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Archive - 2012

March 25th

National Lab Licenses Powerful Microbial Detection Techology to MOgene

On March 22, 2012, Lawrence Livermore National Laboratory (LLNL) announced that it has licensed its microbial detection array technology to a St. Louis, Missouri-based company, MOgene LC, a supplier of DNA microarrays and instruments. Known formally as the Lawrence Livermore Microbial Detection Array (LLMDA), the technology could enable food safety professionals, law enforcement, medical professionals, and others to detect within 24 hours any virus or bacteria that has been sequenced and included among the array's probes. Developed between October 2007 and February 2008, the LLMDA detects viruses and bacteria with the use of 388,000 probes that fit in a checkerboard pattern in the middle of a one-inch wide, three-inch long glass slide. The current operational version of the LLMDA contains probes that can detect more than 2,200 viruses and more than 900 bacteria. The LLMDA provides researchers with the capability of detecting pathogens over the entire range of known viruses and bacteria. Current multiplex polymerase chain reaction (PCR) techniques can at most offer detection from among 50 organisms in one test. The Livermore team plans to update probes on the array with new sequences of bacteria, viruses, and other microorganisms from GenBank and other public databases about once per year, in addition to using sequences obtained from collaborators for their probes. LLNL's current collaborators include the University of California, San Francisco; the Blood Systems Research Institute; the University of Texas Medical Branch (Galveston); the Statens Serum Institut of Copenhagen, Denmark; the University of California, Davis; Imigene; the U.S. Food & Drug Administration; the Centers for Disease Control and Prevention; the Naval Medical Research Center; and the Marine Mammal Center of Sausalito, California.

Scientists ID Novel Pathway for T-Cell Activation in Leprosy

UCLA researchers and colleagues have pinpointed a new mechanism that potently activates T-cells, the group of white blood cells that plays a major role in fighting infections. In work published March 25, 2012 online in Nature Medicine, the team specifically studied how dendritic cells, immune cells located at the site of infection, become more specialized to fight the leprosy pathogen known as Mycobacterium leprae. Dendritic cells, like scouts in the field of a military operation, deliver key information about an invading pathogen that helps activate the T-cells in launching a more effective attack. It was previously known that dendritic cells were important for a strong immune response and the number of such cells at an infection site positively correlated with a robust reaction. However, until now it was poorly understood how dendritic cells become more specialized to address specific types of infections. The researchers found that a protein called NOD2 triggers a cell-signaling molecule called interleukin-32 that induces general immune cells called monocytes to become specialized information-carrying dendritic cells. "This is the first time that this potent infection-fighting pathway with dendritic cells has been identified, and demonstrated to be important in fighting human disease," said the study's first author Dr. Mirjam Schenk, postdoctoral scholar, division of dermatology, David Geffen School of Medicine at UCLA. In conducting the study, scientists used monocytes taken from the blood of healthy donors and leprosy patients and incubated the cells with the pathogen M. leprae or specific parts of the mycobacteria, known to trigger NOD2 and TLR2, both associated with immune system activation.

March 20th

VSV Viruses Kill Pancreatic Tumors in Preclinical Model

An intra-tumor injection of a virus prevented further growth of some pancreatic tumors and eradicated others in mouse models of pancreatic ductal adenocarcinoma. However, some tumors continued growing despite this treatment, proving resistant to the viruses. The research is published in the March 2012 Journal of Virology. About 95 percent of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAs). PDA is considered to be one of the most lethal malignancies, resulting in a five-year survival rate of only 8-20 percent. In this study, the researchers, led by Dr. Valery Z. Grdzelishvili of the University of North Carolina, Charlotte, tested several species of virus against pancreatic tumors, most notably vesicular stomatitis virus (VSV), a type of virus that is commonly used in the laboratory. Previous studies had demonstrated that some other viruses, including adenoviruses, herpesviruses, and reoviruses, could be used to kill pancreatic cancer cells in some animal models of pancreatic cancer. VSV has several qualities which make it attractive as a potential oncolytic (cancer killing) agent. First, unlike some other viruses (including adenoviruses), VSV replication does not require the cancer cell to express a specific receptor in order to infect that cell, and therefore it can infect most any cancer cell. Second, replication occurs in the cytoplasm of host cells, which means that there is no risk that it will cause healthy host cells to become cancerous, says Dr. Grdzelishvili. Third, this virus's genome is easily manipulated, which would make it fairly practical to adjust levels of foreign gene expression to enhance the virus's specificity for particular cancers, and its ability to kill them. Fourth, unlike with some other viruses, humans have no preexisting immunity to VSV.

March 19th

Genetic Variation in Human Gut Viruses Could Be Raw Material of Inner Evolution

A growing body of evidence underscores the importance of human gut bacteria in modulating human health, metabolism, and disease. Yet bacteria are only part of the story. Viruses that infect those bacteria also shape who we are. Frederic D. Bushman, Ph.D., professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, led a study published March 6, 2012 in the PNAS that sequenced the DNA of viruses -- the virome -- present in the gut of healthy people. Nearly 48 billion bases of DNA, the genetic building blocks, were collected in the stools of 12 individuals. The researchers then assembled the blocks like puzzle pieces to recreate whole virus genomes. Hundreds to thousands of likely distinct viruses were assembled per individual, of which all but one type were bacteriophages — viruses that infect bacteria -- which the team expected. The other was a human pathogen, a human papillomavirus found in a single individual. Bacteriophages are responsible for the toxic effects of many bacteria, but their role in the human microbiome has only recently started to be studied. To assess variability in the viral populations among the 12 individuals studied, Dr. Bushman's team, led by graduate student Samuel Minot, looked for stretches of bases that varied the most. Their survey identified 51 hypervariable regions among the 12 people studied, which, to the team's surprise, were associated with reverse transcriptase genes. Reverse transcriptase enzymes, more commonly associated with replication of retroviruses such as HIV, copy RNA into DNA. Of the 51 regions, 29 bore sequence and structural similarity to one well-studied reverse transcriptase, a hypervariable region in the Bordetella bacteriophage BPP-1. Bordetella is the microbe that causes kennel cough in dogs.

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.