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Archive - Apr 5, 2011

Scientist Works on Solution to Nerve Agent Exposure

Dr. Christopher Hadad, professor of chemistry at The Ohio State University (OSU), is leveraging Ohio Supercomputer Center (OSC) resources to help develop a more effective antidote to lethal chemicals called organophosphorus (OP) nerve agents. “This project is a combination of synthetic and computational organic chemistry conducted through OSC at Ohio State, and biochemical studies conducted by colleagues at the U.S. Army Medical Research Institute of Chemical Defense at Aberdeen Proving Ground in Maryland,” said Dr. Hadad. OP nerve agents inhibit the ability of an enzyme called acetylcholinesterase (AChE) to turn off the messages being delivered by acetylcholine (ACh), a neurotransmitter, to activate various muscles, glands and organs throughout the body. After exposure to OP agents, AChE undergoes a series of reactions, culminating in an “aging” process that inactivates AChE from performing its critical biological function. Without the application of an effective antidote, neurosynaptic communication continues unabated, resulting in uncontrolled secretions from the mouth, eyes and nose, as well as severe muscle spasms, which, if untreated, result in death. Conventional antidotes to OP nerve agents block the activity of the nerve agent by introducing oxime compounds, which have been the focus of a number of studies. These compounds attach to the phosphorus atom of the nerve agent, after the OP is bound to AChE, and then split it away from the AChE enzyme, allowing the AChE to engage with receptors and finally relax the tissues. However, in some cases, the combined nerve agent/AChE molecule undergo a process called aging, in which groups of single-bonded carbon and hydrogen atoms called alkyl groups are removed from the molecule and a phosphonate residue is left behind in the AChE active site.

Genetic Clues to a Major Cause of Kidney Failure

For the first time, researchers have found five regions in the human genome that increase susceptibility to immunoglobulin A (IgA) nephropathy, a major cause of kidney failure worldwide. "The study is unique in identifying the biological pathways that mediate IgA nephropathy, mapping the way for further study that may reveal practical targets for diagnosis and treatment," said Dr. Ali Gharavi, Division of Nephrology at Columbia University in New York City, the principal investigator. "The cause and development of IgA nephropathy is poorly understood. Many biological pathways have been suggested, but none has been conclusive until now," he said. The ongoing genome-wide association study is funded by the National Institutes of Health’s Office of the Director, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Center for Research Resources, under an NIH Challenge Grant. The project is a part of the $10.4 billion provided to NIH through the Recovery Act. Results were published in the April issue of Nature Genetics. Researchers looked at the genes of 3,144 people of Chinese and European ancestry, all of whom have IgA nephropathy. The disease occurs when abnormal IgA antibodies deposit on the delicate filtering portion of the kidney and form tangles. The immune system tries to get rid of the tangles, but the kidneys are caught in the crossfire, further destroying the delicate filters. Worldwide prevalence of IgA nephropathy appears highest in Asia and southern Europe, and is responsible for most cases of kidney failure in those populations. The U.S. prevalence is much lower — up to 10 percent, although Native Americans from New Mexico have reported rates as high as 38 percent. "IgA nephropathy is most common in Asia, intermediate in prevalence in Europeans and rare in Africans.

Genomic Signature May Explain Why Pregnancy Lowers Risk of Breast Cancer

Women who have children, particularly early in life, have a lower lifetime risk of breast cancer compared with women who do not. Now, Fox Chase Cancer Center researchers have identified a gene expression pattern in breast tissue that differs between post-menopausal women who had children and post-menopausal women who did not. The results will help scientists understand why pregnancy reduces breast cancer risk and may help them develop chemopreventive strategies that can provide similar protection for women who did not have children. Pregnancy triggers differentiation and growth of breast tissue; however breast tissue in post-menopausal women looks similar regardless of childbearing history. That similarity has left researchers wondering why pregnancy is protective throughout a woman's life. This study starts to explain that effect, says Dr. Ricardo López de Cicco, a senior research associate at Fox Chase, who presented the work at the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011 on April 5, 2011. "When a woman has multiple pregnancies beginning at a relatively young age, we see a protective effect against breast cancer," Dr. Lopez says. "In this study, we identified a post-pregnancy genomic signature that can still be seen even after menopause. That is very important because it could begin to help us understand why women who have children early benefit from a reduced risk of breast cancer throughout their lives." By comparing gene expression in breast tissue from 44 post-menopausal women who had children and 21 post-menopausal women who did not, the team identified 208 genes that are differentially expressed. The signature was subsequently validated in an independent cohort of 61 post-menopausal women, 38 who had children and 23 who did not.