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Archive - May 2013

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May 5th

BAF Protein Complex May Play Role in Preventing Many Forms of Cancer

Researchers at the Stanford University School of Medicine have identified a group of proteins that are mutated in about one-fifth of all human cancers. This finding suggests that the proteins, which are members of a protein complex that affects how DNA is packaged in cells, normally work to suppress the development of tumors in many types of tissues. The broad reach of the effect of mutations in the complex, called BAF, rivals that of another well-known tumor suppressor called p53. It also furthers a growing notion that these so-called chromatin-regulatory complexes may function as much more than mere cellular housekeepers. "Although we knew that this complex was likely to play a role in preventing cancer, we didn't realize how extensive it would be," said postdoctoral scholar Cigall Kadoch, Ph.D. "It's often been thought that these complexes play supportive, maintenance-like roles in the cell. But this is really changing now." Dr. Kadoch shares lead authorship of the study with postdoctoral scholar Diana Hargreaves, Ph.D. Gerald Crabtree, M.D., professor of developmental biology and of pathology, is the senior author of the study, which was published online on May 5, 2013 in Nature Genetics. Chromatin-regulatory complexes work to keep DNA tightly condensed, while also granting temporary access to certain portions for replication or to allow the expression of genes necessary for the growth or function of the cell. Members of Dr. Crabtree's laboratory have been interested in BAF complexes and their function for many years. Recently, they reported in the journal Nature that switching subunits within these complexes can convert human fibroblasts to neurons, which points to their instructive role in development and, possibly, cancer.

Why Dense Breasts Predispose to Metastasis in Breast Cancer

Researchers at Washington University School of Medicine in St. Louis have discovered why breast cancer patients with dense breasts are more likely than others to develop aggressive tumors that spread. The finding opens the door to drug treatments that may prevent metastasis. It has long been known that women with denser breasts are at higher risk for breast cancer. This greater density is caused by an excess of a structural protein called collagen. "We have shown how increased collagen in the breasts could increase the chances of breast tumors spreading and becoming more invasive," says Gregory D. Longmore, M.D., professor of medicine. "It doesn't explain why women with dense breasts get cancer in the first place. But once they do, the pathway that we describe is relevant in causing their cancers to be more aggressive and more likely to spread." The results were published online on May 5, 2013 in Nature Cell Biology. Working in mouse models of breast cancer and with breast tumor samples from patients, Dr. Longmore and his colleagues showed that a protein that sits on the surface of tumor cells, called DDR2, binds to collagen and activates a multi-step pathway that encourages tumor cells to spread. "We had no idea DDR2 would do this," says Dr. Longmore, also professor of cell biology and physiology. "The functions of DDR2 are not well understood, and it has not been implicated in cancer -- and certainly not in breast cancer -- until now.” At the opposite end of the chain of events initiated by DDR2 is a protein called SNAIL1, which has long been associated with breast cancer metastasis. Dr. Longmore and his colleagues found that DDR2 is one factor helping to maintain high levels of SNAIL1 inside a tumor cell's nucleus, a necessary state for a tumor cell to spread.

Epileptic Seizures Halted in Mouse Model

University of California San Francisco (UCSF) cell therapy raises hope for severe human forms of epilepsy. UCSF scientists controlled seizures in epileptic mice with a one-time transplantation of medial ganglionic eminence (MGE) cells, which inhibit signaling in overactive nerve circuits, into the hippocampus, a brain region associated with seizures, as well as with learning and memory. Other researchers had previously used different cell types in rodent cell transplantation experiments and failed to stop seizures. Cell therapy has become an active focus of epilepsy research, in part because current medications, even when effective, only control symptoms and not underlying causes of the disease, according to Scott C. Baraban, Ph.D., who holds the William K. Bowes Jr. Endowed Chair in Neuroscience Research at UCSF and led the new study. In many types of epilepsy, he said, current drugs have no therapeutic value at all. "Our results are an encouraging step toward using inhibitory neurons for cell transplantation in adults with severe forms of epilepsy," Dr. Baraban said. "This procedure offers the possibility of controlling seizures and rescuing cognitive deficits in these patients." The findings, which are the first ever to report stopping seizures in mouse models of adult human epilepsy, were published online on May 5, 2013 in Nature Neuroscience. During epileptic seizures, extreme muscle contractions and, often, a loss of consciousness can cause seizure sufferers to lose control, fall, and sometimes be seriously injured. The unseen malfunction behind these effects is the abnormal firing of many excitatory nerve cells in the brain at the same time.

May 4th

New Marker Identified for Sleep Loss

For years, Paul Shaw, Ph .D., a researcher at Washington University School of Medicine in St. Louis, has used what he learns in fruit flies to look for markers of sleep loss in humans. Dr. Shaw reverses the process in a new paper, taking what he finds in humans back to the flies and gaining new insight into humans as a result: identification of a human gene that is more active after sleep deprivation. “I’m calling the approach cross-translational research,” says Dr. Shaw, associate professor of neurobiology. “Normally we go from model to human, but there’s no reason why we can’t take our studies from human to model and back again.” Dr. Shaw and his colleagues plan to use the information they are gaining to create a panel of tests for sleep loss. The tests may one day help assess a person’s risk of falling asleep at the wheel of a car or in other dangerous contexts. PLOS ONE published the results online on April 24, 2013. Scientists have known for years that sleep disorders and disruption raise blood serum levels of interleukin 6, an inflammatory immune compound. Dr. Shaw showed that this change is also detectable in saliva samples from sleep-deprived rats and humans. Based on this link, Shaw tested the activity of other immune proteins in humans to see if any changed after sleep loss. The scientists took saliva samples from research participants after they had a normal night’s sleep and after they stayed awake for 30 hours. They found two immune genes whose activity levels rose during sleep deprivation. “Normally we would do additional human experiments to verify these links,” Dr. Shaw says.

May 3rd

New Mechanism Discovered in Meiosis

A research group headed by molecular biologist Dr. Andrea Pichler from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany, has made an important discovery in meiosis research. Dr. Pichler and her group have identified a new mechanism that plays an important role in meiosis. The work was reported online on May 2, 2013 in Molecular Cell. Meiosis, also called reductional division, is a key process in sexual reproduction. It shuffles parental genetic material and thus guarantees genetic variety. In order to control various biological processes, cells are able to selectively alter properties of their proteins, such as their lifespan, activity level, binding partners, or localization of the proteins. This is accomplished, for example, by attaching one or more small ubiquitin-like modifier (SUMO) proteins. This takes place in three sequential enzyme-dependent steps. Scientists have assumed that the enzyme for step 2 was solely an intermediate. As the scientists in Freiburg have now discovered, the step-2 enzyme is itself modified by the SUMO protein and thereby alters how it functions. The surprising effect: the conventional activity of the enzyme is switched off by this change and instead, a new function is gained. It works together with the activated, unaltered enzyme in the formation of SUMO chains. If this effect is blocked, there are serious consequences: the protein structure (synaptonemal complex) that forms between the homologous chromosomes can no longer be established. A tiny amount – less than one percent – of the SUMO-modified step-2 enzyme is sufficient to form a normal protein structure. Researcher Dr. Helene Klug from Dr.

New Middle-Aged Mouse Model Suggests How Type 2 Diabetes Develops

Researchers at Lund University in Sweden have developed a new mouse model that answers the question of what actually happens in the body when type 2 diabetes develops and how the body responds to drug treatment. Long-term studies of the middle-aged mouse model will be better than previous studies at confirming how drugs for type 2 diabetes function in humans. The work was published online in May 2013 in Diabetologia. "The animal models for type 2 diabetes studies that have previously existed have not been optimal because they use young mice. Our idea was to create a model that resembles the situation in the development of type 2 diabetes in humans. We generally get the disease in middle age when we start to put on weight and live a more sedentary, and more stressful, life. Our new middle-aged mouse model has enabled us to study long-term physiological effects of the development and treatment of type 2 diabetes in a completely new way", said Dr. Bilal Omar, one of the researchers behind the study. What the Lund researchers have done is to feed normal mice fatty food over a long period from the age of eight months, i.e. middle age, until the end of their natural lives at the age of two years. The mice become overweight, and develop high blood sugar levels and reduced insulin release, as expected before the onset of type 2 diabetes. "Throughout the period we were able to study the process that leads to the development of type 2 diabetes with a lifestyle like that of people predisposed to the condition," said Dr. Omar. In the study, the researchers could confirm that fatty foods lead to inflammation in the islets of Langerhans in the pancreas, which produce insulin. Researchers have seen inflammation in the islets in people with type 2 diabetes, but in Dr.

Injectable Nano-Network May Control Blood Sugar in Diabetics for Days at a Time

In a promising development for diabetes treatment, researchers have developed a network of nanoscale particles (see image) that can be injected into the body and release insulin when blood sugar levels rise, maintaining normal blood sugar levels for more than a week in animal-based laboratory tests. The work was done by researchers at North Carolina State University, the University of North Carolina at Chapel Hill, the Massachusetts Institute of Technology, and Children’s Hospital Boston. “We’ve created a ‘smart’ system that is injected into the body and responds to changes in blood sugar by releasing insulin, effectively controlling blood sugar levels,” says Dr. Zhen Gu, lead author of a paper describing the work and an assistant professor in the joint biomedical engineering program at NC State and UNC Chapel Hill. “We’ve tested the technology in mice, and one injection was able to maintain blood sugar levels in the normal range for up to 10 days.” When a patient has type 1 diabetes, his or her body does not produce sufficient insulin, a hormone that transports glucose – or blood sugar – from the bloodstream into the body’s cells. This can cause a host of adverse health effects. Currently, diabetes patients must take frequent blood samples to monitor their blood sugar levels and inject insulin as needed to ensure their blood sugar levels are in the “normal” range. However, these injections can be painful, and it can be difficult to determine the accurate dose level of insulin. Administering too much or too little insulin poses its own health risks. The new, injectable nano-network is composed of a mixture containing nanoparticles with a solid core of insulin, modified dextran, and glucose oxidase enzymes.

Gray Hair and Vitiligo Apparently Reversed by Same New Compound

Hair dye manufacturers are on notice: the cure for gray hair is coming. That's right, the need to cover up one of the classic signs of aging with chemical pigments will likely be a thing of the past thanks to a team of European researchers. According to a new research report published online on April 29, 2013 in The FASEB Journal, people who are going gray develop massive oxidative stress via accumulation of hydrogen peroxide in the hair follicle, which causes their hair to bleach itself from the inside out, and most importantly, the report shows that this massive accumulation of hydrogen peroxide can be remedied with a proprietary treatment developed by the researchers and described as a topical, UVB-activated compound called PC-KUS (a modified pseudocatalase). What's more, the study also shows that the same treatment works for the skin condition, vitiligo. "To date, it is beyond any doubt that the sudden loss of the inherited skin and localized hair color can affect those individuals in many fundamental ways," said Karin U. Schallreuter, M.D., study author from the Institute for Pigmentary Disorders in association with E.M. Arndt University of Greifswald, Germany and the Centre for Skin Sciences, School of Life Sciences at the University of Bradford, United Kingdom. "The improvement of quality of life after total and even partial successful repigmentation has been documented." To achieve this breakthrough, Dr. Schallreuter and colleagues analyzed an international group of 2,411 patients with vitiligo. Of that group, 57 or 2.4 percent were diagnosed with strictly segmental vitiligo (SSV), and 76 or 3.2 percent were diagnosed with mixed vitiligo, which is SSV plus non-segmental vitiligo (NSV).

Personalized Medicine Conference Will Focus on Next-Gen Sequencing for Targeted Therapeutics

The sixth annual Personalized Medicine Conference (6.0) organized by San Francisco State University will focus on the amazing technological challenges and advances of “next-generation sequencing,” examining the very latest approaches and how they are leading to profound changes in our understanding of basic biological questions and to more efficacious and cost-effective therapies. The conference is entitled, “Next-Generation Sequencing for Targeted Therapeutics.” Featured speakers include Kimberly J. Popovits, Chairman of the Board, Chief Executive Officer & President of Genomic Health; Dr. Mark Sliwkowski, Distinguished Staff Scientist at Genentech; Professor Atul Butte of Stanford University; and Dr. Carl Borrebaeck, Professor & Chair of Immunotechnology and Director of CREATE Health at Lund University in Sweden. The conference will take place at the South San Francisco Conference Center (http://www.ssfconf.com/directions-top) from 8:00 am to 5:30 pm on Thursday, May 30, 2013, with a reception to follow. Those wishing to attend are urged to register as soon as possible (http://personalizedmedicine.sfsu.edu/register.html). For additional information, to help sponsor the event, or to inquire about special academic rates, contact dnamed@sfsu.edu. The conference organizers, including Michael Goldman, Ph.D., Professor and Chair of San Francisco State’s Department of Biology, noted that with the price of sequencing a complete human genome falling into the $1,000 range, stunning advances are sure to come over the next few years. It is likely that a detailed genome sequence will soon be part of a routine medical history, allowing unprecedented precision in diagnosis and treatment. The DNA and RNA signatures of both complex, common diseases and rare, elusive conditions will yield their secrets.

May 1st

Traditional Dispensing Processes Are Important Source of Error in High-Throughput Screening; Acoustic Approach More Predictive of Biological Activity

In experiments involving the generation of computational pharmacophores based on data derived either by acoustic transfer using direct dilution or by traditional tip-based transfer using serial dilutions, scientists have shown that the acoustic approach generates a pharmacophore that is predictive for biological activity in new compounds. It is also consistent with pharmacophores generated from X-ray crystallographic data. The tip-based approach, on the other hand, generates a pharmacophore that is both non-predictive of biological activity and inconsistent with the X-ray crystallographic data. The authors conclude that traditional tip-based dispensing processes are an important source of error in high-throughput screening that can impact computational and statistical analyses. They suggest that these findings have far-reaching applications in biological research. This study was published online in an open-access article in PLOS ONE on May 1, 2013. The authors were Sean Elkins Ph.D., VP of Science at Collaborative Drug Discovery, Inc., and Adjunct Professor in the Division of Chemical Biology and Medicinal Chemistry at the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill; Joe Olechno, Ph.D., Senior Research Fellow, Labcyte Inc.; and Antony Williams, Ph.D., VP of Strategic Development at the Royal Society of Chemistry. The image is courtesy of Labcyte Inc. [PLOS ONE article]