Gene Shown to Control Hindlimb Identity
Researchers Set To Join Forces in Harvard-wide Cancer
Sleep May Play Bigger Role in Learning
Eating Less Fat, More of Some Carbs May Make Us Hungrier, Heavier
Group Calls for Funding Increase Against Diabetes 'Epidemic'
Many Smokers May Underestimate Their Risk of Disease
How Dendritic Cells March from Blood to Tissues
Novel Inhibitor of Growth Factor Receptor Identified
Affects Cardiac Impulses in Dystrophy
Project ADAPT Training Center Opens
Kogan to Give Recital at Vanderbilt Hall
Honors & Advances
Panel Points Out
Ways to Increase
Diversity in Science
The Feel and Unexpected Weight of the 'Intern Blues'
Group Calls for Funding Increase
Against Diabetes 'Epidemic'
The costs of diabetes are enormous
in human and fiscal terms. The death rate from the disease--called
"the epidemic of our time" by the CDC--has risen more
than 30 percent since the 1980s. One in every 10 health care dollars,
and one in four Medicare dollars, are spent on people with diabetes,
who number 16 million in the U.S. These figures will continue to
rise unless more effective treatments and preventions are found,
according to a report released Feb. 25 by the Congressionally established
Diabetes Research Working Group. The expert group, headed by C.
Ronald Kahn, the Mary K. Iacocca professor of medicine and director
of Joslin Diabetes Center, identified five key areas of opportunity
where recent advances hold the greatest promise for making strides
against the disease.
fellow Malcolm Logan (r) and HMS genetics professor Cliff
Tabin have identified a gene that specifies the leg identity
of a growing limb.
Information Source: Natl.
Center for Health Statistics
First, noting that both juvenile (Type I) and adult-onset (Type
II) diabetes have strong genetic determinants, the group calls for
an intensified and nationally coordinated program of research into
the genetics of diabetes. Second, they recommend research to define
the immunologic basis of Type I diabetes as a step toward immunoprevention
and immediate clinical trials of islet cell transplantation as a
cure. Third, dissecting the cell signaling and cell regulation pathways
underlying diabetes would identify targets for new treatments. Fourth,
research on the causes and biology of obesity should help reduce
this risk for Type II diabetes. Finally, a national network for
clinical trials in diabetes would foster effective testing of new
treatments. To meet these goals, the working group recommends a
$385 million increase in NIH funding for diabetes research, which
would bring the total to $827 million.
Many Smokers May Underestimate
Their Risk of Disease
Despite decades of public
awareness campaigns warning Americans of the dangers of smoking, most
smokers in the U.S. do not view themselves at increased risk for heart
disease or cancer, according to a study by HMS researchers published
in the March 17 JAMA. John Ayanian, assistant professor
of medicine at HMS and Brigham and Women's Hospital, and Paul Cleary,
professor of medical sociology in the Department of Health Care Policy,
analyzed results of a national survey of more than 3,000 randomly
Among current smokers (who made up about 24 percent of respondents),
only 29 percent believed themselves at higher than average risk
for myocardial infarction (MI) and 40 percent for cancer. The corresponding
numbers for two-pack-a-day smokers were 39 percent and 49 percent,
and for former smokers (29 percent of respondents), 15 percent and
18 percent. Older smokers were generally less likely than younger
smokers to perceive themselves at increased risk for the diseases.
"Our nationally representative study demonstrates that most
smokers--even heavy smokers and those with other cardiac risk factors--do
not perceive themselves at increased risk for experiencing an MI
or developing cancer," the authors write. They recommend that
physicians and public health professionals educate smokers about
How Dendritic Cells March
From Blood to Tissues
Dendritic cells (DCs) are specialized
leukocytes that play a central role in acquired immunity by capturing
antigens and presenting them to T cells. In blood, DCs are believed
to be traveling to repopulate lymphoid tissues. To perform this role,
DCs must be able to extravasate--to escape from blood vessels into
tissue. But until now, the cells have not been directly observed to
do so, and the mechanism they use has been undetermined.
In the Feb. 15 Journal of Experimental Medicine, Caroline
Robert and Thomas Kupper, respectively a postdoctoral
fellow and the Thomas B. Fitzpatrick professor of dermatology at
Brigham and Women's Hospital and the Harvard Institutes of Medicine,
with co-authors at BWH and HIM, the Center for Blood Research, MIT,
and MatTek Corporation, describe for the first time the interaction
of DCs with skin endothelium. They propose that DCs are waiting
to be called to sites of inflammation. Their experiments, using
in vitro flow analysis and intravital microscopy in mice, show that
like other leukocytes, DCs enter postcapillary venules via a maneuver
known as "tether and roll," the first step in extravasation.
The researchers also showed that DCs uniformly express P-selectin
glycoprotein ligand 1, an antigen that binds to selectin molecules
on the endothelium.
"We hypothesize that DCs in blood are constitutively poised
at the interface of blood and skin, ready to extravasate upon induction
of inflammation, and we showed that cutaneous inflammation results
in a rapid recruitment of DCs from the blood to tissues," the
Of Growth Factor Receptor Identified
epidermal growth factor receptor (EGFR) mediates crucial events
like cell growth and differentiation. Alterations in this receptor's
signaling have been linked to oncogenesis. In humans, for example,
improper regulation of members of the EGFR family is associated
with more than 30 percent of breast cancers. While many positive
regulators of EGFR and its family of receptors have been described,
only a few inhibitors are known so far.
Now, in the March 19 Cell, research fellow Christian
Ghiglione, instructor in medicine Kermit Carraway, professor
of genetics Norbert Perrimon, and colleagues identify in
flies a novel inhibitor of EGFR that they name kekkon1 (kek1).
According to the authors, kek1 is a new member of a growing
class of inhibitors that behave in a counterintuitive way: they
are part of a negative feedback loop and are transcriptionally activated
by the same genetic pathway that they inhibit.
The authors identified kek1 in a screen to characterize
targets of EGFR signaling, and this relationship was confirmed when
they observed that kek1 gene expression was affected in flies
with mutations in other members of the EGFR signaling pathway. When
kek1 was overexpressed at several stages of development,
the link to EGFR signaling became more evident as dorsal structures
in the eggshell and embryo were lost--a classic phenotype of EGFR
loss of function.
The authors also showed that the extracellular domain of the Kek1
protein, which contains five leucine-rich repeats and one immunoglobulin
motif, physically associates with EGFR and is the main player in
the molecule's inhibitory activity. Because of the association of
EGFR signaling to oncogenesis and since Kek1 is a novel protein
with motifs similar to those in other vertebrate proteins, the authors
speculate that further characterization of Kek1 and related factors
may lead to new approaches for therapeutic use in cancer via inhibition
of the EGFR.
Protein Kinase Affects Cardiac Impulses
Myotonic dystrophy is the most common form of muscular
dystrophy, caused by the expansion of a CTG trinucleotide repeat in
the myotonic dystrophy protein kinase (DMPK) gene on human
chromosome 19. Although it is known that patients with myotonic dystrophy
suffer from cardiac conduction defects at the atrioventricular (A-V)
node--the bundle of specialized cardiac fibers that conducts the cardiac
impulse from the atria to the ventricles--the etiology of cardiac
disease in myotonic dystrophy is poorly understood.
One hypothesis for the origin of the disease is that expansion
of the CTG repeat causes partial loss of DMPK due to nuclear retention
of the mutant protein. To test this hypothesis, Charles Berul,
HMS assistant professor of pediatrics at Children's Hospital,
and his colleagues studied cardiac electrophysiology in mice
lacking the DMPK gene. As reported in the February Journal
of Clinical Investigation, homozygous and heterozygous mice
lacking DMPK suffer from A-Vconduction block in a manner
similar to myotonic dystrophy patients, suggesting that DMPK plays
an important role in causing myotonic dystrophy cardiac disturbances.
Although adult heterozygous mice display A-V block, homozygotes
suffered from more severe disturbances of A-V conduction. This,
according to Berul and his colleagues, indicates that cardiac conduction
is sensitive to the dosage of DMPK. He adds that the results link
the less severe insufficiency of DMPK to the A-V disturbances suffered
by patients with myotonic dystrophy.
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