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Archive - Mar 2010

Date

March 30th

Underexpressed Protein May Play Role in Down Syndrome

Contrary to conventional wisdom that the symptoms of Down syndrome are likely caused by an overabundance of certain proteins due to the additional copy of chromosome 21, scientists at Ohio State University and collaborators have found evidence that at least some of the symptoms may actually be associated with underexpression of a certain protein or proteins due to the presence of five microRNA genes on chromosome 21. MicroRNAs bind to messenger RNA and cause the inhibition of protein synthesis for that messenger RNA. Computer analysis revealed over 1,600 proteins that were potential targets of the five microRNAs on chromosome 21, all of which could cause problems in Down syndrome because they would be underexpressed. Based on other evidence, the researchers selected one of the protein genes (for methyl-CpG-binding protein 2, known as MeCP2) for further study. Among the reasons for selecting this gene was that it is known to be mutated in Rett syndrome, an inherited cognitive disorder. The researchers used just two of the five microRNAs on chromosome 21 for the experiments in this study, miR-155 and miR-802, to match the only microRNAs available in the genetically engineered mouse model of Down syndrome. First, the researchers made copies of the relevant microRNAs. In human brain cell lines, they manipulated levels of those two molecules to show the inverse relationship with MeCP2. If the microRNAs were overexpressed, the level of the MeCP2 protein went down. When the microRNAs were underexpressed, the protein levels went up.

March 28th

Paired Drug Combination Kills Precancerous Colon Polyps

A two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer, according to a team of scientists at The University of Texas M.D. Anderson Cancer Center and INCELL Corporation. The drug regimen, tested so far in mouse models and on human colon cancer tissue in the laboratory, appears to address a problem with chemopreventive drugs--they must be taken continuously long term to be effective, exposing patients to possible side effects, said senior author Dr. Xiangwei Wu, associate professor in M.D. Anderson's Department of Head and Neck Surgery. "This combination can be given short term and periodically to provide a long-term effect, which would be a new approach to chemoprevention," Dr. Wu said. The team found that a combination of Vitamin A acetate (RAc) and TRAIL, (tumor necrosis factor-related apoptosis-inducing ligand), kills precancerous polyps and inhibits tumor growth in mice that have deficiencies in a tumor-suppressor gene. That gene, adenomatous polyposis coli (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all human colon cancers, Dr. Wu said. Early experiments with APC-deficient mice showed that the two drugs combined or separately did not harm normal colon epithelial cells. Separately, they showed no effect on premalignant polyps. RAc and TRAIL together killed premalignant polyps, causing programmed cell death known as apoptosis. RAc, researchers found, sensitizes polyp cells to TRAIL. The scientists painstakingly tracked the molecular cascade caused by APC deficiencies, and found that insufficient APC sensitizes cells to TRAIL and RAc by suppressing a protein that blocks TRAIL. Before human clinical trials can be considered, Dr.

Protein Addition Helps Normalize Blood Glucose in Mouse Study of Type 2 Diabetes

When levels of free protein p85 were increased in the livers of severely obese, diabetic mice, researchers at Children’s Hospital Boston-Harvard Medical School and the University of Tokyo saw improved glucose tolerance and reduced blood glucose levels. The effect lies in the influence of p85 on the transcription factor XBP-1 (X-box binding protein 1), the scientists said. Under the influence of p85, XBP-1 normally moves to the nucleus and turns on genes for numerous chaperone proteins, which reduce stress on the endoplasmic reticulum (ER) by aiding and stabilizing the folding of proteins that are produced there and then dispatched to do their jobs in the cell. In previous work, the authors had shown that the brain, liver, and fat cells of obese mice have increased stress in the ER. In the presence of obesity, the ER is overwhelmed and its operations break down. This so-called "ER stress" activates a cascade of events that suppress the body's response to insulin, and is a key link between obesity and type 2 diabetes. Until now, however, researchers haven't known precisely why obesity causes ER stress to develop. Senior author Dr. Umut Ozcan and colleagues have now shown that XBP-1 is unable to function properly in obese mice. Instead of traveling to the cell nucleus and turning on chaperone genes, XBP-1 becomes stranded. Probing further, the researchers found the reason: XBP-1 fails to interact with p85, which is part of an important protein (phosphotidyl inositol 3 kinase or PI3K) that mediates insulin's effect of lowering blood glucose levels. Dr. Ozcan's group identified a new complex of p85 proteins in the cell, and showed that normally, when stimulated by insulin, p85 breaks off and binds to XBP-1, helping it get to the nucleus.

March 23rd

Amphibious Caterpillars Discovered in Hawaii

Scientists at the University of Hawaii have discovered the first-ever species of insect that are able to survive an entire life stage spent both above and below the water’s surface. In mountain streams across the islands of Hawaii, the researchers observed the larvae (caterpillars) of the moth genus Hyposmocoma feeding and breathing both underwater and away from streams on dry rocks. The scientists said that the caterpillars can breathe and feed indefinitely and equally well both above and below the water’s surface, and can mature either submerged or completely dry. The amphibious caterpillars possess no gills or plastron, common structures for underwater respiration in other insects. When submerged, the caterpillars likely rely on the direct diffusion of oxygen through the hydrophilic skin along their abdomens, the researchers said. Perhaps as a result of their need for direct diffusion, the caterpillars occur only in fast-flowing, well-oxygenated streams, the authors wrote, and quickly die in stagnant water. Genetic analysis of DNA from 89 species of Hyposmocoma indicated that the amphibious lifestyle is an example of parallel evolution; the analysis showed evidence of at least three independent invasions of the water by strictly terrestrial clades (evolutionary groups including a single ancestor and all its descendants), beginning more than six million years ago, before the current “high islands” existed (note: high islands are of volcanic origin and are distinguished from “low islands,” which are formed by sedimentation or uplifting of coral reefs). The authors noted that why and how Hyposmocoma, an overwhelmingly terrestrial group, repeatedly evolved unprecedented aquatic species is unclear, although there are many other evolutionary anomalies across the Hawaiian archipelago.

March 22nd

Nanotech Research May Ultimately Lead to Retinal Implants

Researchers at Tel Aviv University are making progress in work to merge retinal nerve cells with electrodes in the hope of someday being able to create retinal implants for people. But that goal is quite a ways off, said research leader Dr. Yael Hanein. Until then, her team’s current invention might be used by drug developers investigating new compounds or formulations to treat delicate nerve tissues in the brain. "We're working to interface man-made technology with neurons” Dr. Hanein said. "It can be helpful in in vitro and in in vivo applications, and provides an understanding of how neurons work so we can build better devices and drugs," she said. Her group has developed a spaghetti-like mass of nano-sized (one-millionth of a millimeter) carbon tubes, and using an electric current has managed to coax living neurons from the brains of rats to grow on this man-made structure (see image, courtesy of Tel Aviv University). The growth of living cells on the nano substrate is a very complicated process, Dr. Hanein said, but the cells adhere well to the structure, fusing with the synthetic electrical and physical interface. Using the new technology developed in Dr. Hanein's laboratory, graduate student Mark Shein has been observing how neurons communicate and work together. "We are attempting to answer very basic questions in science," Dr. Hanein explained. "Neurons migrate and assemble themselves, and using approaches we've developed, we are now able to 'listen' to the way the neurons fire and communicate with one another using electrical impulses. Listening to neurons 'talking' allows us to answer the most basic questions of how groups of nerves work together. If we can investigate functional neuronal networks in the lab, we can study what can't be seen or heard in the complete brain, where there are too many signals in one place."

Blocking miRNA Might Aid Healing of Chronic Wounds

New results indicate that targeting a specific microRNA (miR-210) with a drug that could be used topically on the skin might offer new strategies for treating chronic wounds, which are sometimes fatal and cost the U.S. health-care system an estimated $25 billion annually. Ohio State University researchers have discovered, in a new animal study, that the presence of miR-210 in wounds with limited blood flow lowers the production of a protein (E2F3) that is needed to encourage skin cells to grow and close over the wound. In a parallel experiment using human skin cells, the researchers silenced the miR-210 with an experimental drug and saw E2F3 protein levels rise. The skin cells multiplied as a result. The research involved wounds that are ischemic, that is, they heal very slowly or are in danger of never healing because they lack blood flow and oxygen at the wound site. These types of wounds affect approximately 6.5 million patients each year, and are common complications of diabetes, high blood pressure, obesity, and other conditions characterized by poor vascular health. "When blood supply is inadequate, many things are deficient at the wound site, including oxygen. That leads to a condition called hypoxia," said Dr. Chandan Sen, senior author of the study. "We have shown that hypoxia induces miR-210, which actually blocks the ability of the cells to proliferate, a step necessary for the wound-closure process.” This research was published online on March 22, 2010 in PNAS. [Press release] [PNAS abstract]

March 21st

Scientists Identify Gene for Lung Cancer in Never-Smokers

Variations in a gene called GPC5 have been identified which might contribute to a significantly higher risk of developing lung cancer in people who have never smoked. The findings, from genome-wide association studies to outline the genetic changes involved in lung cancer in never smokers, suggest that GPC5 might be a new target for investigation and drug development, and could be used to identify high-risk individuals. Lung cancer in people who have never smoked (defined as those who have smoked fewer than 100 cigarettes in their lifetimes) is an increasing public-health problem, responsible for 25 percent of all lung cancer cases worldwide. Despite attempts to identify the specific genetic mechanisms responsible, the causes of lung cancer in never-smokers have remained poorly understood. Recent studies have identified several candidate genes that have a moderate effect on the risk of lung cancer, but no study has identified the genetic basis of lung cancer in never smokers. "This is the first gene that has been found that is specifically associated with lung cancer in people who have never smoked," said the study's senior author, Mayo Clinic genetic epidemiologist Dr. Ping Yang. "What's more, our findings suggest GPC5 may be a critical gene in lung cancer development and genetic variations of this gene may significantly contribute to increased risk of lung cancer," she said. "This is very exciting. Findings from this study concern pure lung cancer that is not caused by smoking, and it gives us some wonderful new avenues to explore. Our suspicion all along is that this is a distinct disease, and that is why we undertook this study," Dr. Yang said.

New Ways to Kill Tuberculos Organism Discovered

Two novel ways to kill the bacterium (Mycobacterium tuberculosis) that causes tuberculoisis (TB) have been discovered by researchers at the Albert Einstein College of Medicine, together with collaborators. TB still kills an estimated 2 million people each year and the scientists believe that their findings could lead to a potent TB therapy and would also prevent resistant TB strains from developing. "This approach is totally different from the way any other anti-TB drug works," said Dr. William R. Jacobs, Jr., the study's senior author and professor of microbiology & immunology and of genetics at Einstein. "In the past few years, extremely drug-resistant strains of TB have arisen that can't be eliminated by any drugs, so new strategies for attacking TB are urgently needed." In searching for a new Achilles' heel for M. tuberculosis, Dr. Jacobs and colleagues focused on an enzyme called GlgE. Previous research had suggested that GlgE might be essential for the growth of TB bacteria. GlgE would also be an excellent drug target because there are no enzymes similar to it in humans or in the bacteria of the human gut. The GlgE research revealed a previously unknown enzymatic pathway by which TB bacteria convert the sugar trehalose (consisting of two glucose molecules) into longer sugar molecules known as alpha glucans, building blocks that are essential for maintaining bacterial structure and for making new microbes through cell division. GlgE was the third of four enzymes involved in this pathway leading to alpha glucans molecules. Sure enough, when the researchers inhibited GlgE, the bacteria underwent "suicidal self-poisoning"--a sugar called maltose 1-phosphate accumulated to toxic levels that damaged bacterial DNA, causing the death of TB bacteria grown in Petri dishes as well as in infected mice.

Nanoparticles Deliver Effective siRNAs to Tumor Cells

A California Institute of Technology (Caltech)-led team of researchers and clinicians has published the first proof that a targeted nanoparticle—used as an experimental therapeutic and injected directly into a patient's bloodstream—can traffic into tumors, deliver double-stranded small interfering RNAs (siRNAs), and turn off an important cancer gene using a mechanism known as RNA interference (RNAi). Moreover, the team provided the first demonstration that this new type of therapy, infused into the bloodstream, can make its way to human tumors in a dose-dependent fashion—i.e., a higher number of nanoparticles sent into the body leads to a higher number of nanoparticles in the tumor cells. These results demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients, and open the door for future "game-changing" therapeutics that attack cancer and other diseases at the genetic level, said lead author Dr. Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech. The scientific results are from an ongoing phase 1 clinical trial of these nanoparticles (image, Caltech/Derek Bartlett) that began treating patients in May 2008. Phase 1 trials are, by definition, safety trials; the idea is to see if and at what level the drug or other therapy turns harmful or toxic. These trials can also provide an in-human scientific proof of concept—which is exactly what is being reported in the current article. The current results were published online on March 21, 2010 in Nature. [Press release] [Nature abstract]

Study of Rare Genetic Disorder Suggests Role for Fibrillin-1 in Scleroderma

By studying the genetics of an autosomal dominant disorder called “stiff skin syndrome,” a rare congenital form of scleroderma, researchers at the Johns Hopkins University School of Medicine and collaborating institutions have learned more about the much more common acquired form of scleroderma, also called systemic sclerosis. Systemic sclerosis affects approximately one in 5,000 people and leads to hardening of the skin, as well as to other debilitating and often life-threatening problems. “[Acquired] scleroderma is a common and often devastating condition, yet its cause remains mysterious. My greatest hope is that this work will facilitate the development of new and better treatments,” said senior author Dr. Harry C Dietz, the Victor A. McKusick Professor of Genetics and Director of the Johns Hopkins William S. Smilow Center for Marfan Syndrome Research. Acquired scleroderma generally affects previously healthy young adults, causing scarring of skin and internal organs that can lead to heart and lung failure. “Most often individuals with [acquired] scleroderma do not have other affected family members, precluding use of genetic techniques to map the underlying genes. Instead, we turned to a rare but inherited form of isolated skin fibrosis called “stiff skin syndrome,” hoping to gain a foothold regarding cellular mechanisms that might prove relevant to both conditions,” said Dr. Dietz. A number of clues led Dr. Dietz and his team to strongly suspect a role for the connective tissue protein fibrillin-1 in these skin conditions. First, excess collagen is a hallmark feature of both stiff skin syndrome and acquired scleroderma.