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July 8th, 2019

Scientists Identify an RNA-Binding Protein (SRSF3) As Essential for Correct Heart Contraction & Survival—Capping of Contraction-Related mRNAs Revealed As Key Process Influenced by SRSF3; This Capping Protects Against Development of Systolic Heart Failure

A team of scientists led by Dr. Enrique Lara Pezzi (photo) at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain, has identified the RNA-binding protein SRSF3 as an essential factor for proper heart contraction and survival. In a study published online on July 5, 2019 in Circulation Research, the researchers found that loss of cardiac expression of SRSF3 leads to a critical reduction in the expression of genes involved in contraction. The new article is titled “Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction.” Knowledge of the mechanism of action of SRSF3 in the heart could open the way to the design of new therapeutic approaches for the treatment of heart disease. Cardiovascular disease is the leading cause of death in the world. In 2015 alone, cardiovascular disease killed 17.7 million people, with 6.7 million of these deaths caused by heart attack. Unfortunately, knowledge is limited about the molecular mechanisms that regulate progression of a myocardial infarction, sytmying the development of new therapeutic approaches. The recent development of massive-scale mRNA sequencing technology has permitted the identification of gene expression patterns associated with the development of heart disease. Nevertheless, understanding of post-transcriptional regulation (a type of gene regulation) remains limited, in particular about the roles played by RNA-binding proteins (RBPs) in myocardial infarction and the development of heart disease. RNA-binding proteins perform important tasks in the cell. "In this study, we have investigated the role of the RBP SRSF3 in the heart, which was unknown until now," explained Dr. Lara Pezzi. Study first author Dr.

Infection-Fighting Protein (HRI) Also Senses Protein Misfolding In Non-Infected Cells; Finding May Offer Insights into Approaches to Prevent/Treat Neurodegenerative Diseases Like Parkinson’s

Researchers at the University of Toronto in Canada have uncovered an immune mechanism by which host cells combat bacterial infection, and, at the same time, found that a protein crucial to that process can sense and respond to misfolded proteins in all mammalian cells. The protein is called heme-regulated inhibitor (HRI), and the researchers showed that during bacterial infection it triggers and coordinates a chain reaction among other proteins that form a larger complex. That larger group or “signalosome” amplifies inflammation and leads to an anti-bacterial response. But HRI can also regulate protein folding in other cell types, the researchers showed. Protein folding, which helps determine the 3-D shape of a protein and is essential for its function, is implicated in non-infectious diseases including the neurodegenerative disorders Parkinson's, Alzheimer's, and ALS. "The innate immune function that we discovered is essentially a mechanism of protein scaffolding, which is important because you want a quick and orderly response to bacterial infection," says Stephen Girardin (photo), PhD, a Professor of Laboratory Medicine and Pathobiology and of Immunology at th U of Toronto. "But we also found that same pathway is important for protein scaffolding and aggregation in other cells, which opens promising research angles for neurodegenerative and other diseases." The findings were published online in Science nline on July 5, 2019. The article is titled “The Heme-Regulated Inhibitor Is a Cytosolic Sensor Of Protein Misfolding That Controls Innate Immune Signaling.” Researchers have studied HRI for over three decades, but mostly in the context of red blood cell disorders.

July 7th

First Complete Wiring Diagram of an Animal (C. elegans) Nervous System Established

In a study published online on July 3, 2019 in Nature, researchers at Albert Einstein College of Medicine in New York describe the first complete wiring diagram of the nervous system of an animal, the roundworm Caenorhabditis elegans, used by scientists worldwide as a model organism. The study includes adults of both sexes and reveals substantial differences between them. The Nature article is titled “Whole-Animal Connectomes of Both C. elegans Sexes.” The article findings mark a major milestone in the field of "connectomics," the effort to map the myriad neural connections in a brain, brain region, or nervous system to find the specific nerve connections responsible for particular behaviors. "Structure is always central in biology," said study leader Scott Emmons, PhD, Professor of Genetics and in the Dominick P. Purpura Department of Neuroscience and the Siegfried Ullmann Chair in Molecular Genetics at Einstein. "The structure of DNA revealed how genes work, and the structure of proteins revealed how enzymes function. Now, the structure of the nervous system is revealing how animals behave and how neural connections go wrong to cause disease." Researchers have hypothesized that some neurological and psychiatric disorders, such as schizophrenia and autism, are "connectopathies," that is, problems caused by "faulty wiring." "This hypothesis is strengthened by the finding that several mental disorders are associated with mutations in genes that are thought to determine connectivity," said Dr. Emmons. "Connectomics has the potential to help us understand the basis of some mental illnesses, possibly suggesting avenues for therapy." Because C.

July 6th

Triplet-Targeted Therapy Improves Survival for Patients with Advanced Colorectal Cancer and BRAF Mutations; Phase III Trial Results May Change Standard of Care for Up to 15% of Colorectal Cancer Patients

The three-drug combination of encorafenib, binimetinib, and cetuximab significantly improved overall survival (OS) in patients with BRAF-mutated metastatic colorectal cancer (mCRC), according to results of the BEACON CRC Phase III clinical trial led by researchers at The University of Texas (UT) MD Anderson Cancer Center. The treatment combination resulted in a median OS of 9 months for the combination therapy compared to 5.4 months for current standard-of-care treatment. Objective response rate (ORR) for the triplet-targeted therapy was 26 percent compared to just two percent for standard therapy. BEACON CRC is the first and only Phase III trial designed to test BRAF/MEK combination targeted therapies in patients with mCRC and the BRAF V600E mutation. BRAF mutations are estimated to occur in up to 15 percent of patients with mCRC, with V600E being the most common BRAF mutation and representing a poor prognosis for these patients. The trial results was reported on July 6at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2019 (https://www.esmo.org/Conferences/ESMO-World-GI-2019) in Barcelona, Spain, by principal investigator Scott Kopetz, MD, Associate Professor of Gastrointestinal Medical Oncology at MD Anderson. The title of the report abstract is BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E–mutant metastatic colorectal cancer. "This study builds on a decade of research into the tumor biology of BRAF-mutated colorectal cancer, and reflects a rationale combination to address the vulnerabilities unique to this tumor," said Dr. Kopetz.

Strain of Oncolytic Common Cold Virus (Coxsackievirus A21) Could Revolutionize Treatment of Bladder Cancer

A strain of the common cold virus has been found to potentially target, infect, and destroy cancer cells in patients with bladder cancer, a new study published online on July 4, 2019 in Clinical Cancer Research reports. No trace of the cancer was found in one patient following treatment with the virus. In the majority of the other 14 treated patients, evidence of cancer cell death was observed. The title of the article is “Viral Targeting of Non-Muscle Invasive Bladder Cancer and Priming of Anti-Tumour Immunity Following Intravesical Coxsackievirus A21.” Researchers from the University of Surrey and Royal Surrey County Hospital investigated the safety and tolerability of exposure to the oncolytic (“cancer-killing”) virus coxsackievirus (CVA21), a naturally occurring strain of the common cold virus, in fifteen patients with non-muscle invasive bladder cancer (NMIBC). NMIBC is found in the tissue of the inner surface of the bladder and is the tenth most common cancer in the UK with approximately 10,000 people each year diagnosed with the illness. Current treatments for this cancer are problematic. Transurethral resection, an invasive procedure that removes all visible lesions, has a high tumor recurrence rate ranging from 50 per cent to 70 per cent as well as a high tumor progression rate between 10 per cent and 20 per cent over a period of two to five years. Another common course of treatment, immunotherapy with Bacille Calmette-Guerin (BCG), a live bacterium used to treat bladder cancer, has been found to have serious side effects in one third of NMIBC patients, while one third do not respond to the treatment at all. During this pioneering study, fifteen NMIBC patients, one week prior to pre-scheduled surgery to remove their tumors, received CVA21 via a catheter in the bladder.

July 4th

Tiny Molecular Change Reverses Prediabetes in Obese Mice; Remarkable Results Point to Potential Diabetes Drug Target and Highlight Possible Role for Ceramides in Sensing Nutrition

A small chemical change -- shifting the position of two hydrogen atoms -- makes the difference between mice that are healthy and mice with insulin resistance and fatty liver, major risk factors for diabetes and heart disease. Making the change prevented the onset of these symptoms in mice fed a high-fat diet and reversed prediabetes in obese mice. The scientists changed the trajectory of metabolic disease by deactivating an enzyme called dihydroceramide desaturase 1 (DES1). Doing so stopped the enzyme from removing the final hydrogens from a fatty lipid called ceramide, having an effect of lowering the total amount of ceramides in the body. The finding highlights a role for ceramides in metabolic health and pinpoints DES1 as a "druggable" target that could be used to develop new therapies for metabolic disorders such as prediabetes, diabetes, and heart disease -- that affect the health of hundreds of millions of Americans. Scientists at University of Utah Health and Merck Research Laboratories led the research, published online in Science on July 4, 2019. The article is titled “Targeting a Ceramide Double Bond Improves Insulin Resistance and Hepatic Steatosis.” "We have identified a potential therapeutic strategy that is remarkably effective, and underscores how complex biological systems can be deeply affected by a subtle change in chemistry," says Scott Summers (at right in photo), PhD, Chair of Nutrition and Integrative Physiology at U of Utah Health, who was co-senior author on the study with David Kelley, MD, formerly of Merck Research Laboratories. "Our work shows that ceramides have an influential role in metabolic health," says Dr. Summers. "We're thinking of ceramides as the next cholesterol." This isn't the first time that Dr.

Scientists Apply Bacterial Homing Capability to Enable Stem Cells to Home to Heart Tissue; Approach Offers “Enormous Potential” for Millions Suffering from Heart Disease Around the Globe

In a world first, scientists have found a new way to direct stem cells to heart tissue. The findings, led by researchers at the University of Bristol in the UK and published recently in Chemical Science, could radically improve the treatment for cardiovascular disease, which causes more than a quarter of all deaths in the UK. The open-access article is titled “Designer Artificial Membrane Binding Proteins to Direct Stem Cells to the Myocardium.” To date, trials using stem cells, which are taken and grown from the patient or donor and injected into the patient's heart to regenerate damaged tissue, have produced promising results. However, while these next-generation cell therapies are on the horizon, significant challenges associated with the distribution of the stem cells have remained. High blood flow in the heart combined with various “tissue sinks” that circulating cells come into contact with, means the majority of the stem cells end up in the lungs and spleen. Now, researchers from Bristol's School of Cellular and Molecular Medicine have found a way to overcome this by modifying stem cells with a special protein so the stem cells “home” to heart tissue. Dr. Adam Perriman, the study's lead author, Associate Professor in Biomaterials, UKRI Future Leaders Fellow and founder of the cell therapy technology company CytoSeek (https://www.cytoseek.uk/), explained: "With regenerative cell therapies, where you are trying to treat someone after a heart attack, the cells rarely go to where you want them to go. Our aim is to use this technology to re-engineer the membrane of cells, so that when they're injected, they'll home to specific tissues of our choice.”

June 29th

New, Low-Cost OCT Retinal Scanner Could Help Prevent Blindness Worldwide; Duke-Led Effort Creates Portable, Much Cheaper Device Nearly As Accurate As Current Very Costly Standard-of-Care OCT Instruments

Biomedical engineers at Duke University in North Carolina have developed a low-cost, portable optical coherence tomography (OCT) scanner that promises to bring the vision-saving technology to underserved regions throughout the United States and abroad. Thanks to a redesigned, 3D-printed spectrometer, the scanner is 15 times lighter and smaller than current commercial systems (image shows example of a typically bulky current commercial system) and is made from parts costing less than a tenth the retail price of commercial systems -- all without sacrificing imaging quality. In its first clinical trial, the new OCT scanner produced images of 120 retinas that were 95 percent as sharp as those taken by current commercial systems, which was sufficient for accurate clinical diagnosis. The results were published online on June 28, 2019 in Translational Vision Science & Technology, an ARVO journal. The open-access article is titled “First Clinical Application of Low-Cost OCT." In use since the 1990s, OCT imaging has become the standard of care for the diagnosis of many retinal diseases, including macular degeneration and diabetic retinopathy, as well as for glaucoma. However, OCT is rarely included as part of a standard screening exam because machines can cost more than $100,000 -- meaning that usually only larger eye centers have them. "Once you have lost vision, it's very difficult to get it back, so the key to preventing blindness is early detection," said Adam Wax, PhD, Professor of Biomedical Engineering at Duke. "Our goal is to make OCT drastically less expensive so more clinics can afford the devices, especially in global health settings." OCT is the optical analogue of ultrasound, which works by sending sound waves into tissues and measuring how long the waves take to come back.

Archaeological Mystery Solved with Modern Genetics -- Y Chromosomes Reveal Population Boom and Bust in Ancient Japan

Researchers at the University of Tokyo conducted a census of the Japanese population of approximately 2,500 years ago using the Y chromosomes of men living on the main islands of modern-day Japan. This is the first time that analysis of modern genomes has estimated the size of an ancient human population before they were met by a separate ancient population. The research was published online on June 17, 2019 in Scientific Reports. The open-access article is titled “Analysis of Whole Y-Chromosome Sequences Reveals the Japanese Population History in the Jomon Period.” "Evidence at archaeological dig sites has been used to estimate the size of ancient human populations, but the difficulty and unpredictability of finding those sites is a big limitation. Now we have a method that uses a large amount of modern data," said Associate Professor Jun Ohashi, PhD, an expert in human evolutionary genetics and leader of the research team that performed the analysis. The current theory on human migrations into Japan is that the original inhabitants, the Jomon people, were met about 2,500 years ago by a separate group coming mainly from the Korean Peninsula, the Yayoi people. Archaeologists have identified fewer Jomon sites from the Late Jomon Period, the era immediately before the Yayoi arrival. Global temperatures and sea levels dropped during that period, which could have made life more difficult for the hunter-gatherer Jomon people. When the Yayoi people arrived, they brought wet rice farming to Japan, which would have led to a more stable food supply for the remaining Jomon people living with the new Yayoi migrants. The lesser amount of archaeological remains from the Late Jomon Period could be evidence of an actual population decline, or just that the archaeological dig sites have not yet been found. Dr.

June 21st

Cancer-Sniffing Dogs 97% Accurate in Identifying Lung Cancer in Blood Serum of Patients Versus Controls

Three beagles successfully showed they are capable of identifying lung cancer by scent, a first step in identifying specific biomarkers for the disease. Researchers say the dogs' abilities may lead to development of effective, safe, and inexpensive means for mass cancer screening. After eight weeks of training, the beagles--chosen for their superior olfactory receptor genes--were able to distinguish between blood serum samples taken from patients with malignant lung cancer and healthy controls with 97% accuracy. The double-blind study was published online on June 17, 2019 in The Journal of the American Osteopathic Association. The open-access article is titled “Accuracy of Canine Scent Detection of Non–Small Cell Lung Cancer in Blood Serum.” "We're using the dogs to sort through the layers of scent until we identify the tell-tale biomarkers," says Thomas Quinn, DO, Professor at Lake Erie College of Osteopathic Medicine and lead author on this study. "There is still a great deal of work ahead, but we're making good progress." The dogs were led into a room with blood serum samples at nose level. Some samples came from patients with non-small cell lung cancer; others were drawn from healthy controls. After thoroughly sniffing a sample, the dogs sat down to indicate a positive finding for cancer or moved on if none was detected. Dr. Quinn and his team are nearing completion of a second iteration of the study. This time the dogs are working to identify lung, breast, and colorectal cancer using samples of patients' breath, collected by the patient breathing into a face mask. Researchers say findings suggest the dogs are as effective detecting cancer using this method.