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Archive - Mar 2012

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March 18th

Bone Marrow Transplant Arrests Symptoms in Model of Rett Syndrome

A paper published online on March 18, 2012 in Nature describes the results of using bone marrow transplant (BMT) to replace faulty immune system cells in models of Rett syndrome. The procedure arrested many severe symptoms of the childhood disorder, including abnormal breathing and movement, and significantly extended the lifespan of Rett mouse models. Exploring the function of microglia deficient in methyl-CpG binding protein 2 (Mecp2), the protein encoded by the "Rett gene," principal investigator Jonathan Kipnis, Ph.D. and his team at the University of Virginia School of Medicine uncovered a completely novel approach to this devastating neurological syndrome. Rett syndrome, the most physically disabling of the autism spectrum disorders, is caused by random mutations in the gene MECP2. Predominantly affecting girls, symptoms usually manifest between 6 and 18 months of age, when a frightening regression begins. Children lose acquired language skills and functional hand use; movement deteriorates as other Rett symptoms appear. These may include disordered breathing, Parkinsonian tremors, severe anxiety, seizures, digestive and circulatory problems, and a range of autonomic nervous system and orthopedic abnormalities Although most children survive to adulthood, many are wheelchair-bound, rely on feeding tubes, are unable to communicate, and require total, lifelong care. Dr. Kipnis was drawn to Rett syndrome from his perspective as a neuroimmunologist. "What began as intellectual curiosity," he explains, "has become an intense personal commitment to studying the correlation between neurological function and the immune system in Rett syndrome.

Single Gene Mutation Can Lead to Uncontrolled Obesity

Researchers at Georgetown University Medical Center have revealed how a mutation in a single gene is responsible for the inability of neurons to effectively pass along appetite suppressing signals from the body to the right place in the brain. What results is obesity caused by a voracious appetite. Their study, published online on March 18, 2012 on Nature Medicine's website, suggests there might be a way to stimulate expression of that gene to treat obesity caused by uncontrolled eating. The research team specifically found that a mutation in the brain-derived neurotrophic factor (Bdnf) gene in mice does not allow brain neurons to effectively pass leptin and insulin chemical signals through the brain. In humans, these hormones, which are released in the body after a person eats, are designed to "tell" the body to stop eating. But if the signals fail to reach correct locations in the hypothalamus, the area in the brain that signals satiety, eating continues. "This is the first time protein synthesis in dendrites, tree-like extensions of neurons, has been found to be critical for control of weight," says the study's senior investigator, Baoji Xu, Ph.D., an associate professor of pharmacology and physiology at Georgetown. "This discovery may open up novel strategies to help the brain control body weight," he says. Dr. Xu has long investigated the Bdnf gene. He has found that the gene produces a growth factor that controls communication between neurons. For example, he has shown that during development, BDNF is important to the formation and maturation of synapses, the structures that permit neurons to send chemical signals between each other. The Bdnf gene generates one short transcript and one long transcript.

BRAF-Inhibitor Shows Promise in Treatment of Some Metastatic Melanomas

An international team of researchers from the United States and Australia, including researchers at the Moffitt Cancer Center in Tampa, Florida, have found that the oral BRAF inhibitor vemurafenib (PLX4032) when tested in a phase II clinical trial offered a high rate of response in patients with previously treated metastatic melanoma and who had the BRAF mutation. More than 50 percent of the patients in the trial had positive, prolonged responses and a median survival of almost 16 months. The study was published in the February 23, 2012 issue of the New England Journal of Medicine. According to study co-author Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt, approximately 50 percent of melanomas harbor the activating (V600) mutation threonine protein kinase B-RAF. Unfortunately, treatment options for these patients are "limited." The BRAF inhibitor vemurafenib had been found effective in phase I and phase III trials. However, to determine the overall response rate in previously treated stage IV melanoma patients, the researchers designed a multi-center, phase II trial with 132 patients with previously treated BRAF V600-mutant metastatic melanoma. The trial was designed by senior academic authors and representatives of the trial sponsor, Hoffman-La Roche, and was open to adults over the age of 18 with histologically proven stage IV melanoma, progressive disease, and at least one prior systemic treatment. "Few patients with metastatic melanoma bearing the BRAF V600 mutation have a response to systemic chemotherapies," said Dr. Weber. "Additionally, most have a median survival of only 6 to 10 months.

March 15th

Cell Signaling Pathway May Play Key Role in Gestational Diabetes

AResearchers at the University of Pittsburgh School of Medicine have identified a cell signaling pathway that plays a key role in increasing insulin secretion during pregnancy and, when blocked, leads to the development of gestational diabetes. Their findings were published online on March 16, 2012 in Diabetes, one of the journals of the American Diabetes Association. During pregnancy, pancreatic beta cells should expand and produce more insulin to adapt to the needs of the growing baby, explained senior investigator Adolfo Garcia-Ocana, Ph.D., associate professor of medicine, Division of Endocrinology and Metabolism, Pitt School of Medicine. Newborns can suffer complications if the mother's blood glucose is abnormally high during pregnancy, a condition known as gestational diabetes. "Not much was known about the maternal mechanisms that lead to increased beta cell number and function during pregnancy," Dr. Garcia-Ocana said. "But research has shown that high blood glucose in pregnancy can have long-term health consequences for the child, as well as a greater risk of hypertension, type 2 diabetes, and high cholesterol for the mother." His team began studying a protein called hepatocyte growth factor (HGF), which was discovered by George K. Michalopoulos, M.D., Ph.D., professor and chair, Department of Pathology, Pitt School of Medicine, in 1990. Blood levels of HGF are markedly increased in pregnancy. The protein interacts with a cell-surface receptor called c-MET. The researchers engineered mice that lacked the c-MET receptor in pancreatic cells and found that their beta cells functioned correctly, keeping blood glucose within normal parameters in adult mice. But when the mice got pregnant, they took on the features of gestational diabetes.

New Psoriasis Treatment May Prevent Heart Attacks and Strokes

A clinical study co-led by the Montreal Heart Institute and Innovaderm Research Inc., which was presented March 16, 2012 at the annual meeting of the American Academy of Dermatology, shows that a new treatment for psoriasis could be associated with a significant decrease in vascular inflammation, a major risk factor of cardiovascular disease. Psoriasis is a chronic inflammatory disease of the skin and joints that affects up to 3% of the population. This disease is associated with a greater risk of heart attack (infarction) and stroke. The goal of this clinical study was to show that a treatment to reduce skin inflammation in psoriasis patients could be associated with a decrease in vascular inflammation. The study had positive results, as vascular inflammation decreased significantly in patients suffering from psoriasis who were treated with adalimumab, a biological anti-inflammatory compound. The study also showed a 51% decrease in C-reactive protein among patients treated with adalimumab compared to a 2% decrease among patients in the control group. These results are significant, as a high level of C-reactive protein is known to be associated with an increased risk of heart attack and stroke. In relation to the treatment of psoriasis, 70% of patients who received the compound presented with a major decrease in skin lesion severity, compared to 20% of patients in the control group. According to Dr.

March 15th

Genetic Marker Discovery May Reduce $600 Million Annual Loss Due to Pig Virus

A collaborative discovery involving Kansas State University researchers may improve animal health and save the U.S. pork industry millions of dollars each year. Dr. Raymond "Bob" Rowland, a virologist and professor of diagnostic medicine and pathobiology, was part of the collaborative effort that discovered a genetic marker that identifies pigs with reduced susceptibility to porcine reproductive and respiratory syndrome, or PRRS, caused by the PRRS virus. PRRS costs the U.S. pork industry more than $600 million each year. "This discovery is what you call a first-first," Dr. Rowland said. "This discovery is the first of its kind for PRRS, but also for any large food animal infectious disease. I have worked in the field for 20 years and this is one of the biggest advances I have seen." Dr. Rowland and researchers Dr. Jack Dekkers from Iowa State University and Dr. Joan Lunney from the Agricultural Research Service discovered a genetic marker called a quantitative trait locus, or QTL, that is associated with PRRS virus susceptibility. This discovery is a first step in controlling and eliminating the virus. The research appeared online on December 28, 2011 in the Journal of Animal Science. The project's beginning and future center around Kansas State University, Dr. Rowland said. It begins at the university because Dr. Rowland is involved with an organization called the PRRS Host Genetics Consortium, or PHGC, which initiated and provided more than $5 million for the research. Dr. Rowland is co-director of the consortium, which is a collaboration among the United States Department of Agriculture, the National Pork Board, and Genome Canada, as well as various universities and industry members. Dr. Rowland is also director of the USDA-funded PRRS Coordinated Agriculture Project, known as PRRS CAP.

March 13th

Circadian Clocks May Hold Key to Treatment of Bipolar Disorder

Scientists have gained insight into why lithium salts are effective at treating bipolar disorder in what could lead to more targeted therapies with fewer side effects. Bipolar disorder is characterized by alternating states of elevated mood, or mania, and depression. It affects between 1% and 3% of the general population. The extreme 'mood swings' in bipolar disorder have been strongly associated with disruptions in circadian rhythms – the 24-hourly rhythms controlled by our body clocks that govern our day and night activity. For the last 60 years, lithium salt (lithium chloride) has been the mainstay treatment for bipolar disorder, but little research has been carried out to determine whether and how lithium impacts the brain and peripheral body clockwork. "Our study has shown a new and potent effect of lithium in increasing the amplitude, or strength, of the clock rhythms, revealing a novel link between the classic mood-stabilizer, bipolar disorder, and body clocks," said lead researcher Dr. Qing-Jun Meng, in the University of Manchester's Faculty of Life Sciences. "By tracking the dynamics of a key clock protein, we discovered that lithium increased the strength of the clockwork in cells up to three-fold by blocking the actions of an enzyme called glycogen synthase kinase or GSK3. Our findings are important for two reasons: firstly, they offer a novel explanation as to how lithium may be able to stabilize mood swings in bipolar patients; secondly, they open up opportunities to develop new drugs for bipolar disorder that mimic and even enhance the effect lithium has on GSK3 without the side effects lithium salts can cause." These side effects include nausea, acne, thirstiness, muscle weakness, tremor, sedation, and/or confusion.

March 12th

New Findings Have Implications for Treatment and Prevention of Virus-Caused Cancers

New research from the Trudeau Institute, in Saranac Lake, New York, addresses how the human body controls gamma-herpesviruses, a class of viruses thought to cause a variety of cancers. The study, carried out in the laboratory of Dr. Marcia Blackman, awaits publication in The Journal of Immunology. Led by postdoctoral fellow Dr. Mike Freeman, with assistance from other laboratory colleagues, the study describes the role of white blood cells in controlling gamma-herpesvirus infections and has implications for the treatment and prevention of certain cancers. One of the many factors that can contribute to the development of cancer is infection with cancer-causing viruses, among them gamma-herpesviruses like the Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. With more than 95 percent of the human population infected with one or both of these viruses, it is important to understand their infection cycles and how immune responses keep them in check in the majority of individuals. Gamma-herpesvirus infections are characterized by two distinct phases. In the initial, active phase, the immune system responds by attacking the virus. The virus, however, has developed a clever mechanism for "sneaking" past the immune response to conceal itself within the body, a process researchers refer to as latent infection. While in hiding, the virus persists in a quiet, inactive state. Occasionally, it can start to reactivate and begin to multiply again, increasing the risk of cancer development. The chance that cancer will develop is greatly increased if the immune system is weakened, such as with immunosuppression following transplantation or as a consequence of other diseases, such as AIDS. Researchers around the globe are asking important questions about the nature of these viruses and working in their labs to answer them.

March 12th

Epstein-Barr-Like Virus Infects and May Cause Cancer in Dogs

More than 90 percent of humans have antibodies to the Epstein-Barr virus (EBV). Best known for causing mononucleosis, or "the kissing disease," the virus has also been implicated in more serious conditions, including Hodgkin's, non-Hodgkin's, and Burkitt's lymphomas. Yet little is known about exactly how EBV triggers these diseases. Now a team of researchers from the University of Pennsylvania School of Veterinary Medicine and Penn's Perelman School of Medicine has the first evidence that an Epstein-Barr-like virus can infect and may also be responsible for causing lymphomas in man's best friend. The findings suggest that domestic dogs possess a similar biology to humans with respect to EBV infection. That could allow scientists to study dogs to help uncover the mechanisms by which EBV leads to cancer in certain people. "There are no large-animal spontaneous models of EBV infection and virus-associated disease, and most studies investigating viral disease are performed in non-human primates, which are very expensive," said Dr. Nicola Mason, senior author of the study and an assistant professor of medicine and pathobiology at Penn Vet. "Discovering that dogs can get infected with this virus like people do may provide us with a long-sought-after model for EBV-associated disease." Dr. Mason's team at Penn Vet included Drs. Shih-Hung Huang, Philip Kozak, Jessica Kim, George Habineza-Ndikuyeze, Charles Meade, Anita Gaurnier-Hausser, and Reema Patel. The team worked closely with Dr. Erle Robertson, professor of microbiology at the Perelman School of Medicine. Their work was published online on March 8, 2012 in the journal Virology. In humans, the Epstein-Barr virus infects B-cells. After an acute phase of infection, of which many people are not even aware, the virus goes into a latent phase.

New Results Could Lead to More Effective Drug Discovery for Cystic Fibrosis

A recent study led by Dr. Gergely Lukacs, a professor at McGill University's Faculty of Medicine, Department of Physiology, and published in the January 20, 2012 issue of Cell, has shown that restoring normal function to the mutant gene product responsible for cystic fibrosis (CF) requires correcting two distinct structural defects. This finding could point to more effective therapeutic strategies for CF in the future. CF, a fatal genetic disease that affects aqpproximately 60,000 people worldwide, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein involved in ion and water transport across the cell surface. As such, CF is characterized by impaired chloride secretion, causing the accumulation of viscous mucus that may cause multiple organ dysfunctions, including recurrent lung infection. The most common mutation in CFTR, known as deltaF508, is caused by a single amino acid deletion and results in a misfolded version of CFTR that is retained within the cell and quickly degrades rather than being trafficked to the cell membrane where it would function as a chloride channel. In 2005, Dr. Lukacs and his lab suggested that the deltaF508 mutation effect is not restricted to the domain (the nucleotide binding domain 1, or NBD1, one of five building blocks of CFTR) where the deltaF508 is located. Specifically, his team found that the mutation destabilizes the NBD1 as well as the NBD2 architecture, suggesting that domain-domain interaction plays a critical role in both normal and pathological CFTR folding. Building on his team's previous work and using computer-generated models of CFTR, Dr. Lukacs and his team set out to determine whether it was possible to correct both NBD1 stability and the domain-domain interaction defect.