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Harvard Researchers Unravel Healing Mechanisms of Extracellular Vesicles (EVs) and Demonstrate Their Healing Power on a Heart-On-A-Chip; Work Shows Endothelial EVs Contain Protective Proteins and Can Rescue Ischemia-Reperfusion Injury

Extracellular vesicles (EVs)--nanometer-sized messengers that travel between cells to deliver cues and cargo--are promising tools for the next generation of therapies for everything from autoimmune and neurodegenerative diseases to cancer and tissue injury. EVs derived from stem cells have already been shown to help heart cells recover after a heart attack, but exactly how they help and whether the beneficial effect is specific to EVs derived from stem cells has remained a mystery. Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have unraveled potential mechanisms behind the healing power of EVs and demonstrated their capacity to not only revive cells after a heart attack, but to keep cells functioning while deprived of oxygen during a heart attack. The researchers demonstrated this functionality in human tissue using a heart-on-a-chip with embedded sensors that continuously tracked the contractions of the tissue. The team also demonstrated that these EVs could be derived from endothelial cells, which line the surface of blood vessels and are more abundant and easier to maintain than stem cells. The research was published in the October14, 2020 issue of Science Translational Medicine (https://stm.sciencemag.org/content/12/565/eaax8005). The article is titled “Endothelial Extracellular Vesicles Contain Protective Proteins and Rescue Ischemia-Reperfusion Injury in a Human Heart-On-Chip.” “Our organ-on-chip technology has progressed to the point where we can now fight drug targets instead of fighting the chip design,” said Kit Parker, PhD, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the study.

Research Shows How Actin-Thin Filaments Are Kept at Exact Same Length in Healthy Heart; Uneven Lengths Lead to Disease; Work Enabled by Atomic-Precision NMR Analysis

It might look like a little game at the molecular scale. Filament-like proteins in heart muscle cells have to be exactly the same length so that they can coordinate perfectly to make the heart beat. Another protein determines when the filament is the right size and puts a small cap on it. But, if that protein makes a mistake and puts the cap on too early, another protein, leiomodin, comes along and knocks the cap out of the way. This little dance at the molecular scale might sound insignificant, but it plays a critical role in the development of healthy heart and other muscles. Reporting in an article published online on September 8, 2020 in the journal PLOS Biology, a Washington State University (WSU) research team has proven for the first time how the mechanism works. The article is titled “Leiomodin Creates a Leaky Cap at the Pointed End of Actin-Thin Filaments.” The finding could someday lead to improved diagnostics and medical treatments for serious and sometimes devastating hereditary heart conditions that come about from genetic mutations in the proteins. One of these conditions, cardiomyopathy, affects as many as one in 500 people around the world and can often be fatal or have lifetime health consequences. A similar condition called nemaline myopathy affects skeletal muscles throughout the body with often devastating consequences. "Mutations in these proteins are found in patients with myopathy," said Alla Kostyukova, PhD, Associate Professor in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering at WSU and leader of the project. "Our work is to prove that these mutations cause these problems and to propose strategies for treatment." Heart muscle is made of tiny thick and thin filaments of proteins.

New Blood Test (IL-6/IL-10 Ratio) Can Predict Which COVID-19 Patients Will Develop Severe Infection, Results Suggest

Scientists have developed, for the first time, a score that can accurately predict which patients will develop a severe form of Covid-19. The study, led by researchers at RCSI (Royal College of Surgeons in Ireland) University of Medicine and Health Sciences, was published published online on October 8, 2020 in The Lancet's translational research journal EBioMedicine (https://doi.org/10.1016/j.ebiom.2020.103026). The open-access article is titled “A Linear Prognostic Score Based on the Ratio of Interleukin-6 to Interleukin-10 Predicts Outcomes in COVID-19.” The measurement, called the Dublin-Boston score, is designed to enable clinicians to make more informed decisions when identifying patients who may benefit from therapies, such as steroids, and admission to intensive care units. Until this study, no COVID-19-specific prognostic scores were available to guide clinical decision-making. The Dublin-Boston score can now accurately predict how severe the infection will be on day seven after measuring the patient's blood for the first four days. The blood test works by measuring the levels of two molecules that send messages to the body's immune system and control inflammation. One of these molecules, interleukin (IL)-6, is pro-inflammatory, and a different one, called IL-10, is anti-inflammatory. The levels of both are altered in severe Covid-19 patients. Based on the changes in the ratio of these two molecules over time, the researchers developed a point system where each 1-point increase was associated with a 5.6 times increased odds for a more severe outcome. "The Dublin-Boston score is easily calculated and can be applied to all hospitalized COVID-19 patients," said RCSI Professor of Medicine Gerry McElvaney, the study's senior author and a consultant in Ireland’s Beaumont Hospital.

NIH Begins Large Phase 3 Clinical Trial to Test Immune Modulators for Treatment of COVID-19; Trial Will Test Infliximab (Johnson & Johnson), Abatacept (Bristol Myers Squibb), and Cenicriviroc (AbbieVie)

On October 16, 2020, it was announced that the NIH has launched an adaptive Phase 3 clinical trial to evaluate the safety and efficacy of three immune modulator drugs in hospitalized adults with COVID-19(see larger image of SARS-CoV-2-infected cell at end). Some COVID-19 patients experience an immune response in which the immune system unleashes excessive amounts of proteins that trigger inflammation--called a “cytokine storm”--that can lead to acute respiratory distress syndrome (ARDS), multiple organ failure, and other life-threatening complications. The clinical trial aims to determine if modulating that immune response can reduce the need for ventilators and shorten hospital stays. The trial, known as ACTIV-1 Immune Modulators (IM), will determine if the therapeutics are able to restore balance to an overactive immune system. Part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (https://www.nih.gov/research-training/medical-research-initiatives/activ) initiative, the trial expects to enroll approximately 2,100 hospitalized adults with moderate to severe COVID-19 at medical facilities in the United States and Latin America. The National Center for Advancing Translational Sciences (NCATS), part of NIH, will coordinate and oversee the trial with funding support from the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, in support of the Trump administration’s Operation Warp Speed (https://www.hhs.gov/coronavirus/explaining-operation-warp-speed/index.html goals.

Study Suggests Higher Dopamine Levels May Be Associated with Better Mobility in Frail & Elderly Adults

Variations in a gene that regulates dopamine levels in the brain may influence, positively or negatively, the mobility of elderly and frail adults, according to new research from the University of Pittsburgh (Pitt) Graduate School of Public Health. These results, published online on October 12, 2020 in the Journal of The American Geriatrics Society, add to a growing body of evidence hinting that lower dopamine levels can contribute to the slower, often disabling walking patterns seen in some elderly populations. The article is titled “Catechol‐O‐Methyltransferase Genotype, Frailty, and Gait Speed in a Biracial Cohort of Older Adults.” "Most people think about dopamine's role in mobility in the context of Parkinson's disease, but not in normal aging," said senior author Caterina Rosano, MD, MPH, Professor of Epidemiology at Pitt Public Health. "We were curious to see if a genetic predisposition to produce more or less dopamine was related to mobility in individuals who had some level of frailty, yet did not have dementia, parkinsonism or any other neurological condition." While several genetic elements control dopamine signaling, Dr. Rosano and her team focused on a gene called COMT (catechol-O-methyltransferase), which breaks down dopamine to control its levels within the brain. They also considered the frailty status of participants, which is a common consequence of aging marked by a decline in physiological function, poor adjustment to stressors and a susceptibility toward adverse health outcomes. The researchers suspected that frail participants could be particularly vulnerable to COMT-driven differences in dopamine levels. Dr.

How Deadly Parasites “Glide” Along and Into Human Cells

In biological terms, gliding refers to the type of movement during which a cell moves along a surface without changing its shape. This form of movement is unique to parasites from the phylum Apicomplexa, such as Plasmodium and Toxoplasma. Both parasites, which are transmitted by mosquitoes and cats, have an enormous impact on global heath. Plasmodium causes 228 million malaria infections and approximately 400,000 deaths per year. Toxoplasma, which infects an estimated one third of the human population, can cause severe symptoms in some people, and is particularly dangerous during pregnancy. Gliding enables the Apicomplexa parasites to enter and move between host cells. For example, upon entering the human body through a mosquito bite, Plasmodium glides through human skin before crossing into human blood vessels. This type of motion relies on actin and myosin, which are the same proteins that enable muscle movement in humans and other vertebrates. Myosin has a form of molecular 'legs' that 'march' along actin filaments and thereby create movement. In Apicomplexa, myosin interacts with several other proteins, which together form a complex called the “glideosome.” The exact mechanism by which the glideosome works is not well understood, among other reasons because the molecular structure of most glideosome proteins are unknown. Yet understanding this mechanism could aid the development of drugs that prevent the assembly of the glideosome and thereby stop the progression of diseases such as malaria and toxoplasmosis. Scientists at European Molecular Biology Laboratory (EMBL) Hamburg analyzed the molecular structure of essential light chains (ELCs), which are glideosome proteins that bind directly to myosin.

Scientists Develop “Unprecedented” 3-D Model of Molecular Machine (BAF Complex) That Regulates Expression of Genes by Modifying Chromatin; Model Has Enabled Investigators to Map Many Cancer-Related Mutations to Locations in BAF Complex

Scientists have created an unprecedented 3-dimensional structural model of a key molecular “machine” known as the BAF complex (mammalian SWI/SNF complex) (https://en.wikipedia.org/wiki/SWI/SNF), which modifies DNA architecture and is frequently mutated in cancer and some other diseases. The researchers, led by Cigall Kadoch (photo), PhD, (http://www.kadochlab.org/ of Dana-Farber Cancer Institute, have reported the first 3-D structural “picture” of BAF complexes purified directly from human cells in their native states--rather than artificially synthesized in the laboratory--providing an opportunity to spatially map thousands of cancer-associated mutations to specific locations within the complex. “A 3-D structural model, or ‘picture,’ of how this complex actually looks inside the nucleus of our cells has remained elusive--until now,” says Dr. Kadoch. The newly obtained model represents “the most complete picture of the human BAF complex achieved to date,” said the investigators, reporting in the journal Cell. The article is titled “A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms.” Dr. Kadoch is Associate Professor of Pediatric Oncology, Dana-Farber Cancer Institute; Affiliated Faculty, Biological Chemistry and Molecular Pharmacology, Harvard Medical School; and Institute Member and Epigenomics Program Co-Director, Broad Institute of MIT and Harvard. The new findings “provide a critical foundation for understanding human disease-associated mutations in components of the BAF complex, which are present in over 20% of human cancers and in several intellectual disability and neurodevelopomental disorders,” the authors said.

Codiak BioSciences, Specializing in Exosome-Based Therapeutics, Announces Pricing ($15/Share) of Initial Public Offering

On October 13, 2020, Codiak BioSciences, Inc., a clinical-stage company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, announced the pricing of its initial public offering (IPO) of 5,500,000 shares of its common stock at a public offering price of $15.00 per share, for gross proceeds of approximately $82.5 million, before deducting underwriting discounts and commissions and offering expenses. [Editor’s Note: CDAK price at end of day October 15 was $12.09/share.] All of the shares are being offered by Codiak. In addition, Codiak has granted the underwriters a 30-day option to purchase up to 825,000 additional shares of common stock at the initial public offering price, less underwriting discounts and commissions. The shares are scheduled to begin trading on the Nasdaq Global Market on October 14, 2020 under the ticker symbol “CDAK,” and the offering is expected to close on October 16, 2020, subject to customary closing conditions. Goldman Sachs & Co. LLC, Evercore ISI, and William Blair are acting as joint book-running managers for the offering and as representatives of the underwriters. Wedbush PacGrow is acting as lead manager for the offering. A registration statement relating to these securities has been filed with the Securities and Exchange Commission and became effective on October 13, 2020. This offering is being made only by means of a prospectus. Copies of the final prospectus, when available, may be obtained from: Goldman Sachs & Co.

Researchers ID Mechanism Underlying Bone Marrow Failure in Fanconi Anemia

Researchers at the University of Helsinki in Finland and the Dana-Farber Cancer Institute in the USA have identified the mechanism behind bone marrow failure developing in children that suffer from Fanconi anemia. The findings may help to develop new therapies for the disorder. Fanconi anemia (FA) is a genetic disease affecting small children and characterized by bone marrow failure, developmental abnormalities, and predisposition to multiple forms of cancer. The molecular mechanisms behind FA are inherited mutations in genes encoding DNA repair proteins, leading to irreversible bone marrow failure. The exact mechanisms of how these genetic mutations lead to the exhaustion of stem cells from the bone marrow have been unknown. Now, the researchers have identified a cause for this failure. The findings were published online on September 29, 2020 in Cell Stem Cell. The article is titled “MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.” “The results open new paths for developing novel therapies for the disease, for which the only curative treatment currently available is stem cell transplantation. Understanding the mechanism of bone marrow failure better can help to plan stem cell transplantations and to develop new therapies for milder forms of Fanconi anemia,” says Anniina Färkkilä (photo), MD, PhD, Docent and Clinical Researcher at the University of Helsinki, and Specialist in Obstetrics and Gynecology at Helsinki University Hospital. In the study, researchers at the University of Helsinki analyzed the gene expression of individual cells, and found, to their surprise, overexpression of the MYC gene in the bone marrow stem cells of patients with Fanconi anaemia. MYC is one of the best-known genes regulating the formation of malignant tumors.

New Study Suggests Crucial Role for T-Cells in Asymptomatic COVID-19 Infection

COVID-19 remains stubbornly inconsistent. More than a million people have died and 35 million have been diagnosed, but a large fraction of people infected with the coronavirus--about 45%, according to recent estimates--show no symptoms at all. A retrospective study of 52 COVID-19 patients, published online on October 7, 2020 in mSphere, an open-access journal of the American Society for Microbiology, may help researchers better understand why not everyone show symptoms of the disease. The article is titled “Descriptive, Retrospective Study of the Clinical Characteristics of Asymptomatic COVID-19 Patients.” The study's authors found that asymptomatic patients hosted viral loads comparable to those of symptomatic patients, but asymptomatic patients showed higher levels of lymphocytes (a type of white blood cell responsible for immune responses), cleared the viral particles faster, and had lower risks of long-term complications. Further analyses suggested the interaction between the virus and the immune system likely played a role in that process. "Our findings suggested an important role for lymphocytes, especially T-cells, in controlling virus shedding," said virologist Yuchen Xia, PhD, at Wuhan University's School of Basic Medical Sciences in China, senior author of the new study. The wide range of COVID-19 symptoms is well documented. Asymptomatic carriers, on the other hand, often go undiagnosed, but can still shed the virus and spread it to others. Understanding why some patients get sick and others don't is one of the most important challenges in curbing the pandemic, Dr. Xia said. "They may cause a greater risk of virus transmission than symptomatic patients, posing a major challenge to infection control." Dr.

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