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Archive - Sep 2014

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September 6th

Origin of Domesticated Peaches Traced Back 7,500 Years

In a study published online on September 5, 2014 in the open-access journal PLOS ONE, Dr. Gary Crawford, a University of Toronto-Mississauga anthropology professor, and two Chinese colleagues propose that the domestic peaches enjoyed worldwide today can trace their ancestry back at least 7,500 years to the lower Yangtze River Valley in Southern China, not far from Shanghai. The study, headed by Dr. Yunfei Zheng from the Zhejiang Institute of Archeology in China’s Zhejiang Province, was done in collaboration with Dr. Crawford and Dr. Xugao Chen, another researcher at the Zhejang Institute. “Previously, no one knew where peaches were domesticated,” said Dr. Crawford. “None of the botanical literature suggested the Yangtze Valley, although many people thought that it happened somewhere in China.” Radiocarbon dating of ancient peach stones (pits) discovered in the Lower Yangtze River Valley indicates that the peach seems to have diverged from its wild ancestors as early as 7,500 years ago. Archeologists have a good understanding of domestication – conscious breeding for traits preferred by people– of annual plants such as grains (rice, wheat, etc.), but the role of trees in early farming and how trees were domesticated is not well documented. Unlike most trees, the peach tree matures very quickly, producing fruit within two to three years, so selection for desirable traits could become apparent relatively quickly. The problem that Dr. Crawford and his colleagues faced was how to recognize the selection process in the archeological record. Peach stones are well represented at archeological sites in the Yangtze valley, so the researchers compared the size and structure of the stones from six sites that spanned a period of roughly 5,000 years.

Researchers Find New Gene Mutations for Wilms Tumor

Researchers at the University of Texas (UT) Southwestern Medical Center (image) and the Gill Center for Cancer and Blood Disorders at Children’s Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children. Wilms tumor is the most common childhood genitourinary tract cancer and the third most common solid tumor of childhood. “While most children with Wilms tumor are thankfully cured, those with more aggressive tumors do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumor patients. We wanted to know – what are the genetic causes of Wilms tumor in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study. The new findings were published online on September 5, 2014 in Nature Communications. Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors. Previous research has identified one or two mutant genes in Wilms tumors, but only about one-third of Wilms tumors had these mutations. “We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumors and identified several new mutated genes,” said Dr.

“Disease-in-a-Dish” Approach Could Aid Huntington's Disease Discovery Efforts

Creating induced pluripotent stem cells or iPS cells allows researchers to establish "disease-in-a-dish" models of conditions ranging from Alzheimer’s disease to diabetes. Scientists at Yerkes National Primate Research Center, Emory University, have now applied the technology to a model of Huntington’s disease (HD) in transgenic nonhuman primates, allowing the researchers to conveniently assess the efficacy of potential therapies on neuronal cells in the laboratory. The results were published online on September 4, 2014 in Stem Cell Reports. "A highlight of our model is that our progenitor cells and neurons developed cellular features of HD such as intranuclear inclusions of mutant Huntingtin protein, which most of the currently available cell models do not present," says senior author Anthony Chan, Ph.D., D.V.M., associate professor of human genetics at Emory University School of Medicine and Yerkes National Primate Research Center. "We could use these features as a read-out for therapy using drugs or a genetic manipulation." Dr. Chan and his colleagues were the first in the world to establish a transgenic nonhuman primate model of HD. HD is an inherited neurodegenerative disorder that leads to the appearance of uncontrolled movements and cognitive impairments, usually in adulthood. It is caused by a mutation that introduces an expanded region where one amino acid (glutamine) is repeated dozens of times in the huntingtin protein. The non-human primate model has extra copies of the huntingtin gene that contains the expanded glutamine repeats. In the non-human primate model, motor and cognitive deficits appear more quickly than in most cases of Huntington’s disease in humans, becoming noticeable within the first two years of the monkeys’ development.

Ovarian Cancer Oncogene Found in “Junk DNA”

Over the years researchers have made tremendous strides in the understanding and treatment of cancer by searching genomes for links between genetic alterations and disease. Most of these studies have focused on the portion of the human genome that encodes protein – a fraction that accounts for just 2 percent of human DNA overall. Yet the vast majority of genomic alterations associated with cancer lie outside protein-coding genes, in what traditionally has been derided as "junk DNA." Researchers today know that "junk DNA" is anything but – much of it is transcribed into RNA, for instance -- but finding meaning in those sequences remains a challenge. Now a team led by Lin Zhang, Ph.D., research associate professor in the Department of Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania (Penn), has mined those sequences to identify a non-protein-coding RNA whose expression is linked to ovarian cancer. The study is published online in Cancer Cell. Supported by the Basser Research Center for BRCA in Penn's Abramson Cancer Center, Dr. Zhang and his team built a DNA copy number profile for nearly 14,000 long non-coding RNAs (lncRNAs) (image), across 12 cancer types, including ovarian and breast cancers -- the two major BRCA-related cancers. They found that the number of copies of lncRNA genes on a chromosome consistently changes in 12 different cancer types and lncRNA genes are widely expressed in cancer cells. What these non-protein-coding RNAs do is still relatively unknown. However, given their vast numbers in the human genome, researchers believe that they likely play important roles in normal human development and response to disease.

Physicists Create Active Vesicles, A First Step Toward Fabricating Artificial Cells

Working with a team of scientists from the Technical University of Munich (TU Munich), Brandeis University, and Leiden University in the Netherlands, Dr. M. Cristina Marchetti and Dr. Mark Bowick, professors in the Soft Matter Program in the College of Arts and Sciences at Syracuse University, have engineered and studied “active vesicles." These purely synthetic, molecularly thin sacs are capable of transforming energy, injected at the microscopic level, into organized, self-sustained motion. The team’s findings are the subject of a cover story in the September 5, 2014 issue of Science. The ability to generate spontaneous motion and stable oscillations is a hallmark of living systems. Cells crawl to heal wounds and the heart contracts periodically to pump blood through the entire body. Reproducing and understanding this behavior, both theoretically and experimentally, remains one of the great challenges of 21st-century science. By confining cell extracts of important biological ingredients (i.e., bundles of long filamentary proteins known as microtubules and kinesin motor proteins) to the surface of a lipid vesicle, the TU Munich and Brandeis experimental part of the team has created "active vesicles" that undergo spontaneous oscillations and striking changes in shape. These biomimetic sacs are fueled by energy-consuming kinesins–i.e., nanomachines capable of transforming chemical energy into mechanical work–and may be thought of as the first step toward fabricating artificial cells. Fueled by kinesins, these defects form spatial patterns that oscillate between distinct configurations, turning the active vesicle into a robust miniature clock with tunable frequency. When confined, the long microtubule bundles coat the surface of the vesicle, forming a liquid crystal, where the filaments are, on average, aligned in a common direction.

September 5th

Advance Reported in Treatment of Triple-Negative Breast Cancer

Dr. William M. Sikov, a medical oncologist in the Breast Health Center and associate director for clinical research in the Program in Women's Oncology at Women & Infants Hospital of Rhode Island, served as study chair and lead author for a recently-published major national study that could lead to improvements in outcomes for women with triple-negative breast cancer, an aggressive form of the disease that disproportionately affects younger women. The study, "Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-Per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)," was accepted as a rapid publication and published online on August 4, 2014 in the Journal of Clinical Oncology. The article will come out in print in September. Because of its rapid growth rate, many women with triple-negative breast cancer receive chemotherapy to try to shrink the cancer before undergoing surgery. With the standard treatment, the cancer is eliminated from the breast and lymph nodes in the armpit before surgery in about one third of women. This is referred to as a pathologic complete response (pCR). In patients who achieve pCR, the cancer is much less likely to come back, spread to other parts of the body, and cause the patient's death than if the cancer survives the chemotherapy. Dr. Sikov and his collaborators studied the addition of other drugs – carboplatin and/or bevacizumab – to the standard treatment regimen to see if they could increase response rates. More than 440 women from cancer centers across the country enrolled in this randomized clinical trial.

New-Mode-of-Action Drug (KEYTRUDA) for Advanced Melanoma Granted Accelerated FDA Approval; Available to Patients in One Week

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab) at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation-positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA is the first anti-PD-1 (programmed death receptor-1) therapy approved in the United States and received FDA’s Breakthrough Therapy designation for advanced melanoma, which was granted based on the significance of early study findings and the unmet medical need. For the recommended 2 mg/kg dose based on data in 89 patients, the overall response rate was 24 percent (95% CI: 15, 34), with one complete response and 20 partial responses (21/89). At the time of analysis, 86 percent (18/21) of patients with objective responses had ongoing responses with durations ranging from 1.4+ to 8.5+ months, including eight patients with ongoing responses of 6 months or longer. Fourteen percent (3/21) had progression of disease 2.8, 2.9, and 8.2 months after initial response. KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to fight advanced melanoma. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, and may affect both tumor cells and healthy cells.

September 4th

Ultrasensitive Biosensor from Molybdenite Semiconductor Has Potential for Single Molecule Detection

Move over, graphene. An atomically thin, two-dimensional, ultrasensitive semiconductor material for biosensing developed by researchers at the University of California Santa Barbara (UCSB) promises to push the boundaries of biosensing technology in many fields, from health care to environmental protection to forensic industries. Based on molybdenum disulfide or molybdenite (image), the biosensor material — used commonly as a dry lubricant — surpasses graphene’s already high sensitivity, offers better scalability, and lends itself to high-volume manufacturing. Results of the researchers’ study have been published in the April 22, 2014 issue of ACS Nano., with a correction published in the May 27, 2014 issue of ACS Nano. “This invention has established the foundation for a new generation of ultrasensitive and low-cost biosensors that can eventually allow single-molecule detection — the holy grail of diagnostics and bioengineering research,” said Dr. Samir Mitragotri, co-author and professor of chemical engineering and director of the Center for Bioengineering at UCSB. “Detection and diagnostics are a key area of bioengineering research at UCSB and this study represents an excellent example of UCSB’s multifaceted competencies in this exciting field.” The key, according to UCSB professor of electrical and computer engineering Kaustav Banerjee, who led this research, is molybdenite’s band gap, the characteristic of a material that determines its electrical conductivity. Semiconductor materials have a small but nonzero band gap and can be switched between conductive and insulated states controllably. The larger the band gap, the better the material’s ability to switch states and to insulate leakage current in an insulated state.

Use of Engineered Plant Cells May Help Induce Immune Tolerance in Hemophilia A Patients

Accidents as minor as a slip of the knife while chopping onions can turn dangerous for patients with hemophilia because they lack the necessary proteins in their blood to stem the flow from a wound. People with severe hemophilia typically receive regular injections of these proteins, called clotting factors, as a treatment for the disease. But up to 30 percent of people with the most common form, hemophilia A, develop antibodies that attack these life-saving proteins, making it difficult to prevent or treat excessive bleeding. Now, researchers from the University of Florida (UF) Health and the University of Pennsylvania have developed a way to thwart production of these antibodies by using plant cells to teach the immune system to tolerate rather than attack the clotting factors. The study was published in the September 4, 2014 issue of Blood. “The only current treatments against (antibody) formation cost $1 million and are risky for patients,” said Henry Daniell, Ph.D., interim chairman of biochemistry at the University of Pennsylvania School of Dental Medicine and a co-author on the study. “Our technique, which uses plant-based capsules, has the potential to be a cost-effective and safe alternative.” The study focused on hemophilia A, which occurs when babies are born with a particular defective gene on the X chromosome. Because girls have two X chromosomes — giving them two shots at having a working version of the gene — the disease typically only affects boys. Worldwide, one in 7,500 male babies is born with this disease. After receiving factor VIII treatments, between 20 and 30 percent of patients develop antibodies against the clotting protein. Instead of allowing the protein to do its job, the immune system responds to this foreign protein as an invader that must be attacked and eliminated.

Focus on Bacterial Proteases May Reveal Paths to New Antibiotics

A collaborative team of scientists including biochemist Dr. Peter Chien at the University of Massachusetts, Amherst, has reconstructed how bacteria tightly control their growth and division, a process known as the cell cycle, by specifically destroying key proteins through regulated protein degradation. Regulated protein degradation uses specific enzymes called energy-dependent proteases to selectively destroy certain targets. Because regulated protein degradation is critical for bacterial virulence and invasion, understanding how these proteases function should help to uncover pathways that can be targeted by new antibiotics. All organisms use controlled degradation of specific proteins to alter cellular behavior in response to internal or external cues, says Dr. Chien, an assistant professor of biochemistry and molecular biology. And, a process that has to happen as reliably and stably as cell division also has to be flexible enough to allow the organism to grow and respond to its ever-changing environment. But little has been known about the molecular mechanics of how cells meet these challenges. The current work, done in collaboration with Dr. Kathleen Ryan and colleagues at the University of California, Berkeley, was supported by the NIH's National Institute for General Medical Sciences. Results appeared online on September 2, 2014 in PNAS. Energy-dependent proteases can be thought of as tiny molecular-level machines, says Dr. Chien. By selectively cutting and destroying key proteins at precise time points during cell division, they take charge of when, and at what rate, a cell grows and divides. They are found in all kingdoms of life, but are especially important in bacteria where they help cells overcome stressful conditions such as an attack by antibiotic treatment.