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Archive - 2019

August 19th

Protein (FLRT3) with Roles In Neuron Development & Cell Adhesion May Be a Key Factor in Generation of Neuropathic Pain; Blocking FLRT3 Activity May Offer Possible Avenue to Reducing Such Pain

Researchers from Japan's Osaka University have made an important leap in our understanding of how chronic pain conditions develop. In a study published online on July 25, 2019 in the Journal of Neuroscience, the team explains how a protein previously implicated in neuron growth and cell adhesion is also critical for the development of pain sensitization (see image below). The article is titled “Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3 in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats.” Neuropathic pain is a chronic condition arising from previous nerve injury or certain diseases, including diabetes, cancer, and multiple sclerosis. Affected patients often display hypersensitivity to normally non-painful stimuli such as touch or repetitive movement, with pain commonly manifesting as shooting burning sensations, numbness, or pins and needles. In many cases, the pain cannot be relieved with analgesics. In humans, the spinal cord dorsal horn acts as a sorting station for pain stimuli. Signals coming in from peripheral areas of the body are processed and then transmitted via secondary neurons to the brain. Importantly, this is a key region in the development of neuropathic pain; studies have linked the condition to abnormal neuronal excitability in the spinal cord dorsal horn. However, what causes these neurons to become overly excited remains a mystery. FLRT3 (fibronectin leucine-rich transmembrane protein-3) is a protein commonly found in both embryonic and adult nervous systems. And while researchers don't know exactly what role it plays in adult tissues, FLRT3 has been implicated in synapse formation and cell adhesion in the developing brain.

Phase 1 Trial Will Evaluate Combination of Fecal Transplant & Immunotherapy in Treating Melanoma

According to an August 16, 2019 press release, a multidisciplinary team at Lawson Health Research Institute in Canada is exploring whether fecal transplants can improve outcomes in melanoma patients treated with immunotherapy. Immunotherapy drugs stimulate a person's immune system to attack and destroy cancer. While these immunotherapy drugs can significantly improve survival outcomes in those with melanoma, they are only effective in 40 to 50 per cent of patients. Preliminary research has suggested that the human microbiome - the diverse collection of microbes in our body - may play a role in whether or not a patient responds. "The gut microbiome helps establish immunity from an early age. It makes sense that a healthy gut could improve response to immunotherapy," explains Dr. Jeremy Burton, a Lawson Scientist who specializes in human microbiome research. "This led us to consider the potential of fecal transplants." Fecal transplants involve collecting stool from a healthy donor, preparing it in a lab, and transplanting it to the patient. The goal is to transplant the donor's microbiome so that healthy bacteria will colonize in the patient's gut. In a phase I clinical trial, the research team at Lawson is the first in Canada to study the use of fecal transplants to alter a cancer patient's microbiome and improve their response to anti-PD1 immunotherapy drugs. Research participants will be 20 melanoma patients recruited from the London Regional Cancer Program (LRCP) at London Health Sciences Centre (LHSC) in London, Ontario, Canada. Each patient will undergo a fecal transplant at St. Joseph's Hospital, a part of St. Joseph's Health Care London, followed by immunotherapy at LRCP. The transplant will consist of taking a number of specially-prepared oral capsules.

August 18th

Variant of Peptide Now in Trials for Wound Therapy Could Limit “Bystander Effect” Damage in Heart Attacks; Group Hopes to Develop Exosome-Based Approach to Delivery of Potentially Protective Peptide

Imagine there were a drug that you could take soon after a heart attack that could reduce damage by protecting healthy heart muscle tissue. "Cardiologists say that when a heart attack occurs, time is muscle," said Robert Gourdie (photo), PhD, Director of the Fralin Biomedical Research Institute at VTC (Virginia Tech Carilion) Center for Heart and Reparative Medicine Research. Without oxygen supplied by blood flow, heart cells die -- quickly. But while a heart attack may only reduce blood and oxygen to an isolated section of heart cells -- causing what's called hypoxic ischemic injury -- those dying cells send signals to their neighbors. "The problem is that the area of dying tissue is not quarantined. Damaged heart cells start to send out signals to otherwise healthy cells, and the injury becomes much bigger," said Dr. Gourdie, who is also the Commonwealth Research Commercialization Fund Eminent Scholar in Heart Regenerative Medicine Research and Professor in the Department of Biomedical Engineering and Mechanics in the Virginia Tech College of Engineering. Scientists sometimes call this spread of injury signals to nearby healthy tissues a "bystander effect." But what if there were a way to keep the injury localized to the group of cells that are directly affected by the hypoxic ischemic injury, while allowing the nearby heart muscle cells to remain intact? A study published online on August 19, 2019 in the Journal of the American Heart Association reveals that a new molecule developed by a team of researchers led by Dr. Gourdie could help preserve heart tissue during -- and even after -- a heart attack. The open-access article is titled “Interaction of α Carboxyl Terminus 1 Peptide with the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia‐Reperfusion Injury.” Nearly a decade ago, Dr.

August 18th

Non-Invasive Brain Imaging During Visual Test Identifies Autism with 87% Accuracy & Correctly Indicates Clinically Determined Severity; New Test Has Potential for Early Diagnostic Screening

A Dartmouth-led research team has identified a non-verbal, neural marker of autism. This marker shows that individuals with autism are slower to dampen neural activity in response to visual signals in the brain. This first-of-its kind marker was found to be independent of intelligence and offers an objective way to potentially diagnose autism in the future. The results were published online on August 15, 2019 in Current Biology. The open-access article is titled “Slower Binocular Rivalry in the Autistic Brain.” "Autism is hard to screen for in children, when the first signs are present. A trained clinician may be able to detect autism at 18-months or even younger; yet, the average age of a diagnosis of autism in the US is about four years old," explains lead author Caroline Robertson, PhD, an Assistant Professor of Psychological and Brain Sciences at Dartmouth, and Director of the Dartmouth Autism Research Initiative (https://sites.dartmouth.edu/autismresearchcenter/). "We need objective, non-invasive screening tools that don't depend on assessing a child's behavior. One of the big goals of the field is to develop objective neural markers of autism that can work with non-verbal individuals. This neural marker is just that," she added. People with autism have long been thought to have differences in inhibiting the neural signals in the brain. This is thought to underpin symptoms in autism, such as hypersensitivity to sensory input, which includes differences in processing visual information. When the human brain is presented with two different images at the same time, the images rock back and forth in awareness, toggling between the left and right eye. Prior research led by Dr.

August 16th

Oxygen-Sensing Mechanism Based on Small RNA (sRNA) Is Key to E. coli Locating Region of Colon in Which to Set Up Most Threatening Infections; Discovery May Ultimately Enable Avoidance of These Food-Borne Infections

A pair of University of Virginia (UVA) School of Medicine scientists has revealed how E. coli seeks out the most oxygen-free crevices of the colon to cause the worst infection possible. The discovery could one day let doctors prevent the infection by allowing E. coli to pass harmlessly through the body. The new discovery shows just how the food-borne pathogen knows where and when to begin colonizing the colon on its way to making you sick. By recognizing the low-oxygen environment of the large intestine, the dangerous bacterium gives itself the best odds of establishing a robust infection - one that is punishing for the host. "Bacterial pathogens typically colonize a specific tissue in the host. Therefore, as part of their infection strategies, bacterial pathogens precisely time deployment of proteins and toxins to these specific colonization niches in the human host. This allows the pathogens to save energy and avoid detection by our immune systems and ultimately cause disease," said researcher Melissa Kendall (left in photo), PhD, of UVA's Department of Microbiology, Immunology, and Cancer Biology. "By knowing how bacterial pathogens sense where they are in the body, we may one day be able to prevent E. coli, as well as other pathogens, from knowing where it is inside a human host and allow it (the E. coli) to pass through the body without causing an infection." The UVA research was published in the July 9, 2019 issue of PNAS. The article is titled “The sRNA DicF Integrates Oxygen Sensing to Enhance Enterohemorrhagic Escherichia coli Virulence via Distinctive RNA Control Mechanisms.” E. coli naturally lives in our colons, and most strains do us no harm. But there are several strains that can cause cramps, diarrhea, vomiting, even kidney failure and death. Children are at particular risk. As such, E.

From the Tiny Testes of Flies, Rockefeller Scientists Derive Insights into How New Genes Arise

In the battle of the sexes, males appear to have the innovative edge--from a genetic standpoint, at least. Scientists are finding that the testes are more than mere factories for sperm; these organs also serve as hotspots for the emergence of new genes, the raw material for the evolution of species. Using fruit flies, a Rockefeller University team has gained key insight into how nature's attempts at innovation play out during the development of sperm. In research published online on August 16, 2019 in eLife, they mapped the presence of mutations to DNA at the single-cell level, and the activity of new genes arising from such changes. The open-access article is titled “Testis Single-Cell RNA-Seq Reveals the Dynamics of De Novo Gene Transcription and Germline Mutational Bias in Drosophila.” "Our work offers an unprecedented perspective on a process that enables living things to adapt and evolve, and that ultimately contributes to the diversity of life on Earth," says Rockefeller Assistant Professor Li Zhao, PhD, who led the research. In recent years, studies in animals from flies to humans have turned up a number of young genes that originated in the testes. These and other discoveries suggest that the testes rank among the most productive sites in the body--male or female--for genetic innovation. This mass production of genetic novelties comes with significant risks, however. In humans, for example, a father's sperm acquires two to three times more new mutations than do a mother's eggs in the course of normal development, leaving the sperm riddled with genetic mistakes. In some cases, such mistakes may harm the faather’s offspring, or even derail the prospect of fatherhood altogether.

August 15th

FDA Approves New Drug (Pretomanid) for Treatment-Resistant Forms of Tuberculosis That Affects the Lungs; Approval Signals FDA’s Continued Focus on Facilitating Development of New Treatments to Fight Antimicrobial-Resistant Infections

On August 14, 2019, the U.S. Food and Drug Administration announced approval of Pretomanid Tablets, in combination with bedaquiline and linezolid, for the treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs. “The threat of antimicrobial-resistant infections is a key challenge we face as a public health agency,” said FDA Principal Deputy Commissioner Amy Abernethy, MD, PhD. “The bacterium that causes tuberculosis can develop resistance to the antibiotics used to treat it. Multidrug-resistant TB and extensively drug-resistant TB are public health threats due to limited treatment options. New treatments are important to meet patient national and global health needs. That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections. This approval also marks the second time a drug is being approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, a pathway, advanced by Congress, to spur development of drugs targeting infections that lack effective therapies. We hope we continue to see more development of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs.” Pretomanid (image shows structure), in combination with bedaquiline and linezolid, is approved for treating a limited and specific population of adult patients with extensively drug-resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary TB. Multidrug-resistant TB and extensively drug-resistant TB are difficult to treat due to resistance to available therapies.

First-Ever in Vitro Culture Method for Monkey Malaria Parasite Should Allow Rapid, High-Throughput Testing of Possible Drugs for Relapsing Malaria in Humans & Endangered Penguins

A breakthrough in monkey malaria research by two University of Otago (New Zealand) scientists could help scientists diagnose and treat a relapsing form of human malaria. Malaria is a mosquito-borne infectious disease that affects humans and other animals with more than 200 million cases annually, particularly in Asia, the Pacific, and South America. Symptoms include fever, tiredness, vomiting and headaches and, in severe cases, it can cause seizures, coma, or death. Relapsing malaria is caused by the vivax malaria parasite, which is also the most widely distributed and difficult to treat cause of human malaria. Current efforts to develop new drugs and vaccines against vivax have been stymied by lack of a test tube (in vitro) cultured method. However, in a world-first discovery, Dr. Adelina Chua and Jessica Ong have developed an in vitro method for culturing a monkey malaria parasite which is closely related to the relapsing vivax parasite. "We can't culture vivax malaria, but now we can culture its almost identical sister species which gives us an unprecedented opportunity to develop and rapidly test new antimalarials," explained Ms. Ong, a doctoral candidate from the University of Otago Department of Microbiology and Immunology. An interesting spinoff from this research is that the drugs developed against human relapsing malaria also have a good chance of working against bird malaria, which has been killing the endangered yellow-eyed penguin (image) on the New Zealand mainland. "Before our model there was no high throughput model to screen new antimalarials targeting relapsing malaria," Ms. Ong says. "Our model will play a significant part in not only drug development, but also vaccine and diagnostic research."

August 15th

Study Identifies Gene Mutation (in RABL3 Gene) Linked to Hereditary Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers with limited treatment options. It typically comes with an especially poor prognosis due to its lack of symptoms until advanced stages and its ability to resist many anticancer therapies. Identifying genes involved in its development may lead to earlier diagnoses and improved treatments. Now, a research team led by investigators at Massachusetts General Hospital (MGH), Brigham and Women's Hospital, and Dana-Farber Cancer Institute has found that a mutation in a particular gene is associated with hereditary forms of pancreatic cancer in one family studied. Approximately 10% of pancreatic cancer is believed to be hereditary (see discussion of pancreatic cancer in former US President Jimmy Carter's family below). The research group also uncovered a mechanism by which mutations such as the one they identified may contribute to the development of tumors. In their study, which was published online on August 12, 2019 in Nature Genetics, the researchers sequenced the genomes of a family in which multiple members had pancreatic cancer. The analyses revealed a mutation in the RAS oncogene family-like 3 (RABL3) gene. The article is titled “Mutations in RABL3 Alter KRAS Prenylation and Are Associated with Hereditary Pancreatic Cancer.” To assess the effects of this gene mutation, the investigators recapitulated it in zebrafish, a model which offers large populations for studying the impact of newly discovered genetic mutations on cancer risk. The fish carrying the mutation developed cancers at an accelerated rate and with greater frequency. Additional studies revealed that the protein expressed by RABL3 interacts with components of the RAS signaling pathway, which has been implicated in various forms of cancer and other conditions.

Variants in MS4A4A Gene Influence Levels of Soluble TREM2 and Affect Susceptibility to Alzheimer’s Disease; Results Suggest Increased Focus on Brain’s Immune Cells (Microglia)

An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer's disease. Most genes implicated thus far in Alzheimer's affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain's immune cells. The findings, published online on August 14, 2019 in Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer's symptoms. The article is titled “The MS4A Gene Cluster Is a Key Modulator of Soluble TREM2 and Alzheimer’s Disease Risk.” The identified genes -- known as MS4A4A and TREM2 -- operate in the microglia (image), the brain's immune cells. The genes influence Alzheimer's risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins beta-amyloid and tau from the brain. "The findings point to a new therapeutic strategy," said co-senior investigator Carlos Cruchaga, PhD, a Professor of Psychiatry and Director of the NeuroGenomics and Informatics Group at Washington University School of Medicine. "If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer's disease or slow its development." In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer's disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment.