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Archive - Aug 2017

August 27th

Study of Worm Infection Reveals Cross-Talk in Lymph Nodes

Lymph nodes are small, kidney-shaped organs found throughout the body. Full of immune cells, the lymph nodes’ function is to clear out foreign objects and support the immune system. Lymph nodes communicate with the tissues and with each other through the lymphatic vessels, which carry fluids and objects from the tissues and back out to the bloodstream. Normally, lymphatic vessels grow during the embryo stage, but also in adults during wound healing, cancer, and inflammation. But the exact mechanism of this "lymphangiogenesis" is yet unknown. Ecole Polytechnique Fédérale de Lausanne (EPFL) scientists have now identified the molecules that signal the growth of lymphatic vessels during worm infections. The work was published on August 28, 2017 in Nature Communications. The open-access article is titled “Interactions Between Fibroblastic Reticular Cells and B Cells Promote Mesenteric Lymph Node Lymphangiogenesis.” The lymphatic vessels drain pathogens from tissues to the collecting lymph nodes, where immune responses begin. These vessels also allow lymphocytes and dendritic cells --which expose pathogen material to trigger the immune system -- to flow in and out of the lymph nodes. Because of this, lymphangiogenesis is important for immune responses against infections. But recent studies have shown that lymphangiogenesis can also regulate immune responses during inflammation. This connection between inflammation and lymphangiogenesis is key in our understanding of the adaptive immune response, which is the slower but more specialized wave against infections and involves T and B cells. The lab of Dr. Nicola Harris at EPFL looked at the mesenteric lymph node, which collects fluids and material from the intestine of mice. The research, led by Dr.

Microbes Compete for Nutrients, Affect Metabolism & Development in Mice

"Gut bacteria get to use a lot of our food before we do," says Dr. Federico Rey, a Professor of Bacteriology at the University of Wisconsin-Madison. Then we get their leftovers -- or their waste. The problem, says Dr. Rey, is that if our microbiome overindulges, we might not have access to the nutrients we need. That's the suggestion from new research conducted by Dr. Rey's group that shows mice that harbor high levels of microbes that eat choline are deprived of this essential nutrient. Compared to mice without choline-hungry bacteria, the choline-starved mice had an increased susceptibility to metabolic diseases and gave birth to pups with biochemical alterations in the brain and that exhibited more anxious behaviors. The study was published online on July 31, 2017 in Cell Host & Microbe. UW-Madison Professor of Bacteriology Daniel Amador-Noguez and researchers from Harvard University also contributed to the work. The article is titled “Metabolic , Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption.” Epigenetic regulation -- the decorating of genes with chemical groups that control how much they are expressed -- appears to underlie the effects of gut bacteria that consume too much choline. Choline contributes to the pool of resources that cells use to make these modifications to DNA, and with less choline available, the cell's ability to modify and regulate genes can be impaired. Tissues from the liver to the brain had altered epigenetic patterns in mice with high levels of choline-eating microbes. "Epigenetic modifications change how genes are expressed," explains Kym Romano, a graduate student in Dr. Rey's group and one of the lead authors of the new research.

August 27th

Half-Way Milestone Reached in Development of Kinase Chemogenomic Set

The Structural Genomics Consortium at the University of North Carolina at Chapel Hill (SGC-UNC), in partnership with the DiscoverX Corporation, has reached the milestone halfway point in its development of the Kinase Chemogenomic Set, a potent group of inhibitors which allow deeper exploration of the human kinome, a family of enzymes critical to understanding human disease and developing new therapies. By building this selective set of compounds and making it freely available, UNC-Chapel Hill and its partners are offering the scientific community a better understanding of the roles the kinome plays in human disease and the ability to collaborate on the discovery and advancement of new therapies. The kinome, made up of enzymes called kinases, provides a tremendous opportunity for drug discovery. While more than 30 kinase inhibitors have been approved for the treatment of disease, the kinome has been largely unexplored until SGC-UNC, DiscoverX, and other SGC partner companies embarked on this project. "Through our collaboration with DiscoverX, we screened a large set of compounds that we call Published Kinase Inhibitor Set 2, and these results allowed us to reach the halfway point in constructing the KCGS" said Dr. David Drewry, a Research Associate Professor at the UNC Eshelman School of Pharmacy and SGC-UNC principal investigator who is leading the project to develop the Kinase Chemogenomic Set. "To mark this milestone and in keeping with our mission of open science, we are releasing these results into the public domain. We sincerely thank all of our co-author partners whose vision, generosity and hard work makes the construction of this set possible." A publication describing the team's strategy and progress toward achieving a comprehensive KCGS was posted online in PLOS ONE on August 2, 2017.

New Research on Fragile X Syndrome Reinforces Importance of Early Detection

Fragile X syndrome--the most common heritable cause of autism spectrum disorder--is something of a phantom. It interferes with the production of a protein critical to synapse formation during a brief period in early development when the brain is optimizing its ability to process sensory input. Then it dials way down...leaving behind permanent changes in neural circuit structure that can cause low IQ, learning disabilities, and hypersensitivity, along with other symptoms characteristic of ASD. This picture of the basic nature of Fragile X has been reinforced by a series of studies reported in a paper titled "Fragile X Mental Retardation Protein Requirements in Activity Dependent Critical Period Neural Circuit Refinement" published in the August 7,2017 issue of Current Biology. The article is titled “Fragile X Mental Retardation Protein Requirements in Activity-Dependent Critical Period Neural Circuit Refinement.” The research was conducted by a team of researchers in the Broadie Laboratory at Vanderbilt University--Kendal Broadie, Stevenson Professor of Neurobiology, postdoctoral fellow Dr. Caleb Doll, and graduate student Dominic Vita--who employed a battery of state-of-the-art techniques to document the effects that the lack of a critical protein caused by the syndrome, called the Fragile X Mental Retardation Protein (FMRP), has on the development of the brain and nervous system of the Drosophila disease model."Our research confirms that the Fragile X protein is essential for refining the brain's ability to process sensory information. The brains of individuals with the syndrome look perfectly normal. They can walk, talk, and chew gum, just not at peak performance," Dr. Broadie said.

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.