Scientist from Cuba Studies Cancer Antibodies at the Feinstein

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Alzheimer’s Disease + leukemia research + Foundation News
FALL 2010
Research
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Scientist from Cuba Studies Cancer
Antibodies at the Feinstein
A
na Marie
Hernandez
Vázquez,
PhD, a biochemist at Havana
University and
the Center for
Molecular
Immunology in
Cuba, has been
Ana Marie Hernandez
studying a vacVázquez, PhD
cine to fight cancer.
The vaccine target: glycolipids called
gangliosides that are overexpressed in
many tumors.
Gangliosides exist on cell membranes
and are shed into the bloodstream, where
they depress the immune system. The
vaccine being studied is built around an
immunoglobulin mimic that triggers an
anti-ganglioside response. Dr. Hernandez
hopes the development of this kind of vaccine will initiate an immune response that
may fend off tumor cells more aggressively.
In her current work, Dr. Hernandez
aims to identify cells that produce
antibodies against the ganglioside.
Thomas Rothstein, MD, PhD, is a pioneer in characterizing B cells that make
antibodies and is head of the Center
for Oncology and Cell Biology at The
Feinstein Institute for Medical Research.
Dr. Hernandez met Dr. Rothstein in 2008
at the Eighth International Workshop on
Immunotherapy in Havana. Realizing the
potential for collaboration, Dr. Hernandez
applied for and was subsequently granted
an international fellowship award by the
Human Frontiers Science Project to support
a three-month sabbatical in the Rothstein
laboratory.
“The B1 cells that are studied in the lab
could be very important in fighting the
initial appearance of tumor cells,”
explained Dr. Hernandez. B1 cells make a
natural antibody, and this antibody could
potentially recognize tumor-associated
gangliosides and in that way function normally to block tumors from forming —
similar to what happens on a larger scale
after immunization with the immunoglobulin mimic to foster the production of
anti-ganglioside antibodies.
The collaboration worked beautifully,
and much has been learned about the
B cells that respond to gangliosides and
immunoglobulin mimics. A piece of
equipment that has helped this work
Illustration of cancer cells.
progress is the state-of-the-art cell sorter
in the Rothstein laboratory. This unit
identifies, isolates and collects groups of
cells on the basis of specific surface markers and makes it possible to find responding cells. The information learned here
will help scientists understand how the
immunoglobulin vaccine works and may
suggest ways to improve upon it. Dr.
Hernandez will bring the data she has
generated at the Feinstein back to Havana,
where she works with her mother, Ana
Maria Vázquez, PhD, a senior scientist at
Havana University and the Center for
Molecular Immunology.
“I can’t tell you how wonderful it has
been to collaborate with such a wonderful
group of scientists,” Dr. Hernandez said.
In all of Cuba, not a single cell sorter
exists. “Having this technology has really
brought my research to another level.”
continued on page 2
National Quality
Healthcare Award
Winner 2010
Scientists Identify Genes for Hair Loss
A
team of researchers has conducted
the first genomewide association
study of alopecia areata, a condition
that causes hair loss, and has identified
eight different genetic regions that seem to
have a role in regulating the immune system. It has been thought this unexplained
loss of hair is triggered by an autoimmune
disorder.
Alopecia areata affects about 5.3 million
men and women in the United States.
Angela Christiano, PhD, an associate professor of molecular dermatology at Columbia
University Medical Center, became interested
in hair loss more than a decade ago when
she began losing clumps of hair. In 1998,
she identified a gene that is believed to control the human hair cycle. The gene was
dubbed hairless. A year later, she found a
gene in humans that is equivalent to a
mutated gene in the “nude” mouse. The
gene is on chromosome 17 and a mutation
on the gene causes both complete hair loss
and suppression of the immune system. The
gene defect prevents the development of a
normal thymus, a gland that is critical in
educating the immune system to recognize
what is part of the self and what is not.
Now Dr. Christiano and her colleagues,
including Peter K. Gregersen, MD, head of
the Robert S. Boas Center for Genomics and
Human Genetics at The Feinstein Institute
for Medical Research, have conducted a
genomewide association study testing samples from 1,054 patients with alopecia areata
and 3,278 people with no signs of hair loss.
They identified many genes that are
expressed differently in the patients with
alopecia areata compared with the control
group. Understanding how these genes play
a role in the condition is the first step in
identifying potential new treatments to prevent it, slow it or reverse its course. The
new finding implies the involvement of the
body’s innate immune system. The study
was published in July in Nature.
In another paper published in Nature,
Dr. Gregersen worked with Shiv Pillai, MD,
PhD, of Massachusetts General Hospital to
test a genetic finding that Dr. Pillai originally
made in animals. A gene that makes an
enzyme called sialic acid acetylesterase
(SIAE) is necessary for the maintenance of
immune tolerance in mice. The question
was whether the same gene triggered autoimmune problems in humans. When they
looked at 923 patients of European origin
with an autoimmune disease (primarily
rheumatoid arthritis or type 1 diabetes) they
found that 24 of the 923 patients had one of
a number of rare dysfunctional variants of
SIAE. These variants were either extremely
rare or not present in 648 volunteers without an autoimmune disorder. In the aggregate, these functionally defective SIAE
variants conferred about an eightfold
increased risk of rheumatoid arthritis.
Because this is one of the first examples of
truly rare mutations causing common autoimmune disorders, and because the work
derived directly from elegant studies in the
mouse, the findings are attracting consider-
continued on page 2
Scientist from Cuba Studies Cancer
Antibodies at the Feinstein
Dr. Rothstein believes that the
Feinstein has benefited greatly from this
international collaboration. “Dr.
Hernandez is a brilliant scientist who
has developed very clever ideas regarding B cell immunotherapy for cancer,” he
said. “It has been a sheer pleasure work-
2
FOCUS ON RESEARCH I Fall 2010
ing with her to identify the cells responsible for producing this particular
antibody response. It is great to see that
the Feinstein attracts the very best scientists from around the world. Such collaborations and interchanges are vital for
fueling continued scientific progress.” 
able attention in the
research community.
These two research
papers signify Dr.
Gregersen’s broad
collaborations on
human genetics
studies. “Human
genetics is a great
field because it
Peter K. Gregersen, MD
gives you the
Feinstein Institute
opportunity to
work with talented
and creative people
all over the world
on many different
scientific problems,” said Dr.
Gregersen. “The
Feinstein Institute
has now become a
major center for
this kind of work,
Angela Christiano, PhD
and it is great to
Columbia University
Medical Center
be playing a
significant role in
these new genetic advances.” 
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discove ry zone
Molecular Brain Signatures in Young Individuals
at High Risk for Alzheimer’s Disease
W
hile the majority of Alzheimer’s
researchers focus their attention
on the classic pathological signs
of the mind-robbing disease — the
plaques and tangles — scientists at The
Feinstein Institute for Medical Research
have new evidence that there are molecular indicators of distress in the brains of
people with Alzheimer’s decades before
these signs affect the brain.
Concepcion Conejero-Goldberg, MD,
PhD, and her colleagues have an interest
in prevention, and thus examined a group
of younger adults who carry a risk gene
for Alzheimer’s disease called APOE4. The
researchers were looking for molecular
differences in the brains of people with
one or two copies of the APOE4 gene,
and people who do not carry a copy of
the risk gene. Having one copy of the risk
gene increases the likelihood of developing Alzheimer’s by three to four times.
The researchers were able to obtain brain
tissue from young to middle-aged adults
who died from a variety of causes. They
choose tissue from two different brain
areas, one largely affected by Alzheimer’s
(middle temporal gyrus) and one mildly
affected (primary somatosensory cortex).
Brain tissue from the cerebellum was also
sampled to examine whether the person
had been born with an APOE4 gene.
Tissue was included from 41 people who
had died at around 42 years of age. None
of the samples included such pathological
signs of Alzheimer’s as plaques and tangles.
“We wanted to know whether young
people can give us a lead on the development of the disease,” said Dr. ConejeroGoldberg. In addition to examining brain
tissue and genotype, the researchers also
conducted microarray gene expression
analysis to discover whether having an
APOE4 genotype affects genetic expression of the specific tissue or if tissue
destroyed by the illness is molecularly
distinct from tissue that remained healthy
until the end of the illness.
The findings of the study were published in Molecular Psychiatry.
Dr. Conejero-Goldberg and her colleagues found 70 gene transcripts that differed significantly between those with
APOE4 and those without. Regional differences in the expression of APOE4 itself
were also found. Some of the genes are
known to be involved with pathways that
regulate mitochondrial function, calcium
regulation and cell-cycle re-entry. The differences in the regulation of the genes
between the APOE4 carriers and nonAPOE4 carriers, combined with the finding
that changes were observed in the tissue
largely affected by
Alzheimer’s, suggest to these scientists that during
one’s lifetime
molecular events
may accrue that
eventually lead to
more visible signs
of Alzheimer’s. On
the contrary,
Concepcion ConejeroGoldberg, MD, PhD
changes in the
spared brain area
may be neuroprotective.
“Our findings tell us that something is
going on in the brains of at-risk people
very early on, decades before the plaques
and tangles begin to appear,” said Dr.
Conejero-Goldberg, a researcher at the
Litwin-Zucker Research Center for the
Study of Alzheimer’s Disease. Her collaborators outside of the Feinstein include
researchers from the National Institute of
Mental Health and Albert Einstein College
of Medicine.
None of the genes identified were
involved with the classical Alzheimer’s
pathway that leads to amyloid plaques
and tau tangles. “These findings may give
us clues why some brains are more susceptible to Alzheimer’s than others,”
explained Dr. Conejero-Goldberg. Also,
the identification of genes that damage
pathways may lead to the discovery of
genes that may protect the brain against
the disease. 
Caring for Today. Planning for Tomorrow.
The Feinstein Institute for Medical
Research has a new Web site featuring
research information on all of the diseases
that we study. It is designed for people in
the community and our scientific
colleagues. Visit feinsteininstitute.org.
You can also donate to any of our
research scientists or laboratories
by going to our Web site and clicking
on "Ways to Give" on the upper righthand corner of the home page. You
can also donate to a vast number
of projects under way throughout the
North Shore-LIJ Health System at
NorthShoreLIJ.com/foundation.
SETTING NEW STANDARDS IN HEALTHCARE I feinsteininstitute.org
3
New Model of Leukemia Sheds Light on
Possible Novel Treatment Targets
S
cientists at The Feinstein Institute for Medical Research
have created an innovative model that mimics how leukemia cells conceal themselves in bone marrow niches and
subsequently grow and divide throughout the human body.
Sarah Vaiselbuh, MD, and her colleagues discovered a method
that allows the creation of a human-to-human microenvironment in the laboratory, permitting them to study the disease
process and use their model to test new treatments in the
future. The finding was published in the July issue of Tissue
Engineering.
Understanding how leukemia cells interact with the bone
marrow microenvironment is essential to understanding this
common cancer. Leukemia cells can hide in bone marrow
niches, thereby avoiding chemotherapy, according to Dr.
Vaiselbuh. Once chemotherapy treatment has concluded, the
dormant leukemia cells abandon their niches and begin growing and pushing beyond the territory of the bone marrow. The
Feinstein scientists indicate this might be one explanation for
relapse in leukemia.
To test this theory, Dr. Vaiselbuh created an ectopic human
leukemic stem cell niche by seeding a three-dimensional polyurethane scaffold (provided by Biomerix) with mesenchymal
stem cells from normal human bone marrow. The mesenchymal stem cells in the scaffold created an ectopic human bone
marrow microenvironment complete with fat cells and blood
vessels. To analyze whether the ectopic human microenviron-
ment could support the
growth of human acute
myeloid leukemia cells in
the laboratory model, the
scientists injected human
myeloid leukemia cells
onto the scaffold and
subsequently examined
the cells. They discovered the leukemia cells
require the support of
Sarah Vaiselbuh, MD, won the 2010 Fellowship
the niche microenvironAward for her research. Kevin J. Tracey, MD,
ment to grow.
left, and Ralph Nappi, right, presented her with
Surprisingly, the
the award at the annual fund-raising concert.
human myeloid leukemia
cells grew locally in the niche until three months postinjection,
showing a preference for the human microenvironment above
the host environment. However, at four months postinjection,
the leukemia cells were invading the bone marrow, spleen and
liver of the host model.
“This model mimics the human pathophysiology of leukemia
cells in the bone marrow,” said Dr. Vaiselbuh. Additionally, she
examined the genetic signature of the leukemia cells to help
explain how these cells become invasive. The hope, she said,
is to identify new oncogenic targets that can translate into novel
therapeutic approaches to improve patient outcome. 
Understanding Respiratory Papillomatosis
Human papillomavirus (HPV) is a
ubiquitous virus that can cause a
number of different problems in the
body — from warts on the skin or in
the upper airway (called recurrent
respiratory papillomatosis or RRP)
to cervical cancer. People with RRP
must undergo repeated surgeries to
remove these benign tumors, which
can severely block the airway and
obstruct breathing. Feinstein scientists
are investigating why some people
with the human papillomavirus in their
airway develop papillomas while the
majority of people never do.
Scientists are now beginning to
understand how the immune system
supports a chronic HPV infection and
prevents immune system clearance
of these viruses. This research may
lead to nonsurgical treatments that
could prevent the formation of these
benign tumors in the airway. Vincent
Bonagura, MD, a leader in this field,
was recently invited to write a review
of the immune system’s role in RRP
that was published in Acta Pathologica,
Microbiologica et Immunologica
Scandinavica, the journal of the
Scandinavian Societies for Medical
Microbiology and Pathology.
Dr. Bonagura and his team collect
blood and human papilloma tissue
from patients with RRP to examine how
the body enables the persistence and
propagation of human papillomavirus,
which gives rise to airway tumors.
One of their latest findings shows that
certain types of the body’s natural
killer cells may be necessary to trigger
an effective early
immune response
against these
HPV viruses. “This
may offer a novel
path toward
development of
new treatments,”
said Dr. Bonagura.
Vincent Bonagura, MD
While human papillomaviruses
are common — virtually everyone
is infected with them by the time
they reach adulthood — recurrent
respiratory papillomatosis is rare,
affecting two in every 10,000 people.
Dr. Bonagura and his colleagues have
been looking at how the immune
system responds to these viruses. They
have found that T regulatory cells are a
key player in RRP.
SETTING NEW STANDARDS IN HEALTHCARE I feinsteininstitute.org
4
f o undatio n ne w s
The Feinstein Institute and the Americana
Manhasset: Building a Brighter Future for Women
I
nvestigators at The Feinstein Institute
for Medical Research are collaborating
with North Shore-LIJ Health System
oncologists to collect breast and ovarian
tissue samples for studies aimed at identifying markers for early identification. This
is critically important to survival.
Feinstein geneticist Annette Lee, PhD,
is working with John Lovecchio, MD, and
Andy Menzin, MD, at North Shore
University Hospital, and Iuliana Shapira,
MD, and Richard Gralla, MD, at the
Monter Cancer Center.
The hope of the study is to identify
markers and begin treatment as early as
possible. When diagnosed while still
localized, the five-year survival rate is
98.3 percent for a breast cancer patient
and more than 90 percent for an ovarian
cancer patient. Unfortunately, current
methods of early detection are not effective
until a tumor cell mass has formed, which
may be years after the initial onset of the
disease. Through the new Breast and
Ovarian Cancer Specimen Bank, researchers
are collecting blood and tissue samples from
women who have or are suspected to have
either type of cancer. These samples will
then be used as a resource to discover and
validate new biomarkers for early detection,
prediction of disease course and outcome,
treatment response and risk of relapse.
The Americana Manhasset, a longtime
partner of North Shore-LIJ and advocate
for women’s health, is showing its support
of this groundbreaking new study by
Fifth Annual Benefit Concert Raises $1.1 Million
“Oh, what a night” it was on July 14, 2010, at Planting Fields Arboretum State
Historic Park in Oyster Bay. That’s when world-famous vocalist Frankie Valli took
center stage with a new generation of Four Seasons and brought the crowd to
their feet, belting out such sing-along classics as “Big Girls Don’t Cry,” “Walk Like
a Man,” “Sherry” and, of course, “December 1963 (Oh, What a Night).”
The North Shore-LIJ Health System’s fifth annual benefit concert, attended by
more than 950 people, raised a record-setting $1.1 million for the Feinstein
Institute. Stunning décor,
cocktails and a buffet dinner
were provided by Lawrence
Gottesman, owner and
president of Hicksville-based
Lawrence Scott Events and a
generous supporter of North
Shore-LIJ.
Prior to Valli’s performance,
the winner of the 2010
Fellowship Award was
announced by Kevin J. Tracey,
Left to right: Cecelia Fullam, senior vice president of
MD, president of the Feinstein
the North Shore-LIJ Health System Foundation; Leonard
Feinstein, North Shore-LIJ trustee; Susan Feinstein; and
Institute, and Ralph Nappi,
Robin Ross, consultant for the Feinstein Institute.
chairman of the Feinstein
Institute and president of the
North Shore-LIJ Health System Foundation. This year’s award was named for
Edwin S. Marks, a driving force behind the development of the institute, and
was presented to Sarah Vaiselbuh, MD (see story of her research on page 4).
holding a Wine
Tasting and Auction
on November 5,
2010, at Tiffany &
Co. Americana
Manhasset (1980
Northern Boulevard).
Cocktails begin at
6:30 p.m. and the
auction will take
place promptly at
Annette Lee, PhD
7:45 p.m., with all
proceeds benefiting the Breast and Ovarian
Cancer Specimen Bank. 
Don't Miss the Wine Tasting and
Auction! To learn more, contact
Mindy Reade at 516-465-2563.
Help Us Grow!
At the Feinstein Institute, we are
committed to fulfilling our unique
mission by building on existing
programs and expanding our
scope of research. Community
support helps make this happen.
Our goal is to raise $100 million in
endowments. Your charitable gifts
to the Feinstein Institute mean
that we can continue to develop
the most pioneering approaches to
treating catastrophic illnesses for
many years to come. Thank you.
To learn more about how you can
support the Feinstein Institute,
contact Cecelia Fullam at
516-465-2566 or Robin Ross
at 516-465-8132, or visit
support.northshorelij.com/research.
SETTING NEW STANDARDS IN HEALTHCARE I feinsteininstitute.org
5
Michael Dowling
President and CEO
North Shore-LIJ Health System
Kevin J. Tracey, MD
focus on
Research
Director and CEO
The Feinstein Institute for Medical Research
Terry Lynam
Vice President, Public Relations
Jamie Talan
Science Writer
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Focus on Research is published by The Feinstein Institute for
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Ar ound the institute
Magnesium Sulfate Prevents Maternal
and Fetal Inflammation
P
reterm labor, often induced by
maternal infections, is the major
cause of newborn sickness and
death. For decades, doctors have given
women magnesium sulfate to slow labor
and reduce the risks of an early birth.
Despite its long-time use, the exact mechanism by which magnesium sulfate works
remains unknown. However, a recent
clinical trial revealed that children born to
women who received magnesium sulfate
for preterm labor had a lower incidence of
cerebral palsy, a neurological condition
associated with preterm birth. There is
growing evidence that inflammatory
mediators in the mother and the developing fetus are associated with preterm labor
and scientists at The Feinstein Institute for
Medical Research investigated whether
magnesium sulfate has any role in regulating these inflammatory mediators.
Christine Metz, PhD, head of the
Laboratory of Medicinal Biochemistry,
Hope lives here.SM
studies the effects of maternal infection
and preterm labor. She works closely with
Burton Rochelson, MD, chief of Maternal/
Fetal Medicine, and his colleagues at
North Shore University Hospital. Dr. Metz
and her colleagues designed a study to
explore how magnesium sulfate reduces
preterm labor, particularly in the presence
of maternal infection. The researchers
received umbilical cords from mothers
following the delivery of their babies in
order to isolate umbilical endothelial cells
(cells that line blood vessels). They added
magnesium sulfate to umbilical endothelial
cells in the presence of “infection” and
found this age-old therapy for preterm
labor suppressed endothelial cell activation and inflammatory mediator production. They went on to treat a human
neural cell line with magnesium sulfate
and found it reduced neural inflammation
as well. These observations are important
because excessive and/or sustained endothelial cell activation is associated with
inflammatory-mediated tissue damage.
In her latest study,
Dr. Metz worked
with Hima Tam Tam,
MD, North Shore-LIJ
Health System’s first
maternal/fetal medicine fellow, to test
magnesium sulfate in
laboratory models of Christine Metz, PhD
maternal infection. The study was funded
by Suzanne and Eli Oxenhorn. Results
indicate that magnesium sulfate again
decreased inflammation in laboratory models of the fetal blood and brain tissue, highlighting the anti-inflammatory properties
of magnesium sulfate. Recent studies in
Dr. Metz’s laboratory have shown that
magnesium deficiency is accompanied
by enhanced inflammation. The group
will now go on to study the effects of a
magnesium-deficient diet versus magnesium supplementation during pregnancy
in laboratory models of maternal infection.
This could ultimately have critical effects
on maternal and fetal health. 
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