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Tracking Movement of Immune Cells Identifies Key First Steps in Inflammatory Arthritis

Using a novel approach for imaging the movement of immune cells in living animals, researchers from the Massachusetts General Hospital (MGH) Center for Immunology and Inflammatory Diseases (CIID) have identified what appear to be the initial steps leading to joint inflammation in a model of inflammatory arthritis. In their report, published online on January 19, 2017 in Science Immunology, they describe how expression of a specific molecule - complement C5a (image) - is required to cause the immune cells called neutrophils to adhere to joint surfaces and migrate into the joint, a process known to set off the inflammatory cascade. The article is titled “Complement C5a Receptor Is the Key Initiator of Neutrophil Adhesion Igniting Immune Complex–Induced Arthritis.” "Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors," says Andrew Luster, M.D., Ph.D., Chief of the MGH Division of Rheumatology, Allergy and Immunology, Director of the CIID and senior author of the report. "But when the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process." Inflammatory arthritis includes a number of autoimmune diseases of the joints - including rheumatoid arthritis and lupus – and, in many cases, is caused by a type of inflammation called type III hypersensitivity.

New Technique Enables Continuous Variation of Gene Expression; Powerful Tool for Genetic Engineering

A new technique will help biologists tinker with genes, whether the goal is to turn cells into tiny factories churning out medicines, modify crops to grow with limited water, or study the effects of a gene on human health. The technique, described online on January 20, 2017 in Nature Communications, allows scientists to precisely regulate how much protein is produced from a particular gene. The open-access article is titled “Rapid Generation of Hypomorphic Mutations.” The process is simple yet innovative and, so far, works in everything from bacteria to plants to human cells. "Basically, this is a universal toolkit for modifying gene expression," said Sergej Djuranovic (photo), Ph.D., an Assistant Professor of Cell Biology and Physiology at Washington University School of Medicine in St. Louis, and the study's senior author. "It's a tool that can be used whether you are genetically engineering cells to produce a particular organic molecule, or to study how a gene works." The ability to control the amount of protein produced from a particular gene would be a boon to biologists who design or redesign biological systems - such as the set of biochemical reactions that make up cellular metabolism - to produce a desired product. For example, some drugs - including antibiotics such as vancomycin and cancer drugs such as taxol - are produced by cells as byproducts of metabolism. By fine-tuning certain genes a biologist could maximize the quantity of medicine produced. Dr. Djuranovic himself is interested in modulating gene expression to study disease-related genes, such as ones implicated in cancer. "There are all sorts of complex diseases such as cancer and autism in which we know that expression from a particular gene is dialed down, but nobody knows how that reduction is contributing to the disease," Dr.

Cell Biologists Discover How Peroxisomes and Endoplasmic Reticulum Associate and Work Together

Scientists have made a breakthrough in understanding how different organelles of human cells interact. Organelles are the functional units of a cell. Like organs in a body, they perform specialized functions. To allow survival of the cell, organelles have to interact and cooperate. How this is mediated and regulated in the cell is an important and challenging question in cell biology. Researchers at the University of Exeter (UK) have now discovered how two cell organelles - called peroxisomes and the endoplasmic reticulum (ER) - associate with each other at the molecular level and work together. This cooperation is crucial for the production of specific lipids, which are essential for the function of nerve cells and can protect cells from oxidative damage. Loss of peroxisome function leads to a range of severe or fatal disorders associated with developmental and neurological defects. "Close contacts between peroxisomes and the ER were observed more than 50 years ago in ultrastructural studies, but the molecular mechanism remained a mystery," said lead author Dr. Michael Schrader, of the University of Exeter. "This is the first molecular tether identified in humans, which mediates the contact between these two important cell compartments." The study showed that a protein at the peroxisomes called ACBD5 directly interacts with a protein at the ER, called VAPB. This interaction links both organelles together and allows transfer of lipids between them. When the interaction between VAPB and ACBD5 is lost, the ER and peroxisomes can no longer interact and this lipid transfer appears to be prevented. The researchers are working with experts from the Academic Medical Center in Amsterdam, where a patient with an ACBD5 deficiency has been identified and linked to a peroxisomal defect.

NX Prenatal Appoints Leading Experts to Medical/Clinical Advisory Board; Company’s First Product Will Be Exosome-Based Blood Test to Stratify Risk of Preterm Birth

In a January 19, 2017 press release, NX Prenatal, Inc. announced the formation of its Medical/Clinical Advisory Board. This new board brings together leading clinicians and industry veterans who enhance the range and depth of expertise of the company as it accelerates development of its novel prenatal diagnostic tests. These experts are uniquely positioned to provide medical, clinical, and strategic guidance for the company's product development and commercialization activities. The first product will be a novel exosome-based blood test designed to stratify the risk of preterm birth in women as early as 10-12 weeks of pregnancy to provide physicians with a new decision support tool. Gail Page, NX Prenatal's Executive Chairperson, added, "We are pleased to be surrounded by advisors who have deep knowledge in the fields of maternal fetal medicine, obstetrics, proteomics, and biomarker test commercialization. We recognize the importance of working closely with key opinion leaders to ensure that our diagnostic tests are relevant and address an unmet need in the clinical community that will use them." The advisory board members include the following: KEVIN ROSENBLATT, M.D., PH.D. (CHAIR) Dr. Rosenblatt is Chief Medical & Scientific Officer of NX Prenatal. He previously served as CMO/CSO of CompanionDx Labs, a precision medicine/diagnostics company. Dr. Rosenblatt is recognized internationally for his proteomics and genomics expertise and has published over 60 papers on biomarker development and clinical proteomics. He served as an Associate Professor in the Division of Oncology, Department of Internal Medicine, Associate Professor at the Brown Foundation Institute of Molecular Medicine and as Director of the Proteomics Core for the Center for Clinical and Translational Sciences at UT Health.

Largest Study to Date Shows That "Precision Medicine for Pediatric Brain Tumors Can Now Be a Reality"

Precision medicine - in which diagnosis and treatments are keyed to the genetic susceptibilities of individual cancers - has advanced to the point where it can now impact the care of a majority of children with brain tumors, a new study by investigators at Dana-Farber/Boston Children's Cancer and Blood Disorders Center suggests. In the largest clinical study to date of genetic abnormalities in pediatric brain tumors, researchers performed clinical testing on more than 200 tumor samples and found that a majority had genetic irregularities that could influence how the disease was diagnosed and/or treated with approved drugs or agents being evaluated in clinical trials. The findings, reported online on January 19, 2017 in Neuro-Oncology, demonstrate that testing pediatric brain tumor tissue for genetic abnormalities is clinically feasible and that in many cases the results can guide patients' treatment. The need for new approaches to treating brain cancer in children is urgent, the study authors say. "Although there has been a great deal of progress over the past 30 years in improving survival rates for children with cancer, advances in pediatric brain cancer haven't been as dramatic," says co-lead author Pratiti Bandopadhayay, M.B.B.S., Ph.D., of Dana-Farber/Boston Children's. "In a recent study, brain tumors accounted for 25 percent of all pediatric deaths attributed to cancer. In addition, many of the current therapies can result in long-term difficulties in cognitive or physical functioning." Since emerging from research labs more than a decade ago, targeted therapies for cancer have significantly improved the treatment of certain types of leukemia, digestive system tumors, and breast cancer, among other malignancies.

Acute Myeloid Leukemia Study Supports Knowledge Bank Approach to Personalized Therapy in Cancer

An international collaboration led by clinical researchers at the Wellcome Trust Sanger Institute has shown proof-of-concept that truly personalized therapy will be possible in the future for people with cancer. Details of how a knowledge bank could be used to find the best treatment option for people with acute myeloid leukaemia (AML) were published online on January 16, 2017 in Nature Genetics. The article is titled “Precision Oncology for Acute Myeloid Leukemia Using a Knowledge Bank Approach.” AML is an aggressive blood cancer that develops in bone marrow cells. Earlier this year, the team reported that there are eleven types of AML, each with distinct genetic features. Now they report how a patient's individual genetic details can be incorporated into predicting the outcome and treatment choice for that patient. The scientists built a knowledge bank using data from 1,540 patients with AML who participated in clinical trials in Germany and Austria, combining information on genetic features, treatment schedule, and outcome for each person. From this, the team developed a tool that shows how the experience captured in the knowledge bank could be used to provide personalized information about the best treatment options for a new patient. There are two major treatment options for young patients with AML - a stem cell transplant or chemotherapy. Stem cell transplants cure more patients overall, but up to one in four people die from complications of the transplant and a further one in four experience long-term side effects. Weighing up the benefits of better cure rates with transplant against the risks of worse early mortality is a harrowing decision for patients and their clinicians. The team showed that these benefits and risks could be accurately calculated for an individual patient, enabling therapeutic choices to become personalized.

Genetically Altered Rabies Viruses Reveal Wiring in Transparent Mouse Brains; Viral Tool for Assessing Connectivity of Cell Transplants

Scientists under the leadership of the University of Bonn have harnessed rabies viruses for assessing the connectivity of nerve cell transplants: coupled with a green fluorescent protein, the viruses show where replacement cells engrafted into mouse brains have connected to the host neural network. A clearing procedure which turns the brain into a “glass-like state” and light sheet fluorescence microscopy are used to visualize host-graft connections in a whole-brain preparation. The approach opens exciting prospects for predicting and optimizing the ability of neural transplants to functionally integrate into a host nervous system. The results were published online on January 19, 2017 in Nature Communications. The open-access article is titled “Whole-Brain 3D Mapping of Human Neural Transplant Innervation.” Many diseases and injuries result in a loss of nerve cells. Scientists are working on tackling this challenge by transplanting neurons. In Parkinson’s disease, for instance, this is attempted with implanted dopamine-producing nerve cells. The key question for such techniques is whether the implanted cells actually connect with the existing neural network of the host brain and thus compensate the functional loss. “Previous methods only provided an incomplete or very small-scale insight into the functional integration of implanted neurons in the brain,” says Professor Oliver Brüstle from the Institute of Reconstructive Neurobiology at the University of Bonn and LIFE & BRAIN GmbH.

Millions with Metabolic Syndrome May Need More Vitamin E; Conventional Blood Tests Found Inadequate

New research has shown that people with metabolic syndrome need significantly more vitamin E - which could be a serious public health concern, in light of the millions of people who have this condition that's often related to obesity. A study published online on January 11, 2017 in the American Journal of Clinical Nutrition also made it clear that conventional tests to measure vitamin E levels in the blood may have limited accuracy compared to tests made in research laboratories, to the point that conventional tests can actually mask an underlying problem. The new article is titled “Metabolic Syndrome Increases Dietary alpha-Tocopherol Requirements As Assessed Using Urinary and Plasma Vitamin E Catabolites: A Double-Blind, Crossover Clinical Trial.” Vitamin E - one of the more difficult micronutrients to obtain by dietary means - is an antioxidant important for cell protection. It also affects gene expression, immune function, aids in repair of wounds and the damage of atherosclerosis, is important for vision and neurologic function, and largely prevents fat from going rancid. Nutrition surveys have estimated that 92 percent of men and 96 percent of women in the United States fail to get an adequate daily intake of vitamin E in their diet. It is found at high levels in almonds, wheat germ, various seeds and oils, and at much lower levels in some vegetables and salad greens, such as spinach and kale. This study was done by researchers in the Linus Pauling Institute at Oregon State University (OSU) and the Human Nutrition Program at The Ohio State University, as a double-blind, crossover clinical trial focusing on vitamin E levels in people with metabolic syndrome. It was supported by the National Institutes of Health, the National Dairy Council, and DSM Nutrition.

Scientists Discover Mechanism by Which Stress Hormone FGF21 Protects Pancreas from Digestive Enzymes; Finding May Lead to New Therapies for Pancreatitis, a Key Adverse Effect of Alcoholism

University of Texas (UT) Southwestern Medical Center researchers have uncovered the mechanism by which the stress hormone FGF21 keeps digestive enzymes from damaging the pancreas. The research, published online on January 12, 2017 in Cell Metabolism, points to the possibility of new therapies for pancreatitis, a potentially life-threatening inflammation of the pancreas. The article is titled “FGF21 Is an Exocrine Pancreas Secretagogue.” Pancreatitis can have many causes, including heavy, long-term alcohol drinking, gallstones, and certain hereditary conditions. Approximately 210,000 U.S. residents are hospitalized with acute pancreatitis annually, according to the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases. Dr. David Mangelsdorf (left in photo) and Dr. Steven Kliewer (right in photo) – who have run a joint laboratory at UT Southwestern since 2002 – earlier reported that the liver hormone FGF21, or fibroblast growth factor 21, acts via the brain’s reward pathway to reduce the desire for sugar and alcohol in mammals. In November 2016, they published a collaborative study with European researchers comparing the genomes of more than 105,000 light and heavy social drinkers. That investigation identified a gene variant for the brain’s FGF21 receptors that suppresses the desire to drink alcohol. The researchers then turned their attention from FGF21’s effects in the central nervous system to the digestive system, where another mystery awaited. “Previous studies had shown that FGF21 protected the pancreas, but it was unknown how or by what mechanism,” said Dr. Mangelsdorf, Chair of Pharmacology and a Howard Hughes Medical Institute Investigator.

Caloric Restriction Improves Health and Survival in Rhesus Monkeys

Settling a persistent scientific controversy, a long-awaited report shows that restricting calories does indeed help rhesus monkeys live longer, healthier lives. A remarkable collaboration between two competing research teams -- one from the University of Wisconsin (UW)-Madison and one from the National Institute on Aging (NIA) -- is the first time the groups worked together to resolve one of the most controversial stories in aging research. The findings by the collaboration -- including Senior Scientist Ricki Colman of the Wisconsin National Primate Research Center and UW-Madison Associate Professor of Medicine Rozalyn Anderson; and NIA Staff Scientist and Nonhuman Primate Core Facility Head Julie Mattison and Senior Investigator and Chief of the Translational Gerontology Branch Rafael de Cabo -- were published online on January 17, 2017) in the journal Nature Communications. The open-access article is titled “Caloric restriction improves health and survival of rhesus monkeys.” In 2009, the UW-Madison study team reported significant benefits in survival and reductions in cancer, cardiovascular disease, and insulin resistance for monkeys that ate less than their peers. In 2012, however, the NIA study team reported no significant improvement in survival, but did find a trend toward improved health. "These conflicting outcomes had cast a shadow of doubt on the translatability of the caloric-restriction paradigm as a means to understand aging and what creates age-related disease vulnerability," says Dr. Anderson, one of the report's corresponding authors. Working together, the competing laboratories analyzed data gathered over many years and including data from almost 200 monkeys from both studies. Now, scientists think they know why the studies showed different results.

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