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Archive - Dec 6, 2012

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Unprecedented Genomic Sequencing of Metastatic Triple-Negative Breast Cancer Patients Yields Potential Drug Targets

Genomic sequencing has revealed therapeutic drug targets for difficult-to-treat, metastatic triple-negative breast cancer (TNBC), according to an unprecedented study by the Translational Genomic Research Institute (TGen) and US Oncology Research. The study was published online on November 19, 2012 in the journal Molecular Cancer Therapeutics. By sequencing, or spelling out, the billions of letters contained in the genomes of 14 tumors from ethnically diverse metastatic TNBC patients, TGen and US Oncology Research investigators found recurring significant mutations and other changes in more than a dozen genes. In addition, the investigators identified mutations previously unseen in metastatic TNBC and took the sequencing data into account in selection of therapeutic protocols specific to each patient's genetic profile. "This study stands as a one-of-a-kind effort that has already led to potentially beneficial clinical trials, and sets the stage for future investigations," said Dr. John Carpten, Ph.D., TGen's Deputy Director of Basic Science and Director of TGen's Integrated Cancer Genomics Division, and the study's senior author. The most frequently mutated gene among the tumors (7 of 14) was the TP53 tumor suppressor, and aberrations were observed in additional tumor suppressor genes including CTNNA1, which was detected in two of six African-American patients (who typically have more aggressive and treatment-resistant disease). Alterations were also seen in the ERBB4 gene, known to be involved in mammary-gland maturation during pregnancy and lactation, but not previously linked to metastatic TNBC. The study included an "outlier analysis," which assessed expression patterns for each tumor when compared against the other tumors examined in the study.

Bilirubin Can Prevent Damage from Cardiovascular Disease

Each year, approximately 610,000 Americans suffer their first heart attack, according to the Centers for Disease Control and Prevention. Heart attacks and other symptoms of cardiovascular disease can be caused when blockage occurs in the arteries. In a new study from the University of Missouri (MU), a scientist has discovered a natural defense against arterial blockage: bilirubin. Bilirubin is typically something parents of newborns hear about when their children are diagnosed with jaundice. Generated during the body's process to recycle worn-out red blood cells, bilirubin is metabolized by the liver and, usually, leaves the body harmlessly. (Many babies' livers are not developed enough to metabolize the bilirubin, which results in the infants being diagnosed with jaundice, or high levels of bilirubin in their systems.) Now MU scientists have found that bilirubin can be used to inhibit the clogging of arteries, and thus prevent the deadly consequences often experienced by individuals with cardiovascular disease. "Bilirubin is generated daily in the human body, but it's not a waste product; it has important functions, including being an antioxidant," said Dr. William Durante, professor of medical pharmacology and physiology and lead author on the study. "What we found in our study is that bilirubin can prevent or limit the damage that occurs to blood vessels in individuals who have, or are at risk for, cardiovascular diseases, such as atherosclerosis." When arteries are damaged, smooth muscle cells in blood vessels become activated and grow at the injury sites creating lesions inside the arteries. These lesions can block the flow of blood in arteries of the heart leading to chest pains or deadly heart attacks, Dr. Durante said.

Nuclear Import of Transcriptional Repressor in Jasmonate Signaling

Researchers examining how the hormone jasmonate works to protect plants and promote their growth have discovered how a transcriptional repressor of the jasmonate signaling pathway makes its way into the nucleus of the plant cell. The scientists hope that this recently published discovery will eventually help farmers experience better crop yields with less use of potentially harmful chemicals. “This is a small piece of a bigger picture, but it is a very important piece,” said Dr. Maeli Melotto, a University of Texas at Arlington (UT Arlington) assistant professor of biology. Dr. Melotto recently co-authored a paper that advances current understanding of plant defense mechanisms with her collaborator Dr. Sheng Yang and his team at Michigan State University’s Department of Energy Plant Research Laboratory (DOE-PRL). Dr. Yeng is a Howard Hughes Medical Institute-Gordon and Betty Moore Foundation investigator. The collaborative paper was published in the December 4, 2012 issue of PNAS. Jasmonate signaling has been a target of intense research because of its important role in maintaining the balance between plant growth and defense. In healthy plants, jasmonates play a role in reproductive development and growth responses. But, when stressors such as herbivorous insects, pathogen attack, or drought come into play, jasmonate signaling shifts to defense-related cellular processes. The team from UT Arlington and Michigan State focused on the role of jasmonate signaling repressors referred to as JAZ. Specifically, the scientists looked at how JAZ interacts with a major transcription factor called MYC2 and a protein called COI1, which is a receptor necessary for jasmonate signaling.

Novel Drug Reduces Depression Scores within Hours in Phase IIa Trial

Naurex Inc., a clinical stage company developing innovative treatments to address unmet needs in psychiatry and neurology, today reported positive results from a Phase IIa clinical trial of its lead antidepressant compound, GLYX-13. GLYX-13 is a novel partial agonist of the NMDA receptor. The Phase Ila results are being presented at the 51st Annual Meeting of the American College of Neuropsychopharmacology (ACNP), being held December 2-6, 2012 in Hollywood, Florida. The Phase IIa results show that a single administration of GLYX-13 produced statistically significant reductions in depression scores in subjects who had failed treatment with one or more antidepressant agents. The reductions were evident within 24 hours and persisted for an average of seven days. Importantly, the effect size, a measure of the magnitude of the drug's antidepressant efficacy, observed at 24 hours and at seven days after a single administration of GLYX-13, was nearly double the effect size seen with most other antidepressant drugs after 4-6 weeks of repeated dosing. In the Phase IIa trial, GLYX-13 was well tolerated. Reported side effects were mild to moderate and were consistent with those observed in subjects receiving placebo. Consistent with previous studies, GLYX-13 did not produce any of the schizophrenia-like psychotomimetic effects associated with other drugs that modulate the NMDA receptor. "These data are an important step in validating Naurex's mission of developing breakthrough therapies for depression and other CNS disorders," said Derek Small, CEO of Naurex. "Our founder discovered a new class of drugs that appeared to have the remarkable antidepressant efficacy of ketamine-like compounds, but without their limiting side effects.