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Depletion of “Reelin” Protein May Be Effective in Multiple Sclerosis, and Chronic Inflammatory Conditions Such As Psoriasis, Crohn’s Disease, and Rheumatoid Arthritis

In an animal model of multiple sclerosis (MS), decreasing the amount of a protein (“Reelin”) (image) made in the liver significantly protected against development of the disease’s characteristic symptoms and promoted recovery in symptomatic animals, scientists the University of Texas Southwestern (UTSW) Medical Center report. The findings, published online on August 12, 2020 in Science Translational Medicine, could lead to a new treatment strategy for this neurological disease and other conditions marked by chronic inflammation. The article is titled “Reelin Depletion Protects Against Autoimmune Encephalomyelitis By Decreasing Vascular Adhesion Of Leukocytes.” In 1997, researchers discovered a protein secreted in the brain called “Reelin.” Subsequent work showed that Reelin appears to help the brain organize itself during development and assists in forming connections between brain cells during adulthood. However, as researchers learned more about Reelin, they discovered that large amounts of it are produced in the liver and that cells lining blood vessels have receptors for this protein. A 2016 study by Joachim Herz, MD, Director of the UTSW’s Center for Translational Neurodegeneration Research and Professor in the Departments of Molecular Genetics, Neurology and Neurotherapeutics, and Neuroscience at UTSW, and his colleagues showed that depleting levels of circulating Reelin protected mice from atherosclerosis. Probing deeper into the mechanism behind this phenomenon, the researchers found that Reelin appears to regulate the production of adhesion molecules on blood vessel walls that capture circulating monocytes, a type of inflammation-inducing immune cell.

45-Year Cancer Mystery Solved; Epigenetic Silencing of Key Enzyme Prevents Synthesis of “Y” Nucleotide in Phenylalanine tRNA Causes Certain Small, But Highly Aggressive Tumors

Before the first oncogene mutations were discovered in human cancer in the early 1980s, the 1970s provided the first data suggesting alterations in the genetic material of tumors. In this context, in 1975 Nature published an article describing the existence of a specific alteration in the transformed cell: a transfer RNA (tRNA) responsible for carrying the amino acid phenylalanine to build proteins was missing a piece, the enigmatic nucleotide "Y” a hypermodulated guanine (https://pubmed.ncbi.nlm.nih.gov/163007/). After that seminal observation, silence and ignorance have reigned for forty-five years on the causes and consequences of not having that correct base in that tRNA. In an article that was just published online on August 10, 2020 in PNAS by the group of Manel Esteller (photo) (https://www.carrerasresearch.org/esteller-manel_124337), MD, PhD, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Professor of Genetics at the University of Barcelona in Spain, this 45-year-old mystery appears to have been solved by results showing that in certain cancer cells the enzyme (tRNA wybutosine-synthesizing protein 2) that generates the nucleotide "Y" is epigenetically inactivated, causing small, but highly aggressive tumors. The open-access PNAS article is titled "Epigenetic Loss of the Transfer RNA-Modifying Enzyme TYW2 Induces Ribosome Frameshifts in Colon Cancer." “Since the original discovery in 1975, there has been much biochemical work to characterize the enzymes involved in the different steps that lead to the desired nucleotide ‘Y,’ a hypermodified guanine, but without connecting this characterization with its defect in tumor biology.

Key Brain Region Was “Recycled” As Humans Developed Ability to Read; Part of Visual Cortex Dedicated to Recognizing Objects Appears Predisposed to Identifying Words & Letters, MIT Study Finds

Humans began to develop systems of reading and writing only within the past few thousand years. Our reading abilities set us apart from other animal species, but a few thousand years is much too short a timeframe for our brains to have evolved new areas specifically devoted to reading. To account for the development of this skill, some scientists have hypothesized that parts of the brain that originally evolved for other purposes have been “recycled” for reading. As one example, they suggest that a part of the visual system that is specialized to perform object recognition has been repurposed for a key component of reading called orthographic processing--the ability to recognize written letters and words. A new study from MIT neuroscientists offers evidence for this hypothesis. The findings suggest that even in nonhuman primates, who do not know how to read, a part of the brain called the inferotemporal (IT) cortex is capable of performing tasks such as distinguishing words from nonsense words, or picking out specific letters from a word. “This work has opened up a potential linkage between our rapidly developing understanding of the neural mechanisms of visual processing and an important primate behavior--human reading,” says James DiCarlo, PhD, the Head of MIT’s Department of Brain and Cognitive Sciences, an investigator in the McGovern Institute for Brain Research and the Center for Brains, Minds, and Machines, and the senior author of the study. Rishi Rajalingham, PhD, an MIT postdoc, is the lead author of the study, which was published online on August 4, 2020 in Nature Communications. The open-access article is titled “The Inferior Temporal Cortex Is a Potential Cortical Precursor of Orthographic Processing in Untrained Monkeys.” Other MIT authors on this article are postdoc Kohitij Kar, PhD, and technical associate Sachi Sanghavi.

“Breakthrough Article” in Nucleic Acids Research Presents Data Supporting Full-Scale Clinical Development of Antisense Oligonucleotides (ASOs) for Possible Treatment of Prion Diseases Such As Fatal Familial Insomnia & Creutzfeldt-Jakob Disease

Research teams led by Sonia Vallabh (photo), PhD, whose mother died of the hereditary prion disease fatal familial insomnia, and Eric Minikel, PhD, at Harvard Medical School and The Broad Institute, Holly Kordasiewicz, PhD, at Ionis Pharmaceuticals, and Deborah Cabin, PhD, at McLaughlin Research Institute, have reported the results of preclinical studies of an antisense therapy against different strains of prion disorders, including mechanistic experiments and validation in animal model systems, in an article titled “Prion Protein Lowering is a Disease-modifying Therapy Across Prion Strains, Stages, and Endpoints,” and published online on August 10, 2020 in Nucleic Acids Research. This article was designated by NAR as a “Breakthrough Article,” that is, an article that “describes studies that provide exceptional new insight and understanding into an area of research that will clearly motivate and guide new research opportunities and directions.” “Breakthrough Articles” represent the top papers that NAR receives for publication, and are selected by the Editors based on nominations and subsequent recommendations by the reviewers and editorial board members. Prion diseases are rapidly fatal and currently untreatable neurodegenerative diseases. They include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru in humans, bovine spongiform encephalitis (BSE) (Mad Cow Disease) in cattle, and scrapie in sheep. These diseases are caused by disruption of the structure of a normal prion protein (PrP). The disrupted PrP is characterized by a beta-sheet structure rather than the alpha-helix structure that characterizes the normal PrP.

CytoDyn Announces Clinically Significant Top-line Results from Its Phase 2 Trial of Leronlimab in Mild-to-Moderate COVID-19 Patients; Results “Bode Well for Leronlimab’s Activity In Patients With More Severe Illness,” Senior Science Advisor Says

On August 11, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company headquartered in Seattle, Washington, announced the Top-Line results from its recently completed, randomized, double-blind, Phase 2 trial of leronlimab for COVID-19 patients with mild-to-moderate symptoms. The primary endpoint showed early clinical improvement in symptom score at Day 3 in patients receiving leronlimab. In addition, leronlimab also demonstrated statistically significant improvement versus placebo in key secondary efficacy endpoint, National Early Warning Score 2 scale (NEWS2). The results will be reported to the United States FDA, the United Kingdom MHRA, and the European Union regulatory agency, EMA. Harish Seethamraju, MD, Lead Principal Investigator at Montefiore Medical Center, New York City, stated, “The results demonstrate that CCR5 blockade by leronlimab given as a weekly subcutaneous injection in mild-to-moderate COVID-19 patients is reasonably safe and associated with rapid improvement in viral symptoms with fewer adverse events than when compared to placebo.” Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn, stated, “In the mild- to-moderate population, it is important to have a therapeutic option for COVID-19 in patients who are showing signs of rapid clinical deterioration. Patients receiving leronlimab showed a statistically significant improvement using NEWS2 clinical parameters. We will make a case for immediate approval of leronlimab for this population of COVID-19 patients, not only in the U.S., but also in the UK and other countries around the world.” Scott A. Kelly, MD, Chief Medical Officer of CytoDyn, said, “We are thrilled with the results of leronlimab in mild-to-moderate COVID-19 patients.

Malaria Research Suggests Targeting Key Red Blood Cell Kinases with Existing Anti-Cancer Drugs May Thwart Disease; Targeting Key Host Enzymes with Repurposed Drugs Could Have Far Wider Application, Including in Anti-Viral Treatment for COVID-19

New research into malaria suggests targeting enzymes from the human host, rather than from the pathogen itself, could offer effective treatment for a range of infectious diseases, including COVID-19. The study, conducted by an international team and led by RMIT University's Professor Christian Doerig, PhD, outlines a strategy that could save years of drug discovery research and millions of dollars in drug development by repurposing existing treatments designed for other diseases such as cancer. The approach shows so much promise it has received government funding for its potential application in the fight against COVID-19. The study, published online on August 11, 2020 in Nature Communications, demonstrated that the parasites that cause malaria are heavily dependent on enzymes in red blood cells (RBCs) where the parasites hide and proliferate. The open-access article is titled “Analysis of Erythrocyte Signalling Pathways During Plasmodium falciparum Infection Identifies Targets for Host-Directed Antimalarial Intervention.” The study also revealed that drugs developed for cancer, and which inactivate these human enzymes, known as protein kinases, are highly effective in killing the parasite and represent an alternative to drugs that target the parasite itself. Lead author, RMIT's Dr. Jack Adderley, said the analysis revealed which of the host cell enzymes were activated during infection, revealing novel points of reliance of the parasite on its human host. "This approach has the potential to considerably reduce the cost and accelerate the deployment of new and urgently needed anti-malarials," he said.

Telomerase-Directed Gene Therapy May Prove Effective Approach to Treating/Curing Idiopathic Pulmonary Fibrosis (IPF) Caused by Mutations or by Physioligcial Aging, New Results in Mouse Model Suggest

Idiopathic pulmonary fibrosis (IPF) is a potentially lethal disease for which there is currently no cure and that is associated with certain mutations or advanced age. The Telomeres and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) had previously developed an effective therapy for mice with fibrosis caused by genetic defects. Now, these researchers have shown that the same therapy can be used successfully to treat mice with age-related fibrosis. "With respect to humans, our results indicate that it may be possible to devise a treatment to prevent the development of pulmonary fibrosis associated with aging," says Maria Blasco, PhD, Director of the CNIO and Head of the CNIO’s Telomeres and Telomerase Group, and principal investigator of the study that was published online on August 10, 2020 in The Journal of Cell Biology. The open-access article is titled “Telomerase Treatment Prevents Lung Profibrotic Pathologies Associated with Physiological Aging.” The treatment tested in mice is a gene therapy that activates the production of telomerase in the body. Telomerase is an enzyme that repairs the telomeres at the end of chromosomes. According to Dr. Blasco, this therapy was highly effective in animal models and no side effects were observed. Pulmonary fibrosis affects approximately 8,000 people in Spain and approximately 3 million individuals worldwide. Median lifespan from time of diagnosis is 2 to 4 years. In this disease, the lung tissue becomes stiff and scarred, and patients develop progressive shortness of breath. It is thought to be caused by a combination of genetic and environmental factors. Exposure to toxic substances plays an important role, but for the disease to manifest itself the patient must be of advanced age or have an underlying genetic condition.

Extraordinary Anglerfish Trade Adaptive Immunity for Reproductive Success; Much-Enhanced Innate Immunity Predicted; Male Fuses Its Body to Female in Rare Example of Sexual Parasitism in These Deep-Sea Fish

Deep-sea anglerfishes employ an incredible reproductive strategy. Tiny dwarfed males become permanently attached to relatively gigantic females, fuse their tissues, and then establish a common blood circulation. In this way, the male becomes entirely dependent on the female for nutrient supply, like a developing fetus in the womb of her mother or a donor organ in a transplant patient. In anglerfishes, this unusual phenomenon is referred to as sexual parasitism and contributes to the reproductive success for these animals living in the vast space of the deep sea, where females and males otherwise rarely meet. The permanent attachment of males to females represents a form of anatomical joining, which is otherwise unknown in nature except for the rare occurrence in genetically identical twins. The immune system represents an extraordinary obstacle here. It attacks foreign tissue as it would destroy cells infected by pathogens. Just witness the difficulties surrounding organ transplantation in humans, which requires the careful cross-matching of donor and recipient tissue characters, together with immunosuppressive drugs, to ensure the long-term survival of the organ graft. But how is it possible then that, in case of anglerfishes, that individuals of the same species accept each other so readily when tissue-rejection is the usual and expected result of any such union? The phenomenon of sexual parasitism has posed an enigma that has existed for 100 years, ever since the first attached couple was discovered by an Icelandic fisheries biologist in 1920. Now, scientists from Germany and the USA have solved this century-old conundrum and report their findings online on July 30, 2020 in Science.

Inhibition of BBOX1 Enzyme Might Be Effective Therapeutic Approach in Triple-Negative Breast Cancer

One member of a larger family of oxygen-sensing enzymes could offer a viable target for triple-negative breast cancer (TNBC) therapy, researchers from the University of Texas Southwestern (UTSW) report in a new study. The findings, published online on July 20, 2020 in Cancer Discovery, might offer hope to this subset of patients who have few effective treatment options and often face a poor prognosis. The article is titled “Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer.” TNBC – so called because it lacks estrogen receptors, progesterone receptors, and overexpression of the growth-promoting protein HER2 – makes up only 15 to 20 percent of all breast cancers. However, explains Qing Zhang, PhD, Associate Professor in the Department of Pathology at UTSW and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, it’s the deadliest of all breast cancers, with a five-year survival rate of 77 percent compared with 93 percent for other types. Unlike other cancers which are hormone receptor or HER2 positive, TNBC has no targeted treatments, so patients must rely only on surgery, chemotherapy, and radiation, which are less effective than targeted treatments and can harm healthy tissue. Dr. Zhang’s lab studies how cancers can thrive in low-oxygen environments. Looking for viable drug targets for TNBC, Dr. Zhang and his colleagues zeroed in on 2-oxoglutarate (2OG)-dependent enzymes, a family of 70 enzymes including some that function as oxygen sensors in cells. To determine their role in TNBC, the researchers used a library of short interfering RNAs (siRNAs)--snippets of genetic material that can shut off the expression of specific genes--to individually turn off each member of the 2-OG-dependent family in different TNBC and healthy breast cell lines.

Tumor-Derived Exosomes Containing GTPase Rab11a Can Drive Cancer Growth and Treatment Resistance, New Results from University of Oxford Suggest

Collaborative Cancer Research UK-funded studies from University of Oxford researchers have revealed a new mechanism by which cancer cells adapt to the stresses they encounter as they grow and respond to therapies. This mechanism involves cells releasing small vesicles, known as exosomes. These exosomes can contain complex mixtures of proteins, RNAs, and other molecules, which can reprogram surrounding cells. Exosomes are thought to be released by all cells in the body and play important roles in many processes in healthy individuals, such as immunity and reproduction. But, in cancer, they can sometimes drive pathological changes such as tumor growth and metastasis. Up until now, research has suggested that exosomes are made in compartments in cells, known as late endosomes, which are also used to keep cells healthy by clearing out damaged proteins and cell structures. By combining complementary analysis in fruit flies and human cancer cells, the collaborative teams have shown that exosomes are also made in the cell’s recycling system, which diverts reusable proteins away from the waste disposal system. They are called Rab11a-exosomes and carry a different set of cargos that may help cancers to grow and survive current treatments. As a tumor grows larger, the cells within it are starved of key nutrients such as amino acids, and these stressed cells produce Rab11a-exosomes loaded with molecules made by the cancer cells. According to Associate Professor Deborah Goberdhan (photo), who led the research, “These ‘bad exosomes’ can then give other cells around them a growth-promoting boost and can potentially lead to selection of more aggressive cell types and a worse outcome.

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