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RESEARCH BRIEFS Group Calls for Funding Increase
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 UnderestimateTheir 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 selected adults. 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 these risks. How Dendritic Cells MarchFrom 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 authors write. Novel Inhibitor 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 ImpulsesIn Dystrophy 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. Back to Top |
