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Archive - Sep 2014

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September 4th

Existing Drug (Ouabain) Possibly Effective Against Ebola Virus

Researchers from the University of Liverpool, in collaboration with Public Health England, have investigated new ways to identify drugs that could be used to treat Ebola virus infection. The scientists looked at what proteins inside a cell are critical for the functions of Ebola virus and are hijacked by the virus to help with infection. One of the proteins they have targeted is known as VP24. This protein disrupts signaling in infected human cells and disrupts the body’s immune system and the fight against the virus. Once the team identified these cellular proteins they were able to find out whether any drugs were already in existence that could block the function of the particular protein. One such drug identified was ouabain, which can be used in the treatment of heart disease. Administering this drug reduced Ebola virus replication in treated cells. The study was led by Professor Julian Hiscox from the University’s Institute of Infection and Global Health and Professor Roger Hewson at Public Health England (PHE). Disrupting cellular proteins important for viruses also has the potential to tackle the problem of resistance to medication. Professor Hiscox said: “This study shows how existing therapeutics can be identified and potentially repurposed for anti-viral therapy. The technique of using existing and tested drugs for a different purpose can save considerable time and ultimately, lives.” Disrupting cellular proteins important for viruses also has the potential to tackle the problem of resistance to medication. Because the cellular proteins are effectively evolutionarily static, the virus won’t be able to adapt to defeat it – as is increasingly the case with treatment by anti-virals used against viral proteins such as is seen with influenza virus and HIV infection. The study, which also involved Dr.

BitSeq Method Yields Most Accurate Measures of Gene Expression

RNA-sequencing allows measuring the gene expression of humans or other organisms. The method has recently become very popular in bioscience and medical research, and it is being adopted to clinical applications. Compared to previous methods, RNA-sequencing enables the study of alternative gene isoforms or transcripts, which are formed, for example, through the process of alternative splicing. The analysis of the large amount of data produced by RNA-sequencing requires many advanced computational methods. Analysis of transcript level data is especially demanding and the differences between alternative methods can be large. In the recent assessment (“A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium,” published online in Nature Biotechnology on August 24, 2014), the BitSeq method developed by the University of Helsinki and the University of Manchester researchers produced clearly the most reliable results in this task. In one subtask, BitSeq could produce equally accurate results using only half the data needed by a very popular alternative method. The BitSeq method (http://bioinformatics.oxfordjournals.org/content/28/13/1721) is based on probabilistic modelling that allows comparing different possible origins for observed sequences that cannot be identified uniquely. This allows computing probability distributions over the expression levels of each transcript of every gene in a way that captures the uncertainty and possible sources of error in the measurements. Accounting for this uncertainty through probabilities is essential for the accuracy of the method.

Breast-Conserving Therapy Shows Survival Benefit Compared to Mastectomy in Early-Stage Patients in Retrospective Study

When factoring in what is now known about breast cancer biology and heterogeneity, breast-conserving therapy (BCT) may offer a greater survival benefit over mastectomy to women with early-stage, hormone-receptor-positive disease, according to research from The University of Texas MD Anderson Cancer Center. The study findings defy the conventional belief that the two treatment interventions offer equal survival, and highlight the need to revisit some standards of breast cancer practice in the modern era. The research was presented on September 4, 2014 at the Breast Cancer Symposium 2014 (September 4-6) in San Francisco, California, by Catherine Parker, M.D., formerly a fellow at MD Anderson, and now at the University of Alabama-Birmingham. In the 1980s, both US-based and international randomized clinical studies found that BCT and mastectomy offered women with early-stage breast cancer equal survival benefit. However, those findings come from a period in time when very little was understood about breast cancer biology, explains Isabelle Bedrosian, M.D., associate professor, surgical oncology at MD Anderson. "Forty years ago, very little was known about breast cancer disease biology – such as subtypes, differences in radio-sensitivities, radio-resistances, local recurrence, and in metastatic potential," explains Dr. Bedrosian, the study's senior author. "Since then, there's been a whole body of biology that's been learned – none of which has been incorporated into patient survival outcomes for women undergoing BCT or a mastectomy. We thought it was important to visit the issue of BCT versus mastectomy by tumor biology," Dr. Bedrosian stated. The researchers hypothesized that they would find that patients' surgical choice would matter and impact survival with tumor biology considered.

Bats Change Foraging Strategy When Food Is Scarce

Echolocating bats have historically been classified into two groups: 'loud' aerial hawkers who catch flying insects on the wing and 'whispering' gleaners that pick up prey from the ground. While some bat species can forage in multiple ways, others have limited flexibility in the amplitude of their echolocation calls. Dr. Talya Hackett from the University of Bristol (UK) and colleagues studied the desert long-eared bat (Otonycteris hemprichii) (image), said to be a passive 'whispering' gleaner that picks up ground-dwelling invertebrates, such as scorpions, from the desert floor. Using an acoustic tracking system, the researchers recorded the bats flying at four different foraging and drinking sites in the Arava and Judean Deserts in Israel. They then compared the bats' flight height, flight speed, call duration, pulse interval, and source levels with those of other gleaning bats. The results were reported in the September 1, 2014 issue of the Journal of Experimental Biology. Differences were found in all these variables, with the most striking being the source levels: bats were recorded calling at an average of 119 decibels, akin to a 747 jet on take-off, when around 75, akin to a car engine, is more usual when gleaning (though these sounds occur at a high frequency, beyond the range of human hearing). Analysis of the bats' feces also indicated that their diet included prey species capable of flight, such as flies, moths, and beetles. This suggests that the bats switched from passive gleaning to capturing airborne insects (aerial hawking). Dr. Hackett said: "Although whispering bats have been known to opportunistically catch insects on the wing, this doesn't appear to be the case here.

September 3rd

Insights into Severe Form of Dwarfism

A better understanding of the pathology of a severe form of dwarfism, as well as a possible window of treatment, have been discovered by researchers at The University of Texas Health Science Center at Houston (UTHealth). The preclinical research was published in the May 2014 issue of the Journal of Bone and Mineral Research. Pseudoachondroplasia (PSACH) is a disorder that affects the cells in the growth plate, resulting in dwarfism, limb deformities, joint pain, and early-onset osteoarthritis. Children with PSACH show no signs of it at birth. Slowing of the long bone growth begins around age 2 and the cellular damage becomes extensive by age 4. The disorder is caused by mutations in the cartilage oligomeric matrix protein (COMP) that is situated near cells known as chondrocytes, which play a key role in bone formation. “By the time patients are in their late 20s, many have had both knees and hips replaced. They have severe joint pain and their mobility is very restricted,” said first author Karen Posey, Ph.D., assistant professor of pediatrics at the UTHealth Medical School. Previous studies of PSACH have been limited, relying on cultured PSACH cells or samples taken from human biopsies, and have not led to the development of feasible treatment options. Researchers recognized that they need a better method to study the disorder, which affects approximately 1 in 30,000 people. “We generated a mouse with the human COMP gene that contains the most common mutation causing PSACH. Similarly to how the disease manifests in humans, these genetically engineered mice appear normal at birth, but later show symptoms of PSACH, giving us a unique opportunity to potentially pinpoint when changes occur and when treatment may be most effective,” Dr. Posey said.

Study ID’s Genetic Factors Involved in Pediatric Ulcerative Colitis

UCLA researchers were part of a team that has discovered the interplay of several genetic factors that may be involved in the development of early-onset ulcerative colitis, a severe type of inflammatory bowel disease. The early research findings in mice suggest possible new targets for prevention and treatment strategies to address the inflammation generated by early-onset ulcerative colitis. This rare disease affects infants and young children and can lead to early development of colon cancer and an increased risk of liver damage. Scientists from the David Geffen School of Medicine at UCLA and Pusan National University in South Korea also created a first-of-its-kind animal model that mimics early-onset ulcerative colitis and can be used to help test new drug candidates to treat the disease. Their findings are published onlinw in Gastroenterology. "We hope that identifying these key genetic factors and providing a unique research model will help lead to new approaches to treat early-onset ulcerative colitis, a devastating disease that currently has no cure," said Dr. Sang Hoon Rhee, the study's senior author and an associate adjunct professor of medicine in the Division of Digestive Diseases at the David Geffen School of Medicine at UCLA. Although inflammatory bowel disease can occur at any age, approximately 25 percent of cases develop in people 18 years of age or younger, some of whom have early-onset ulcerative colitis. Those who develop the disease at such a young age are at a higher risk of developing colon cancer. They also have an increased risk for liver damage because the inflammation caused by the disease leads to a narrowing of the bile ducts that connect to the liver.

Scientists Discover HIV Antibody That Binds to Novel Target on Virus

An NIH-led team of scientists has discovered a new vulnerability in the armor of HIV that a vaccine, other preventive regimen, or treatment could exploit. The site straddles two proteins, gp41 and gp120, that jut out of the virus (see image) and augments other known places where broadly neutralizing antibodies (bNAbs) bind to HIV. This newly identified site on the viral spike is where a new antibody found by the scientists in an HIV-infected person binds to the virus. Called 35O22, the antibody prevents 62 percent of known HIV strains from infecting cells in the laboratory and is extremely potent, meaning even a relatively small amount of it can neutralize the virus. The work was reported online on Septmber 3, 2014 in Nature. Following their discoveries, the scientists found that 35O22-like antibodies were common in a group of HIV-infected people whose blood contained antibodies that potently neutralized a broad array of HIV strains. According to the researchers, this suggests that it might be easier for a vaccine to elicit 35O22 than some other known bNAbs, which are less common. Because 35O22 binds only to forms of the viral spike that closely resemble those that naturally appear on HIV, the scientists believe a vaccine that elicits 35O22-like antibodies would need to mimic the natural shape of the spike as closely as possible. This would require a different approach than that used in many previous experimental HIV vaccines, which have included just parts of the viral spike rather than a structure that looks like the entire native viral spike. In addition, the researchers report, the HIV strains that 35O22 neutralizes complement strains neutralized by other bNAbs.

Algorithm Developed to Identify “Synthetic Lethal Pairs” in Cancer Cells

Despite the revolutionary biotechnological advancements of the last few decades, an ideal anti-cancer treatment — one that is immediately lethal to cancer cells, harmless to healthy cells, and resistant to cancer's relapse — is still a dream. But a concept called "synthetic lethality" holds great promise for researchers. Two genes are considered synthetically lethal when their combined inactivation is lethal to cells, while inhibiting just one of them is not. Synthetic lethality promises to deliver personalized, more effective, and less toxic therapy. If a particular gene is found to be inactive in a tumor, then inhibiting its synthetic lethal partner with a drug is likely to kill only the cancer cells, causing little damage to healthy cells. While this promising approach has been widely anticipated for almost two decades, its potential could not be realized due to the difficulty of experimentally identifying synthetic lethal pairs in cancer. Now new research published in the August 28, 2014 issue of Cell overcomes this fundamental hurdle and presents a novel strategy for identifying synthetic lethal pairs in cancer with the potential to bust cancer cells. Tel Aviv University (TAU) researchers, together with collaborators at The Beatson Institute for Cancer Research (Cancer Research UK) and the Broad Institute of Harvard and MIT, have developed a computational data-driven algorithm, which identifies synthetic lethal interactions. In their comprehensive, multidisciplinary study, Dr. Eytan Ruppin of TAU's Blavatnik School of Computer Science and the Sackler School of Medicine and Ms. Livnat Jerby-Arnon of TAU's Blavatnik School of Computer Science worked together with other researchers from TAU, The Beatson Institute for Cancer Research (Cancer Research UK), and the Broad Institute of Harvard and MIT.

Zone in with Zon--Focus on ALS (Lou Gehrig's Disease)

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, September 3, 2014, describes the origin and history of the recent phenomenally successful fund-raising effort known as the ALS Ice Bucket Challenge, as well as the current status of research on this terrible disease. For those of you who don’t know, the Ice Bucket Chalenge is an effort to raise funds for research on the disease amyotrophic lateral sclerosis (ALS), which killed the famous baseball player Lou Gehrig and is also termed “Lou Gehrig’s disease.” The ALS Ice Bucket Challenge involves dumping a bucket of ice water on someone’s head to promote awareness of ALS and to encourage donations—typically $100—to research on the disease. The challenge dares nominated participants to be recorded having a bucket of ice water poured on their heads, and challenging others to do the same. A common stipulation is that nominated people have 24 hours to comply or forfeit by way of a charitable financial donation. Although there is certainly an aspect of fun to this effort, Dr. Zon points out the grim reality that there is presently no cure for this deadly disease that affects 350,000 people around the globe and kills 100,000 annually. He further notes that the disease can impact anyone anywhere, regardless of age, ethnicity, or socioeconomic background. Although usually rapidly fatal, ALS does not always kill quickly. Famous British physicist Stephen Hawking has lived with ALS for many years and is now 72 years of age. Dr. Zon briefly discusses what is known about the genetics of ALS, while giving the caveat that the genetics appears very complex. He notes that a defect in the gene for superoxide dismutase (SOD) on chromosome 21 is associated with approximately 20% of familial ALS and approximately 2% of ALS cases overall, that is including sporadic or non-familial cases. Dr.

ASHG and NHGRI Award Genetics and Public Policy Fellowship Fellowship

The American Society of Human Genetics (ASHG) and the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, have named Katherine D. Blizinsky (image, courtesy of Dr. Blizinsky), Ph.D., a neuroscientist at Northwestern University in Chicago, the newest ASHG/NHGRI Genetics and Public Policy Fellow. The 16-month appointment began on September 2, 2014. The Genetics and Public Policy Fellowship is intended to help early-career genetics professionals develop and implement genetics-related health and research policy at a national level. Fellows in the program gain policy experience in diverse settings by completing rotations in the non-profit science advocacy sector at ASHG, in the executive branch at NHGRI, and in the legislative branch as staff members on Capitol Hill. ASHG and NHGRI have jointly sponsored the fellowship since 2002. Dr. Blizinsky has served in various genetics research roles since 2008, studying varying topics in the areas of psychiatric neurogenetics and genomics, gene-environment coevolution of psychiatric susceptibility, and imaging genetics of neurological and psychiatric conditions. She received the Sage Bionetworks Young Investigator Award in 2012 and co-founded the Science Policy Initiative Northwestern, an organization that fosters science policy dialogue in the university community through panel discussions, lectures, and interactive debates. “With her diversity of experience inside and outside the genetics laboratory, Dr. Blizinsky will bring her practical knowledge of genetics research to settings where the potential impact of that research can be more fully realized and disseminated,” said Joseph McInerney, MA, MS, executive vice president of ASHG.