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Archive - Apr 2013


April 7th

Seven New Loci Associated with Age-Related Macular Degeneration

Genetic variants associated with age-related macular degeneration (AMD) are reported in a study published online on March 3, 2013 in Nature Genetics. AMD is a common cause of blindness and visual impairment in older adults. Dr. Gonçalo Abecasis and colleagues report a meta-analysis of genome-wide association studies for AMD, including over 17,100 individuals with advanced disease and over 60,000 healthy controls. This included 18 international studies from the AMD Gene Consortium. The researchers identified seven genomic regions newly associated with AMD risk, and 19 associated regions overall. Their analyses across studies including populations of European and Asian ancestry provide insight into differential associations across ancestry. The authors suggest that pathways in complement activity, lipid metabolism, and extracellular matrix remodeling and angiogenesis are involved in the development of AMD. [Press release] [Nature Genetics abstract]

Four Genes Newly Associated with Severe Childhood Obesity

Researchers have identified four genes newly associated with severe childhood obesity. They also found an increased burden of rare structural variations in severely obese children. The new work was reported online on April 7, 2013 in Nature Genetics. The research team found that structural variations can delete sections of DNA that help to maintain protein receptors known to be involved in the regulation of weight. These receptors are promising targets for the development of new drugs against obesity. As one of the major health issues affecting modern societies, obesity has increasingly received public attention. Genes, behavior, and environment, all contribute to the development of obesity. Children with severe obesity are more likely to have a strong genetic contribution. This study has enhanced understanding of how both common and rare variants around specific genes and genetic regions are involved in severe childhood obesity. “We’ve known for a long time that changes to our genes can increase our risk of obesity. For example, the gene FTO has been unequivocally associated with body-mass index (BMI), obesity, and other obesity-related traits,” says Dr. Eleanor Wheeler, first author from the Wellcome Trust Sanger Institute. “In our study of severely obese children, we found that variations in or near two of the newly associated genes seem to have a comparable or greater effect on obesity than the FTO gene: PRKCH and RMST.” The team found that different genes can be involved in severe childhood obesity compared to obesity in adults. Rare genetic changes in one of the newly associated genes, LEPR, are known to cause a severe form of early-onset obesity. The team identified a more common variant in this gene, found in 6 per cent of the population, that can increase a person’s risk of obesity.

New Blood Test Provides Fuller Picture of Cancer Mutations Than Biopsies

A new blood test revealed more of the gene mutations that sustain certain digestive-tract tumors than did a DNA analysis of a traditional tumor biopsy, Dana-Farber Cancer Institute investigators reported in an April 6, 2013 press conference at the American Association for Cancer Research (AACR) annual meeting in Washington, D.C., April 6-10, 2013. The findings (Abstract LB-295) will also be released in an oral presentation on Tuesday, April 9, 3:35 – 3:50 p.m., ET, in Salon A-B, East Hall, in the Washington Convention Center. The results come from a study in which researchers used advanced amplification technology to search for abnormal DNA circulating in blood samples from patients in a clinical trial of a new therapy for gastrointestinal stromal tumor (GIST). GIST is a mutation-driven cancer of the digestive system that arises in approximately 5,000 people in the United States each year. The technique is particularly valuable, the investigators said, because it can comprehensively detect many different cancer-related mutations from multiple tumors within a single patient, whereas conventional biopsies are able to provide information only on small bits of tumors which are sampled. At a time when therapies are increasingly targeted at specific cancer-causing mutations and where resistance to such therapies is known to be caused by other mutations, it is important for doctors to know the full slate of mutations in all the cancer cells within a patient. Because different GIST cells within a single patient can have different sets of mutations, biopsies of one or two tumors often uncover only a portion of the mutational landscape.

Personalized Immunotherapy Shows Significant Promise for Ovarian Cancer

As many as three quarters of advanced ovarian cancer patients appeared to respond to a new two-step immunotherapy approach -- including one patient who achieved complete remission -- according to research from the Perelman School of Medicine at the University of Pennsylvania that was presented April 6, 2013 in a press conference at the American Academy of Cancer Research (AACR) Annual Meeting 2013 (Presentation #LB-335) in Washington, D.C. The immunotherapy has two steps – a personalized dendritic cell vaccination and adoptive T-cell therapy. The scientific team reports that in the study of 31 patients, vaccination therapy alone showed about a 61 percent clinical benefit, and the combination of both therapies showed about a 75 percent benefit. The findings offer new hope for the large number of ovarian cancer patients who relapse following treatment. The first step of the immunotherapy approach is to preserve the patient's tumor cells alive, using sterile techniques at the time of surgery so they can be used to manufacture a personalized vaccine that teaches the patient's own immune system to attack the tumor. Then, the Penn Medicine team isolates immune cells called dendritic cells from patients' blood through a process called apheresis, which is similar to the process used for blood donation. Researchers then prepare each patient's personalized vaccine by exposing her dendritic cells to the tumor tissue that was collected during surgery. Because ovarian cancer symptoms can be non-obvious and easily mistaken for other issues – constipation, weight gain, bloating, or more frequent urination – more than 60 percent of patients are diagnosed only after the disease has spread to their lymph nodes or other distant sites in the body, when treatment is much less likely to produce a cure compared to when the disease is detected early.

April 6th

Tel Aviv Scientists Present Potential Parkinson’s Treatment in Fly Model

Researchers from Tel Aviv University described experiments that could lead to a new approach for treating Parkinson's disease (PD) using a common sweetener, mannitol. This research was presented at the Genetics Society of America's 54th Annual Drosophila Research Conference in Washington, D.C., on April 6, 2013. Mannitol is a sugar alcohol familiar as a component of sugar-free gum and candies. Originally isolated from flowering ash, mannitol is believed to have been the "manna" that rained down from the heavens in biblical times. Fungi, bacteria, algae, and plants make mannitol, but the human body can't. For most commercial uses, it is extracted from seaweed although chemists can synthesize it. And it can be used as more than just a sweetener. The Food and Drug Administration approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these tiniest blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for about 30 minutes. Mannitol has another, less-explored capability: preventing a sticky protein called α-synuclein from gumming up the substantia nigra part of the brains of people with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate, and then extend, forming gummy fibrils. Certain biochemicals, called molecular chaperones, normally stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone.

Genome Sequence of Mountain Pine Beetle Could Be Potent Weapon Versus Infestations

Twenty researchers — more than half of them Simon Fraser University (SFU) graduates and/or faculty — could become eastern Canada’s knights in shining white lab coats. A paper detailing their newly created sequencing of the mountain pine beetle’s (MPB) genome will be gold in the hands of scientists trying to stem the beetle’s invasion into eastern forests. The research was published in an open-access article in Genome Biology on March 27, 2013. “We know a lot about how beetle infestations can devastate forests, just as the mountain pine beetle (MPB) has been doing to British Columbia’s lodgepole pines,” says Dr. Christopher Keeling, the paper’s lead author. The SFU graduate, now a research associate in Dr. Joerg Bohlmann’s Lab at the University of British Columbia’s Michael Smith Laboratories, says, “It’s the beetle’s genome that will help us figure out exactly how it does its damage and hopefully stop it.” The genome reveals large variations among individuals in the MPB species — about four times greater than the variation among humans. “As the beetles’ range expands and as they head into jack pine forests where the defensive compounds may be different, this variation could allow them to be more successful in new environments,” explains Dr. Keeling. Eastern Canadians are bracing for the British Columbia (B.C.) MPB’s threat to appear in Ontario, Quebec, and Maritime forests during the next two decades. The rice grain-sized insect has already wiped out an area of B.C. lodgepole pine forest five times larger than the size of Vancouver Island. It is becoming the scourge of Alberta’s forests and is headed for Saskatchewan. “The MPB genome allows us to examine the population differences for beetles at various parts of an outbreak.

April 5th

Potential Drug Therapy Found for Prion Diseases

Human diseases caused by misfolded proteins known as prions are some of the most rare yet terrifying on the planet—incurable with disturbing symptoms that include dementia, personality shifts, hallucinations, and coordination problems. The most well-known of these is Creutzfeldt-Jakob disease, which can be described as the naturally occurring human equivalent of mad cow disease. Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time identified a pair of drugs already approved for human use that show anti-prion activity and, for one of them, great promise in treating these universally fatal disorders. The study, led by TSRI Professor Corinne Lasmézas and performed in collaboration with TSRI Professor Emeritus Charles Weissmann and Director of Lead Identification Peter Hodder, was published online on April 1, 2013 in PNAS. The new study used an innovative high-throughput screening technique to uncover compounds that decrease the amount of the normal form of the prion protein (PrP, which becomes distorted by the disease) at the cell surface. The scientists found two compounds that reduced PrP on cell surfaces by approximately 70 percent in the screening and follow up tests. The two compounds are already marketed as the drugs tacrolimus and astemizole. Tacrolimus is an immune suppressant widely used in organ transplantation. Tacrolimus could prove problematic as an anti-prion drug, however, because of issues that include possible neurotoxicity. However, astemizole is an antihistamine that has potential for use as an anti-prion drug. While withdrawn voluntarily from the U.S. over-the-counter market in 1999 because of rare cardiac arrhythmias when used in high doses, it has been available in generic form in more than 30 countries and has a well-established safety profile.

Whole-Genome DNA Sequencing Explains Rise in Cystic Fibrosis Patient Infections

Researchers at Papworth Hospital, the University of Cambridge, and the Wellcome Trust Sanger Institute have discovered why a new type of dangerous bacterial infection has become more common among people with cystic fibrosis (CF) around the world. Through their ground-breaking research, the team has developed new measures to protect CF patients. People with CF are prone to serious infection in part because they have sticky mucus that can clog up their lungs. In recent years, doctors have observed a global increase in the number of infections caused by the antibiotic-resistant bacterial species Mycobacterium abscessus (M. abscessus). M. abscessus is distantly related to the bacterium that causes tuberculosis and is usually found in water and soil. Until now, experts had thought it could not be passed from person to person. "There has been worldwide concern about the rising number of M. abscessus infections in people with cystic fibrosis and anxiety that spread from person to person might be responsible," said Dr. Andres Floto, Research Director of the Cystic Fibrosis Unit at Papworth Hospital, Principal Investigator at the Cambridge Institute for Medical Research, University of Cambridge, and lead author of the research published online on March 29, 2013 in The Lancet. "Our work has allowed us to lead the world in changing hospital infection control: we used state-of-the-art DNA sequencing technology to understand how the infection is being spread, which conventional techniques would have missed. Our results will help to protect patients from this serious infection." The team used the latest methods to sequence the genomes of almost 170 isolates of M. abscessus from CF patients collected over a five-year period.

Tokyo Team Achieves Fundamental Breakthrough in Crystallography

A research team led by Professor Makoto Fujita of the University of Tokyo, Japan, and complemented by Academy Professor Kari Rissanen of the University of Jyväskylä, Finland, has made a fundamental breakthrough in single-crystal X-ray analysis, the most powerful method for molecular structure determination. The team's breakthrough was reported online in Nature on March 27, 2013. X-ray single-crystal diffraction (SCD) analysis has the intrinsic limitation that the target molecule must be obtained in the form of single crystals. Now, Professor Fujita's team, together with Academy Professor Rissanen, has established a new protocol for SCD analysis that does not require the crystallization of the target molecule. In this method, a very small crystal of a porous complex absorbs the target molecule from the solution, enabling the crystallographic analysis of the structure of the absorbed guest along with the host framework. As the SCD analysis is carried out with only one crystal, smaller than 0.1 mm x 0.1 mm x 0.1 mm in size, the required amount of the target molecule can be as low as 80 ng. Dr. Fujita's and Dr. Rissanen's work reports the structure determination of a scarce marine natural product from only 5 µg of the material. Many natural and synthetic compounds for which chemists have almost given up the hope of analyzing crystallographically can now be easily and precisely characterized by this new method. [Press release] [Nature abstract]

Light Switches Show How Inter-Neuron Communication Creates Rat’s GPS

Researchers at the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology (NTNU) have developed a range of advanced techniques that enable them to identify which neurons communicate with each other at different times in the rat brain, and in doing so, create the animal’s sense of direction. Their findings have been published in the 5 April 2013 edition of Science magazine. There are cells in your brain that recognize very specific places, and have that and nothing else as their job. These cells, called “place” cells, are found in an area behind your temple called the hippocampus. While these cells must be sent information from nearby cells to do their job, so far no one has been able to determine exactly what kind of cells work with “place” cells to craft the code they create for each location. Neurons come in many different types with specialized functions. Some respond to edges and borders, others to specific locations, others act like a compass and react to which way you turn your head. “A rat's brain is the size of a grape. Inside there are about fifty million neurons that are connected together at a staggering 450 billion places,” explains Professor Edvard Moser, director of the Kavli Institute. “Inside this grape-sized brain are areas on each side that are smaller than a grape seed, where we know that memory and the sense of location reside. This is also where we find the neurons that respond to specific places, the ‘place’ cells. But from which cells do these place cells get information?” The problem is, of course, that researchers cannot simply cut open the rat brain to see which cells have had contact.