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Chronic Pain--Scientists Close in on Origins; New Human Study ID’s Top 10 Genes for Future Focus—All 10 Are Involved in Immune Signaling & Response; Expression of These Genes “Strikingly” Different in Males vs Females; Results "Should Have Broad Impact"

A new study by researchers at The University of Texas (UT) at Dallas, UT MD Anderson Cancer Center, UT Health Science Center at Houston, and Baylor College of Medicine has produced evidence of the source of chronic pain in humans, revealing several new targets for pain treatment. The research reported in the paper--published online on March 19, 2019 in Brain, one of the world's oldest neurology journals--examined specialized nerve cells clustered near the base of the spine. The open-access article is titled “Electrophysiological and Transcriptomic Correlates of Neuropathic Pain in Human Dorsal Root Ganglion Neurons.” Researchers took advantage of an exceedingly rare opportunity to study these nerves, called dorsal root ganglia (DRG), removed from cancer patients undergoing surgery at MD Anderson. The researchers catalogued variations in RNA expression in the dorsal root ganglia cells of patients differing by pain state and sex. Using RNA sequencing, a specialized form of gene sequencing, on those DRG cells yielded a list of promising biochemical pathways for which researchers might be able to devise analgesic (pain-relieving) drugs. "This surgery is not done at many places," said Dr. Ted Price, PhD, a senior author of the paper and Eugene McDermott Professor of Neuroscience in the UT Dallas School of Behavioral and Brain Sciences. "Our patient cohort of 21, though it doesn't sound like many, is huge, relative to any prior human chronic pain study using RNA sequencing." Chronic pain is labeled as neuropathic when it is caused by damage to nerve cells. Examples include phantom limb syndrome, pain resulting from a stroke, and the "pins and needles" sensations associated with diabetes.

New Class of Drugs (PARG Inhibitors) Could Treat Ovarian Cancer

A team of researchers across The University of Manchester (UK) has shown that a new class of drugs is able to stop ovarian cancer cells from growing. The Cancer Research UK- and Wellcome Trust-funded study, publishedon online on March 18, 2019 in Cancer Cell (https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30099-6), showed that the drugs, called poly ADP (adenosine diphosphate) ribose glycohydrolase (PARG) inhibitors, can kill ovarian cancer cells by targeting weaknesses in their ability to copy their DNA. The open-access article is titled “DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly (ADP-ribose) Glycohydrolase Inhibitors.” The first-in-class PARG inhibitor PDD00017273, was discovered in the Drug Discovery Unit at the Cancer Research UK Manchester Institute, part of The University of Manchester, as part of a targeted program to discover PARG inhibitors for the clinic. This program is currently being progressed through a collaboration with IDEAYA Biosciences, Inc. (https://www.ideayabio.com/), an oncology-focused biotechnology company committed to the discovery of breakthrough synthetic lethality medicines and immuno-oncology therapies. These findings are promising for patients diagnosed with ovarian cancer, the sixth most common cause of cancer in women in the UK and a cancer that causes more than 4,000 deaths each year in the UK. "Sadly, for the majority of women diagnosed with ovarian cancer, the cancer relapses within 12 to 18 months of their first treatment, and so there is a pressing need to develop new therapies to treat this condition" said lead scientist Professor Stephen Taylor from The University of Manchester.

Mobile DNA Element Found in Mosquito Parasite (Wolbachia) Has Potential for Infectious Disease Control

Controlling mosquito-borne illnesses, such as Dengue or West Nile virus, has historically been difficult due to a lack of effective vaccines and concerns about the environmental impact of insecticides. Thus, scientists have turned to manipulating Wolbachia, a parasitic bacterium within mosquitoes, as a way to control the reproductive fitness of mosquito populations that transmit human disease. In a new study published on March 5, 2019 in Nature Communications, an international team, including scientists from the Marine Biological Laboratory (MBL) and the University of Chicago, identified a new mobile DNA element in Wolbachia, which may contribute to improved control strategies for mosquito vectors of disease. The open-access article is titled “The Wolbachia Mobilome in Culex pipiens Includes a Putative Plasmid.” Led by former MBL scientists Julie Reveillaud, PhD, of INRA, France, and Sarah Bordenstein of Vanderbilt University (USA), the researchers reconstructed near-complete genomes of Wolbachia isolated from individual ovaries of four Culex pipiens mosquitoes. In the process, the scientists identified a novel plasmid -- a circular piece of DNA that can replicate independently of the chromosomes. Because a plasmid is a mobile DNA element, it can transfer from one cell to another and can have great implications for the fitness and evolution of a microbial species. Mobile genetic elements that can spread through different Wolbachia cells, and thus across a Wolbachia population, hold promise for controlling mosquito populations that may carry disease. "Our data show that this novel plasmid is widespread across natural Wolbachia populations that infect C. pipiens mosquitoes throughout the world, which implies it has an essential role.

Guided by Human “Super Smeller,” Scientists Use Mass Spectrometry to ID Volatile Biomarkers for Parkinson’s Disease; Novel Findings May Enable Development of Noninvasive, Biomarker-Based Test That Will Permit Early Detection of Parkinson’s

Parkinson's disease (PD) is a neurodegenerative disorder that leads to progressive brain cell death and extensive loss of motor function. Despite much research being conducted on this disease, there are no definitive diagnostic tests currently available. Now, researchers report the identification of compounds that make up the signature odor of the disease with the help an individual who can detect PD through smell. They reported their findings on March 20, 2019 in ACS Central Science, published by the American Chemical Society. The open-access article is titled “Discovery of Volatile Biomarkers of Parkinson’s Disease from Sebum.” Ancient physicians, including Hippocrates, Galenus, and Avicenna, used scent as a diagnostic tool, and although olfactory tests are not common in modern medicine, diseases such as diabetes are often associated with a particular smell. However, there has been little evidence to tie scent to neurodegenerative disorders. Enter Joy Milne (photo), a "Super Smeller," a grandmother whose late husband Les was diagnosed with PD in 1986. Milne has an extremely sensitive sense of smell, and this enables her to detect and discriminate odors not normally detected by those of average olfactory ability. Milne can distinguish the unique odor of PD, which she can detect in subjects' sebum long before clinical symptoms appear. Sebrum is a light yellow, waxy, lipid-based biofluid that is secreted by the sebaceous glands and moisturizes and protects the hair and the skin, particularly the skin on the forehead and upper back. Sebum is made up of triglycerides, free fatty acids, wax esters, squalene, cholesterol esters, and cholesterol. Excessive production of sebrum is a known symptom of PD.

University of Wisconsin-Madison Team Finds Key to Common Cancer Pathway-- Novel Regulators of p53 Identified; Discovery Related to “Guardian of the Genome” Protein Could Unlock New Therapies

Scientists have long known that the protein p53, when mutated, is a critical factor in the onset of many different kinds of cancer. In its unmutated form, however, it is known to protect against cancer. These dueling qualities make the p53 protein and the gene that codes for it among the most studied in biology, yet the molecular mechanisms that govern its stability and function have yet to be fully understood. On March 18, 2019, in Nature Cell Biology, a team led by University of Wisconsin-Madison (UW-Madison) cancer researchers Richard A. Anderson PhD, Professor, Head of Phosohoinositide Signaling Laboratory, and Vincent Cryns, MD, Chief of the Division of Endocrinology, Diabetes & Metabolism at the University of Wisconsin School of Medicine and Public Health, reported the discovery of an unexpected regulator of the critical protein, opening the door to the development of drugs that could target it. The article is titled “A Nuclear Phosphoinositide Kinase Complex Regulates p53.” "p53, like Janus, has two faces," says Dr. Anderson, referencing the two-faced Roman god of gates and doorways. "The p53 gene is the most frequently mutated gene in cancers, and, when mutated, it switches its function from a tumor suppressor to an oncogene that drives the majority of cancers." Typically, explains Dr. Anderson of the UW School of Medicine and Public Health, the p53 protein serves as "the guardian of the genome," initiating the repair of DNA damaged by ultraviolet radiation, chemicals, or other means, and preventing tumor growth. When mutated, however, the protein goes rogue, becoming more stable and abundant than its unmutated counterpart, accumulating in the nucleus of the cell and causing cancer. The UW research team, which includes study lead authors and postdoctoral fellows Dr. Suyong Choi and Dr.

Scientists Characterize, Target, & Manipulate Critical Subset of Neurons Responsible for Excessive Drinking; Major Breakthrough in Identifying Key Brain Cells May Open Door to Developing Drug Therapies or Even Gene Therapies for Alcohol Addiction

Scientists at Scripps Research Institute (La Jolla, California) have found that they can reverse the desire to drink in alcohol-dependent rats--with the flip of a switch. The researchers were able to use lasers to temporarily inactivate a specific neuronal population, reversing alcohol-seeking behavior and even reducing the physical symptoms of withdrawal. "This discovery is exciting--it means we have another piece of the puzzle to explain the neural mechanism driving alcohol consumption," says Olivier George, PhD, an Associate Professor at Scripps Research and senior author of the new study, published on March 18, 2019 in Nature Communications. The open-access article is titled “Inactivation of a CRF-Dependent Amygdalofugal Pathway Reverses Addiction-Like Behaviors in Alcohol-Dependent Rats.” Although the laser treatment is far from ready for human use, Dr. George believes identifying these neurons opens the door to developing drug therapies or even gene therapies for alcohol addiction. "We need compounds that are specific to this neuronal circuitry," Dr. George says. According to the National Institute on Alcohol Abuse and Alcoholism, more than 15.1 million adults in the United States suffer from alcohol use disorder. Previous work at Scripps Research has shown that transitioning from casual drinking to dependent drinking occurs alongside fundamental changes in how the brain sends signals. These signals drive the intense cravings that make it so difficult for many people to scale back their alcohol consumption. Dr. George and his colleagues have been hunting for the brain cells that driving drinking in an alcohol-addicted rat model. In 2016, they reported that they had found a possible source: a neuronal "ensemble," or group of connected cells in a brain region called the central nucleus of the amygdala (CeA).

Inflammation Links Heart Disease & Depression, New Study Finds

People with heart disease are more likely to suffer from depression, and the opposite is also true. Now, scientists at the University of Cambridge (UK) believe they have identified a link between these two conditions: inflammation - the body's response to negative environmental factors, such as stress. While inflammation is a natural response necessary to fight off infection, chronic inflammation (which may result from psychological stress as well as lifestyle factors such as smoking, excessive alcohol intake, physical inactivity, and obesity) is harmful. The link between heart disease and depression is well documented. People who have a heart attack are at a significantly higher risk of experiencing depression. Yet, scientists have been unable to determine whether this is due to the two conditions sharing common genetic factors or whether shared environmental factors provide the link. "It is possible that heart disease and depression share common underlying biological mechanisms, which manifest as two different conditions in two different organs--the cardiovascular system and the brain," says Dr Golam Khandaker (https://www.neuroscience.cam.ac.uk/directory/profile.php?Golam), PhD, a Wellcome Trust Intermediate Clinical Fellow at the University of Cambridge in the UK. "Our work suggests that inflammation could be a shared mechanism for these conditions." In a study published on March 19, 2019 in Molecular Psychiatry, Dr. Khandaker and colleague Dr Stephen Burgess led a team of researchers from Cambridge who examined this link by studying data relating to almost 370,000 middle-aged participants of UK Biobank.

New Evidence Supports Suggestion That Narcolepsy Is Autoimmune Disease; Cytotoxic Autoreactive CD8 T Cells Found in Patients with Narcolepsy

Researchers from the University of Copenhagen have discovered autoreactive cells in persons suffering from narcolepsy. This is a new, important proof that the sleep disorder is an autoimmune disease. This knowledge may lead to better treatment of the chronic condition, the researchers behind the new discovery believe. For many years, scientists have suspected that the sleep disorder narcolepsy is an autoimmune disease, though without being able to prove it conclusively. Now, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen, together with the Technical University of Denmark and Rigshospitalet, have found a new, important proof that their presumptions were correct. The new research results were on February 19, 2019 in Nature Communications. The open-access article is titled “CD8+ T Cells from Patients with Narcolepsy and Healthy Controls Recognize Hypocretin Neuron-Specific Antigens.” “We have found autoreactive cytotoxic CD8 T cells in the blood of narcolepsy patients. That is, the cells recognize the neurons that produce hypocretin, which regulates a person's waking state. It does not prove that they are the CD8 T cells are the ones that killed the neurons, but it is an important step forward. Now we know what the cells are after,” says the article’s senior author, Associate Professor Birgitte Rahbek Kornum (photo), PhD, from the Department of Neuroscience at the University of Copenhagen. The immune system is designed to recognize viruses and bacteria. When its cells are autoreactive - which is the case in autoimmune diseases - the immune system recognizes the body's own cells as foreign and attacks them. That the immunr cells are cytotoxic means that they are capable of killing other cells.

Blood Test Using Vibrational Spectroscopy Accurately Spots Molecular Signature of Fibromyalgia; “Could Lead to Better, More Directed Treatment for Patients," Lead Researcher Says; Unusual Collaboration with Food Science Group Key to Advance

For the first time, researchers have evidence that fibromyalgia can be reliably detected in blood samples -- work they hope will pave the way for a simple, fast diagnosis. In a study published in the February 15, 2019 issue of the Journal of Biological Chemistry, researchers from The Ohio State University report success in identifying biomarkers of fibromyalgia and differentiating it from a handful of other related diseases. Their article is titled “Metabolic Fingerprinting for Diagnosis of Fibromyalgia and Other Rheumatologic Disorders.” The discovery could be an important turning point in care of patients with a disease that is frequently misdiagnosed or undiagnosed, leaving them without proper care and advice on managing their chronic pain and fatigue, said lead researcher Kevin Hackshaw (photo), MD, an Associate Professor in Ohio State's College of Medicine and a rheumatologist at the University's Wexner Medical Center. Identification of biomarkers of the disease - a "metabolic fingerprint" like that discovered in the new study - could also open up the possibility of targeted treatments, he said. To diagnose fibromyalgia, doctors now rely on patient-reported information about a multitude of symptoms and a physical evaluation of a patient's pain, focusing on specific tender points, he said. But there's no blood test - no clear-cut, easy-to-use tool to provide a quick answer. "We found clear, reproducible metabolic patterns in the blood of dozens of patients with fibromyalgia. This brings us much closer to a blood test than we have ever been," Dr. Hackshaw said.

Huntington Disease Rate of Progression Determined by Length of Uninterrrupted CAG Repeats in DNA, Not Length of Polyglutamine Segment of Mutant Huntingtin Protein; Results Point to Importance of DNA Maintenance Mechanisms

HIn a preprint posted on January 24, 2019 by Cold Spring Harbor Laboratory’s bioRxiv, the Genetic Modifiers of Huntington’s Disease Consortium (GeM-HD), including such prominent HD experts as James Gusella, PhD, and Marcy MacDonald, PhD, both of the Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital; and Jane Paulsen, PhD, Departments of Psychiatry and Neurology, University of Iowa, make the provocative suggestion that some property of the uninterrupted CAG repeat segment in exon 1 of the huntingtin-coding gene (HTT), distinct from the resulting too-lengthy polyglutamine segment of the huntingtin protein, determines the rate at which HD develops. The article is titled “Huntington's Disease Onset Is Determined by Length of Uninterrupted CAG, Not Encoded Polyglutamine, and Is Modified by DNA Maintenance Mechanisms” ((https://www.biorxiv.org/content/biorxiv/early/2019/01/24/529768.full.pdf). According to the article abstract, “The timing of onset shows no significant association with HTT cis-eQTLs, but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms.

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