Research
Roundup
Impacting
Smoking Cessation
Smokers
with a specific genetic variant may be more vulnerable to cigarette cravings
and relapse when trying to quit smoking, a study by researchers from the
Tobacco Use Research Center of Penn's School of Medicine indicates. This
study also shows that the anti-depressant drug bupropion--better known
by its brand name, Zyban--may lessen these effects, especially among females.
The study, "Pharmacogenetic Investigation of Smoking Cessation Treatment," appeared
in the November issue of Pharmacogenetics.
While
previous research has shown that bupropion
is an effective smoking cessation
aid, smokers experience variability
in response to this drug and only
30-45 percent remain abstinent. By
identifying the genetic factors that
influence response to bupropion, researchers
hope to aid in the development of
more effective treatment strategies
that are tailored to individual smokers.
Lead
author Dr. Caryn Lerman, associate
director for Cancer Control and Population
Science at the Abramson Cancer Center
and professor in the School of Medicine
and the Annenberg Public Policy Center,
led a research team that examined
426 smokers enrolled in a randomized
clinical trial of bupropion for smoking
cessation.
The
researchers found that participants
with a decreased activity variant
of the CYP2B6 gene reported greater
increases in cravings for cigarettes
following the quit date and were about
one and a half times more likely to
relapse during the treatment phase.
"This
study provides an important first
step toward utilizing genotype to
identify smokers who are more vulnerable
to relapse and who may benefit most
from more intensive smoking cessation
treatment," said Dr. Lerman.
The
research was funded by the National
Cancer Institute and the National
Institute on Drug Abuse and was conducted
by the University of Pennsylvania/Georgetown
University Transdisciplinary Tobacco
Use Research Center.
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Averting
Parkinson's Disease in Fruit
Flies
Scientists
at Penn have averted the onset of neurodegenerative disease in fruit flies
by administering medication to flies genetically predisposed to a disorder
akin to Parkinson's disease.
The
result suggests a new approach to
the treatment of human disorders including
Parkinson's and Alzheimer's diseases.
Penn professor of biology and investigator
with the Howard Hughes Medical Institute
Dr. Nancy M. Bonini and graduate student
Pavan K. Auluck reported the finding
in the November issue of Nature
Medicine.
Parkinson's--the
second most common human neurodegenerative
disorder-- is characterized by tremors,
postural rigidity and progressive
deterioration of dopaminergic neurons
in specific areas of the brain. Despite
the evolutionary gulf separating humans
and fruit flies, neurotoxicity unfolds
in a similar manner in both species.
Like humans, Drosophila melanogaster
experiences neuronal loss upon expression
of alpha-synuclein, a protein implicated
in the onset of Parkinson's disease
in both species.
Dr.
Bonini and Mr. Auluck fed flies a
naturally occurring antibiotic called
geldanamycin. When fed geldanamycin-supplemented
food as adults, flies with a genetic
susceptibility to neurodegenerative
disease--flies that would normally
experience a 50 percent loss of dopaminergic
neurons by 20 days of age--maintained
normal numbers of these neurons.
Geldanamycin
tweaks the activity of Hsp90, one
of a class of proteins known as molecular
chaperones. Dr. Bonini, Mr. Auluck
and colleagues showed last year that
molecular chaperones can block the
progression of neurodegenerative disease
in Drosophila, suggesting that diseases
like Parkinson's and Alzheimer's may
result from reduced chaperone levels
and might be averted by pharmacologically
boosting chaperone activity.
Dr.
Bonini and Mr. Auluck's work is funded
by grants from the David and Lucile
Packard Foundation, the National Institute
on Aging, the NIH and the Alzheimer's
Association.
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Challenging
the Way Race is Used in Research
Researchers
at Penn's School of Medicine and Stanford University are challenging
the way that race is used as a variable in genetic research. The paper, "Toward
a New Vocabulary of Human Genetic Variation,"appeared in the November
15 issue of the journal Science, proposes a new framework for analyzing the
use of race in research.
According
to Dr. Pawela Sankar, assistant
professor of bioethics in the department
of Medical Ethics and Center for Bioethics,
the recent debate over race
in genetic research has focused on
whether or not race exists. This is
misguided for two reasons. First,
the term race is understood in different
ways; some assume that "race" refers
to historically racist theory of human
subspecies, while others assume it
refers to genetic differences
that are associated with population
history, and is simply descriptive.
The
second issue is that researchers use
race in very different ways. Some
use it as a proxy for environmental
exposures, and others as a way of
selecting subjects that are more or
less genetically similar to
one another. The fact that
race is used in so many different
ways in genetic research is one of
the reasons that ethnicity or genetic
markers cannot simply replace race,
as some have suggested.
The
paper comes at a time when new research
efforts are unfolding, now
that the human genome has been completely
sequenced. The paper asks researchers
to carefully consider for what purpose
they are using race, to define the
term and then use it consistently. "The
practice of science requires a precise
language and oddly, the word ‘race,'
although used frequently in the literature,
has escaped the kind of scientific
scrutiny that other words have had," said
Dr. Sankar. "In one paper researchers
will have used the term three different
ways and not defined it."
Stanford
University researcher Dr. Mildred.
K. Cho--formerly of Penn's Center
for Bioethics--was also involved in
this study.
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Beating
Pneumonia by a Nose
According
to a team of researchers from the School of Medicine, an electronic nose--a
relatively new version of a sensor previously used in the food, wine and
perfume industries--can quickly and accurately diagnose pneumonia in critically
ill, mechanically ventilated patients. The results were presented at the
CHEST 2002 Annual Meeting in November.
"We
wanted to further explore using the
e-nose after the exciting results
of an initial study we conducted back
in 1997 with only 20 patients," said
Dr. C. William Hanson, III, professor
of anesthesia, surgery and internal
medicine, and lead author of the study.
When it comes to lower pulmonary infections,
especially in critically ill patients,
time is of the essence for disease
control.
The
e-nose contains an array of sensors
consisting of carbon-black/polymer
composites. The patient's exhaled
breath gas was passed over these sensors
which interact with volatile molecules
to produce unique patterns that are
displayed in two-dimensional "maps," or
dot patterns on a computer screen.
The results were analyzed using pattern
recognition algorithms and assessed
for a correlation between the actual
CPIS scores and the one predicted
by the nose. Dr. Hanson and his colleagues
found that the e-nose made clear distinctions
between the patients who were infected
and those who were not. Cyrano Sciences,
Inc., donated a "Cyranose" electronic
nose for use in this study.
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Fighting
the West Nile Virus
The
protein that forms the protective capsid surrounding the West Nile virus
genetic material may contribute to the deadly inflammation associated
with the virus. West Nile virus, which has rapidly spread across the United
States, causes neurological symptoms and encephalitis, which can result
in paralysis or death. According to researchers at Penn's School of Medicine,
the West Nile virus capsid (WNV-Cp) is a destructive protein that can
trigger apoptosis--the automatic self-destructive program within cells--inside
infected cells, possibly adding to the damage caused by the virus. Their
findings were presented in the December issue of the journal Emerging
Infectious Diseases.
The
Penn researchers first began studying
WNV-Cp when they noticed a striking
similarity between the gene that encodes
for it and that of an HIV regulatory
protein. "We hope to extend the
lessons they have learned in trying
to develop therapeutics for HIV in
fighting West Nile," said Dr.
Weiner. "In addition to the possibility
of creating a vaccine for West Nile,
our results support the idea that
a specific portion of the capsid protein--
called the 3' terminal region--is
required for the protein's pathogenicity.
If we can find a way to block that
region's function, this might help
slow the virus down."
By
itself, the WNV-Cp protein can cause
inflammation. Dr. Weiner and his colleagues
found that WNV-Cp drives apoptosis
in cell cultures through what is called
the mitochondrial pathway. The protein
begins the process of cell suicide
by somehow disrupting the membrane
potential of the cell's mitochondria,
which then leads to the activation
of proteins such as caspase-9 and
caspase-3 that start a cascade of
reactions to subsequently cause the
cell to digest itself.
Since
the protein enters the nucleus of
the cell, it is possible that WNV-Cp
changes the host cell's transcriptional
machinery, resulting in an over production
of certain proteins related to an
apoptotic program, which consequently
feed back to the mitochondria. Alternatively,
as WNV-Cp moves from the cytoplasm
to the nucleus, it may inactivate
an important part of the cell's natural
control system that keeps apoptosis
in check--overpowering the guard as
it were--thus inducing the cell suicide.
Funding for this work was supported
by grants from the NIH.
Almanac, Vol. 49, No. 17, January 14, 2003
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