors, less distress, and low cortisol in people
with HIV/AIDS. Annals of Behavioral Medicine
24:34-48, 2002.
Freedland, KE, Skala, JA, Carney, RM, Raczynski,
JM, Taylor, CB, Mendes De Leon, CF, Ironson,
G, Youngblood, ME, Rama Krishnan, KR, and
Veith, RC. The Depression Interview and Structured Hamilton (DISH): rationale, development,
characteristics, and clinical validity. Psychosomatic Medicine 64:897-905, 2002.
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates the
association between psychological distress and
immune status among HIV-positive men and
women on combination antiretroviral therapy.
Journal of Psychosomatic Research 54:185-9, 2003.
165
P UBLIC ATIONS 200 2-200 3
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Stanley, H,
Ironson, G, Schneiderman, N, Brondolo, E,
Tobin, JN, and Weiss, S. Cognitive-behavioral
interventions improve quality of life in women
with AIDS. Journal of Psychosomatic Research
54:253-61, 2003.
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,
MA, McGuffey, L, Balbin, E, Schneiderman, N,
and Solomon, G. Emotional expression and
depth processing of trauma and their relation to
long-term survival in patients with HIV/AIDS.
Journal of Psychosomatic Research 54:225-35,
2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, Fletcher, MA, and
O’Sullivan, MJ. Stress as a predictor of symptomatic genital herpes virus recurrence in women
with human immunodeficiency virus. Journal of
Psychosomatic Research 54:237-44, 2003.
Pereira, DB, Antoni, MH, Danielson, A, Simon,
T, Efantis-Potter, J, Carver, CS, Duran, RE,
Ironson, G, Klimas, N, and O’Sullivan, MJ. Life
stress and cervical squamous intraepithelial lesions in women with human papillomavirus and
human immunodeficiency virus. Psychosomatic
Medicine 65:427-34, 2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological distress among symptomatic HIV+ men who have
sex with men. Annals of Behavioral Medicine
25:203-13, 2003.
Chen, AJ, Zhou, G, Juan, T, Colicos, SM, Cannon, JP, Cabriera-Hansen, M, Meyer, CF, Jurecic,
R, Copeland, NG, Gilbert, DJ, Jenkins, NA,
Fletcher, F, Tan, TH, and Belmont, JW. The dual
specificity JKAP specifically activates the c-Jun
N-terminal kinase pathway. Journal of Biological
Chemistry 277:36592-601, 2002.
166
Spassov, DS and Jurecic, R. Cloning and comparative sequence analysis of PUM1 and PUM2
genes, human members of the Pumilio family of
RNA-binding proteins. Gene 299:195-204,
2002.
Spassov, DS and Jurecic, R. Mouse Pum1 and
Pum2 genes, members of the Pumilio family of
RNA-binding proteins, show differential expression in fetal and adult hematopoietic stem cells
and progenitors small star, filled. Blood, Cells,
Molecules & Diseases 30:55-69, 2003.
Komatsu, M, Mammolenti, M, Jones, M,
Jurecic, R, Sayers, TJ, and Levy, RB. Antigenprimed CD8+ T cells can mediate resistance, preventing allogeneic marrow engraftment in the
simultaneous absence of perforin-, CD95L-,
TNFR1-, and TRAIL-dependent killing. Blood
101:3991-99, 2003.
Spassov, DS and Jurecic, R. The PUF Family of
RNA-binding Proteins: Does Evolutionarily
Conserved Structure Equal Conserved Function?
IUBMB Life 55: 359-66, 2003.
Liang, H, Chen ,Q, Coles, AH, Anderson, SJ,
Pihan, G, Bradley, A, Gerstein, R, Jurecic, R, and
Jones, SN. Wnt5a inhibits B cell proliferation
and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4:349-60, 2003.
Kloc, M, Dougherty, MT, Bilinski, S, Chan, AP,
Brey, E, King, ML, Patrick, CW, Jr, and Etkin,
LD. Three-dimensional ultrastructural analysis of
RNA distribution within germinal granules of
Xenopus. Developmental Biology 241:79-93,
2002.
Bubunenko, M, Kress, TL, Vempati, UD,
Mowry, KL, and King, ML. A consensus RNA
signal that directs germ layer determinants to the
vegetal cortex of Xenopus oocytes. Developmental Biology 248:82-92, 2002.
Zhou, Y, Zhang, J, and King, ML. Xenopus
ARH couples lipoprotein receptors with the AP-2
complex in oocytes and embryos and is required
for vitellogenesis. Journal of Biological Chemistry
278:44584-92, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Bruce, AE, Howley, C, Zhou, Y, Vickers, SL, Silver, LM, King, ML, and Ho, RK. The maternally
expressed zebrafish T-box gene eomesodermin
regulates organizer formation. Development
130:5503-17, 2003.
Kirsner, RS , Fastenau, J, Falabella, A, Valencia, I,
Long, R, and Eaglstein, WH. Clinical and economic outcomes with graftskin for hard-to-heal
venous leg ulcers: a single-center experience. Dermatologic Surgery 28:81-82, 2002.
Federman, DG, Kravetz, JD, and Kirsner, RS .
Skin cancer screening by dermatologists: prevalence and barriers. Journal of the American Academy of Dermatology 46:710-14, 2002.
Federman, DG and Kirsner, RS . The patient
with skin disease: an approach for
nondermatologists. Ostomy/Wound Management 48:22-8; quiz 29-30, 2002.
Federman, DG, Moriarty, JP, Kravetz, JD, and
Kirsner, RS . Thrombosis: new culprits in an old
disorder. Panminerva Medica 44:107-13, 2002.
Harrison-Balestra, C, Eaglstein, WH, Falabela,
AF, and Kirsner, RS . Recombinant human platelet-derived growth factor for refractory nondiabetic ulcers: a retrospective series. Dermatologic
Surgery 28:755-59; discussion 759-60, 2002.
Sullivan, TP, Elgart, GW, and Kirsner, RS . Pemphigus and smoking. International Journal of
Dermatology 41:528-30, 2002.
Sullivan, TP and Kirsner, RS . Surgical pearl:
punch technique to improve granulation over
exposed tendons in chronic wounds. Journal of
the American Academy of Dermatology 47:43940, 2002.
Greenberg, JE, Lynn, M, Kirsner, RS , Elgart,
GW, and Hanly, AJ. Mucocutaneous pigmented
macule as a result of zinc deposition. Journal of
Cutaneous Pathology 29:613-15, 2002.
Martin, LK and Kirsner, RS . Use of a meshed
bilayered cellular matrix to treat a venous ulcer.
Advances in Skin & Wound Care 15:260, 262,
264, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Banta, MN and Kirsner, RS . Modulating diseased skin with tissue engineering: actinic purpura treated with Apligraf. Dermatologic Surgery
28:1103-06, 2002.
Federman, DG and Kirsner, RS : Timing of hypercoagulable screens. Archives of Internal Medicine 162:613-4, 2002.
Trent, JT and Kirsner, RS. Diagnosing necrotizing fasciitis. Advances in Skin & Wound Care
15:135-38, 2002.
Sullivan, TP and Kirsner, RS. Surgical pearl:
punch technique to improve granulation over
exposed tendons in chronic wounds. Journal of
the American Academy of Dermatology 47:43940, 2002.
Zacur, H and Kirsner, RS. Debridement: Rationale and therapeutic options. Wounds 14:2E-7E,
2002.
Trent, JT and Kirsner, RS. Necrotizing fasciitis.
Wounds 14:284-92, 2002.
Kirsner, R . New approaches to a timeless dilemma. Ostomy/Wound Management 49:12-14,
2003.
Li, J, Zhang YP, and Kirsner, RS . Angiogenesis in
wound repair: angiogenic growth factors and the
extracellular matrix. Microscopy Research and
Technique 60:107-14, 2003.
Trent, JT, Kirsner, RS , Romanelli, P, and Kerdel,
FA. Analysis of intravenous immunoglobulin for
the treatment of toxic epidermal necrolysis using
SCORTEN: The University of Miami Experience. Archives of Dermatology 139:39-43, 2003.
Trent, JT and Kirsner, RS . Wounds and malignancy. Advances in Skin & Wound Care 16:3134, 2003.
de Araujo, T, Valencia, I, Federman, DG, and
Kirsner, RS . Managing the patient with venous
ulcers. Annals of Internal Medicine 138:326-34,
2003.
167
P UBLIC ATIONS 200 2-200 3
Kirsner, R . Wound bed preparation. Ostomy/
Wound Management Supplement:2-3, 2003.
Jacob, SE, Lodha, R, Cohen, JJ, Romanelli, P,
and Kirsner, RS . Paraneoplastic eosinophilic
fasciitis: a case report. Rheumatology International 23:262-4, 2003.
Martin, LK and Kirsner, RS . Ulcers caused by
bullous morphea treated with tissue-engineered
skin. International Journal of Dermatology
42:402-04, 2003.
Trent, JT and Kirsner, RS . Identifying and treating mycotic skin infections. Advances in Skin &
Wound Care 16:122-29, 2003.
Ayyalaraju, RS, Finlay, AY, Dykes, PJ, Trent, JT,
Kirsner, RS , and Kerdel, FA. Hospitalization for
severe skin disease improves quality of life in the
United Kingdom and the United States: a comparative study. Journal of the American Academy
of Dermatology 49:249-54, 2003.
Banta, MN, Eaglstein, WH, and Kirsner, RS .
Healing of refractory sinus tracts by dermal matrix injection with Cymetra. Dermatologic Surgery 29:863-66, 2003.
Geren, SM, Kerdel, FA, Falabella, AF, and
Kirsner, RS . Infliximab: a treatment option for
ulcerative pyoderma gangrenosum. Wounds
15:49-53, 2003.
Kirsner, RS. Infection and intervention. Wounds
15:127-28, 2003.
Drosou, A, Falabella, AF, and Kirsner, RS . Antiseptics on wounds: an area of controversy.
Wounds 5:149-166, 2003
Koniaris, LG . Induction of MIC-1/growth differentiation factor-15 following bile duct injury.
Journal of Gastrointestinal Surgery 7:901-5,
2003.
Koniaris, LG , Seibel, JA, Geschwind, JF, and
Sitzmann, JV. Can ethanol therapies injure the
bile ducts? Hepato-gastroenterology 50:69-72,
2003.
168
Hendrickson, RJ, Diaz, AA, Salloum, R, and
Koniaris, LG . Benign rectal ulcer: an underground cause of inpatient lower gastrointestinal
bleeding. Surgical Endoscopy 17:1759-65, 2003.
Koniaris, LG , Schoeniger, LO, Kovach, S, and
Sitzmann, JV. The quick, no-twist, no-kink portal confluence reconstruction. Journal of the
American College of Surgeons 196:490-94, 2003.
Schoeniger, LO, Bankey, P, Drugas, GT, and
Koniaris, LG . Optimal closure of the complex
abdomen. Archives of Surgery 138:458, 2003.
Koniaris, LG , Drugas, G, Katzman, PJ, and
Salloum, R. Management of gastrointestinal lymphoma. Journal of the American College of Surgeons 197:127-41, 2003.
Koniaris, LG , Wilson, S, Drugas, G, and
Simmons, W. Capnographic monitoring of ventilatory status during moderate (conscious) sedation. Surgical Endoscopy 17:1340, 2003.
Koniaris, LG , McKillop, IH, Schwartz, SI, and
Zimmers, TA. Liver regeneration. Journal of the
American College of Surgeons 197:634-59, 2003.
Zimmers, TA, McKillop, IH, Pierce, RH, Yoo,
JY, and Koniaris, LG . Massive liver growth in
mice induced by systemic interleukin 6 administration. Hepatology 38:326-34, 2003.
Senn, JJ, Klover, PJ, Nowak, IA, Zimmers, TA,
Koniaris, LG , Furlanetto, RW, and Mooney, RA.
Suppressor of cytokine signaling-3 (SOCS-3), a
potential mediator of interleukin-6-dependent
insulin resistance in hepatocytes. Journal of Biological Chemistry 278:13740-46, 2003.
Klover, PJ, Zimmers, TA, Koniaris, LG , and
Mooney, RA. Chronic exposure to interleukin-6
causes hepatic insulin resistance in mice. Diabetes
52:2784-89, 2003.
Krishan, A. Flow cytometric monitoring of hormone receptor expression in human solid tumors.
Proceedings of SPIE 4622: 211-17, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Arya, P, Andritsch, IH, and Krishan, A . Androgen receptor expression in archival human breast
tumors. Methods in Cell Science 24:61-64, 2002.
Krishan, A. Flow cytometric monitoring of drug
resistance in human tumor cells. Methods in Cell
Science 24:55-60, 2002.
Thomas, RA, Krishan, A , and Brochu, M. High
resolution flow cytometric analysis of electronic
nuclear volume and DNA content in normal and
abnormal human tissue. Methods in Cell Science
24:11-18, 2002.
Adiga, SK, Andritsch, IH, Rao, RV, and Krishan,
A. Androgen receptor expression and DNA content of paraffin-embedded archival human prostate tumors. Cytometry 50:25-30, 2002.
Frankfurt, OS and Krishan, A. Apoptosis-based
drug screening and detection of selective toxicity
to cancer cells. Anticancer Drugs 14:555-61,
2003.
Frankfurt, OS and Krishan, A . Microplate
screening for apoptosis with antibody to singlestranded DNA distinguishes anticancer drugs
from toxic chemicals. Journal of Biomolecular
Screening 8:185-90, 2003.
Frankfurt, OS and Krishan, A . Apoptosis enzyme-linked immunosorbent assay distinguishes
anticancer drugs from toxic chemicals and predicts drug synergism. Chemico-Biological Interactions 145:89-99, 2003.
Krishan, A. Flow cytometric monitoring of drug
resistance in human tumor cells. Methods in Cell
Science 24:55-60, 2003.
Abdel-Wahab, M, Krishan, A, Milikowski, C,
Wahab, AA, Walker, G, and Markoe, A. Androgen receptor antigen density and s-phase fraction
in prostate cancer—a pilot study. Prostate Cancer
and Prostatic Diseases 6:294-300, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress management and immune system reconstitution in
symptomatic HIV-infected gay men over time:
effects on transitional naive T cells
(CD4(+)CD45RA(+)CD29(+)). American Journal of Psychiatry 159:143-5, 2002.
Ironson, G, Solomon, GF, Balbin, EG,
O’Cleirigh, C, George, A, Kumar, M, Larson, D,
and Woods, TE. The Ironson-Woods Spirituality/
Religiousness Index is associated with long survival, health behaviors, less distress, and low cortisol in people with HIV/AIDS. Annals of
Behavioral Medicine 24:34-48, 2002.
Kumar, M, Kumar, AM, Waldrop, D, Antoni,
MH, Schneiderman, N, and Eisdorfer, C. The
HPA axis in HIV-1 infection. Journal of Acquired Immune Deficiency Syndromes 31
Supplement 2:S89-93, 2002.
Mitchell, A and Kumar, M . Psychological coping
and cancer. Search strategy used is inadequate.
British Medical Journal 326:598; author reply
598, 2003.
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ .
Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:174551, 2002.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and
Lampidis, TJ . Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ , Robles, C, Furst, AJ, and Feun, L.
Overexpression of mutated MRP4 in cisplatin
resistant small cell lung cancer cell line: collateral
sensitivity to azidothymidine. International Journal of Oncology 23:173-9, 2003.
169
P UBLIC ATIONS 200 2-200 3
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,
Schneiderman, N, Brondolo, E, Tobin, J, and
Weiss, S. Cognitive-behavioral interventions improve quality of life in women with AIDS. Journal of Psychosomatic Research 54: 253-61, 2003.
Lechner, SC, Zakowski, SG, Antoni, MH,
Greenhawt, M, Block, K, and Block, P. Do
sociodemographic and disease-related factors influence benefit-finding in cancer patients?
Psycho-oncology 12: 491-99, 2003.
Lee, DJ, Gomez-Marin, O, Lam, BL, and Zheng,
DD. Visual acuity impairment and mortality in
U.S. adults. Archives of Ophthalmology
120:1544-50, 2002.
Lee, DJ, Trapido, E, and Rodriguez, R. Self-reported school difficulties and tobacco use among
fourth- to seventh-grade students. Journal of
School Health 72:368-73, 2002.
Fleming, LE, Gomez-Marin, O, Zheng, D, Ma,
F, and Lee, DJ. National Health Interview Survey
mortality among U.S. farmers and pesticide
applicators. American Journal of Industrial
Medicine 43:227-33, 2003.
Goodkin, K, Heckman, T, Siegel, K, Linsk, N,
Khamis, I, Lee, DJ, Lecusay, R, Poindexter, CC,
Mason, SJ, Suarez, P, and Eisdorfer, C. “Putting a
face” on HIV infection/AIDS in older adults: a
psychosocial context. Journal of Acquired Immune
Deficiency Syndromes 33:S171-S184, 2003.
Lee, DJ, Gomez-Marin, O, Lam, BL, and Zheng,
DD. Glaucoma and survival: the National Health
Interview Survey 1986-1994. Ophthalmology
110:1476-83, 2003.
Lee, DJ, Gómez-Marín, O, Ma, F, and Lam, BL.
Uncorrected binocular distance visual acuity impairment and survival: The National Health and
Nutrition Examination Survey I. Ethnicity and
Disease 13: 485-91, 2003.
170
Lee, DJ, Trapido, E, and Rodriguez, R. Secondhand smoke and earaches in adolescents: the
Florida Youth Cohort Study. Nicotine and Tobacco Research 5: 1-4, 2003.
Gray Parkin, K, Stephan, RP, Apilado, RG, LillElghanian, DA, Lee, KP, Saha, B, and Witte, PL.
Expression of CD28 by bone marrow stromal
cells and its involvement in B lymphopoiesis.
Journal of Immunology 169:2292-302, 2002.
Baumgartner, R, Durant, P, van Gessel, Y,
Chattopadhyay, S, Beswick, RL, Tadaki, DK,
Lasbury, M, Lee, CH, Perrin, P, and Lee, KP.
Evidence for the requirement of T cell
costimulation in the pathogenesis of natural
Pneumocystis carinii pulmonary infection.
Microbial Pathogenesis 33:193-201, 2002.
Strbo, N, Yamazaki, K, Lee, KP, Rujkavina, D
and Podack, ER. Heat shock fusion protein
gp96-Ig mediates strong CD8 CTL expansion
in vivo. American Journal of Reproductive
Immunology 48:220-25, 2002.
Bahlis, NJ, McCafferty-Grad, J, JordanMcMurry, I, Neil, J, Reis, I, Kharfan-Dabaja, M,
Eckman, J, Goodman, M, Fernandez, HF, Boise,
LH, and Lee, KP. Feasibility and correlates of
arsenic trioxide combined with ascorbic acidmediated depletion of intracellular glutathione
for the treatment of relapsed/refractory multiple
myeloma. Clinical Cancer Research 8:3658-68,
2002.
Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and
Harlan, DM. Porcine CD80: cloning, characterization, and evidence for its role in direct human
T-cell activation. Xenotransplantation 10: 25258, 2003.
Lindner, I, Kharfan-Dabaja, M, Ayala, E,
Kolonias, D, Cejas, P, and Lee, KP. Induced
differentiation of chronic myelogenous leukemia
to dendritic cells downregulates BCR-ABL gene
expression. Journal of Immunology 171:1780-91,
2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
McCafferty-Grad, J, Bahlis, NJ, Krett, N, Reis, I,
Lee, KP, and Boise, LH. Arsenic trioxide utilizes
caspase dependent and caspase independent
death pathways in myeloma cells. Molecular Cancer Therapeutics 2:1155-64, 2003.
Hernandez, A, Lindner, I, Blomberg, BB,
Hussini, S, Burger, M, Mathew, JM, Carreno, M,
Garcia-Morales, R, Fuller, L, Jin, Y, Rosen, A,
Lee, KP, Miller, J, and Esquenazi, V. Suppression
of allogeneic T cell proliferation through blocking of NF-κB in the differentiation process of
human dendritic cells. Human Immunology
64:S128, 2003.
Levis, S, Quandt, SA, Thompson, D, Scott, J,
Schneider, DL, Ross, PD, Black, D, Suryawanshi,
S, Hochberg, M, and Yates, J. Alendronate reduces the risk of multiple symptomatic fractures:
results from the fracture intervention trial. Journal of the American Geriatric Society 50:409-15,
2002.
Bohlman, MC, Morzunov, SP, Meissner, J, Taylor, MB, Ishibashi, K, Rowe, J, Levis, S, Enria,
D, and St Jeor, SC. Analysis of hantavirus genetic
diversity in Argentina: S segment-derived phylogeny. Journal of Virology 76:3765-73, 2002.
Seijo, A, Pini, N, Levis, S, Coto, H, Deodato, B,
Cernigoi, B, de Bassadoni, D, and Enria, D.
Medicina (Buenos Aires) 63:193-96, 2003.
Hernandez-Cassis, C, Vogel, CK, Hernandez, TP,
Econs, MJ, Iglesias, M, Iglesias, A, Levis, S,
Roos, BA, Howard, GA, and Gamarra, AI. Autosomal dominant hyperostosis/osteosclerosis with
high serum alkaline phosphatase activity. Journal
of Clinical Endocrinology and Metabolism
88:2650-55, 2003.
Jiang, Z, Adams, GB, Hanash, AM, Scadden,
DT, and Levy, RB. The contribution of cytotoxic
and noncytotoxic function by donor T-cells that
support engraftment after allogeneic bone marrow transplantation. Biology of Blood and Marrow Transplantation 8:588-96, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Chill, JH, Nivasch, R, Levy, RB, Albeck, S,
Schreiber, G, and Anglister, J. The human interferon receptor: NMR-based modeling, mapping
of the IFN-alpha 2 binding site, and observed
ligand-induced tightening. Biochemistry
41:3575-85, 2002.
Levy, RB and Aoki, C. Alpha7 nicotinic acetylcholine receptors occur at postsynaptic densities
of AMPA receptor-positive and -negative excitatory synapses in rat sensory cortex. Journal of
Neuroscience 22:5001-15, 2002.
Yu, A, Zhou, J, Marten, N, Bergmann, CC,
Mammolenti, M, Levy, RB, and Malek, TR. Efficient induction of primary and secondary T celldependent immune responses in vivo in the
absence of functional IL-2 and IL-15 receptors.
Journal of Immunology 170:236-42, 2003.
Calautti, E, Grossi, M, Mammucari, C, Aoyama,
Y, Pirro, M, Ono, Y, Li, J, and Dotto, GP. Fyn
tyrosine kinase is a downstream mediator of Rho/
PRK2 function in keratinocyte cell-cell adhesion.
Journal of Cell Biology 156:137-48, 2002.
Li, J, Zhang, YP, and Kirsner, RS. Angiogenesis
in wound repair: angiogenic growth factors and
the extracellular matrix. Microscopy Research
and Technique 60:107-14, 2003.
Li, J, Tzu, J, Chen, Y, Zhang, YP, Nguyen, NT,
Gao, J, Bradley, M, Keene, DR, Oro, AE, Miner,
JH, and Marinkovich, MP. Laminin-10 is crucial
for hair morphogenesis. EMBO Journal
22(10):2400-10, 2003.
Vincel, V, Knowles, J, Li, J, and Nassiri, M. Expression of p63 mRNA isoforms in normal human tissue. Anticancer Research, 23:3945-48,
2003.
Zhou, J, Zhang, J, Lichtenheld, MG, and Meadows, GG. A role for NF-kappa B activation in
perforin expression of NK cells upon IL-2 receptor signaling. Journal of Immunology 169:131925, 2002.
171
P UBLIC ATIONS 200 2-200 3
Lu, Q, Wu, A, Ray, D, Deng, C, Attwood, J,
Hanash, S, Pipkin, M, Lichtenheld, MG, and
Richardson, B. DNA methylation and chromatin
structure regulate T cell perforin gene expression.
Journal of Immunology 170:5124-32, 2003.
Adams, MJ, Lipshultz, SE , Schwartz, C, Fajardo,
LF, Coen, V, and Constine, LS. Radiation-associated cardiovascular disease: manifestations and
management. Seminars in Radiation Oncology
13:346-56, 2003.
Beaupre, D, Grad, J, Bahlis, N, Boise, L, and
Lichtenheld, MG. Farnesyl transferase inhibitors
sensitize to death receptor signals and induce
apoptosis of multiple myeloma cells. Leukemia &
Lymphoma 44:2123-34, 2003.
Lipshultz, SE , Fisher, SD, Lai, WW, and Miller,
TL. Cardiovascular risk factors, monitoring, and
therapy for HIV-infected patients. AIDS 17
Supplement 1:S96-122, 2003.
Lipshultz, SE , Lipsitz, SR, Sallan, SE, Simbre,
VC 2nd, Shaikh, SL, Mone, SM, Gelber, RD,
and Colan, SD. Long-term enalapril therapy for
left ventricular dysfunction in doxorubicintreated survivors of childhood cancer. Journal of
Clinical Oncology 20:4517-22, 2002.
Harmon, WG, Dadlani, GH, Fisher, SD, and
Lipshultz, SE . Myocardial and pericardial disease
in HIV. Current Treatment Options in Cardiovascular Medicine 4:497-509, 2002.
Lipshultz, SE , Giantris, AL, Lipsitz, SR, Kimball,
Dalton, V, Asselin, BL, Barr, RD, Clavell, LA,
Hurwitz, CA, Moghrabi, A, Samson, Y, Schorin,
MA, Gelber, RD, Sallan, SE, and Colan, SD.
Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber
91-01 acute lymphoblastic leukemia protocol.
Journal of Clinical Oncology 20:1677-82, 2002.
Zareba, KM and Lipshultz, SE . Cardiovascular
complications in patients with HIV infection.
Current Infectious Disease Reports 5:513-20, 2003.
Constine, LS, Hinkle, AS, French, CA,
Kozlowski, AM, Proukou, C, Lipsitz, SR, Miller,
TL, Vermilion, RP, Rifai, N, and Lipshultz, SE .
Radiation-associated risk factors for premature
cardiovascular disease in childhood cancer survivors include accelerated atherosclerosis. International Journal of Radiation Oncology Biology
Physics 57(2 Supplement):S199-200, 2003.
172
Fisher, SD, Bowles, NE, Towbin, JA, and
Lipshultz, SE . Mediators in HIV-associated cardiovascular disease: a focus on cytokines and
genes. AIDS 17 Supplement 1:S29-35, 2003.
Lipshultz, SE , Somers, MJ, Lipsitz, SR, Colan,
SD, Jabs, K, and Rifai, N. Serum cardiac troponin and subclinical cardiac status in pediatric
chronic renal failure. Pediatrics 112:79-86, 2003.
Al-Attar, I, Orav, EJ, Exil, V, Vlach, SA, and
Lipshultz, SE . Predictors of cardiac morbidity
and related mortality in children with acquired
immunodeficiency syndrome. Journal of the
American College of Cardiology 41(9):1598-605,
2003.
Benun, J, Fisher, SD, Orav, EJ, Schwartz, ML,
Exil, V, Messere, C, and Lipshultz, SE . Cardiac
management by pediatricians versus pediatric cardiologists in an inpatient academic center. American Heart Journal 145:424-9, 2003.
Dadlani, GH, Harmon, WG, Simbre, II VC,
Tisma-Dupanovic, S, and Lipshultz, SE .
Cardiomyocyte injury to transplant: pediatric
management. Current Opinion in Cardiology
18:91-7 (Review), 2003.
Adams, MJ, Hardenbergh, PH, Constine, LS,
and Lipshultz, SE . Radiation-associated cardiovascular disease. Critical Reviews in Oncology/
Hematology 45:55-75 (Review), 2003.
Saika, S, Ohnishi, Y, Ooshima, A, Liu, CY, and
Kao, WW. Epithelial repair roles of extracellular
matrix. Cornea 21 (supplement.): S23-S29,
2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Wang, IJ, Carlson, EC, Liu, CY, Kao, CW, Hu,
FR, and Kao, WW. Cis-regulatory elements of
the mouse Krt1.12 gene. Molecular Vision 8: 94101, 2002.
Austin, BA, Coulon, C, Liu, CY, Kao, WW, and
Rada, JA. Altered collagen fibril formation in the
sclera of lumican-deficient mice. Investigative
Ophthalmology & Visual Science 43:1695-1701,
2002.
Paradis, H, Liu, CY, Saika, S, Muhamad, A,
Doetschman, T, Good, W, Nayak, R, Laver, N,
Kao, C, Kao, WW, and Gendron, R. Tubedown1 in remodeling of the developing vitreal vasculature in vivo and regulation of capillary outgrowth
in vitro. Developmental Biology 249:140-55,
2002.
Nikitin, AY, Liu, CY, Flesken-Nikitin, A, Chen,
CF, Chen, PL, and Lee, WH. Cell lineagespecific effects associated with multiple deficiencies of tumor susceptibility genes in Msh2-/-Rb+/mice. Cancer Research 62: 5134-38, 2002.
Carlson, EC, Mamiya, K, Liu, CY, Gendron, RL,
Birk, DE, Funderburgh, JL, and Kao, WW. Role
of 41Cys in the N-terminal domain of lumican in
ex vivo collagen fibrillogenesis by cultured corneal
stromal cells. Biochemical Journal 369:461-68,
2003.
Kao, WW and Liu, CY. The use of transgenic
and knockout mice in the investigation of ocular
surface cell biology. The Ocular Surface 1: 5-19,
2003.
Saika, S, Miyamoto, T, Tanaka, S, Tanaka, T,
Ishida, I, Ohnishi, Y, Ooshima, A, Ishiwata, T,
Asano, G, Chikama, T, Shiraishi, A, Liu, CY,
Kao, CW, and Kao, WW. Response of lens epithelial cells to injury: role of lumican in epithelial-mesenchymal transition. Investigative
Ophthalmology & Visual Science 44:2094-102,
2003.
Zhang, L, Wang, W, Hayashi, Y, Jester, JV, Birk,
DE, Gao, M, Liu, CY, Kao, WW, Karin, M, and
Xia, Y. A role for MEK kinase 1 in TGF-beta/
activin-induced epithelium movement and
embryonic eyelid closure. EMBO Journal 22:
4443-54, 2003.
Espana, E M, Kawakita, T, Romano, A,
DiPascuale, M, Smiddy, R, Liu, CY, and Tseng,
SC. Stromal niche controls the plasticity of
limbal and corneal epithelial differentiation in a
rabbit model of recombined tissue. Investigative
Ophthalmology & Visual Science 44: 5130-35,
2003.
Espana, EM, He, H, Kawakita, T, Di Pascuale,
MA, Raju, VK, Liu, CY, and Tseng, SC. Human
keratocytes cultured on amniotic membrane
stroma preserve morphology and express
keratocan. Investigative Ophthalmology &
Visual Science 44: 5136-41, 2003.
Carlson, EC, Wang, IJ, Liu, CY, Brannan, P,
Kao, CW, and Kao, WW. Altered KSPG expression by keratocytes following corneal injury. Molecular Vision 9:615-23, 2003.
Meek, KM, Quantock, AJ, Boote, C, Liu, CY,
and Kao, WW. An X-ray diffraction investigation
of corneal structure in keratocan-deficient mice.
Matrix Biology 22:467-75, 2003.
Whitlatch, LW, Young, MV, Schwartz, GG,
Flanagan, JN, Burnstein, KL, Lokeshwar, BL ,
Rich, ES, Holick, MF, and Chen, TC. 25Hydroxyvitamin D-1alpha-hydroxylase activity is
diminished in human prostate cancer cells and is
enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40, 2002.
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, ME, and Pflugfelder, SC.
A mouse model of keratoconjunctivitis sicca. Investigative Ophthalmology & Visual Science
43:632-38, 2002.
Liu, CY, Birk, DE, Hassell, JR, Kane, B, and
Kao, WW. Keratocan-deficient mice display alterations in corneal structure. Journal of Biological
Chemistry 278:21672-677, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
173
P UBLIC ATIONS 200 2-200 3
Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block,
NL, and Golub, LM. Inhibition of cell proliferation, invasion, tumor growth and metastasis by
an oral non-antimicrobial tetracycline analog
(COL-3) in a metastatic prostate cancer model.
International Journal of Cancer 98:297-309, 2002.
Dursun, D, Wang, M, Monroy, D, Li, DQ,
Lokeshwar, BL , Stern, M, and Pflugfelder, SC.
Experimentally induced dry eye produces ocular
surface inflammation and epithelial disease. Advances in Experimental Medicine and Biology
506(Pt A):647-55, 2002.
Chen, TC, Holick, MF, Lokeshwar, BL ,
Burnstein, KL, and Schwartz, GG. Evaluation of
vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research
164:273-88, 2003.
Li de, Q, Shang, TY, Kim, HS, Solomon, A,
Lokeshwar, BL , and Pflugfelder, SC. Regulated
expression of collagenases MMP-1, -8, and -13
and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells. Investigative Ophthalmology and Visual Science 44:2928-36,
2003.
Dandekar, DS, Lokeshwar, VB, CevallosArellano, E, Soloway, MS, and Lokeshwar, BL .
An orally active Amazonian plant extract (BIRM)
inhibits prostate cancer growth and metastasis.
Cancer Chemotherapy and Pharmacology
52(1):59-66, 2003.
Lokeshwar, VB and Soloway, MS. Re: Urine
based markers of urological malignancy. Journal
of Urology 167:1406-07, 2002.
Lokeshwar, VB , Schroeder, GL, Selzer, MG,
Hautmann, SH, Posey, JT, Duncan, RC, Watson,
R, Rose, L, Markowitz, S, and Soloway, MS.
Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic
acid-hyaluronidase and BTA-Stat tests. Cancer
95:61-72, 2002.
Lokeshwar, VB , Schroeder, GL, Carey, RI,
Soloway, MS, and Iida, N. Regulation of hyaluronidase activity by alternative mRNA splicing.
Journal of Biological Chemistry 277:33654-63,
2002.
Posey, JT, Soloway, MS, Ekici, S, Sofer, M,
Civantos, F, Duncan, RC, and Lokeshwar, VB .
Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Research 63:2638-44, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB . Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45,
2003.
Dandekar, DS, Lokeshwar, VB , CevallosArellano, E, Soloway, MS, and Lokeshwar, BL.
An orally active Amazonian plant extract (BIRM)
inhibits prostate cancer growth and metastasis.
Cancer Chemotherapy and Pharmacology 52:5966, 2003.
Simon, MA, Lokeshwar, VB , and Soloway, MS.
Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003.
Sun, QL, Charyulu, V, Lobo, D, and Lopez,
DM. Role of thymic stromal cell dysfunction in
the thymic involution of mammary tumor-bearing mice. Anticancer Research 22:91-6, 2002.
Lopez, DM, Charyulu, V, and Adkins, B. Influence of breast cancer on thymic function in mice.
Journal of Mammary Gland Biology and Neoplasia 7:191-99, 2002.
Torroella-Kouri, M, Keith, JC, Ivanova, M, and
Lopez, DM. IL-11-induced reduction of C/EBP
transcription factor binding may contribute to the
IL-12 downregulation in tumor-bearing mice. International Journal of Oncology 22:439-48, 2003.
Ekici, S and Lokeshwar, VB . Mesane tumoru
belirleyicileri ve HA-Haase testi. Uroloji Bulteni
13:133-40, 2002.
174
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Owen, JL, Iragavarapu-Charyulu, V, GunjaSmith, Z, Herbert, LM, Grosso, JF, and Lopez,
DM. Up-regulation of matrix metalloproteinase9 in T lymphocytes of mammary tumor bearers:
role of vascular endothelial growth factor. Journal
of Immunology 171(8):4340-51, 2003.
Lossos, IS , Or, R, Ginzburg, V, Christensen,
TG, Mashriki, Y, and Breuer, R. Cyclosporin A
upmodulates bleomycin-induced pulmonary fibrosis in BALB/c mice. Respiration 69:344-49, 2002.
Auffermann-Gretzinger, S, Lossos, IS , Vayntrub,
TA, Leong, W, Grumet, FC, Blume, KG,
Stockerl-Goldstein, KE, Levy, R, and Shizuru,
JA. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant
recipients. Blood 99:1442-48, 2002.
Bokstein, F, Lossos, A, Lossos, IS , and Siegal, T.
Central nervous system relapse of systemic nonHodgkin’s lymphoma: results of treatment based
on high-dose methotrexate combination chemotherapy. Leukemia & Lymphoma 43:587-93, 2002.
Huang, JZ, Sanger, WG, Greiner, TC, Staudt,
LM, Weisenburger, DD, Pickering, DL, Lynch,
JC, Armitage, JO, Warnke, RA, Alizadeh,
AA, Lossos, IS , Levy, R, and Chan, WC. The
t(14;18) defines a unique subset of diffuse large
B-cell lymphoma with a germinal center B-cell
gene expression profile. Blood 99:2285-90, 2002.
Lossos, IS , Thorstenson, YR, Wayne, TL, Oefner,
PJ, Levy, R, and Chu, G. Mutation of the ATM
gene is not involved in the pathogenesis of either
follicle center lymphoma or its transformation to
higher-grade lymphoma. Leukemia & Lymphoma
43:1079-85, 2002.
Lossos, IS , Alizadeh, AA, Diehn, M, Warnke,
R, Thorstenson, Y, Oefner, PJ, Brown, PO,
Botstein, D, and Levy, R. Transformation of follicular lymphoma to diffuse large-cell lymphoma:
alternative patterns with increased or decreased
expression of c-myc and its regulated genes.
Proceedings of the National Academy of Sciences
USA 99:8886-91, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Lossos, IS , Warnke, R, and Levy, R. BCL-6
mRNA expression in higher grade transformation
of follicle center lymphoma: correlation with somatic mutations in the 5' regulatory region of the
BCL-6 gene. Leukemia 16:1857-62, 2002.
Lossos, IS , Natkunam, Y, Levy, R, and Lopez,
CD. Apoptosis stimulating protein of p53
(ASPP2) expression differs in diffuse large B-cell
and follicular center lymphoma: correlation with
clinical outcome. Leukemia & Lymphoma
43:2309-17, 2002.
Lossos, IS , Alizadeh, AA, Rajapaksa, R,
Tibshirani, R, and Levy, R. HGAL is a novel
interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma.
Blood 101:433-40, 2003.
Lossos, IS , Czerwinski, DK, Wechser, MA, and
Levy, R. Optimization of quantitative real-time
RT-PCR parameters for the study of lymphoid
malignancies. Leukemia 17:789-95, 2003.
Martinez-Climent, JA, Alizadeh, AA, Segraves, R,
Blesa, D, Rubio-Moscardo, F, Albertson, DG,
Garcia-Conde, J, Dyer, MJ, Levy, R, Pinkel, D,
and Lossos, IS . Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy
number and gene expression alterations. Blood
101:3109-17, 2003.
Akasaka, T, Lossos, IS , and Levy, R. BCL6 gene
translocation in follicular lymphoma: a harbinger
of eventual transformation to diffuse aggressive
lymphoma. Blood 102:1443-48, 2003.
Lossos, IS and Levy, R. Diffuse large B-cell lymphoma: insights gained from gene expression profiling. International Journal of Hematology
77:321-29, 2003.
Lossos, IS and Levy, R. Higher grade transformation of follicular lymphoma: phenotypic tumor
progression associated with diverse genetic lesions.
Seminars in Cancer Biology 13:191-202, 2003.
175
P UBLIC ATIONS 200 2-200 3
Lossos, IS , Akasaka, T, Martinez-Climent, JA,
Siebert, R, and Levy, R. The BCL6 gene in B-cell
lymphomas with 3q27 translocations is expressed
mainly from the rearranged allele irrespective of
the partner gene. Leukemia 17:1390-97, 2003.
Do, B, Lossos, IS , Thorstenson, Y, Oefner, PJ,
and Levy, R. Analysis of FAS (CD95) gene mutations in higher-grade transformation of follicle
center lymphoma. Leukemia & Lymphoma
44:1317-23, 2003.
Malek, TR . T helper cells, IL-2 and the generation of cytotoxic T-cell responses. Trends in Immunology 23:465-67, 2002.
Molano, RD, Pileggi, A, Berney, T, Poggioli, R,
Zahr, E, Oliver, R, Malek, TR , Ricordi, C, and
Inverardi, L. Long-term islet allograft survival in
nonobese diabetic mice treated with tacrolimus,
rapamycin, and anti-interleukin-2 antibody.
Transplantation 75:1812-19, 2003.
Lossos, IS , Akasaka, T, and Levy, R. Multiple
BCL6 translocation partners in individual cases
of gastric lymphoma. Blood 102:1931-32, 2003.
Bathe, OF, Dalyot-Herman, N, and Malek,
TR. Therapeutic limitations in tumor-specific
CD8+ memory T cell engraftment. BMC
Cancer 3:21, 2003.
Everhart, D, Reiller, E, Mirzoian, A, McIntosh,
JM, Malhotra, A, and Luetje, CW. Identification
of residues that confer α-conotoxin-PnIA sensitivity on the α3 subunit of neuronal nicotinic
acetylcholine receptors. Journal of Pharmacology
and Experimental Therapeutics 306: 664-70, 2003.
Hou, VC, Lersch, R, Gee, SL, Ponthier, JL, Lo,
AJ, Wu, M, Turck, CW, Koury, M, Krainer,
AR, Mayeda, A, and Conboy, JG. Decrease in
hnRNP A/B expression during erythropoiesis
mediates a pre-mRNA splicing switch. EMBO
Journal 21:6195-204, 2002.
Del Campo, M, Ofengand, J, and Malhotra, A .
Purification and crystallization of Escherichia
coli pseudouridine synthase RluD. Acta
Crystallographica Section D., 59:1871-73, 2003.
Liu, X, Mayeda, A, Tao, M, and Zheng, Z-M.
Exonic splicing enhancer-dependent selection of
bovine papillomavirus type 1 nucleotide 3225 3'
splice site can be rescued in a cell lacking splicing
factor ASF/SF2 through activation of the
phosphatidylinositol 3-kinase/Akt pathway.
Journal of Virology 77:2105–15, 2003.
Del Campo, M, Ofengand, J, and Malhotra, A .
Crystal structure of the catalytic domain of
RluD, the only rRNA pseudouridine synthase
required for normal growth of Escherichia coli.
RNA 10:231-39, 2003.
Olosz, F and Malek, TR . Structural basis for
binding multiple ligands by the common
cytokine receptor gamma-chain. Journal of
Biological Chemistry 277:12047-52, 2002.
Demirci, G, Gao, W, Zheng, XX, Malek, TR,
Strom, TB, and Li, XC. On CD28/CD40 ligand
costimulation, common gamma-chain signals,
and the alloimmune response. Journal of Immunology 168:4382-90, 2002.
Malek, TR , Yu, A, Vincek, V, Scibelli, P, and
Kong, L. CD4 regulatory T cells prevent lethal
autoimmunity in IL-2Rbeta-deficient mice.
Implications for the nonredundant function of
IL-2. Immunity 17:167-78, 2002.
176
Domsic, JK, Wang, Y, Mayeda, A, Krainer, AR,
and Stoltzfus, CM. HIV-1 hnRNP A/B-dependent exonic splicing silencer ESSV antagonizes
binding of U2AF65 to viral polypyrimidine
tracts. Molecular and Cellular Biology 23:876272, 2003.
Hu, D, Mayeda, A, Trembley, JH, Lahti, JM,
and Kidd, VJ. CDK11 complexes promote premRNA splicing. Journal of Biological Chemistry
278:8623–29, 2003.
Manabe, T, Katayama, T, Sato, N, Gomi, F,
Hitomi, J, Yanagida, T, Kudo, T, Honda, A,
Mori, Y, Matsuzaki, S, Imaizumi, K, Mayeda, A,
and Tohyama, M. Induced HMGAIa expression
causes aberrant splicing of presenilin-2 premRNA in sporadic Alzheimer’s disease. Cell
Death and Differentiation 10:698–708, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Amada, N, Tezuka, T, Mayeda, A, Araki, K,
Takei, N, Todokoro, K, and Nawa, H. A novel
rat orthologue and homologue for the Drosophila
crooked neck gene in neural stem cells and their
immediate descendants. Journal of Biochemistry
135:615–623, 2003.
Diaz, F, Bayona-Bafaluy, MP, Rana, M, Mora, M,
Hao, H, and Moraes, CT. Human mitochondrial
DNA with large deletions repopulates organelles
faster than full-length genomes under relaxed
copy number control. Nucleic Acids Research
30:4626-33, 2002.
Regev, A, Berho, M, Jeffers, LJ, Milikowski, C ,
Molina, EG, Pyrsopoulos, NT, Feng, ZZ, Reddy,
KR, and Schiff, ER. Sampling error and
intraobserver variation in liver biopsy in patients
with chronic HCV infection. American Journal
of Gastroenterology 97:2614-18, 2002.
Manfredi, G, Kwong, JQ, Oca-Cossio, JA,
Woischnik, M, Gajewski, CD, Martushova, K,
D’Aurelio, M, Friedlich, AL, and Moraes, CT .
BCL-2 improves oxidative phosphorylation and
modulates adenine nucleotide translocation in
mitochondria of cells harboring mutant mtDNA.
Journal of Biological Chemistry 278:5639-45,
2003.
Abdel-Wahab, M, Krishan, A, Milikowski, C ,
Abdel-Wahab, A, Walker G, and Markoe, A. Androgen receptor antigen density and S-phase fraction in prostate cancer: a pilot study. Prostate
Cancer and Prostatic Diseases 6:294-300, 2003.
Fishman, JE, Milikowski, C , Ramsinghani, R,
Velasquez, MV, and Aviram, G. US-guided coreneedle biopsy of the breast: How many specimens
are necessary? Radiology 226:779-82, 2003.
Pasquale, M and Milikowski, C . Three millimeter apocrine adenoma in a man: case report and
review of the literature. Archives of Pathology
and Laboratory Medicine 127:1498-500, 2003.
Moraes, CT , Srivastava, S, Kirkinezos, I, OcaCossio, J, van Waveren, C, Woischnick, M, and
Diaz, F. Mitochondrial DNA structure and function. International Review of Neurobiology 53:323, 2002.
Moraes, CT. Studying mitochondria of animal
cells. Methods 26:291, 2002.
Woischnik, M and Moraes, CT. Pattern of organization of human mitochondrial pseudogenes in
the nuclear genome. Genome Research12:88593, 2002.
Lanza, RP, Chung, HY, Yoo, JJ, Wettstein, PJ,
Blackwell, C, Borson, N, Hofmeister, E, Schuch,
G, Soker, S, Moraes, CT , West, MD, and Atala,
A. Generation of histocompatible tissues using
nuclear transplantation. Nature Biotechnology
20:689-96, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Bacman, SR, Atencio, DP, and Moraes, CT . Decreased mitochondrial tRNALys steady-state levels and aminoacylation are associated with the
pathogenic G8313A mitochondrial DNA mutation. Biochemical Journal 374:131-36, 2003.
Bayona-Bafaluy, MP, Manfredi, G, and Moraes,
CT. A chemical enucleation method for the
transfer of mitochondrial DNA to rho(o) cells.
Nucleic Acids Research 31:e98, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology and Rehabilitation
22:220-22, 2003.
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M,
Malow, R, Costa, P, and Schneiderman, N. Personality, quality of life and HAART adherence
among men and women living with HIV/AIDS.
Journal of Psychosomatic Research 54:271-78,
2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological distress among symptomatic HIV+ men who have
sex with men. Annals of Behavioral Medicine
25:203-13, 2003.
177
P UBLIC ATIONS 200 2-200 3
Carraway, KL, Perez, A, Idris, N, Jepson, S,
Arango, M, Komatsu, M, Haq, B, Price-Schiavi,
SA, Zhang, J, and Carraway, CA. Muc4/
sialomucin complex, the intramembrane ErbB2
ligand, in cancer and epithelia: to protect and to
survive. Progress in Nucleic Acid Research and
Molecular Biology 71:149-85, 2002.
Laskarin, G, Tokmadzic, VS, Strbo, N, Bogovic,
T, Szekeres-Bartho, J, Randic, L, Podack, ER,
and Rukavina, D. Progesterone induced blocking
factor (PIBF) mediates progesterone induced suppression of decidual lymphocyte cytotoxicity.
American Journal of Reproductive Immunology
48:201-9, 2002.
Perez, A, Barco, R, Fernandez, I, Price-Schiavi,
SA, and Carraway, KL. PEA3 transactivates the
Muc4/sialomucin complex promoter in mammary epithelial and tumor cells. Journal of Biological Chemistry 278:36942-52, 2003.
Par, G, Rukavina, D, Podack, ER, Horanyi, M,
Szekeres-Bartho, J, Hegedus, G, Paal, M,
Szereday, L, Mozsik, G, and Par, A. Decrease in
CD3-negative-CD8dim(+) and Vdelta2/
Vgamma9 TcR+ peripheral blood lymphocyte
counts, low perforin expression and the impairment of natural killer cell activity is associated
with chronic hepatitis C virus infection. Journal
of Hepatology 37:514, 2002.
Metkar, SS, Wang, B, Aguilar-Santelises, M, Raja,
SM, Uhlin-Hansen, L, Podack, E, Trapani, JA,
and Froelich, CJ. Cytotoxic cell granule-mediated
apoptosis: perforin delivers granzyme B-serglycin
complexes into target cells without plasma membrane pore formation. Immunity 16:417-28, 2002.
Kawasaki, C, Ohshima, K, Muta, H, Muta, K,
Deyev, V, Podack, ER, and Kikuchi, M. Prognostic value of Bcl 10 rearrangement in diffuse large
B-cell lymphoma. Leukemia & Lymphoma
43:823-26, 2002.
Merger, M, Viney, JL, Borojevic, R, Steele-Norwood,
D, Zhou, P, Clark, DA, Riddell, R, Maric, R,
Podack, ER, and Croitoru, K. Defining the roles
of perforin, Fas/FasL, and tumour necrosis factor
alpha in T cell induced mucosal damage in the
mouse intestine. Gut 51:155-63, 2002.
Harlin, H, Podack, ER, Boothby, M, and
Alegre, ML. TCR-independent CD30 signaling
selectively induces IL-13 production via a TNF
receptor-associated factor/p38 mitogen-activated
protein kinase-dependent mechanism. Journal
of Immunology 169:2451-59, 2002.
Nam, SY, Cho, KS, Heo, YM, Ha, JC, Kim,
YH, Keun, Yi H, Han Hwang, P, Kim, HM,
and Podack, ER. Regulation of lymphocyte
clustering by CD30-mediated ICAM-1 up-regulation. Cellular Immunology 219:38-47, 2002.
178
Strbo, N, Yamazaki, K, Lee, K, Rukavina, D, and
Podack, ER. Heat shock fusion protein gp96-Ig
mediates strong CD8 CTL expansion in vivo.
American Journal of Reproductive Immunology
48:220-25, 2002.
Tokmadzic, VS, Tsuji, Y, Bogovic, T, Laskarin, G,
Cupurdija, K, Strbo, N, Koyama, K, Okamura,
H, Podack, ER, and Rukavina, D. IL-18 is
present at the maternal-fetal interface and enhances cytotoxic activity of decidual lymphocytes.
American Journal of Reproductive Immunology
48:191-200, 2002.
Podack, ER, Strbo, N, Sotosec, V, and Muta, H.
CD30-governor of memory T cells? Annals of the
New York Academy of Sciences 975:101-13,
2002.
Dai, J, Liu, B, Caudill, MM, Zheng, H, Qiao, Y,
Podack, ER, and Li, Z. Cell surface expression of
heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of
tumor-specific T cell memory. Cancer Immunology 3:1, 2003.
Dix, RD, Podack, ER, and Cousins, SW. Loss of
the perforin cytotoxic pathway predisposes mice
to experimental cytomegalovirus retinitis. Journal
of Virology 77:3402-8, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Strbo, N, Oizumi, S, Sotosek-Tokmadzic, V, and
Podack, ER. Perforin is required for innate and
adaptive immunity induced by heat shock protein gp96. Immunity 18:381-90, 2003.
Gulan, G, Ravlic-Gulan, J, Strbo, N, Sotosek, V,
Nemec, B, Matovinovic, D, Rubinic, D, Podack,
ER, and Rukavina, D. Systemic and local expression of perforin in lymphocyte subsets in acute
and chronic rheumatoid arthritis. Journal of
Rheumatology 30:660-70, 2003.
Dix, RD, Podack, ER, and Cousins, SW. Murine
cytomegalovirus retinitis during retrovirus-induced immunodeficiency (MAIDS) in mice:
interleukin-2 immunotherapy correlates with increased intraocular levels of perforin mRNA. Antiviral Research 59:111-19, 2003.
Raez, L, Cassileth, PA, Schlesselman, JJ,
Padmanabhan, S, Fisher, EZ, Baldie, PA, Sridhar,
K, and Podack, ER. Induction of CD8 T cell-Ifng response and positive clinical outcome after immunization with gene modified allogeneic tumor
cells in advanced non-small cell lung carcinoma.
Cancer Gene Therapy 10:850-58, 2003.
Santos, ES, Raez, LE, Salvatierra, J,
Morgensztern, D, Shanmugan, N, and Neff, GW.
Primary hepatic non-Hodgkin’s lymphomas: a
case report and review of the literature. American
Journal of Gastroenterology (Review) 98:278993, 2003.
Raez, LE, Cassileth, PA, Schlesselman, JJ,
Padmanabhan, S, Fisher, EZ, Baldie, PA, Sridhar,
K, and Podack, ER. Induction of CD8 T-cell-Ifngamma response and positive clinical outcome
after immunization with gene modified allogeneic tumor cells in advanced non-small cell lung
carcinoma. Cancer Gene Therapy 10:850-58,
2003.
Riley, RL, Knowles, J, and King, AM. Levels of
E2A protein expression in B cell precursors are
stage-dependent and inhibited by stem cell factor
(c-kit ligand). Experimental Hematology
30:1412-18, 2002.
Van Der Put, E, Sherwood, EM, Blomberg, BB,
and Riley, RL. Aged mice exhibit distinct B cell
precursor phenotypes differing in activation, proliferation, and apoptosis. Experimental Gerontology 38:1137-47, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Sherwood, EM, Xu, W, and Riley, RL . B cell precursors in senescent mice exhibit decreased recruitment into proliferative compartments and
altered expression of Bcl-2 family members.
Mechanisms of Ageing and Development
124:147-53, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Effects of aging on proliferation and E47
transcription factor activity induced by different
stimuli in murine splenic B cells. Mechanisms of
Ageing and Development 124:361-69, 2003.
Frasca, D, Nguyen, D, Van Der Put, E, Riley,
RL, and Blomberg, BB. The age-related decrease
in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrowderived B cell precursors. Frontiers in Bioscience
8:A110-6, 2003.
Frasca, D, Nguyen, D, Riley, RL, and Blomberg,
BB. Decreased E12 and/or E47 transcription factor activity in the bone marrow as well as in the
spleen of aged mice. Journal of Immunology
170:719-26, 2003.
Santos, ES, Raez, LE, Kharfan-Dabaja, MA,
Angulo, J, Restrepo, A, and Byrnes, JJ. Survival
of renal allograft following de novo hemolytic
uremic syndrome after kidney transplantation.
Transplantation Proceedings 35:1370-74, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
179
P UBLIC ATIONS 200 2-200 3
Wilson, EL, Sherwood, EM, King, AM, and
Riley, RL. A phenotypically distinct subset of
bone marrow immature B cells exhibits partial
activation, increased survival, and preferential
expression of VhS107. European Journal of Immunology 33:3398, 2003.
Rocha Lima, CM , Herndon, JE 2nd, Kosty, M,
Clamon, G, and Green, MR. Therapy choices
among older patients with lung carcinoma: an
evaluation of two trials of the Cancer and Leukemia Group B. Cancer 94:181-87, 2002.
Rocha Lima, CM , Savarese, D, Bruckner, H,
Dudek, A, Eckardt, J, Hainsworth, J, Yunus, F,
Lester, E, Miller, W, Saville, W, Elfring, GL,
Locker, PK, Compton, LD, Miller, LL, and
Green, MR. Irinotecan plus gemcitabine induces
both radiographic and CA 19-9 tumor marker
responses in patients with previously untreated
advanced pancreatic cancer. Journal of Clinical
Oncology 20:1182-91, 2002.
Rocha Lima, CM , Leong, SS, Sherman, CA,
Perkel, JA, Putman, T, Safa, AR, and Green, MR.
Irinotecan and gemcitabine in patients with solid
tumors: phase I trial. Oncology (Huntington)
16:19-24, 2002.
Rocha Lima, CM and Centeno, B. Update on
pancreatic cancer. Current Opinion in Oncology
14:424-30, 2002.
Rocha Lima, CM and Joppert, MG.
Topoisomerase I-based nonplatinum combinations in non-small cell lung cancer. Oncology
(Huntington) 16:25-31, 2002.
Freitas, JR and Rocha Lima, CM . Therapy of
advanced non-small cell lung cancer with irinotecan
and gemcitabine incombination. Clinical Lung
Cancer 4: Supplement 1(S26-90), 2002.
Coutinho, AK and Rocha Lima, CM . Metastatic
colorectal cancer: systemic treatment in the new
millennium. Cancer Control 10:224-38, 2003.
180
Rocha Lima, CM and Chiappori, A. Treatment
of relapsed small-cell lung cancer—a focus on the
evolving role of topotecan. Lung Cancer 40:22936, 2003.
Bhargava, P, Jani, CR, O’Donnel, JL, Stuart,
KE, and Rocha Lima, CM . Gemcitabine and
irinotecan in locally advanced or metastatic
biliary cancer. Oncology 17: 23-26, 2003.
Chiappori, AA, and Rocha Lima, CM. New
agents in the treatment of small-cell lung cancer:
focus on gemcitabine. Clinical Lung Cancer 4
(Supplement 2): S56-63, 2003.
Simon, GR, Ruckdeschel, JC, Williams, C,
Cantor, A, Chiappori, A, Rocha Lima, CM ,
Antonia, S, Haura, E, Wagner, H, Robinson, L,
Sommers, E, Alberts, M, and Bepler, G. Gefitinib
(ZD1839) in previously treated advanced nonsmall cell lung cancer: experience from a single
institution. Cancer Control 10:388-95, 2003.
Yang, ES, Maiorino, CA, Roos, BA, Knight, SR,
and Burnstein, KL. Vitamin-D mediated growth
inhibition of an androgen-ablated LNCaP cell
line model of human prostate cancer. Molecular
and Cellular Endocrinology 186:69–79, 2002.
D’Ippolito, G, Schiller, PC, Balkan, W, Roos,
BA, and Howard, GA. Cooperative anabolic
actions of HGF and 1,25-dihydroxyvitamin D3
in osteoblastic differentiation of human vertebral
marrow stromal fibroblasts. Bone 31:269–75, 2002.
Perez-Stable, CM, Schwartz, GG, Farinas, A,
Finegold, M, Binderup, L, Howard, GA, and
Roos, BA. The Gγ/T-15 transgenic mouse model
of androgen-independent prostate cancer: target
cells of carcinogenesis and the effect of the vitamin D analog EB 1089. Cancer Epidemiology,
Biomarkers and Prevention 11:555–63, 2002
Signorile, JF, Carmel, MP, Czaja, SJ, Asfour, SS,
Morgan, RO, Khalil, TM, Ma, F, and Roos, BA.
Differential increases in average isokinetic power
by specific muscle groups of older women due to
variations in training and testing. Journal of Gerontology: Medical Sciences 57:M683–M690, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Signorile, JF and Roos, BA. Resistance training
for power, strength, and functionality: a longterm prescription. Australian Journal of Medical
Science 398-402, Sept/Oct, 2002.
Hernandez-Cassis, C, Vogel, CK, Hernandez,
TP, Econs, MJ, Iglesias, M, Iglesias, A, Levis, S,
Roos, BA, Howard, GA, and Gamarra, AI. Autosomal dominant hyperostosis/osteosclerosis with
high serum alkaline phosphatase activity. Journal
of Clinical Endocrinology and Metabolism
88:2650-55, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-22, 2003.
Lancet, JE, Rosenblatt, JD , and Karp, JE.
Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in
high-risk leukemias. Seminars in Hematology
39:31-35, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented
antitumor activity. Cancer Research 62:654551, 2002.
Rosenblatt, JD , Shin, SU, Nechustan, H, Yi,
KH, and Tolba, K. Potential role of chemokines
in immune therapy of cancer. Israel Medical
Association Journal 4:1054-59, 2002.
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD .
HSV amplicon mediated delivery of LIGHT
enhances the antigen-presenting capacity of
chronic lymphocytic leukemia. Molecular
Therapy 6:455-63, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Andela, VB, Rosenblatt, JD , Schwarz, EM,
Puzas, EJ, O’Keefe, RJ, and Rosier, RN. Synergism of aminobisphosphonates and farnesyl
transferase inhibitors on tumor metastasis.
Clinical Orthopaedics and Related Research
397:228-39, 2002.
Khorana, AA, Rosenblatt, JD , Sahasrabudhe,
DM, Evans, T, Ladrigan, M, Marquis, D, Rosell,
K, Whiteside, T, Phillippe, S, Acres, B, Slos, P,
Squiban, P, Ross, M, and Kendra, K. A phase I
trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients
with malignant melanoma. Cancer Gene Therapy
10:251-9, 2003.
Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ,
O’Keefe, RJ, Rosenblatt, JD , and Rosier, RN.
The mevalonate synthesis pathway as a therapeutic target in cancer. (Review) Clinical Orthopaedics 415 (Supplement):S59-66, 2003.
Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A,
Lu, C, McNair, C, Abboud, CN, and Rosenblatt,
JD. Effects of the farnesyl transferase inhibitor
R115777 on normal and leukemic hematopoiesis. Leukemia 17:1806-12, 2003.
Rosenblatt, JD and Harrington, WJ Jr. Leukemia
and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation
21:323-24, 2003.
Yang, X, Salas, PJ , Pham, TV, Wasserlauf, BJ,
Smets, MJ, Myerburg, RJ, Gelband, H,
Hoffman, BF, and Bassett, AL. Cytoskeletal
actin microfilaments and the transient outward
potassium current in hypertrophied rat
ventriculocytes. Journal of Physiology 541:
411-21, 2002.
Figueroa, Y, Wald, FA, and Salas, PJ . p34cdc2mediated phosphorylation mobilizes microtubule-organizing centers from the apical
intermediate filament scaffold in CACO-2
epithelial cells. Journal of Biological Chemistry
277:37848-54, 2002.
181
P UBLIC ATIONS 200 2-200 3
Ramsauer, VP, Carothers Carraway, CA, Salas,
PJ, and Carraway, KL. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized
epithelial cells. Journal of Biological Chemistry
278:30142-47, 2003.
Ameen, NA, Marino, C, and Salas, PJ . cAMPdependent exocytosis and vesicle traffic regulate
CFTR and fluid transport in rat jejunum in vivo.
American Journal of Physiology: Cell Physiology
284:C429-38, 2003.
Wald, FA, Figueroa, Y, Oriolo, AS, and Salas, PJ .
Membrane repolarization is delayed in proximal
tubules after ischemia-reperfusion: possible role
of microtubule-organizing centers. American
Journal of Physiology: Renal Physiology
285:F230-40, 2003.
Feun, LG, Modiano, M, Lee, K, Mao, J, Marini,
A, Savaraj, N , Plezia, P, Almassian, B, Colacino,
E, Fischer, J, and MacDonald, S. Phase I and
pharmacokinetic study of 3-aminopyridine-2carboxaldehyde thiosemicarbazone (3-AP) using a
single intravenous dose schedule. Cancer Chemotherapy and Pharmacology 50:223-29, 2002.
Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG,
Xu, R, Xu, J, and Savaraj, N . Procollagen-like
protein as a molecular target in the treatment of
primary brain tumor. Scientific World Journal.
2:125-26, 2002
Feun, LG, O’Brien, C, Molina, E, Rodriguez, M,
Jeffers, L, Schiff, ER, Marini, A, Savaraj, N , and
Ardalan, B. Recombinant leukocyte interferon,
doxorubicin, and 5FUDR in patients with hepatocellular carcinoma—a phase II trial. Journal of
Cancer Research and Clinical Oncology 129:1720, 2003.
Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L,
Donnelly, E, Solomon, J, Sundaram, M, Feun,
LG, and Savaraj, N . Phase II study of vinorelbine
with low dose prednisone in the treatment of
hormone-refractory metastatic prostate cancer.
Oncology Report 10:885-89, 2003.
Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT,
Lampidis, TJ, Robles, C, Furst, AJ, and Feun,
LG. Overexpression of mutated MRP4 in
cisplatin resistant small-cell lung cancer cell line:
collateral sensitivity to azidothymidine. International Journal of Oncology 23:173-9, 2003.
Hu, YP, Haq, B, Carraway, KL, Savaraj, N , and
Lampidis, TJ. Multidrug resistance correlates
with overexpression of Muc4 but inversely with
P-glycoprotein and multidrug resistance related
protein in transfected human melanoma cells.
Biochemical Pharmacology 65:1419-25, 2003.
Walker, GR, Schlesselman, JJ , and Ness, RB.
Family history of cancer, oral contraceptive use,
and ovarian cancer risk. American Journal of
Obstetrics and Gynecology 186:8-14, 2002.
Feun LG, Savaraj N , Hurley J, and Marini A.
Phase II trial of paclitaxel and dacarbazine with
filgrastim administration in advanced malignant
melanoma. Cancer Investigation 20:357-61,
2002.
Sofer, M, Hamilton-Nelson, KL, Schlesselman,
JJ, and Soloway, MS. Risk of positive margins
and biochemical recurrence in relation to nervesparing radical prostatectomy. Journal of Clinical
Oncology 20:1853-8, 2002.
Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ.
Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy
(Model C). Biochemical Pharmacology 64:174551, 2002.
Collins, JA and Schlesselman, JJ . Perimenopausal
use of reproductive hormones effects on breast
and endometrial cancer. Obstetrics and Gynecology Clinics of North America 29:511-25, 2002.
182
Schlesselman, JJ and Collins, JA. Evaluating systematic reviews and meta-analyses. Seminars in
Reproductive Medicine 21:95-106, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Antoni, MH, Cruess, DG, Klimas, N, Maher, K,
Cruess, S, Kumar, M, Lutgendorf, S, Ironson, G,
Schneiderman, N, and Fletcher, MA. Stress
management and immune system reconstitution
in symptomatic HIV-infected gay men over
time: effects on transitional näive T cells
(CD4(+)CD45RA(+)CD29(+)). American
Journal of Psychiatry 159:143-45, 2002.
Kumar, M, Kumar, AM, Waldrop, D, Antoni,
MH, Schneiderman, N, and Eisdorfer, C.
The HPA axis in HIV-1 infection. Journal of
Acquired Immune Deficiency Syndromes 31
(2 Supplement):S89-93, 2002.
Williams, R, Schneiderman, N, Relman, A, and
Angell, M. Resolved: psychosocial interventions
can improve clinical outcomes in organic disease—rebuttals and closing arguments. Psychosomatic Medicine 64:564-67, 2002.
Williams, RB and Schneiderman, N. Resolved:
psychosocial interventions can improve clinical
outcomes in organic disease (pro). Psychosomatic
Medicine 64:552-57, 2002.
Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB,
Evans, JD, McDonald, PA, and Schneiderman,
N. Hemodynamic response patterns: responder
type differences in reactivity and recovery. Psychophysiology 39:739-46, 2002.
Perna, FM, Antoni, MH, Baum, A, Gordon, P,
and Schneiderman, N. Cognitive behavioral
stress management effects on injury and illness
among competitive athletes: a randomized clinical trial. Annals in Behavioral Medicine 25:6673, 2003.
Cruess, DG, Antoni, MH, Gonzalez, J, Fletcher,
MA, Klimas, N, Duran, R, Ironson, G, and
Schneiderman, N. Sleep disturbance mediates
the association between psychological distress
and immune status among HIV-positive men
and women on combination antiretroviral
therapy. Journal of Psychosomatic Research
54:185-89, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Motivala, SJ, Hurwitz, BE, Llabre, MM, Klimas,
NG, Fletcher, MA, Antoni, MH, LeBlanc, WG,
and Schneiderman, N. Psychological distress is
associated with decreased memory helper T-cell
and B-cell counts in pre-AIDS HIV seropositive
men and women but only in those with low viral
load. Psychosomatic Medicine 65:627-35, 2003.
O’Cleirigh, C, Ironson, G, Antoni, M, Fletcher,
MA, McGuffey, L, Balbin, E, Schneiderman, N ,
and Solomon, G. Emotional expression and depth
processing of trauma and their relation to longterm survival in patients with HIV/AIDS. Journal of Psychosomatic Research 54:225-35, 2003.
Lechner, SC, Antoni, MH, Lydston, D,
LaPerriere, A, Ishii, M, Devieux, J, Ironson, G,
Schneiderman, N, Brondolo, E, Tobin, J, and
Weiss, S. Cognitive-behavioral interventions improve quality of life in women with AIDS. Journal of Psychosomatic Research 54, 253-61, 2003.
Penedo, FJ, Gonzalez, JS, Dahn, JR, Antoni, M,
Malow, R, Costa, P, and Schneiderman, N. Personality, quality of life and HAART adherence
among men and women living with HIV/AIDS.
Journal of Psychosomatic Research 54:271-78,
2003.
Penedo, FJ, Gonzalez, JS, Davis, C, Dahn, J,
Antoni, MH, Ironson, G, Malow, R, and
Schneiderman, N. Coping and psychological
distress among symptomatic HIV+ men who
have sex with men. Annals of Behavioral Medicine 25:203-13, 2003.
Penedo, FJ, Dahn, JR, Gonzalez, JS, Molton, I,
Carver, CS, Antoni, MH, Roos, BA, and
Schneiderman, N. Perceived stress management
skill mediates the relationship between optimism
and positive mood following radical prostatectomy. Health Psychology 22:220-22, 2003.
183
P UBLIC ATIONS 200 2-200 3
Treiber, FA, Kamarck, T, Schneiderman, N,
Sheffield, D, Kapuku, G, and Taylor, T. Cardiovascular reactivity and development of preclinical
and clinical disease states. Psychosomatic Medicine 65:46-62, 2003.
Berkman, LF, Blumenthal, J, Burg, M, Carney,
RM, Catellier, D, Cowan, MJ, Czajkowski, SM,
DeBusk, R, Hosking, J, Jaffe, A, Kaufmann, PG,
Mitchell, P, Norman, J, Powell, LH, Raczynski,
JM, and Schneiderman, N. Enhancing recovery
in coronary heart disease patients investigators
(ENRICHD). Effects of treating depression and
low perceived social support on clinical events
after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients
(ENRICHD) Randomized Trial. Journal of the
American Medical Association 289:3106-16,
2003.
Watkins, LL, Schneiderman, N, Blumenthal,
JA, Sheps, DS, Catellier, D, Taylor, CB, and
Freedland, KE. ENRICHD Investigators. Cognitive and somatic symptoms of depression are
associated with medical comorbidity in patients
after acute myocardial infarction. American Heart
Journal 146:48-54, 2003.
Fernander, AF, Durán, REF, Saab, PG, Llabre,
MM, and Schneiderman, N. Assessing the reliability and validity of the John Henry Active
Coping Scale in an urban sample of African
Americans and White Americans. Ethnicity &
Health 8:147-61, 2003.
Kline, KA, Saab, PG, Llabre, MM, Spitzer, SB,
Evans, JD, McDonald, PAG, and Schneiderman,
N. Hemodynamic response patterns: responder
type differences in reactivity and recovery.
Psychophysiology 39:739-46, 2003.
Shonukan, O, Bagayogo, I, McCrea, P, Chao, M,
and Hempstead, B. Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Oncogene
22:3616-23, 2003.
184
Miguez-Burbano, MJ, Pineda-Medina, L,
Lecusay, R, Page, JB, Castillo, G, Burban, X,
Rodriguez, A, Rodriguez, N, and Shor-Posner,
G. Continued high risk behaviors in HIV infected drug abusers. Journal of Addictive Disorders 21:67-80, 2002.
Shor-Posner, G , Miguez, MJ, Pineda, LM,
Rodriguez, A, Ruiz, P, Castillo, G, Burbano, X,
Lecusay, R, and Baum, M. Impact of selenium
status on the pathogenesis of mycobacterial disease in HIV-1-infected drug users during the era
of highly active antiretroviral therapy. Journal of
Acquired Immune Deficiency Syndromes
29:169-73, 2002.
Miguez-Burbano, MJ, Burbano, X, Rodriguez, A,
Lecusay, R, Rodriguez, N, and Shor-Posner, G .
Development of thrombocytosis in HIV+ drug
users: impact of antiretroviral therapy. Platelets
13:183-85, 2002.
Miguez, MJ, Burbano, X, Archer, H, and ShorPosner, G. Limited impact of highly active
antiretroviral therapy in thrombocytopenia. Journal of Acquired Immune Deficiency Syndromes
30:260-61, 2002.
Miguez-Burbano, MJ, Navas, R, Forero, MG,
Burbano, X, Rodriguez, N, and Shor-Posner, G .
Evaluation of HIV prevention and counseling
practices of obstetrician/gynecologists in Bogota,
Colombia: impact on women’s knowledge and
risk practices. AIDS Education and Prevention
14:72-80, 2002.
Shor-Posner, G , Lecusay, R, Morales, G, Campa,
A, and Miguez-Burbano, MJ. Neuroprotection in
HIV-positive drug users: implications for antioxidant therapy. Journal of Acquired Immune Deficiency Syndromes 31 Supplement 2:S84-88,
2002.
Burbano, X, Miguez-Burbano, MJ, McCollister,
K, Zhang, G, Rodriguez, A, Ruiz, P, Lecusay, R,
and Shor-Posner, G . Impact of a selenium
chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clinical
Trials 3:483-91, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Shor-Posner, G , Lecusay, R, Miguez-Burbano,
MJ, Morales, G, and Campa, A. Neuroprotection
in HIV+ drug users: implications for antioxidant
therapy. Journal of Acquired Immune Deficiency
Syndromes 31:S84-S88, 2002.
Miguez-Burbano, MJ, Archer, H, Rodriguez, M,
and Shor-Posner, G . Discontinuation of secondary prophylaxis and the risk of Pneumocystis
carinii pneumonia. AIDS 17:140-41, 2003.
Shor-Posner, G , Lecusay, R, Miguez, MJ,
Moreno-Black, G, Zhang, G, Rodriguez, N,
Burbano, X, Baum, M, and Wilkie, F. Psychological burden in the era of HAART: impact of
selenium therapy. International Journal of Psychiatry in Medicine 33:55-69, 2003.
Miguez, MJ, Shor-Posner, G , Morales, G,
Rodriguez, A, and Burbano, X. HIV treatment in
drug abusers: impact of alcohol use. Addiction
Biology 8:33-37, 2003.
Miguez-Burbano, MJ, Burbano, X, Ashkin, D,
Pitchenik, A, Allan, R, Pineda, L, Rodriguez, N,
and Shor-Posner, G . Impact of tobacco use on
the development of opportunistic respiratory infections in HIV seropositive patients on
antiretroviral therapy. Addiction Biology 8:39-43,
2003.
Perez-Then, E, Peña, R, Tavarez-Roja, M,
Peña,C, Quiñonez, S, Buttler, M, Ammann, A,
Hernandez, W, Goyanes, M, Miguez, MJ, ShorPosner, G, and PMTCT Group. Preventing
mother-to-child HIV transmission in a developing country: the Dominican Republic experience.
Journal of Acquired Immune Deficiency Syndromes 34:506-11, 2003.
Singal, R, vanWert, JM, and Ferdinand, L, Jr.
Methylation of alpha-type embryonic globin gene
alpha pi represses transcription in primary erythroid cells. Blood 100:4217-22, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and
Ginder, GD. Methylation of promoter proximal
transcribed sequences of an embryonic globin
gene inhibits transcription in primary erythroid
cells and promotes formation of a cell type-specific methyl cytosine binding complex. Journal of
Biological Chemistry 277:1897-1905, 2002.
Noss, KR, Singal, R, and Grimes, SR. Methylation state of the prostate specific membrane antigen (PSMA) CpG island in prostate cancer cell
lines. Anticancer Research 22:1505-11, 2002.
Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal,
R, and Gill, S. Gynecomastia attributable to human chorionic gonadotropin-secreting giant cell
carcinoma of lung. Endocrine Practice 9:233-35,
2003.
Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH,
Kotchetkov, R, Sandhu, C, Milic, A, and
Slingerland, JM . Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth
factor beta-mediated G(1) arrest. Molecular and
Cellular Biology 22:2993-3002, 2002.
Liang, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R,
Connor, MK, Han, K, Lee, JH, Ciarallo, S,
Catzavelos, C, Beniston, R, Franssen, E, and
Slingerland, JM . PKB/Akt phosphorylates p27,
impairs nuclear import of p27 and opposes p27mediated G1 arrest. Nature Medicine 8:1153-60,
2002.
Donovan, JC, Rothenstein, JM, and Slingerland,
JM. Non-malignant and tumor-derived cells differ in their requirement for p27Kip1 in transforming growth factor-beta-mediated G1 arrest.
Journal of Biological Chemistry 277:41686-92,
2002.
Connor, MK, Kotchetkov, R, Cariou, S, Resch,
A, Lupetti, R, Beniston, RG, Melchior, F,
Hengst, L, and Slingerland, JM . CRM1/Ranmediated nuclear export of p27(Kip1) involves a
nuclear export signal and links p27 export and
proteolysis. Molecular Biology of the Cell
14:201-13, 2003
185
P UBLIC ATIONS 200 2-200 3
Liang, J and Slingerland, JM . Multiple roles of
the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339-45, 2003.
Carastro, LM, Tan, CK, Selg, M, Jack, HM, So,
AG, and Downey, KM. Identification of delta
helicase as the bovine homolog of HUPF1: demonstration of an interaction with the third subunit of DNA polymerase delta. Nucleic Acids
Research 30:2232-43, 2002.
Meyer, PR, Matsuura, SE, Tolun, AA, Pfeifer, I,
So, AG, Mellors, JW, and Scott, WA. Effects of
specific zidovudine resistance mutations and substrate structure on nucleotide-dependent primer
unblocking by human immunodeficiency virus
type 1 reverse transcriptase. Antimicrobial Agents
and Chemotherapy 46:1540-5, 2002.
Lu, X, Tan, CK, Zhou, JQ, You, M, Carastro,
LM, Downey, KM, and So, AG. Direct interaction of proliferating cell nuclear antigen with the
small subunit of DNA polymerase delta. Journal
of Biological Chemistry 277:24340-5, 2002.
Lokeshwar, VB and Soloway, MS . Re: Urine
based markers of urological malignancy. Journal
of Urology 167:1406-07, 2002.
Lokeshwar, VB, Schroeder, GL, Selzer, MG,
Hautmann, SH, Posey, JT, Duncan, RC, Watson,
R, Rose, L, Markowitz, S, and Soloway, MS .
Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic
acid-hyaluronidase and BTA-stat tests. Cancer
95:61-72, 2002.
Lokeshwar, VB, Schroeder, GL, Carey, RI,
Soloway, MS , and Iida, N. Regulation of hyaluronidase activity by alternative mRNA splicing.
Journal of Biological Chemistry 277:33654-63,
2002.
Simon, MA, Lokeshwar, VB, and Soloway, MS .
Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003.
186
Posey, JT, Soloway, MS , Ekici, S, Sofer, M,
Civantos, F, Duncan, RC, and Lokeshwar, VB.
Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Research 63:2638-44, 2003.
Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X,
Pater, A, and Liepins, A. The alkaloid sanguinarine is effective against multidrug resistance in
human cervical cells via bimodal cell death. Biochemical Pharmacology 63:1415-21, 2002.
Ding, Z, Green, AG, Yang, X, Chernenko, G,
Tang, S-C, and Pater, A. Retinoic acid inhibits
telomerase activity and downregulates expression
but does not affect splicing of hTERT: correlation with cell growth rate inhibition in an in vitro
cervical carcinogenesis/multidrug-resistance
model. Experimental Cell Research 272:185-91,
2002.
Ding, Z, Tang, S-C, Weerasinghe, P, Yang, X,
Chernenko, G, Pater, A, and Liepins, A. The alkaloid sanguirine is effective against multidrug
resistance in human cervical cells via bimodal cell
death. Biochemical Pharmacology 63:1415-21,
2002.
Tang, S-C. BAG-1, an anti-apoptotic tumor
marker. (Invited Review) IUBMB Life 53:99105, 2002.
Chen, J, Chernenko, G, Xiong, J, and Tang, SC. Distinct BAG-1 isoforms have different antiapoptotic functions in BAG-1-transfected C33A
human cervical carcinoma cell line. Oncogene
21:7050-59, 2002.
Tang, S-C. Differential anti-apoptotic function
of BAG-1 isoforms in human malignancy. Recent
Research and Development in Biophysics and
Biochemistry 3:427-44, 2003.
Thomas, GR , Regalado, JJ, and McClinton, M.
A rare case of mucoepidermoid carcinoma of the
nasal cavity. Ear, Nose & Throat Journal 81:51922, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Pandey, M, Chandramohan, K, Thomas, G ,
Mathew, A, Sebastian, P, Somanathan, T,
Abraham EK, Rajan B, and Krishnan Nair, M.
Soft tissue sarcoma of the head and neck region
in adults. International Journal of Oral and
Maxillofacial Surgery 32:43-48, 2003.
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD.
HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic
lymphocytic leukemia. Molecular Therapy 6:45563, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented
antitumor activity. Cancer Research 62:6545-51,
2002.
Rosenblatt, JD, Shin, SU, Nechustan, H, Yi,
KH, and Tolba, KA. Potential role of chemokines
in immune therapy of cancer. Israel Medical
Association Journal 4:1054-59, 2002.
Torroella-Kouri, M, and Lopez, D. Mammary
tumor derived TGF-β impairs crucial innate
immune responses in tumor hosts. Journal of
Immunological Immunopathology 5:31-38, 200.
Torroella-Kouri, M Keith, JC, Ivanova, M, and
Lopez, DM. IL-11-induced reduction of C/EBP
transcription factor binding may contribute to
the IL-12 downregulation in tumor-bearing mice.
International Journal of Oncology 22:439-48,
2003.
Wright, TC, Jr, Cox, JT, Massad, LS, Twiggs,
LB, and Wilkinson, EJ. ASCCP-Sponsored
Consensus Conference. 2001 consensus guidelines for the management of women with cervical
cytological abnormalities. Journal of the American Medical Association 287:2120-29, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Wright, TC, Jr, Cox, JT, Massad, LS, Carlson, J,
Twiggs, LB , and Wilkinson, EJ. American Society for Colposcopy and Cervical Pathology. 2001
consensus guidelines for the management of
women with cervical intraepithelial neoplasia.
American Journal of Gynecology 189:295-304,
2003.
Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F.
Control of cell polarity in fission yeast by association of Orb6p kinase with the highly conserved
protein methyltransferase Skb1p. Journal of Biological Chemistry, 2003.
Hou, MC, Wiley, DJ, Verde, F, and McCollum,
D. Mob2p interacts with the protein kinase
Orb6p to promote coordination of cell polarity
with cell cycle progression. Journal of Cell Science 116:125-35, 2003.
Kim, H, Yang, P, Catanuto, P, Verde, F, Lai, H,
Du, H, Chang, F, and Marcus, S. The kelch repeat protein, Tea1, is a potential substrate target
of the p21-activated kinase, Shk1, in the fission
yeast, Schizosaccharomyces pombe. Journal of
Biological Chemistry 278:30074-82, 2003.
Malek, TR, Yu, A, Vincek, V, Scibelli, P, and
Kong, L. CD4 regulatory T cells prevent lethal
autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2.
Immunity 17:167-78, 2002.
Morales, A, Essenfeld, H, Dubane, C, Vincek, V,
and Nadji, M. Continuous-specimen flow, highthroughput, 1-hour tissue processing. Archives of
Pathology & Laboratory Medicine 126:584-90,
2002.
Vincek, V, Knowles, J, and Nassiri, M. p63
mRNA expression in normal human tissue. Anticancer Research 23:3945-48, 2003.
Vincek, V, Nassiri, M, Knowles, J, Nadji, M, and
Morales, AR. Preservation of tissue RNA in normal saline. Laboratory Investigation 83:137-38,
2003.
187
P UBLIC ATIONS 200 2-200 3
Jacob, SE, Nassiri, M, Kerdel, FA, and Vincek, V.
Rapid measurement of multiple cytokines in psoriasis patients and correlation with disease severity. Mediators of Inflammation 12:309-13, 2003.
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, Voti, L, and Peace,
S. Cancer trends among Hispanic men in South
Florida, 1981-1998. Cancer 94:1183-90, 2002.
Adkins, B, Bu, Y, Vincek, V, and Guevara, P.
The primary responses of murine neonatal lymph
node CD4+ cells are Th2-skewed and are sufficient for the development of Th2-biased memory.
Clinical Developments in Immunology 10:4351, 2003.
Wilkinson, JD, Wohler-Torres, B, Trapido, E,
Fleming, LE, MacKinnon, J, and Peace, S. Cancer among Hispanic women in South Florida: an
18-year assessment: a report from the Florida
Cancer Data System. Cancer 95:1752-58, 2002.
Vincek, V, Nassiri, M, Nadji, M, and Morales,
AR. A novel tissue preservative that protects
macromolecules (DNA, RNA, protein) and
histomorphology in clinical samples. Laboratory
Investigation 83:1-9, 2003.
Jacob, SE, Berman, B, Nassiri, M, and Vincek, V.
Topical application of imiquimod 5% cream to
keloids alters expression genes associated with
apoptosis. British Journal of Dermatology 149:14, 2003.
Franzmann, EJ, Schroeder, GL, Goodwin, WJ,
Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.
International Journal of Cancer 106:438-45,
2003.
Civantos, FJ, Gomez, C, Duque, C, Pedroso, F,
Goodwin, WJ, Weed, DT, Arnold, D, and
Moffat, F. Sentinel node biopsy in oral cavity
cancer: correlation with PET scan and immunohistochemistry. Head and Neck 25:1-9, 2003.
Foster, PK and Weed, DT. Tongue viability after
bilateral lingual artery ligation and surgery for
recurrent tongue-base cancer. Ear, Nose & Throat
Journal 82:720-724, 2003.
Oltra, E, Pfeifer, I, and Werner, R. Ini, a small
nuclear protein that enhances the response of the
connexin43 gene to estrogen. Endocrinology
144:3148-58, 2003.
188
Abdel-Wahab, M, Wolfson, AH, Ossi, P, Raub,
W, and Markoe, A. University of Miami experience using one versus two intracavitary
brachytherapy implants. American Journal of
Clinical Oncology 25:313-7, 2002.
Lambrou, NC, Mirhashemi, R, Wolfson, AH,
Thesiger, P, and Penalver, M. Malignant
peripheral nerve sheath tumor of the vulva:
a multimodal treatment approach. Gynecologic
Oncology 85:365-71, 2002.
Lu, JJ, Bains, YS, Abdel-Wahab, M, Brandon,
AH, Wolfson, AH, Raub, WA, Wilkinson, CM,
and Markoe, AM. High-dose-rate remote
afterloading intracavitary brachytherapy for the
treatment of extrahepatic biliary duct carcinoma.
Cancer Journal 8:74-8, 2002.
Wolfson, AH, Wu, X, Takita, C, Shao, H, Luo,
C, Watzich, M, Diaz, D, Walker, GR, PatinoFlynn, VT, and Markoe, AM. A novel applicator
for low-dose-rate brachytherapy of gynecological
cancers. International Journal of Gynecological
Cancer. 13:532-40, 2003.
Han, Z, Wei, W, Dunaway, S, Darnowski, JW,
Calabresi, P, Sedivy, J, Hendrickson, EA, Balan,
KV, Pantazis, P, and Wyche, JH. Role of p21 in
apoptosis and senescence of human colon cancer
cells treated with camptothecin. Journal of Biological Chemistry 277:17154-60, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
P UBLIC ATIONS 200 2-200 3
Han, Z, Ribbizi, I, Pantazis, P, Wyche, J,
Darnowski, J, and Calabresi, P. The antibacterial
drug taurolidine induces apoptosis by a mitochondrial cytochrome c-dependent mechanism.
Anticancer Research 22:1959-64, 2002.
Zimmers, TA , Davies, MV, Koniaris, LG,
Haynes, P, Tomkinson, KN, McPherron, AC,
Wolfman, NM, and Lee, S-J. Cachexia induced
by systemic myostatin administration in mice.
Science 296:1486-1488, 2002.
Hu, X, Han, Z, Wyche, JH, and Hendrickson,
EA. Helix 6 of tBid is necessary but not sufficient
for mitochondrial binding activity. Apoptosis
8:277-89, 2003.
Sean, JJ, Klover, PJ, Nowak, IA, Zimmers, TA ,
Koniaris, LG, Furlanetto, RW, and Mooney, RA.
Suppressor of cytokine signaling-3, a potential
mediator of interleukin-6 dependent insulin resistance in hepatocytes. Journal of Biological Chemistry 278:13740-13746, 2003.
Pantazis, P, Han, Z, Balan, K, Wang, Y,
and Wyche, JH. Camptothecin and 9nitrocamptothecin (9NC) and anti-cancer,
anti-HIV, and cell-differentiation agents:
Development of resistance, enhancement of
9NC-induced activities, and combination
treatments in cell and animal models. Anticancer
Reserch 23:3623-38, 2003.
Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche,
JH, Han, Z, and Pantazis, P. Differential susceptibility to 9-nitrocamptothecin (9-NC)-induced
apoptosis in clones derived from a human ovarian
cancer cell line: possible implications in the treatment of ovarian cancer patients with 9-NC. Anticancer Drugs.14:427-36, 2003.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Koniaris, LG, McKillop, IH, Schwartz, SI, and
Zimmers, TA . Liver regeneration. Journal of the
American College of Surgeons 197:634-59, 2003.
Zimmers, TA , McKillop, IH, Pierce, RH, Yoo,
JY, and Koniaris, LG. Massive liver growth in
mice induced by systemic interleukin 6 administration. Hepatology 38:326-34, 2003.
Klover, PJ, Zimmers, TA , Koniaris, LG, and
Mooney, RA. Chronic exposure to interleukin-6
causes hepatic insulin resistance in mice. Diabetes
52:2784-89, 2003.
189
P UBLIC ATIONS 200 2-200 3
190
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
GLOSSARY
GLOSSARY
2-DG—2 deoxyglucose
ES—embryonic stem
ACDU—Automatic Cell Deposition Unit
ACS—American Cancer Society
ALL—acute lymphocytic leukemia
AMC—AIDS Malignancy Consortium
EST—expressed sequence tag
FAMRI—Flight Attendant Medical Research
Institute
AML—acute myeloid leukemia
APC—antigen presenting cell
ATL—adult T-cell leukemia
AZT—azidothymidine
BEA—blastocyst engraftment assay
BF—benefit-finding
BMT—bone marrow transplantation
CBSM—cognitive-behavioral stress management
CBCTR—Cooperative Breast Cancer
Tissue Resource
CDC—Centers for Disease Control
Cdk—cyclin-dependent kinase
CK—cytokeratin
CLL—chronic lymphocytic leukemia
CMT—chemically-modified tetracycline
CNS—central nervous system
COL-3—chemically modified non-antimicrobial
tetracycline
CPOR—Center for Psycho-Oncology Research
CPT—natural product camptothecin
CTL—cytotoxic T lymphocytes
DC—dendritic cells
DLBCL—diffuse large B-cell lymphoma
DR3—death receptor 3
DSMB—Data and Safety Monitoring Plan
EBV—Epstein-Barr virus
ECM—extracellular matrix
EGF—epidermal growth factor
EMSA—electromobility shift assay
ER—estrogen receptor
ERM—ezrin, radixin, and moesin
ER/PR—estrogen receptor/progesterone receptor
FDA—Food and Drug Administration
FCCCI—Florida Comprehensive Cancer
Control Initiative
FCDS—Florida Cancer Data System
FDOH—Florida Department of Health
FLRF—fetal liver ring finger
FRAP—fluorescence recovery after photo
bleaching
FRET—fluorescence resonance energy transfer
GC—germinal center
GCRC—General Clinical Research Center
GI—gastrointestinal
GIS—geographic information system
GM-CSF—granulocyte macrophage-colony
stimulating factor
GPI—glycosil-phosphatidil-inositil
GVHD—graft versus host disease
HA—hyaluronic acid
HAASE—hyaluronidase
HAM/TSP—HTLB-associated myelomathy/
tropical spastic paraparesis
HCC—hepatocellular carcinoma
HCV—hepatitis C virus
HGAL—human germinal center-associated
lymphoma
HHV—human herpes virus
HIF—hypoxic inducible factor
HIV—human immunodeficiency virus
HNSCC—head and neck squamous cell carcinoma
HPV—human papilloma virus
HSC—hematopoietic stem cells
HSV—herpes simplex virus
HTLV-I—human T-lymphotropic virus type I
HYAL1—hyaluronidase
IF—intermediate filament
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
191
GLOSSARY
IFN—interferon
NPC—nuclear pore complexes
IL—interleukin
INCA—National Cancer Institute of Brazil
IND—Investigational New Drug
INOS—inducible nitric oxide synthase
Nups—nucleoporins
ORF—open reading frame
OXPHOS—oxidative phosphorylation
PCMR—Pediatric Cardiomyopathy Registry
IRB—Institutional Review Board
KO—knock-out
LAK—lymphokine-activated killer cells
PCNA—proliferating cell nuclear antigen
PCR—polymerase chain reaction
PDIP1—polymerase delta interacting protein-1
LCM—laser capture dissection microscope
LSC—laser scanning cytometer
MAPK—mitogen-activated protein kinase
PDK1—phosphoinositide-dependent protein
kinase-1
PEL—primary effusion lymphomas
MDR—multiple drug resistance
MHC—major histocompatability complex
MIC-1—macrophage inflammatory cytokine-1
PEMs—peritoneal elicited macrophages
PGCs—primordial germ cells
PH—pleckstrin homology
MIS—MetaMorph Imaging System
MM—multiple myeloma
MMPs—matrix metalloproteinases
PKB—protein kinase B
PKC—protein kinase C
Polε—polymerase epsilon
mRNA—messenger RNA
mtDNA—human mitochondrial DNA
MTOC—microtubule organizing centers
QLACS—quality of life in adult cancer survivors
Rb—retinoblastoma
RENCA—renal cell carcinoma
MUC1—human mucin 1
NASA—National Aeronautics and
Space Administration
RT—reverse transcriptase
RTOG—Radiation Therapy Oncology Group
SCCA—squamous cell carcinoma
NCI—National Cancer Institute
NCI-DTP—National Cancer InstituteDevelopmental Therapeutics Program
SCID—severe combined immunodeficiency
disease
SIL—squamous intraepithelial lesions
NGF—nerve growth factor
NHL—non-Hodgkin lymphoma
NHLBL—National Heart, Lung, and
Blood Institute
NIEHS—National Institute of Environmental
Health Sciences
SIR—standardized incidence ratios
SMC—sialomucin complex
TBIO—thermodynamically balanced inside-out
TGF-α—transforming growth factor-alpha
NIH—National Institutes of Health
NIOSH—National Institute of Occupational
Safety and Health
NK—natural killer
NKB—Dutch Cancer Foundation
NKCC—natural killer cell cytotoxicity
NMR—nuclear magnetic resonance
TGF-β—transforming growth factor-beta
TNF—tumor necrosis factor
UM/Sylvester—University of Miami Sylvester
Comprehensive Cancer Center
VEGF—vascular endothelial growth factor
VSV—vesicular stomatitis virus
wt—wild type
NO—nitric oxide
192
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
University of Miami Sylvester Comprehensive Cancer Center
1475 N.W. 12th Avenue
Miami, Florida 33136
UM/Sylvester at Deerfield Beach
1192 East Newport Center Drive, Suite 100
Deerfield Beach, Florida 33442
www.sylvester.org
305-243-1000 / 1-800-545-2292