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Archive - Jul 8, 2012

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Exome Sequencing of Health Condition Extremes Can Reveal Susceptibility Genes

Comparing the DNA from patients at the best and worst extremes of a health condition can reveal genes for resistance and susceptibly. This approach has led to the discovery of rare variations in the DCTN4 gene among cystic fibrosis patients most prone to early, chronic airway infections. The DCTN4 gene codes for dynactin 4. This protein is a component of a molecular motor that moves trouble-making microbes along a cellular conveyer belt into miniscule chemical vats, called lysosomes, for annihilation. This study, led by the University of Washington (UW), is part of the National Heart Lung and Blood Institute GO Exome Sequencing Project and its Lung GO, both major National Institutes of Health chronic disease research efforts. Similar "testing the extremes" strategies may have important applications in uncovering genetic factors behind other more common, traits, such as healthy and unhealthy hearts. The results of the cystic fibrosis infection susceptibility study were published online on July 8, 2012 in Nature Genetics. The infection in question was Pseudomonas aeruginosa, an opportunistic soil bacterium that commonly infects the lungs of people with cystic fibrosis and other airway-clogging disorders. The bacteria can unite into a slithery, hard-to-treat biofilm that hampers breathing and harms lung tissue. Chronic infections are linked to poor lung function and shorter lives among cystic fibrosis patients. These bacteria rarely attack people with normal lungs and well-functioning immune systems. In the study, these rare variations in DCTN4 did not appear in any of the cystic fibrosis patients who were the most resistant to Pseudomonas infection. The study subjects most susceptible to early, chronic infection had at least one DCTN4 missense variant. A missense variant produces a protein that likely can't function properly.

Inhibitor of Melanoma Growth Identified

Researchers from Brigham and Women's Hospital (BWH) in Boston have made a potentially groundbreaking discovery that may shape the future of melanoma therapy. The team, led by Thomas S. Kupper, M.D., chair of the BWH Department of Dermatology, and Rahul Purwar, Ph.D., found that high expression of a cell-signaling molecule, known as interleukin-9, in immune cells inhibits melanoma growth. Their findings were published online on July 8, 2012 in Nature Medicine. After observing mice without genes responsible for development of an immune cell called T helper cell 17 (TH17), researchers found that these mice had significant resistance to melanoma tumor growth, suggesting that blockade of the TH17 cell pathway favored tumor inhibition. The researchers also noticed that the mice expressed high amounts of interleukin-9. "These were unexpected results, which led us to examine a possible contribution of interleukin-9 to cancer growth suppression." said Dr. Purwar. The researchers next treated melanoma-bearing mice with T helper cell 9 (TH9), an immune cell that produces interleukin-9. They saw that these mice also had a profound resistance to melanoma growth. This is the first reported finding showing an anti-tumor effect of TH9 cells. Moreover, the researchers were able to detect TH9 cells in both normal human blood and skin, specifically in skin-resident memory T cells and memory T cells in peripheral blood mononuclear cells. In contrast, TH9 cells were either absent or present at very low levels in human melanoma. This new finding paves the way for future studies that will assess the role of interleukin-9 and TH9 cells in human cancer therapy. "Immunotherapy of cancer is coming of age, and there have been exciting recent results in patients with melanoma treated with drugs that stimulate the immune system," said Dr.