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Archive - Aug 2020

Date

August 29th

Inflammatory Bowel Disease Linked to Specialized Tissue-Resident Memory T-Cell Run Amok; Finding May Provide New Therapeutic Target

Inflammatory bowel disease (IBD) is a group of intestinal disorders affecting an estimated six to eight million people worldwide. Although there are many treatments for IBD, a number of patients fail to respond long-term, leaving those afflicted with a host of chronic issues, from abdominal pain and cramping to frequent, bloody stools. In a new study, published August 21, 2020 in Science Immunology, an international team of researchers, led by scientists at the University of California San Diego School of Medicine, report that the lasting nature of IBD may be due to a type of long-lived immune cell that can provoke persistent, damaging inflammation in the intestinal tract. The open-access article is titled” Heterogeneity and Clonal Relationships of Adaptive Immune Cells in Ulcerative Colitis Revealed by Single-Cell Analyses.” Led by co-senior authors John T. Chang, MD, Professor of Medicine, and Gene W. Yeo, PhD, Professor of Cellular and Molecular Medicine, the research team performed mRNA and antigen receptor sequencing from immune cells isolated from samples taken from rectal biopsies or blood of IBD patients and healthy controls. "We took advantage of a state-of-the-art approach allowing us to generate mRNA and antigen receptor sequencing data from the same single-cells," said Dr. Yeo, "and analyzed thousands of individual cells, which is quite exciting." It has long been believed that immune system dysfunction, in concert with genetic susceptibility and changes in the gut microbiome, plays a significant role in IBD. However, the types of immune cells involved and their specific contributions to IBD have remained unclear.

August 19th

Observational Study Identifies Drug (Tocilizumab) That Improves Survival in Sickest COVID-19 Patients

Researchers at Hackensack Meridian Health, New Jersey's largest and most comprehensive health network, have utilized its statewide observational database of more than 5,000 hospitalized COVID-19 patients to show that a drug (tocilizumab) normally used in rheumatoid arthritis and cancer treatments, improves hospital survival in critically-ill patients admitted to the intensive care unit (ICU). The findings were published online on August 14, 2020 in The Lancet Rheumatology, and Hackensack Meridian Health researchers have updated the U.S. FDA and other national leaders of the findings to potentially accelerate improved outcomes. The Lancet article is titled “Tocilizumab Among Patients with COVID-19 in the Intensive Care Unit: A Multicentre Observational Study.” "Our clinicians and researchers at Hackensack Meridian Health have moved quickly and intelligently since the start of this global health crisis," said Robert C. Garrett, FACHE, Chief Executive Officer of Hackensack Meridian Health. "Their work in treating this terrible virus, and learning more about it each day, continues to benefit thousands of patients as the pandemic continues." The study included 630 patients who were admitted to the ICUs of 13 Hackensack Meridian Health hospitals from March 1 to April 22--the height of the pandemic in New Jersey. Among other treatments, tocilizumab was considered for off-label usage for the patients whose respiratory symptoms were declining; many of whom were requiring mechanical ventilator support. In the observational study 210 patients received tocilizumab, and the other 420 did not.

August 18th

Preexisting Drug (Ebselen) Shows Promise in Fight Against COVID-19; Drug Interferes with Key Virus Enzyme

First appearing in late 2019 in Wuhan City, China, the SARS-CoV-2 virus continues to cause sickness and death across the globe. Researchers and scientists have been looking at multiple solutions to treat COVID-19, including repurposing approved pharmaceutical drugs. This research points to very promising treatment options. A team of researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago used state-of-the-art computer simulations to identify a preexisting drug that could fast-track a solution to this worldwide pandemic. Their findings appear in the open-access artilce, "Molecular Characterization of Ebselen Binding Activity to SARS CoV 2 Main 4 Protease," which was published online on August 14, 2020 in Science Advances. Early in February, concerned by the rapid progress of the pandemic, Professor Juan de Pablo, PhD, and his students used their molecular modeling expertise to help find a treatment against the disease. They were not the only ones. Other groups around the world were beginning to use supercomputers to rapidly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus. "By virtue of the large number of compounds considered in high-throughput screens, those calculations must necessarily involve a number of simplifications, and the results must then be evaluated using experiments and more refined calculations," Dr. de Pablo explained. Researchers first focused on finding a weakness in the virus to target. They chose its main protease: Mpro. Mpro is a key coronavirus enzyme that plays a central role in the virus' life cycle. It facilitates the virus' ability to transcribe its RNA and replicate its genome within the host cell. A pharmaceutical drug that shows promise as a weapon against Mpro is Ebselen (image).

August 17th

New Research Reveals Subtype of Autism Associated With Lipid Abnormalities

Researchers at Harvard Medical School, Massachusetts Institute of Technology, and Northwestern University have identified a subtype of autism arising from a cluster of genes that regulate cholesterol metabolism and brain development. The researchers say their findings, published online on August 10, 2020 in Nature Medicine, can inform both the design of precision-targeted therapies for this specific form of autism and enhance screening efforts to diagnose autism earlier. The article is titled “A Multidimensional Precision Medicine Approach Identifies an Autism Subtype Characterized by Dyslipidemia.” The team identified the shared molecular roots between lipid dysfunction and autism through DNA analysis of brain samples--findings that they then confirmed by examining medical records of individuals with autism. Indeed, both children with autism and their parents had pronounced alterations in lipid blood, the analysis showed. The results of the study, the researchers said, raise many questions; key among them are: Just how do lipid alterations drive neurodevelopmental dysfunction and could normalizing lipid metabolism affect disease outcomes? The new findings set the stage for future studies to answer these questions and others. "Our results are a striking illustration of the complexity of autism and the fact that autism encompasses many different conditions that each arise from different causes--genetic, environmental, or both," said study senior investigator Isaac Kohane, MD, PhD, Chair of the Department of Biomedical Informatics in the Blavatnik Institute at Harvard Medical School. "Identifying the roots of dysfunction in each subtype is critical to designing both treatments and screening tools for correct and timely diagnosis--that is the essence of precision medicine."

August 16th

Progress Made in Understanding How Selective Serotonin-Reuptake Inhibitors (SSRIs) Work to Ease Depression

Some highly effective medications also happen to be highly mysterious. Such is the case with the antidepressant drugs known as selective serotonin re-uptake inhibitors, or SSRIs: They are the most common treatment for major depression and have been around for more than 40 years, yet scientists still do not know exactly how they work. Nor is it known why only two out of every three patients respond to SSRI treatment, or why it typically takes several weeks for the drugs to take effect—a significant shortcoming when you’re dealing with a disabling mood disorder that can lead to impaired sleep, loss of appetite, and even suicide. New research by a team of Rockefeller University scientists helps elucidate how SSRIs combat depression. Their work, published online on May 21, 2020 in Molecular Psychiatry (https://www.nature.com/articles/s41380-020-0767-8#Abs1), could one day make it possible to predict who will respond to SSRIs and who will not, and to reduce the amount of time it takes for the drugs to act. The open-access article is titled “AP-1 Controls the p11-Dependent Antidepressant Response.” Major depression—also known as clinical depression—is firmly rooted in biology and biochemistry. The brains of people who suffer from the disease show low levels of certain neurotransmitters, the chemical messengers that allow neurons to communicate with one another. And studies have linked depression to changes in brain volume and impaired neural circuitry.

DNA Test Accurately IDs People Whose Gonorrhea Can Be Cured with Simple Oral Antibiotic

A test designed by UCLA researchers can pinpoint which people with gonorrhea will respond successfully to the inexpensive oral antibiotic ciprofloxacin, which had previously been sidelined over concerns the bacterium that causes the infection was becoming resistant to it. In research published online on August 7, 2020 in Clinical Infectious Diseases, a UCLA-led team found that of 106 subjects the test identified as having a strain of gonorrhea called wild-type gyrA serine, all were cured with a single dose of oral ciprofloxacin. Though the test has been available for three years, this is the first time it has been systematically studied in humans. The new test gives doctors more choices to treat the sexually transmitted infection and could help slow down the spread of drug-resistant gonorrhea, said Jeffrey Klausner, MD, MPH, the study’s lead author and a Professor of Medicine in the Division of Infectious Diseases at the David Geffen School of Medicine at UCLA. The article is titled “Resistance-Guided Treatment of Gonorrhea: A Prospective Clinical Study.” “Gonorrhea is one of the most common drug-resistant infections worldwide and is becoming harder to treat. Current treatment methods require an antibiotic injection, which is expensive and painful,” said Dr. Klausner, who is also an adjunct professor of epidemiology at the UCLA Fielding School of Public Health. “This new test could make it easier and safer to treat gonorrhea with different antibiotics, including one pill given by mouth. Using a pill instead of a shot would also make it easier and faster to treat sex partners of patients with gonorrhea,” he added.

Is the COVID-19 Virus Pathogenic Because It Depletes Specific Host MicroRNAs?

Why is the COVID-19 virus deadly, while many other coronaviruses are fairly innocuous and just cause colds? A team of University of Alabama at Birmingham (UAB) and Polish researchers propose an answer--the COVID-19 virus acts as a microRNA "sponge." This action modulates host microRNA levels in ways that aid viral replication and stymy the host immune response. This testable hypothesis results from analysis of current literature and a bioinformatic study of the COVID-19 virus and six other coronaviruses. The hypothesis was published online on August 5, 2020, as a perspective in the American Journal of Physiology-Lung Cellular and Molecular Physiology. Human microRNAs (miRNAs) are short, non-coding RNAs made up of about 22 bases. They act to regulate gene expression by their complementary pairing with specific messenger RNAs of the cell. That pairing silences the messenger RNA, preventing it from being translated into a protein. Thus, miRNAs are a fine-tuned controller of cell metabolism or the cell's response to stress and adverse challenges, such as infection by a virus. The miRNAs are only about 0.01 percent of total human cell and tissue RNA, while replicating viral RNA of a virus like the COVID-19 virus may reach 50 percent of the total cellular RNA. So, the UAB and Polish researchers say, if the COVID-19 virus has binding sites for specific miRNAs -- and these sites are different from the binding sites for miRNAs found on coronaviruses that cause colds--the more pathogenic COVID-19 virus may selectively sponge up certain miRNAs to dysregulate the cell in ways that make it a dangerous human coronavirus. The sponge idea is not novel.

August 15th

Researchers Use Organ-on-a-Chip Microsystem to Investigate How Ovarian Cancer Cells Gain Access to Platelets, an Interaction That Leads to Ovarian Cancer Metastasis

Abhishek Jain (photo), PhD, Assistant Professor in the Department of Biomedical Engineering and the Department of Medical Physiology in the College of Medicine, collaborated with researchers from the Departments of Gynecologic Oncology and Cancer Biology at MD Anderson Cancer Center to gain a better understanding of the interaction among ovarian cancer tumors, blood vessels, and platelets. The scientists found that tumors break the blood vessel barriers and this allows them to communicate with blood cells, including platelets. When these tumors come into contact with platelets, they can then metastasize. The results of this collaborative research were published online on July 27, 2020 in Blood Advances. The article is titled “OvCa-Chip Microsystem Recreates Vascular Endothelium–Mediated Platelet Extravasation in Ovarian Cancer.” Previously, researchers understood that platelets are one of the initiators of ovarian cancer metastasis but did not know what led to the introduction of the platelets to the tumor cells. Instead of struggling to view this relationship in animal models, Dr. Jain's team brought a new solution to the table: organ-on-a-chip research. Organs-on-a-chip are microfluidic medical devices the size of a USB drive. The team designed the OvCa-Chip to give researchers an easier window to view the biological processes between tumors and platelets.In an interview with the International Society on Thrombosis and Hemostasis, Dr. Jain explained that "it basically is a microenvironment where ovarian tumor cells can be co-cultured along with their blood vessels, and then they can interact with blood cells.

Gene Expressed in Oligodendrocytes May Be Possible Target for Treatment in Multiple Sclerosis (MS)

The disease multiple sclerosis (MS) attacks the central nervous system and, with time, can give rise to muscle tremors, a loss of balance, and other symptoms. Researchers at Karolinska Institutet in Sweden have now identified a gene, Gsta4, coding for glutathione S-transferase A4 (image), that protects a certain kind of cell (oligodendrocyte) in the brain from being destroyed. It is hoped that the results of the study, which were published on August13, 2020 in Nature Communications, can help to improve the treatment of this serious disease. The open-access article is titled “Gsta4 Controls Apoptosis of Differentiating Adult Oligodendrocytes During Homeostasis and Remyelination Via the Mitochondria-Associated Fas-Casp8-Bid-Axis.” “Taken together, our findings are particularly interesting for several reasons,” says corresponding author Karl Carlström, Researcher at the Department of Clinical Science at Karolinska Institutet in Sweden. “Too little is known about the mechanisms behind progressive MS, by which I mean the phase of the disease in which oligodendrocytes and neurons in the brain die without re-forming.” Brain neurons can be likened to electric wires, the protective and insulating sheathes of which are essential to their purpose. The cells that provide such insulation are called oligodendrocytes and it is these cells that the immune system attacks in an early phase of MS. Researchers at Karolinska Institutet have studied possible mechanisms influencing both how well oligodendrocytes mature into functional cells and their survival during this process. MS is a disease of the central nervous system (the brain and spinal cord) and can last for many years, leading in many cases to, among other problems, loss of sensation, tremors, difficulties walking, mood swings, and visual impairment.

Progress in Development of Oral Vaccine for Anthrax in Ranging Livestock and Wildlife

There may soon be a new weapon in the centuries-old battle against anthrax in wildlife thanks to ground-breaking work at the Texas A&M University College of Veterinary Medicine & Biomedical Sciences (CVMBS). Anthrax, a disease caused by a bacterium called Bacillus anthracis, contaminates surface soil and grasses, where it may be ingested or inhaled by livestock or grazing wildlife. This is especially common in the western Texas Hill Country, where each year the disease kills livestock and wildlife. While normally not an attention-grabbing problem, a spike of cases in 2019 made headlines around the state. According to Jamie Benn Felix, PhD, a postdoctoral research associate in the Cook Wildlife Lab led by CVMBS Department of Veterinary Pathobiology's (VTPB) Dr. Walt Cook, that spike may have been responsible for the deaths of more than 10,000 animals. "If you assume the economic value for each animal was $1,000, which is probably extremely low given the number of exotic species on some of the ranches, you're looking at an economic loss of $10 million in just a few months," she said. "And given the problems with reporting cases, it could be significantly higher than that." The good news is that there is already a vaccine for anthrax, which many livestock owners administer annually. Unfortunately, it can only be administered with an injection that is time-consuming for livestock and not feasible for wildlife. With that in mind, Dr. Benn Felix and the Cook Wildlife Lab team, in collaboration with VTPB researchers Dr. Allison Rice-Ficht and Dr. Thomas Ficht, went to work to attempt to create a formulation to deliver the vaccine orally, which would allow for potential distribution to wildlife. Dr.