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Women More Susceptible To Harmful Effects Of Smoking
Women may be more susceptible to the lung damaging effects of smoking than men, according to new research by Inga-Cecilie Soerheim, M.D., and her colleagues from Channing Laboratory, Brigham and Women"s Hospital and University of Bergen, Norway.

Diarrhea Spreads In Parts Of Bangladesh In Cyclone Aila's Aftermath
Health officials on Sunday said that a diarrhea outbreak has spread across Bangladesh"s southwest due to the effects of Cyclone Aila, which hit parts of Bangladesh and India on May 25, AFP/Google.com reports. Diarrhea broke out at an "alarming rate" because inundation and water logging have destroyed large amounts of land and supplies of drinking water near Sundarbans, the world"s largest mangrove forest, according to health workers.
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Obama Administration's Filings On Asylum For Abused Foreign Women Brings 'Overdue Dose Of Clarity,' Editorial Says
The Obama administration recently laid out "a clear but narrow pathway" toward asylum for foreign women who have experienced severe physical or sexual abuse, a New York Times editorial states, noting that the U.S. government has debated the issue for 15 years. According to the editorial, the "question is not the fact of persecution, but whether the women would qualify for protection under the law, which limits asylum to those who suffer due to their race, religion, nationality, political opinion or "membership in a particular social group."" It adds that attorneys general under former Presidents Clinton and George W. Bush "have gone both ways and in circles" in their decisions.Although "[n]ot all victims will qualify," the Obama administration "made it clear that some could," the editorial states. "A petitioner would have to demonstrate to a judge that domestic violence was widely tolerated by society and government in her country, that women were viewed as subordinate to men and that she had no place within its borders to find a safe haven," the editorial adds.Department of Homeland Security lawyers say the new definition could apply to a severely abused Mexican woman, identified only by her initials, whose asylum petition is before a San Francisco immigration court. The editorial notes that DHS "did not immediately recommend asylum" for the woman, but "it did urge that she be allowed to continue to gather evidence and to refine her case according to the standards it proposed." The editorial concludes, "Advocates who have fought for years to advance women"s rights are celebrating the department"s action, which brings reasoned compassion, and an overdue dose of clarity, to an issue of anguish and difficulty" (New York Times, 7/19).
Public Health

Determining Success Or Failure In Cholesterol-Controlling Drugs

Researchers at the University of California, San Diego have discovered that a complex network of interactions between drugs and the proteins with which they bind can explain adverse drug effects. Their findings suggest that adverse drug effects might be minimized by using single or multiple drug therapies in order to fine-tune multiple off-target interactions. "The traditional way of thinking of one drug binding to only one receptor to treat a single disease is outmoded," said Philip Bourne, professor of pharmacology with UC San Diego"s Skaggs School of Pharmacy and Pharmaceutical Sciences. "We found that a drug may have a cumulative effect through acting on multiple receptors at the same time, rather than acting on a single receptor." The term polypharmacology has been coined to describe this phenomenon, which may explain the failure of an anti-cholesterol drug called Torcetrapib which - after 15 years of research and $850 million in development costs - was withdrawn from stage III clinical trials as a result of instances of cardiovascular disease which resulted in death. "Torcetrapib actually acted on a dozen different receptors, resulting in an unanticipated side effect," said Bourne. "This multi-inhibitor binding pattern may not be at all unusual." In studying protein-drug interaction networks of a class of drugs known as cholesteryl ester transfer protein (CETP) inhibitors, and aided by computational modeling done at the San Diego Supercomputer Center (SDSC) at UC San Diego, the research team found evidence that CETP inhibitors bind to a variety of receptors. Their work, published in the May 15 issue of PLoS Computational Biology, uses a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale. In this case, the strategy was applied to explain the molecular mechanisms associated with adverse drug effects. "At this time we do not have a complete structural proteome to analyze, one that maps all the protein structures in the genome - either experimental or model - to which drugs could bind," said Bourne, director of structural bioinformatics and an SDSC Distinguished Scientist. "So though we still may not have a complete understanding of off-target binding, this strategy is already useful." Studying the panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome, the researchers mapped those targets to biological pathways using the existing literature. "The predicted protein-ligand network is consistent with experimental results from multiple s and reveals that the side-effects of CETP inhibitors are modulated through the combinatorial control of multiple, interconnected biochemical pathways," said Li Xie, lead author on the study. In other words, Xie explained, a combination of many different pathways, impacted when a molecule or ligand binds to several receptors, possibly inhibiting a number of different proteins - all lead to the overall physiological effect of that drug. Besides the CETP inhibitor, Torcetrapib, two related drugs, Anacetrapib and JTT-705, were also analyzed. The final panel of off-targets for these drugs is associated with many physiological processes including cell proliferation, inflammation and hypertension. "Ironically, Torcetrapib is more specific than JTT705, yet it is less effective in controlling cholesterol levels with minimal side effects," said Lei Xie, a senior scientist in the Bourne group and the major developer of the computational methodology. "This is contrary to conventional wisdom, which implies that the more specific the binding, the fewer the side-effects." For example, JTT-705 has a binding profile that impacts numerous biological pathways, but none of them result in hypertension - a side effect that is observed in the Torcetrapib, which binds more specifically. Among a number of cumulative effects, the scientists predicted different binding profiles of CETP inhibitors to several nuclear receptors. They discovered that JTT-705, unlike Torcetrapib, is involved in the activation of nuclear receptors that contribute to both positive and negative control of aldosterone, a hormone responsible for increased blood pressure. This differs from Torcetrapib, which only increases aldosterone production and therefore has a purely positive, or increased, effect on blood pressure. Mapping the off-targets to biochemical pathways that are currently known provides new insights with the potential to improve the design of effective and safe pharmaceuticals. "This work extends the scope of chemogenomics - the study of genomic responses to chemical compounds - and exemplifies the role that systems biology has in the future of drug discovery," Bourne said. An additional contributor includes Jerry Li, from Torrey Pines High School in San Diego. This work was supported by a grant from the National Institutes of Health. Debra Kain University of California - San Diego


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