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Archive - Aug 3, 2014

New Genetic Risk Markers Found for Pancreatic Cancer

A large DNA analysis of people with and without pancreatic cancer has identified several new genetic markers that signal increased risk of developing the highly lethal disease, report scientists from Dana-Farber Cancer Institute (http://www.dana-farber.org/) in Boston. The markers are variations in the inherited DNA code at particular locations along chromosomes. Several of these variations in the DNA code were identified that influence an individual's risk for pancreatic cancer. The discovery of these markers – along with four that were previously identified is important for several reasons, said Brian Wolpin, M.D., M.P.H, first author of the report published online on August 3, 2014 by Nature Genetics. One is that further study of these DNA variants may help explain on the molecular level why some people are more or less susceptible to pancreatic cancer than the average person. A second is the potential to identify people at increased risk who then might be candidates to undergo MRI or ultrasound scanning to look for early, treatable pancreatic tumors. "Currently there is no population screening program for pancreatic cancer, which in 80 percent of cases is discovered when it's too late to allow curative surgery – the cancer has already spread," said Dr. Wolpin. The only healthy individuals currently screened for pancreatic cancer are members of high-risk families due to multiple family members with pancreatic cancer. "But the field has been struggling to find factors that can identify people at highest risk in the general population, when a strong family history is not present," Dr. Wolpin said. The study findings represent analyses of DNA from 7,683 patients with pancreatic cancer and 14,397 control patients without this cancer, all of European descent, from the United States, Europe, Canada, and Australia.

Rare Developmental Disorder Linked to Tumor-Suppressing Protein p53

CHARGE, which affects 1 in 10,000 babies, is an acronym whose letters stand for some of the more common symptoms of the condition: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness. Originally, the researchers were examining the tumor-suppressive properties of the protein, called p53, not investigating developmental disorders. But when a mouse model developed a strange set of deficiencies, the researchers followed a trail of clues that led them to link p53 with CHARGE syndrome. "It was a very big surprise and very intriguing," said Jeanine Van Nostrand, Ph.D., lead author of a paper describing the research and a former Stanford graduate student, now at The Salk Institute for Biological Studies. "p53 had never before been shown to have a role in CHARGE." The paper was published online on August 3, 2014 in Nature. The senior author is Laura Attardi, Ph.D., professor of radiation oncology and of genetics. The researchers originally created a mouse model that expressed a mutated form of the protein, known as p53, to investigate the behavior of p53 in suppressing tumors. Mice expressing only the mutated protein survived. But to the team’s surprise, heterozygous mice, or those with one copy of the mutated p53 and one normal copy, developed symptoms of CHARGE and died in utero. p53 is a cellular quality-control regulator. When it spots an ailing cell, it triggers other proteins to kill the cell or arrest its division. In a developing human or mouse, other proteins switch off p53 so it doesn't inadvertently kill important cells. The mutated form of p53 created by the researchers had a disabled off-switch, but it also couldn't communicate with other proteins to spark the cellular death.

'Normal' Bacteria Vital for Keeping Intestinal Lining Intact

Scientists at Albert Einstein College of Medicine of Yeshiva University have found that bacteria that aid in digestion help keep the intestinal lining intact. The findings, reported online on July 24, 2014, 2014 in the journal Immunity, could yield new therapies for inflammatory bowel disease (IBD) and a wide range of other disorders. The research involved the intestinal microbiome, which contains some 100 trillion bacteria. The role of these microorganisms in promoting or preventing disease is a major emerging field of study. Einstein scientists found that absorption of a specific bacterial byproduct is crucial for maintaining the integrity of the intestinal epithelium—the single-cell layer responsible for keeping intestinal bacteria and their toxins inside the gut and away from the rest of the body. Breaching of the intact intestinal epithelium is associated with a number of diseases. "Intestinal bacteria secrete a wide variety of chemicals known as metabolites," said Sridhar Mani, M.D., co-corresponding author of the paper. "These bacteria and their metabolites were known to influence the intestinal epithelium's integrity, but precisely how they did so wasn't known." Dr. Mani is professor of medicine and of genetics and the Miriam Mandel Faculty Scholar in Cancer Research at Einstein and attending physician, oncology at the Montefiore Einstein Center for Cancer Care and Montefiore Medical Center. Dr. Mani and his colleagues suspected that bacterial metabolites exert their influence by binding to and activating a protein in the nuclei of intestinal epithelial cells called the pregnane X receptor (PXR). PXR was known to be activated by chemicals within the body (such as bile acids) as well as by drugs including steroids and antibiotics.

Researchers Create Most Detailed Molecular Map of Eye Region Associated with Vision Loss

University of Iowa (UI) researchers have created the most detailed map to date of the abundance of thousands of proteins in the choroid, a region of the human eye long associated with blinding diseases. By seeing differences in protein abundance, the researchers can begin to figure out which proteins may be the critical actors in vision loss and eye disease. Understanding eye diseases is tricky enough. Knowing what causes them at the molecular level is even more confounding. Now, University of Iowa researchers have created the most detailed map to date of a region of the human eye long associated with blinding diseases, such as age-related macular degeneration. The high-resolution molecular map catalogs thousands of proteins in the choroid, which supplies blood and oxygen to the outer retina, itself critical in vision. By seeing differences in the abundance of proteins in different areas of the choroid, the researchers can begin to figure out which proteins may be the critical actors in vision loss and eye disease. “This molecular map now gives us clues why certain areas of the choroid are more sensitive to certain diseases, as well as where to target therapies and why,” says Dr. Vinit Mahajan, assistant professor in ophthalmology at the UI and corresponding author on the paper, published online on July 24, 2014 in the journal JAMA Ophthalmology. “Before this, we just didn’t know what was where.” What vision specialists know is many eye diseases, including age-related macular degeneration (AMD), are caused by inflammation that damages the choroid and the accompanying cellular network known as the retinal pigment epithelium (RPE). Yet they’ve been vexed by the anatomy: Why does it seem that some areas of the choroid-RPE are more susceptible to disease than others, and what is happening at the molecular level?

Understanding How Neurons Regulate Metabolism in Response to a High-Fat Diet

The brain plays a central role in regulating appetite and whole-body metabolism. A protein known as PPARgamma is important in the brain's control of food intake and body weight, but the identity of the neurons regulating this process has been unclear. A new study published online on August 1, 2014 in the Journal of Clinical Investigation demonstrates that PPARgamma activity in a type of neuron known as pro-opiomelanocortin (POMC) neurons is critical in mediating the response to high-fat diet. Sabrina Diano, Ph.D., and colleagues at Yale University School of Medicine found that mice lacking PPARγ specifically in POMC neurons gained less weight, were more active, and had improved glucose metabolism when fed a high-fat diet. Moreover, animals without PPARgamma in POMC neurons did not gain weight when given PPARgamma activators. The results of this study indicate that PPARgamma expression in POMC neurons regulates whole-body energy balance. The findings also shed light on why PPARgamma activators, which are used clinically to increase insulin sensitivity in patients with type 2 diabetes, have a side effect. Image shows PPAR gamma bound to DNA. [Press release] [Journal of Clinical Investigation article]