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August 27th, 2017

PCSK9 Is a Co-Activator of Platelet Function Beyond Its Role In Cholesterol Homeostasis

PCSK9 is a co-activator of platelet function beyond its role in cholesterol homeostasis, according to research presented at European Society of Cardiology (ESC) Congress on August 27, 2017, in Barcelona (August 26-30). The findings suggest that PCSK9 inhibitors, a new class of cholesterol-lowering treatments, may also reduce thrombosis by interfering with platelet activation. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a main player in cholesterol homeostasis by inducing degradation of the low-density lipoprotein (LDL) cholesterol receptor. Emerging evidence indicates that plasma levels of PCSK9 predict recurrent cardiovascular events, for example myocardial infarction and angina, in patients with coronary artery disease, even in those with well controlled LDL cholesterol levels. "We hypothesized that the contribution of PCSK9 to cardiovascular events might be mediated by as yet unknown cholesterol-independent pathways," said last author Dr. Marina Camera, Associate Professor of Pharmacology, University of Milan, Italy. "It has been reported that increased plasma levels of PCSK9 are associated with platelet reactivity. However, no study has so far evaluated whether or not PCSK9 directly affects the function of platelets." Platelets play a key role in the acute, thrombotic complications of atherosclerosis by causing life-threatening ischemic events at a late stage of the disease. Increased platelet activation (called platelet hyperreactivity) has been reported in patients with coronary artery disease and type 2 diabetes mellitus. This study evaluated whether PCSK9 modulates platelet activation. It also assessed whether PCSK9 is expressed in platelets from healthy subjects, stable angina patients, and patients with type 2 diabetes mellitus.

August 25th

CareFirst BlueCross BlueShield and Exosome Diagnostics Announce Evidence Development Collaboration for Molecular Diagnostic Tests

On August 24, 2017, CareFirst BlueCross BlueShield (CareFirst) and Exosome Diagnostics, Inc. (ExoDx) announced that they have signed an agreement to collaborate on evidence development studies for ExoDx® diagnostic tests. The collaboration is designed to evaluate new products using clinical outcome and cost analyses with the goal of accelerating health plan coverage for products demonstrating measurable benefits for patient care. The agreement is the first in a series of such agreements through CareFirst’s new HealthWorx program, which enables CareFirst to work with small, early-stage companies to bring new technologies and care advances to CareFirst’s members and providers with the goal of improving health care quality and reducing costs. Under the terms of the agreement, CareFirst will become ExoDx’s preferred partner for evidence development studies. CareFirst and ExoDx will mutually agree on the diagnostic tests to be studied, the extent and qualifications of providers participating in these studies, and the study endpoints. The initial collaboration between ExoDx and CareFirst will center on the company’s EPI test (ExoDx® Prostate IntelliScore). The EPI test is a “rule out” test designed to more accurately predict whether a patient presenting for an initial biopsy does not have high-grade prostate cancer and, thus, could potentially avoid the discomfort, complications and cost of an initial biopsy and, instead, continue to be monitored. “One of the challenges presented by prostate-specific antigen (PSA) cancer screenings is the relatively high number of false positives detected from PSA results which often fall into a ‘gray’ zone and require further testing through biopsies,” said Dr. Rahul Rajkumar, CareFirst’s Chief Medical Officer.

August 24th

Tyrosine Kinase Inhibitor Slows Cyst Growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD) in New Study

A cancer drug called bosutinib may inhibit the growth of cysts in patients with autosomal dominant polycystic kidney disease (ADPKD), according to a study published online on August 24, 2017 in the Journal of the American Society of Nephrology (JASN). The JASN article is titled “Bosutinib Versus Placebo for Autosomal Dominant Polycystic Kidney Disease." The findings point to a potential new treatment strategy for affected patients, but the long-term benefits remain to be determined. ADPKD is an inherited disorder that affects up to 1 in 1000 people and is characterized by cysts in the kidney and other organs. As patients' kidney volume increases due to cyst growth, they gradually lose their kidney function and often develop kidney failure. Current treatments are primarily supportive, such as focusing on hypertension and other secondary complications. The inherited mutations that cause ADPKD affect a protein involved in various signaling pathways that often involve enzymes called tyrosine kinases. Therefore, a team led by Vladimir Tesar, MD, PhD (Charles University and General University Hospital, in the Czech Republic) tested the potential of an investigational drug called bosutinib that inhibits a particular tyrosine kinase called Src/Bcr-Abl. (Bosutinib is approved for the treatment of certain cases of chronic myeloid leukemia). The phase 2 study included patients with ADPKD who were randomized 1:1:1 to bosutinib 200 mg/day, bosutinib 400 mg/day, or placebo. Of 172 patients enrolled, 169 received at least one treatment. The higher dose of bosutinib was not well tolerated. The annual rate of kidney enlargement was reduced by 66% for patients receiving bosutinib 200 mg/day vs. those receiving placebo (1.63% vs. 4.74%, respectively) and by 82% for all patients receiving bosutinib vs.

Scientists Develop Innovative System to Characterize Regulatory DNA Sequences Responsible for Human Diseases

Scientists from the Children’s Medical Center Research Institute at the University of Texas (UT) Southwestern (CRI) have developed an innovative system to identify and characterize the molecular components that control the activities of regulatory DNA sequences in the human genome. The genome, which is the complete complement of human DNA, including all protein-coding genes, has nearly 3 billion base pairs. Despite its vast size, only 2 percent of our genome codes for proteins. The other 98 percent is comprised of noncoding regions that regulate where and when the protein-coding genes are activated. These noncoding regions have repeatedly been identified by human genetics and cancer genomic studies as potential drivers for human diseases such as cancer. A better understanding of these regulatory regions and the underlying principles that guide when genes are turned on and off is necessary to uncover how diseases develop and to find new treatments. However, the tools to identify these noncoding regions and to understand how they work are limited. They require the prior identification of the protein factors that regulate these regions, depend on the availability of reagents such as antibodies, and often need sophisticated genetic manipulations. The new system, developed by researchers in the Dr. Jian Xu lab and published in the August 24, 2017 issue of Cell, is paving the way for an in-depth look at these regulatory genetic elements. This system, named CAPTURE (CRISPR Affinity Purification in situ of Regulatory Elements), provides an approach to simultaneously isolate genomic sequence-associated proteins, as well as their RNA and DNA interactions.

August 21st

Gut Microbes May Communicate with Brain Metabolites through Cortisol; Finding May Suggest Potential Mechanism to Explain Characteristics of Autism

Gut microbes have been in the news a lot lately. Recent studies show these microbes can influence human health, behavior, and certain neurological disorders, such as autism. But just how do they communicate with the brain? Results from a new University of Illinois (U of I) study suggest a pathway of communication between certain gut bacteria and brain metabolites, by way of a compound in the blood known as cortisol. And unexpectedly, the finding provides a potential mechanism to explain the characteristics of autism. The new work was published online on July 13, 2017 in Gut Microbes and the open-access article is titled "Serum Cortisol Mediates the Relationship Between Fecal Ruminococcus and Brain N-Acetylaspartate in the Young Pig.” "Changes in neuro-metabolites during infancy can have profound effects on brain development, and it is possible that the microbiome -- or collection of bacteria, fungi, and viruses inhabiting our gut -- plays a role in this process," says Austin Mudd, a doctoral student in the Neuroscience Program at U of I. "However, it is unclear which specific gut bacteria are most influential during brain development and what factors, if any, might influence the relationship between the gut and the brain." The researchers studied 1-month-old piglets, which are remarkably similar to human infants in terms of their gut and brain development. The scientists first identified the relative abundances of bacteria in the feces and ascending colon contents of the piglets, then quantified concentrations of certain compounds in the blood and in the brain. "Using the piglet as a translatable animal model for human infants provides a unique opportunity for studying aspects of development which are sometimes more difficult or ethically challenging to collect data on in human infants," Mudd says.

August 21st

Linus Pauling Lives--Scientists Discover Vitamin C Regulates Stem Cell Function and Suppresses Leukemia Development

Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at the University of Texas (UT) Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia. “We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of the CRI. The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published online on August 21, 2017 in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells. The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures – taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) – a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet as humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans.

Mutational Signature Points to Ways, in Addition to BRCA1 and BRCA2 Mutations, That DNA Repair Mechanism Can Be Shut Off in Breast Cancer

A mutation pattern or “signature” linked to defects in two genes points to other ways an important DNA repair mechanism can be shut off in breast cancer. Breast cancer cells with defects in the DNA damage repair-genes BRCA1 and BRCA2 have a mutational signature (a pattern of base exchanges -- e.g., T's for G's, C's for A's -- throughout a genome) known in cancer genomics as "Signature 3." But not all breast tumor cells exhibiting Signature 3 have BRCA1 or BRCA2 mutations. Therefore, some consider Signature 3 a biomarker for "BRCAness," a sign of a breakdown in BRCA-related DNA repair (a process called homologous recombination, or HR) in general and not BRCA damage in particular. The question is, what else might deactivate HR and give rise to Signature 3? And beyond that, might Signature 3 have a role in the clinic? To find out, an international team led by Drs. Paz Polak, Jaegil Kim, Lior Braunstein, and Gad Getz of the Broad Institute's Cancer Program, and Dr. William Foulkes of McGill University reanalyzed data from nearly 1,000 breast cancer tumors collected by The Cancer Genome Atlas (TCGA). Their findings, reported online on August 21, 2017 in Nature Genetics, hint that mutational signatures like Signature 3 might fuel a precision medicine approach that uses a tumor's full scope of mutations to guide risk and treatment decisions, instead of focusing on individual genes. The article is titled “A Mutational Signature Reveals Alterations Underlying Deficient Homologous Recombination Repair in Breast Cancer.” Among the breast tumors exhibiting Signature 3, the researchers found that: (1) Tumors with germline (inherited) or somatic (acquired) BRCA1 or BRCA2 mutations were overwhelmingly positive for Signature 3.

People Who Hear Voices Can Detect Disguised Speech in Unusual Sounds

People who hear voices that other people can't hear may use unusual skills when their brains process new sounds, according to research led by Durham University and University College London (UCL). The study, published online on August 20, 2017 in the academic journal Brain, found that voice-hearers could detect disguised speech-like sounds more quickly and easily than people who had never had a voice-hearing experience. The open-access article is titled “Distinct processing of ambiguous speech in people with non-clinical auditory verbal hallucinations.” The findings suggest that voice-hearers have an enhanced tendency to detect meaningful speech patterns in ambiguous sounds. The researchers say this insight into the brain mechanisms of voice-hearers tells us more about how these experiences occur in voice-hearers without a mental health problem, and could ultimately help scientists and clinicians find more effective ways to help people who find their voices disturbing. The study involved people who regularly hear voices, also known as auditory verbal hallucinations, but do not have a mental health problem. Participants listened to a set of disguised speech sounds known as sine-wave speech while they were having an MRI brain scan. Usually these sounds can only be understood once people are either told to listen out for speech, or have been trained to decode the disguised sounds. Sine-wave speech is often described as sounding a bit like birdsong or alien-like noises. However, after training, people can understand the simple sentences hidden underneath (such as "The boy ran down the path" or "The clown had a funny face"). In the experiment, many of the voice-hearers recognized the hidden speech before being told it was there, and on average they tended to notice it earlier than other participants who had no history of hearing voices.

Carbohydrates in Mother’s Milk Show Antimicrobial Activity

Mother's milk, which consists of a complex and continually changing blend of proteins, fats, and sugars, helps protect babies against bacterial infections. In the past, scientists have concentrated their search for the source of its antibacterial properties on the proteins it contains. However, an interdisciplinary team of chemists and doctors at Vanderbilt University has discovered that some of the carbohydrates in human milk not only possess antibacterial properties of their own, but also enhance the effectiveness of the antibacterial proteins also present. "This is the first example of generalized, antimicrobial activity on the part of the carbohydrates in human milk," said Assistant Professor of Chemistry Steven Townsend, who directed the study. "One of the remarkable properties of these compounds is that they are clearly non-toxic, unlike most antibiotics." The results were presented on August 20, 2017 at the annual meeting of the American Chemical Society (ACS) in Washington, DC by doctoral student Dorothy Ackerman and published in the ACS Infectious Diseases journal on June 1, 2017 in a paper titled "Human Milk Oligosaccharides Exhibit Antimicrobial and Anti-Biofilm Properties Against Group B. Streptococcus." The basic motivation for the research was the growing problem of bacterial resistance to antibiotics, which the Center for Disease Control and Prevention (CDC) estimates causes 23,000 deaths annually."We started to look for different methods to defeat infectious bacteria. For inspiration, we turned to one particular bacteria, Group B Strep. We wondered whether its common host, pregnant women, produces compounds that can either weaken or kill strep, which is a leading cause of infections in newborns worldwide," Dr. Townsend said.

Researchers Discover lincRNA That May Hold Key to Triggering Regeneration & Repair of Damaged Heart Cells

New research has discovered a potential means to trigger damaged heart cells to self-heal. The discovery could lead to ground-breaking forms of treatment for heart diseases. For the first time, researchers have identified a long intergenic non-coding ribonucleic acid (lincRNA) that regulates genes controlling the ability of heart cells to undergo repair or regeneration. This novel RNA, which researchers have named "Singheart,” may be targeted for treating heart failure in the future. The discovery was made jointly by A*STAR's Genome Institute of Singapore (GIS) and the National University Health System (NUHS), and was published online on August 9, 2017 in Nature Communications. The open-access article is titled “Single Cardiomyocyte Nuclear Transcriptomes Reveal a lincRNA-Regulated De-Differentiation and Cell Cycle Stress-Response In Vivo.” Unlike most other cells in the human body, heart cells do not have the ability to self-repair or regenerate effectively, making heart attack and heart failure severe and debilitating. Cardiovascular disease (CVD) is the leading cause of death worldwide, with an estimated 17.7 million people dying from CVD in 2015. CVD also accounted for close to 30% of all deaths in Singapore in 2015. In this project, the researchers used single cell technology to explore gene expression patterns in healthy and diseased hearts. The team discovered that a unique subpopulation of heart cells in diseased hearts activates gene programs related to heart cell division, uncovering the gene expression heterogeneity of diseased heart cells for the first time. In addition, the scientists also found the "brakes" that prevent heart cells from dividing and thus from self-healing. Targeting these "brakes" could help trigger the repair and regeneration of heart cells.