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Archive - Mar 2017

March 10th

Mayo Clinic Study Provides Critical Information on Tumor Sequencing and Chemotherapy in Breast Cancer

Tumor sequencing is increasingly used to select treatment for patients with cancer, but its role in women with newly diagnosed breast cancer is unknown. Mayo Clinic researchers reported on March 9, 2017, in the Journal of the National Cancer Institute (JNCI), the results of a prospective tumor sequencing study in women receiving chemotherapy prior to breast surgery. The article is titled “Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer.” The goal was to determine whether tumor genomic alterations could differentiate patients with chemotherapy-sensitive and chemotherapy-resistant disease and to generate patient-derived xenografts (mouse avatars) to validate their findings. "There is great interest to use tumor sequencing data to guide therapy," says Matthew Goetz, M.D., Medical Oncologist and Co-Chair of the Breast Cancer Genome-Guided Therapy (BEAUTY) study. "However, there are limited data as to whether this approach is useful in women with newly diagnosed breast cancer who are recommended chemotherapy prior to breast surgery," he added. The main findings of the BEAUTY study, published in the JNCI, demonstrated that the most common genetic changes were not more commonly observed in chemotherapy-resistant compared to chemotherapy-sensitive tumors. However, Mayo investigators identified that an uncommon type of an aggressive breast cancer, the luminal androgen receptor subtype of triple-negative breast cancer (TNBC), was less likely to respond to chemotherapy, and was more likely to contain a unique type of mutation in p53, a tumor suppressor gene commonly mutated in TNBC.

March 10th

Scientists Study Genetics Underlying Novel Egg-Laying Behavior of Fruit Fly Species That Causes Enormous Damage to Soft-Fruit Crops

In contrast to other members of the Drosophila family, the spotted-wing fly D. suzukii deposits its eggs in ripe fruits. Biologists from Ludwig-Maximilians-Universitaet (LMU) in Munich, Germany, have now elucidated the sensory basis of D. suzukii’s ability to exploit a novel ecological niche. Unlike most species of the genus Drosophila, which deposit their eggs in fermenting fruits, D. suzukii lays its eggs in ripe fruits. This apparently minor difference in behavior can have catastrophic consequences for commercial fruit-growers, and has made the species into a crop pest--for the puncture made by the female's ovipositor facilitates infections, while the hatched larvae feed on the fruit pulp. As a result, these infestations cause enormous damage to soft-fruit crops, such as cherries, raspberries, grapes, and strawberries. LMU biologists led by Professor Nicolas Gompel, in a collaboration with the groups of Dr. Benjamin Prud'homme (CNRS, France) and Professor Ilona Grunwald Kadow (Technical University, Munich), have begun to explore the genetic basis for this unusual egg-laying behavior. Their findings were published online on March 9, 2017 in Current Biology. The article is titled “Evolution of Multiple Sensory Systems Drives Novel Egg-Laying Behavior in the Fruit Pest Drosophila suzukii.” The researchers combined behavioral tests and genetic methods to determine how the closely related Drosophilid species D. melanogaster, D. biarmipes, and D. suzukii go about choosing the ideal nursery for their brood, each in their own way. The experiments showed that, in the search for egg-laying sites, the flies respond to the texture of the fruit, to the chemical composition of the surface and to characteristic odor compounds. In other words, they use the senses of smell, touch, and taste. D.

Researchers Find a Gene That Causes Very Rare Opitz C Syndrome

Opitz C syndrome is an extremely rare genetic disease that causes severe disabilities in patients and has been diagnosed in three people in the Iberian Peninsula, and sixty people in the world. A team led by the Professors Daniel Grinberg and Susana Balcells, from the Group on Human Molecular Genetics of the University of Barcelona and the Biomedical Research Networking Center of Rare Diseases (CIBERER) has now identified a gene that causes the Opitz C syndrome in the only patient in Catalonia, Spain, diagnosed with this severe congenital disease. This new scientific advance is a first step to discover the genetic bases of this syndrome which, so far, does not offer treatment possibilities, prenatal diagnosis, or genetic counseling. The new study, published online on March 10, 2017 in the journal Scientific Reports, has the participation of several researchers at the CRG, including members of the Genomic and Epigenomic Variation in Disease laboratory, the Genomics Unit, and the Bioinformatics Unit. It also had the participation of John M. Opitz (University of Utah, United States), Giovanni Neri (Catholic University of the Sacred Heart, Italy) and experts at the Department of Clinical and Molecular Genetics of the University Hospital Vall d'Hebron (VHIR). The open-access article is titled “A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed As Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes.” The genetic bases of this very rare disease, described for the first time in 1969 by Dr. John M. Opitz, are still unknown. It is generally thought that its origin can be traced to the occurrence of dominant, maternally silenced de novo mutations.

Fungal Protein Stimulates Axon Regeneration Via 14-3-3 Protein-Protein Stabilization; Work Identifies Possible Targets of Future Drug Development for Spinal Cord Injury & Stroke

A foray into plant biology has led one researcher to discover that a natural molecule can stimulate the repair of axons, the thread-like projections that carry electrical signals between neurons. Axonal damage is the major culprit underlying disability in conditions such as spinal cord injury and stroke. Andrew Kaplan, a Ph.D. candidate at the Montreal Neurological Institute and Hospital of McGill University in Canada, was looking for a pharmacological approach to axon regeneration, with a focus on 14-3-3, a family of proteins with neuroprotective functions that have been under investigation in the laboratory of Dr. Alyson Fournier, Professor of Neurology and Neurosurgery and senior author on the study. During Kaplan’s search, he found research describing how plants respond to a specific type of fungal infection. When plants are exposed to fusicoccin-A, a small molecule produced by a certain strain of fungus, the leaves of the plant wilt, but the roots grow longer. Fusicoccin-A affects 14-3-3 activity by stabilizing its interactions with other proteins. "While 14-3-3 is the common denominator in this phenomenon, the identity of the other proteins involved and the resulting biological activities differ between plants and animals," says Kaplan. He theorized that fusicoccin-A could be an effective way of harnessing 14-3-3 to repair axons. To test this theory, he and his fellow researchers treated mechanically damaged neurons in culture with the molecule and observed the results. "When I looked under the microscope the following day, the axons were growing like weeds, an exciting result that led us to determine that fusicoccin-A can stimulate axon repair in the injured nervous system," says Kaplan. The new work was published online on March 8, 2017 in Neuron.

March 9th

Innovative Technique Greatly Increases Sensitivity of DNA Sequencing; New Molecular Barcode Technology Reduces Error Rate in Genomic Sequencing to 1 In 10,000

Ontario Institute for Cancer Research (OICR) researchers in Canada, together with international collaborators, have invented a technique to avoid a major problem with common laboratory techniques and improve the sensitivity of important cancer tests. The findings, published online on March 2, 2017 in Nature Protocols, describe a process by which the sensitivity of DNA sequencing can be improved. The technology, called SiMSen-Seq, could aid in detecting the recurrence of cancers, catching possible disease relapses faster than current methods and improving patient outcomes. The new article is titled “Simple Multiplexed PCR-Based Barcoding of DNA for Ultrasensitive Mutation Detection by Next-Generation Sequencing.” To sequence DNA, scientists often use a technique called polymerase chain reaction (PCR) to increase the amount of DNA available from a sample. However, PCR can introduce mistakes that can limit researchers' ability to detect real mutations in the original DNA molecules. To track the original molecules in a sample, molecular tags called DNA barcodes are added. This technique is essential for sensitive detection of mutations but can lead to other errors, as components of the tags can interfere with each other and affect the final results. "We created a DNA barcode with a hairpin structure that opens up to be read when heated and contracts when cooled. This allows us to 'hide' the barcode and analyze more patient DNA fragments in a single reaction," said Dr. Paul Krzyzanowski, Program Manager of OICR's Genome Technologies Program. Dr. Krzyzanowski led the development of the analysis pipeline software used in SiMSen-Seq. This software flags errors in sequencing results and corrects them computationally.

Tasmanian Devils Cured of Deadly Transmissible Cancer (DFTD) in Immunotherapy Trial

An international study involving multiple institutions over six years has shown that immunotherapy can cure Tasmanian devils of the deadly devil facial tumor disease (DFTD) (https://en.wikipedia.org/wiki/Devil_facial_tumour_disease), one of only two known naturally occurring transmissible cancers (the other being canine transmissible venereal tumor) (http://www.nature.com/onc/journal/v27/n2s/abs/onc2009350a.html). The new research was published in Scientific Reports. The open-access article is titled “Regression of Devil Facial Tumour Disease Following Immunotherapy in Immunised Tasmanian Devils.” The research was led by researchers from the University of Tasmania's Menzies Institute for Medical Research with input from scientists from the School of Medicine. It also involved researchers from the Walter and Eliza Hall Institute of Medical Research, CSL Ltd, and the Universities of Sydney, Southampton, Southern Denmark, and Cambridge. Professor Greg Woods, the leader of the DFTD team at Menzies, said scientists used immunotherapy on devils with golf-ball sized tumors and then observed the tumors gradually shrinking and disappearing over three months. "This is almost a Eureka moment for us because it's the first time we can say for sure that it was the immunotherapy that was making the tumor shrink," Professor Woods said. Building a good understanding of the devil's immune system, which goes hand in hand with the development of a vaccine, involves years of painstaking laboratory work. The process is incremental, but with each step, scientists are closing in on the disease. This breakthrough is the next step on from work published in 2015 that showed that the devil's immune system is capable of mounting an immune response to DFTD.

Mayo Clinic Researchers Identify Three New Agents (Senolytics) That May Delay Onset of Aging

Mayo Clinic researchers have identified three new agents to add to the emerging repertoire of drugs that are intended to delay the onset of aging by targeting senescent cells, i.e., cells that contribute to frailty and other age-related conditions. A recent study of human cell cultures shows that the drugs—the flavone fisetin and two BCL-XL inhibitors (A1331852 and A1155463)--cleared senescent cells in vitro. Findings were published online on March 8, 2017 in Aging. The open-access article is titled “New Agents That Target Senescent Cells: The Flavone, Fisetin, and The BCL-XL Inhibitors, A1331852 and A1155463.” "Senescent cells accumulate with age and at sites of multiple chronic conditions, such as in fat tissue in diabetes, the lungs in chronic pulmonary diseases, the aorta in vascular disease, or the joints in osteoarthritis," says James Kirkland, M.D., Ph.D., Director of the Mayo’s Robert and Arlene Kogod Center on Aging. "At Mayo Clinic, we discovered the first senolytic drugs - agents that selectively eliminate senescent cells while leaving normal cells unaffected. These senolytic agents alleviated a range of age- and disease-related problems in mice. We used the hypothesis-driven approach that we used to discover the first senolytic drugs, two published in early 2015 and another later in 2015, to discover these three new senolytic drugs." Mayo Clinic researchers, working in collaboration with the University Medical Center Groningen and The Scripps Research Institute, induced senescence in human cell cultures by radiating human primary preadipocytes, human umbilical vein endothelial cell cultures, and IMR90 cell cultures. Then, using an ATPLite and a crystal violet assay, researchers measured cell viability and demonstrated that fisetin and BCL-XL inhibitors A1331852 and A1155463 cleared senescent cells in vitro.

Stress-Induced Exosome Secretion Can Disrupt Communication Between Parasites That Spread Disease; New Intervention Approach May Lead to Development of Drugs to Treat and Prevent the Spread of Sleeping Sickness, Leshmaniasis, and Chagas Disease

Professor Shulamit Michaeli, Dean of Bar-Ilan's Mina and Everard Goodman Faculty of Life Sciences, and member of the Bar-Ilan Institute of Nanotechnology and Advanced Materials (BINA) in Israel, has demonstrated how parasite migration can be controlled by creating an unfavorable environment or by damaging cell health, because parasites under stress secrete vesicles (exosomes) that disrupt their socially coordinated movement in groups. This research was published online on March 3,2017 in PLOS Pathogens. The open-access article is titled “Exosome Secretion Affects Social Motility in Trypanosoma brucei.” Dr. Michaeli's team, including students Dror Eliaz and Sriram Kannan, study trypanosomatids, single-cell parasites that cause major diseases such as African sleeping sickness, leishmaniasis, and Chagas disease, affecting millions of people. Leishmaniasis, for example, is found in 88 countries and over 300 million people are at risk of infection. African trypanosomes infect cattle and the annual economic loss due to this disease is estimated at about US$2 billion. The American Chagas' disease causes major heart and intestinal malfunction. Approximately 90 million people are at risk of infection, with five to eight million people affected annually. Trypanosome parasites are transmitted to mammals by the blood-sucking tsetse fly. The parasites' stopover in the insect host has two stages. They live in the insect's gut for two to three weeks and then migrate to the saliva glands. When the fly has its next meal, the parasites are transferred via the saliva to the mammal prey, infecting the prey’s bloodstream. In this way, the mammal now becomes host to the parasite, and the disease is spread.

Stanford Biologists Identify Ancient Stress Response in Corals

Stanford marine biologists have discovered that corals activate a specific group of ancient, defensive genes when exposed to stressful environmental conditions. These stress-induced genes could serve as a kind of warning sign for coral bleaching events. In the study, researchers monitored three coral colonies in a lagoon on Ofu Island, American Samoa, for their response to stressors like high temperatures, oxygen, and ocean acidity. On the hottest days, the researchers saw a significant change in which genes the corals were activating within their cells. "They started using a whole set of genes that they had just not been using before," said Steve Palumbi, Ph.D., a Professor of Marine Sciences, Director of Hopkins Marine Station, and an author of the paper that outlines the study, published online on March 8, 2017 in Science Advances. The open-access article is titled “Tidal Heat Pulses on a Reef Trigger a Fine-Tuned Transcriptional Response in Corals to Maintain Homeostasis.” In 2016, the Great Barrier reef saw the worst coral bleaching event on record as corals across hundreds of miles turned stark white. These bleaching events can eventually lead to coral death. Scientists predict that global climate change and the continued increase in ocean temperatures will increase the frequency of coral bleaching worldwide. The tricky part is, corals don't show visible signs of bleaching beforehand. The genes identified in this study could give scientists a snapshot indication of coral health - and an idea of when bleaching is likely to occur. Under stressful conditions, a coral's normal cellular functions begin to fail. In response, the group of genes identified in this study triggers a process, called the unfolded protein response, that works to restore normal conditions within the cell.

March 8th

Immune Response to Yeast & Increased Purine Metabolism May Exacerbate Crohn’s Disease

A new study reports that a strain of intestinal-dwelling yeast may exacerbate Crohn's disease, and blocking the fungus from causing problems in the gut could alleviate the symptoms of inflammatory bowel disorder in some patients. Approximately 1.6 million Americans currently live with inflammatory bowel disorders (IBD), and as many as 70,000 new cases are diagnosed every year. No cure exists for IBD, though many patients manage their symptoms with anti-inflammatory drugs. While several studies have illuminated links between intestinal bacteria and IBD, scant attention has been paid to the other types of microbes living in the gut, even though almost 70% of Crohn's disease patients are predisposed to mount immune reactions against yeast. In work that served as the cover story of the March 8, 2017 issue of Science Translational Medicine, Dr. Tyson Chiaro of the University of Utah School of Medicine and colleagues demonstrated that a strain of Saccharomyces cerevisiae aggravated intestinal damage in mouse models of colitis. The researchers determined that the yeast caused the rodents to produce elevated amounts of uric acid in their intestines. They gave yeast-colonized animals allopurinol (a clinical drug used to reduce uric acid), which reversed intestinal disease. To determine if yeast might cause similar effects in humans, the scientists examined serum from 168 healthy volunteers and observed a positive correlation between uric acid levels and circulating antibodies against S. cerevisiae. Testing Crohn’s disease patients for uric acid and immune responses to yeast could inform more targeted therapeutic interventions, the authors say. The open-access Science Translational Medicine article is titled “A Member of the Gut Mycobiota Modulates Host Purine Metabolism Exacerbating Colitis in Mice.”

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