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Archive - Aug 2013

August 16th

Female Tree Frogs Prefer Males Who Can Multitask

From frogs to humans, selecting a mate is complicated. Females of many species judge suitors based on many indicators of health or parenting potential. But it can be difficult for males to produce multiple signals that demonstrate these qualities simultaneously. In a study of Cope’s grey tree frogs, a team of University of Minnesota researchers discovered that females prefer males whose calls reflect the ability to multitask effectively. In this species (Hyla chrysoscelis), males produce "trilled" mating calls that consist of a string of pulses. Typical calls can range in duration from 20-40 pulses per call and occur at the rate of between 5-15 calls per minute. Males face a trade-off between call duration and call rate, but females preferred calls that are longer and more frequent, which is no simple task. The findings were published in the August 2013 issue of Animal Behaviour. "It’s kind of like singing and dancing at the same time," says Dr. Jessica Ward, a postdoctoral researcher who is lead author for the study. Dr. Ward works in the laboratory of Dr. Mark Bee, a professor in the College of Biological Sciences’ Department of Ecology, Evolution and Behavior. The study supports the multitasking hypothesis, which suggests that females prefer males who can do two or more hard-to-do things at the same time because these are especially good-quality males, Dr. Ward says. The hypothesis, which explores how multiple signals produced by males influence female behavior, is a new area of interest in animal behavior research. By listening to recordings of 1,000 calls, Dr. Ward and colleagues learned that males are indeed forced to trade off call duration and call rate. That is, males that produce relatively longer calls only do so at relatively slower rates.

Supercomputers Shed Light on How DNA Repair Helps Prevent Cancer

The biological information that makes us unique is encoded in our DNA. DNA damage is a natural biological occurrence that happens every time cells divide and multiply. External factors such as overexposure to sunlight can also damage DNA. Understanding how the human body recognizes damaged DNA and initiates repair fascinates Dr. Michael Feig, professor of biochemistry and molecular biology at Michigan State University. Dr. Feig studies the proteins MutS and MSH2-MSH6, which recognize defective DNA and initiate DNA repair. Natural DNA repair occurs when proteins like MutS (the primary protein responsible for recognizing a variety of DNA mismatches) scan the DNA, identify a defect, and recruit other enzymes to carry out the actual repair. "The key here is to understand how these defects are recognized," Dr. Feig explained. "DNA damage occurs frequently and if you couldn't repair your DNA, then you wouldn’t live for very long." This is because damaged DNA, if left unrepaired, can compromise cells and lead to diseases such as cancer. Dr. Feig, who has used national supercomputing resources since he was a graduate student in 1998, applied large-scale computer simulations to gain a detailed understanding of the cellular recognition process. Numerical simulations provide a very detailed view down to the atomistic level of how MutS and MSH2-MSH6 scan DNA and identify which DNA needs to be repaired. Because the systems are complex, the research requires large amounts of computer resources, on the order of tens of millions of CPU core hours over many years. "We need high-level atomic resolution simulations to get insights into the answers we are searching for and we cannot run them on ordinary desktops," Dr. Feig said.

Exome Sequencing Reveals Two New Genes, 25 De Novo Mutations in Severe Childhood Epilepsies

A genetic study of childhood epilepsies has linked two new genes to severe forms of disease and provides a novel strategy for identifying therapy targets. This study used exome sequencing to search for new mutations that are not inherited. The results suggest that this may be a highly effective way to find and confirm many disease-causing gene mutations. "It appears that the time for using this approach to understand complex neurological disorders has arrived," said David Goldstein, Ph.D., director of the Human Genome Variation Center at Duke University Medical Center, Durham, North Carolina, and a leader of the study. "This moderately-sized study identified an unusually large number of disease-causing mutations and provides a wealth of new information for the epilepsy research community to explore." The study is part of a worldwide, $25 million project, largely funded by the National Institutes of Health, called Epilepsy 4000 (Epi4K). Epi4K's mission is to use the latest genetic techniques to sequence and analyze DNA from 4000 epilepsy patients and their relatives. To do this, the researchers and NIH staff involved organized a team of international research institutions devoted to the mission, called the Epilepsy Centers without Walls. This approach facilitates the sharing and analysis of DNA sequences and patient information among the dozens of institutions participating in the project. The study, published online on August 11, 2013 in Nature by the Epi4K and Epilepsy Phenome/Genome Project (EPGP) Investigators, found as many as 25 epilepsy-causing mutations in new and previously identified genes.

Treatment-Resistant Lymphomas “Reprogrammed” to Respond to Cancer Drugs

A phase I clinical trial showed diffuse, large B-cell lymphomas (DLBCLs) resistant to chemotherapy can be reprogrammed to respond to treatment using the drug azacitidine, according to a study published online on August 16, 2013 in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). Patients whose lymphomas recur after initial chemotherapy are treated with a combination of approaches, including high-dose chemotherapy followed by a stem cell transplant. However, some patients have tumors that do not respond to these extensive second treatments, and many of these patients die within two years of diagnosis. "When lymphomas are formed, they shut down the cellular programs that sense that something is wrong in the cells. Once these fail-safe mechanisms that trigger cell death are shut down, it becomes difficult to kill the tumor with chemotherapy," said senior author Leandro Cerchietti, M.D., assistant professor at the Hematology and Oncology Division of Weill Cornell Medical College in New York. "Our study showed that using low concentrations of the DNA methyltransferase inhibitors decitabine or azacitidine, these fail-safe mechanisms can slowly be awakened to induce lymphoma cell death when chemotherapy is administered." Dr. Cerchietti and an international group of colleagues conducted a phase I trial in patients with newly diagnosed DLBCL. Eleven of the 12 patients enrolled were more than 60 years old when diagnosed, which meant that they were at high risk for tumor recurrence after initial treatment. The patients were treated with azacitidine, in escalating doses, eight days prior to initiation of six cycles of standard chemotherapy. Side effects from pretreatment with azacitidine were minimal.

August 15th

NIH Targets $17 Million to Study of Extracellular RNA and Cell-Cell Communication

The National Institutes of Health announced on August 13, 2013 that it will award $17 million this year for 24 research projects designed to improve scientists' understanding of a newly discovered type of cell-to-cell communication based on extracellular RNA, also called exRNA. Through these awards, scientists will explore basic exRNA biology and develop tools and technologies that apply new knowledge about exRNA to the research, diagnosis and treatment of diseases. To unlock the potential of this new scientific field, the awarded research projects will address conditions in which exRNA could play a role, including many types of cancer, bone marrow disorders, heart disease, Alzheimer's disease, and multiple sclerosis. The collaborative, cross-cutting Extracellular RNA Communication program is supported by the NIH Common Fund and led by a trans-NIH team that includes the National Center for Advancing Translational Sciences (NCATS); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Institute on Drug Abuse (NIDA); and National Institute of Neurological Disorders and Stroke (NINDS). "We have a tremendous opportunity to explore a recently discovered novel way that cells communicate," said NIH Director Francis S. Collins, M.D., Ph.D. "Expanding our understanding of this emerging scientific field could help us determine the role extracellular RNA plays in health and disease, and unlocking its mysteries may provide our nation's scientists with new tools to better diagnose and treat a wide range of diseases." Scientists think exRNA can regulate many functions in the body and may have an important role in a variety of diseases, but they still know very little about basic exRNA biology. Most RNA works inside cells to translate genes into proteins that are necessary for organisms to function.

World’s Largest Owl Is Indicator of Primary Forest Health in Russia’s Far East

A study spearheaded by the Wildlife Conservation Society and the University of Minnesota has shown that the world's largest owl -- and one of the rarest -- is also a key indicator of the health of some of the last great primary forests of Russia's Far East. The study found that Blakiston's fish owl relies on old-growth forests along streams for both breeding and to support healthy populations of its favorite prey: salmon. The large trees provide breeding cavities for the enormous bird, which has a two-meter (six-foot) wingspan. And when these dead, massive trees topple into adjacent streams, they disrupt water flow, forcing the gushing river around, over, and under these new obstacles. The result is stream channel complexity: a combination of deep, slow-moving backwaters and shallow, fast-moving channels that provide important microhabitats critical to salmon in different developmental stages. The study was published online on August 6, 2013 in the journal Oryx. Authors include Dr. Jonathan Slaght of the Wildlife Conservation Society, Dr. R. J. Gutiérrez of the University of Minnesota, and Dr. Sergei Surmach of the Institute of Biology and Soils (Russian Academy of Sciences). The authors studied the foraging and nesting characteristics of Blakiston's fish owl in Primorye, Russia, where they looked at nesting habitat over 20,213 square kilometers (7,804 square miles). They found that large old trees and riparian old-growth forest were the primary distinguishing characteristics of both nest and foraging sites. The authors say that management and conservation of old-growth forests is essential for sustaining this species because they are central to the owls' nesting and foraging behavior.

Analysis of Vitamin D-Related Molecular Switches Predicts Childhood Bone Mass

Researchers at the MRC (Medical Research Council) Lifecourse Epidemiology Unit, University of Southampton in the UK, have demonstrated that the degree to which a gene related to vitamin D action is switched on or off, when measured at birth, predicts bone density of the child at four years of age. The results were published online on August 1, 2013 in the Journal of Bone and Mineral Research. In the study, 230 boys and girls were assessed at 4 years as part of the Southampton Women's Survey (SWS), a large ongoing mother-offspring cohort. The children visited the Osteoporosis Centre at Southampton General Hospital for measurement of their bone size and density using a DXA scanner. The researchers were able to measure the extent to which a particular gene, RXRA, is switched on or off by measuring epigenetic marks on the DNA sequence of the gene in cells taken from umbilical cord tissue which had been collected at birth. They found that the less marking (which usually means greater gene activity), at birth, the greater the bone density of the child at four years old. Furthermore, one of the epigenetic marks was related to the mother's blood vitamin D concentrations in late pregnancy. Dr. Nicholas Harvey, Senior Lecturer at the MRC Lifecourse Epidemiology Unit, University of Southampton, who led this project said, "RXRA is essential for the action of vitamin D and several other hormones; taken together with the relationship we found between mothers' vitamin D levels and RXRA marking, this study provides further support for the potential importance of vitamin D in pregnancy.

“Zone in with Zon”—30 Years of Automated Amidite DNA Oligo Synthesis

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, August 12, 2013, hails the introduction of automated synthesis of DNA oligonucleotides (oligos) in 1983 by Applied Biosystems (ABI) as “the most enabling biotechnology yet.” Dr. Zon briefly outlines the history of this technology, beginning with the development of the phosphoramidite (amidite) methodology for oligo synthesis by Professor Marvin H. Caruthers’s research group at the University of Colorado-Boulder. This group included Serge Beaucage, Mark Matteucci, Bill Efcavitch, Curt Becker, and Lincoln McBride. The latter three joined ABI to commercialize automated oligo synthesis. Beaucage joined Beckman, which introduced its amidite-based DNA oligo synthesizer shortly after ABI. Matteuci joined Genentech to work on oligo synthesis. Dr. Zon described his role, first as a test site for ABI’s first amidite-based oligo synthesizer while he was at FDA/NIH, and later, after joining ABI in 1986 to help commercialize new applications. At ABI, Dr. Zon focused on the development of modified oligos as potential antisense inhibitors of mRNA function. In 1992, Lynx Therapeutics was spun out of ABI in order to focus on antisense therapeutics. Today, Dr. Zon reports that this field is led by Isis Pharmaceuticals and that company has recently announced FDA approval of an antisense drug to treat familial hypercholesterolemia. The Isis CEO described the drug as “the first systemic antisense drug to reach the market.” Dr. Zon went on to describe the “stunning scalability” of automated oligo synthesis, noting that the production scale of the first automated oligo synthesizer was 1 micromolar and today is approximately 750 millimolar. In addition, there are now manufacturing methods for producing small batch sizes for many thousands of different oligos. Dr.

August 11th

New Weapon Added to Multi-Pronged Internal Anti-Cancer Nano Drug

A unique nanoscale drug that can carry a variety of weapons and sneak into cancer cells to break them down from the inside has a new component: a protein that stimulates the immune system to attack HER2-positive breast cancer cells. The research team developing the drug, led by scientists at the Nanomedicine Research Center, part of the Maxine Dunitz Neurosurgical Institute in the Department of Neurosurgery at Cedars-Sinai Medical Center in Los Angeles, conducted the study in laboratory mice with implanted human breast cancer cells. Mice receiving the drug lived significantly longer than untreated counterparts and those receiving only certain components of the drug, according to an article available online on June 12, 2013 in the Journal of Controlled Release. Researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, the Division of Surgical Oncology at UCLA, and the Molecular Biology Institute at UCLA also participated in the study. Unlike other drugs that target cancer cells from the outside, often injuring normal cells as a side effect, this therapy consists of multiple drugs chemically bonded to a "nanoplatform" that functions as a transport vehicle. HER2-positive cancers – making up 25 to 30 percent of breast and ovarian cancers – tend to be more aggressive and less responsive to treatment than others because the overactive HER2 gene makes excessive amounts of a protein that promotes cancer growth. One commonly used drug, Herceptin (trastuzumab), often is effective for a time, but many tumors become resistant within the first year of treatment and the drug can injure normal organs it contacts. But Herceptin (see image) is an antibody to the HER2 gene – it naturally seeks out this protein – so the research team used key parts of Herceptin to guide the nanodrug into HER2-positive cancer cells.

August 10th

Researchers ID Four Gene Variations in Lung Cancer Patients That May Help Predict an Individual’s Treatment Response

Researchers at the Moffitt Cancer Center in Tampa, Florida have identified four inherited genetic variants in non-small cell lung cancer (NSCLC) patients that can help predict survival and treatment response. The findings could help lead to more personalized treatment options and improved outcomes for patients. The researchers analyzed DNA sequence variations in 651 NSCLC patients, paying close attention to 53 inflammation-related genes. They found that four of the top 15 variants associated with survival were located on one specific gene (TNFRSF10B). In the study, these variants increased the risk of death as much as 41 percent. The researchers also found that patients with these gene variations had a greater risk of death if their treatment plans included surgery without chemotherapy compared to patients who were treated with chemotherapy following surgery. “There are few validated biomarkers that can predict survival or treatment response for patients with NSCLC,” said study lead author Matthew B. Schabath, Ph.D., assistant member of the Cancer Epidemiology Program at Moffitt. “Having a validated genetic biomarker based on inherited differences in our genes may allow physicians to determine the best treatments for an individual patient based on (his or her) unique genetics.” Lung cancer is the leading cause of cancer-related deaths in the United States for both men and women. Additionally, NSCLC represents more than 80 percent of lung cancer diagnoses. “NSCLC has an extremely poor five-year survival rate. Only about 16 percent of all patients survive for five years and tragically, only about four percent of patients with late-stage disease live longer than five years,” explained Dr. Schabath. “Part of the difficulty in treating lung cancer is the genetic diversity of patients and their tumors.