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January 5th

Brown Fat May Protect Against Numerous Chronic Diseases, Rockefeller Study of 50,000 People Suggests; May Also Hold Clues to New Obesity Treatments

Brown fat may be an almost magical tissue you might want more of. Unlike white fat, which stores calories, brown fat burns energy and scientists hope it may hold the key to new obesity treatments. But it has long been unclear whether people with ample brown fat truly enjoy better health. For one thing, it has been hard to even identify such individuals because brown fat is hidden deep inside the body. Now, a new study in Nature Medicine (https://www.nature.com/articles/s41591-020-1126-7), published online on January 4, 2021, and conducted by Rockefeller University scientists and collaborators, offers strong evidence. The research team found that, among over 52,000 participants, those who had detectable brown fat were less likely than their peers to suffer cardiac and metabolic conditions ranging from type 2 diabetes to coronary artery disease, which is the leading cause of death in the United States. The Nature Medicine article is titled “Brown Adipose Tissue Is Associated with Cardiometabolic Health.” This study, by far the largest of its kind in humans, confirms and expands the health benefits of brown fat suggested by previous studies. "For the first time, it reveals a link to lower risk of certain conditions," says Paul Cohen (https://www.rockefeller.edu/our-scientists/heads-of-laboratories/1112-pa...), MD, PhD, the Albert Resnick, Assistant Professor and Senior Attending Physician at The Rockefeller University Hospital. "These findings make us more confident about the potential of targeting brown fat for therapeutic benefit." Although brown fat has been studied for decades in newborns and animals, it was only in 2009 that scientists appreciated it can also be also found in some adults, typically around the neck and shoulders.

January 3rd

DNA from Seabiscuit’s Hooves Offers Clues to Famous Race Horse’s Gifts of Speed & Stamina

[Editor’s Note: The following is a reprint of an article authored by Steven Tammariello (https://www.binghamton.edu/biology/people/profile.html?id=tammarie), PhD, that appeared in The Conversation (https://theconversation.com/can-seabiscuits-dna-explain-his-elite-racing...) on October 29, 2018 and was reprinted in Smithsonian Magazine (https://www.smithsonianmag.com/history/scientists-extract-dna-from-seabi...). It is reprinted here in BioQuick News in accordance with the pertinent Creative Commons License. Dr. Tammriello is Associate Professor of Biological Sciences and Director of the Institute for Equine Genomics, Binghamton University, State University of New York.]--Seabiscuit (http://www.americanclassicpedigrees.com/seabiscuit.html) (https://en.wikipedia.org/wiki/Seabiscuit) was not an impressive-looking horse. He was considered quite lazy, preferring to eat and sleep in his stall rather than exercise. He’d been written off by most of the racing industry after losing his first 17 races. But Seabiscuit eventually became one of the most beloved thoroughbred champions of all time – voted 1938 Horse of the Year after winning his legendary match race (https://www.theguardian.com/sport/2013/nov/01/seabiscuit-war-admiral-hor...) as an underdog against Triple Crown winner War Admiral in 1938 [photo shows Seabiscuit in the lead over War Admiral in their match race at Baltimore’s Pimlico Race Track on November 1, 1938 (Credit: AP)]. As a molecular physiologist, the concept of understanding how specific gene variants can affect performance--whether in athletics, learning, or even how an organism develops--has always intrigued me.

January 2nd

Adaptation of Forward Genetics Technique Leads to ID of Gene (KDM5A) Newly Associated with Autism Spectrum Disorder (ASD); Approach May Open Door to ID of More ASD-Associated Mutations and Advance Future Treatments; Article Co-Author Is Nobelist

University of Texas (UT) Southwestern (UTSW) scientists have adapted a classic research technique called forward genetics to identify new genes involved in autism spectrum disorder (ASD). In a study published online on December 22, 2020 in eLife (https://elifesciences.org/articles/56883), the researchers used this approach in mice to find one such gene called KDM5A. The open-access eLife article is titled “KDM5A Mutations Identified in Autism Spectrum Disorder Using Forward Genetics.” Approximately 1 in 54 children in the U.S. is diagnosed with ASD, a neurodevelopmental disorder that causes disrupted communication, difficulties with social skills, and repetitive behaviors. As a disease with a strong genetic component, it is hypothesized that thousands of genetic mutations may contribute to ASD. But to date, only about 30 percent of cases can be explained by known genetic mutations. For decades, forward genetics (https://www.google.com/search?client=firefox-b-1-d&q=reverse+genetics+an... ) has been used to find mutations that cause disease. It involves inducing genetic mutations in mice, screening for certain phenotypes, and then identifying the causative mutation through sequencing all of the organism’s genome. “The difficult part in the beginning was finding the mutations. It had to be done by laborious cloning,” says Nobel Laureate Bruce Beutler (https://profiles.utsouthwestern.edu/profile/10593/bruce-beutler.html) (https://www.nobelprize.org/prizes/medicine/2011/beutler/biographical/), MD, Director of the Center for the Genetics of Host Defense (https://www.utsouthwestern.edu/education/medical-school/departments/gene...) at UTSW and study co-author.

Nanoparticle Drug-Delivery System Developed to Aid Treatment of Brain Disorders/Diseases; Use in Mouse Models Results In Unprecedented Penetration of siRNA Across Intact Blood-Brain Barrier; System Could Be “Game-Changer” in Treatment of CNS Diseases

In the past few decades, researchers have identified biological pathways leading to neurodegenerative diseases and developed promising molecular agents to target them. However, the translation of these findings into clinically approved treatments has progressed at a much slower rate, in part because of the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain. To facilitate successful delivery of therapeutic agents to the brain, a team of bioengineers, physicians, and collaborators at Brigham and Women's Hospital and Boston Children's Hospital created a nanoparticle platform, which can facilitate therapeutically effective delivery of encapsulated agents in mice with a physically breached or intact BBB. In a mouse model of traumatic brain injury (TBI), the scientists observed that the delivery system showed three times more accumulation in brain than conventional methods of delivery and was therapeutically effective as well, which could open possibilities for the treatment of numerous neurological disorders. Findings were published online on January 1, 2021 in Science Advances. The article is titled “BBB Pathophysiology Independent Delivery of siRNA in Traumatic Brain Injury.” Previously developed approaches for delivering therapeutics into the brain after TBI rely on the short window of time after a physical injury to the head, when the BBB is temporarily breached. However, after the BBB is repaired within a few weeks, physicians lack tools for effective drug delivery. "It's very difficult to get both small and large molecule therapeutic agents delivered across the BBB," said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham's Department of Anesthesiology, Perioperative and Pain Medicine.

January 1st

Traditional Medicines Used in Ghana Show Promise Against Tropical Diseases, Including Schistosomiasis, River Blindness, and Elephantiasis

The discovery of new drugs is vital to achieving the eradication of neglected tropical diseases (NTDs) in Africa and around the world. Now, researchers reporting in PLOS Neglected Tropical Diseases have identified traditional Ghanaian medicines which work in the lab against schistosomiasis, onchocerciasis, and lymphatic filariasis, three diseases endemic to Ghana. The open-access article was published online on December 31, 2020, and is titled “Antischistosomal, Antionchocercal and Antitrypanosomal Potentials of Some Ghanaian Traditional Medicines and Their Constituents.” The major intervention for NTDs in Ghana is currently mass drug administration of a few repeatedly recycled drugs, which can lead to reduced efficacy and the emergence of drug resistance. Chronic infections of schistosomiasis, onchocerciasis, and lymphatic filariasis can be fatal. Schistosomiasis is caused by the blood flukes Schistosome haematobium and S. mansoni. Onchocerciasis, or river blindness, is caused by the parasitic worm Onchocerca volvulus. Lymphatic filariasis, also called elephantiasis, is caused by the parasitic filarial worm Wuchereria bancrofti. In the new work, Dorcas Osei-Safo (photo), PhD, of the University of Ghana, and colleagues obtained--from the Ghana Federation of Traditional Medicines Practitioners Association--15 traditional medicines used for treating NTDs in local communities. The medicines were available in aqueous herbal preparations or dried powdered herbs. In all cases, crude extracts were prepared from the herbs and screened in the laboratory for their ability to treat various NTDs. Two extracts, NTD-B4-DCM and NTD-B7-DCM, displayed high activity against S. mansoni adult worms, decreasing the movement of the worms by 78.4% and 84.3% respectively.

December 31st, 2020

New Virtual Screening Strategy Identifies Existing Lymphoma Drug (Pralatrexate) That Inhibits SARS-CoV-2 Virus Replication; Drug Targets Viral RNA-Dependent RNA Polymerase (RdRP); Viral Inhibition Is Stronger Than That Achieved by Remdesivir

A novel computational drug screening strategy, combined with lab experiments, suggest that pralatrexate, a chemotherapy medication originally developed to treat lymphoma, could potentially be repurposed to treat COVID-19. Haiping Zhang, PhD, of the Shenzhen Institutes of Advanced Technology in Shenzhen, China, and colleagues presented these findings in the open-access journal PLOS Computational Biology in an article published on December 31, 2020. The article is titled “A Novel Virtual Screening Procedure Identifies Pralatrexate As Inhibitor of SARS-CoV-2 Rdrp and It Reduces Viral Replication in Vitro.” With the COVID-19 pandemic causing illness and death worldwide, better treatments are urgently needed. One shortcut could be to repurpose existing drugs that were originally developed to treat other conditions. Computational methods can help identify such drugs by simulating how different drugs would interact with SARS-CoV-2, the virus that causes COVID -19. To aid virtual screening of existing drugs, Dr. Zhang and colleagues combined multiple computational techniques that simulate drug-virus interactions from different, complementary perspectives. They used this hybrid approach to screen 1,906 existing drugs for their potential ability to inhibit replication of SARS-CoV-2 by targeting a viral protein called RNA-dependent RNA polymerase (RdRP). The novel screening approach identified four promising drugs, which were then tested against SARS-CoV-2 in lab experiments. Two of the drugs, pralatrexate and azithromycin, successfully inhibited replication of the virus. Further lab experiments showed that pralatrexate more strongly inhibited viral replication than did remdesivir, a drug that is currently used to treat some COVID -19 patients.

Article Reporting Anecdotal Success of CytoDyn’s Leronlimab (Vyrologix™) in Treatment of Critically Ill COVID-19 Patients Accepted for Journal Publication; Four Patients, Initially on Mechanical Ventilators, Fully Recover After Leronlimab Treatment

On Decembr 30, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing Vyrologix™ (leronlimab) (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced that a research manuscript submitted by first author Nicholas J. Agresti, MD, has been accepted for publication in the Journal of Translational Autoimmunity. The research findings of Dr. Agresti and colleagues were based on four critically ill COVID-19 patients treated with leronlimab under an FDA-approved emergency investigational new drug (eIND) application. All four were on mechanical ventilators and fully recovered following leronlimab treatment. Dr. Agresti is a gastroenterologist in the Southeast Georgia Health System. The manuscript (Ms. No. JTAUTO-D-20-00043R1) is entitled “Disruption of CCR5 Signaling to Treat COVID-19-Associated Cytokine Storm: Case Series of Four Critically Ill Patients Treated with Leronlimab.” The accepted research paper can be accessed here (https://d1io3yog0oux5.cloudfront.net/cytodyn/files/pages/cytodyn/db/256/...). Additional authors on the paper included Bruce Patterson, MD, CEO and Founder, Incell Dx; Kabir Mody, MD, Mayo Clinic; Jacob Lalezari, MD, CytoDyn advisor, now CMO at Virion; Jonah B. Sacha, PhD, Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon; Harish Seethamraju, MD, Medical Director, Advanced Lung Failure and Lung Transplant, Montefiore Medical Center; Seth Gross, MD, NYU Langone Gastroenterology Associates; Scott Kelly, MD, CMO, CytoDyn; Nader Pourhassan, PhD, President and CEO, CytoDyn, and Kush Dody, MBBS, Vice President, Clinical Operations, Amarex Clinical Research, among others. Dr.

Study Points Way to Possibly Boost CAR-T Immunotherapy Against Breast Cancer, Other Solid Tumors; Addition of STING Agonist cGAMP Reduces Tumor Growth & Enhances Survival in Mouse Model; Possible “Game-Changer” for Treatment of Solid Tumors

Boosting immune system T cells to effectively attack solid tumors, such as breast cancers, can be done by adding a small molecule to a treatment procedure called chimeric antigen receptor-T (CAR-T) cell therapy (https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell), according to a study by researchers at the University of North Crolina (UNC) Lineberger Comprehensive Cancer Center. The boost helps recruit more immune cells into battle at the tumor site. The findings were published online on December 31, 2020 in the Journal of Experimental Medicine. The JEM article is titled “STING Agonist Promotes CAR T Cell Trafficking and Persistence in Breast Cancer.” CAR-T immunotherapy, in which T cells are modified in the laboratory to express chimeric antigen receptors, CARs, that in turn target surface proteins on cancer cells, has been most effective in the treatment of patients with B-cell leukemia or lymphoma. But this new research, conducted in mouse models, points to the potential for using CAR-T therapy effectively against solid tumors as well. "We know that CAR T cells are safe for patients with solid tumors but so far they have not been able to cause significant tumor regression in the overwhelming majority of people treated," said Jonathan S. Serody, MD, the Elizabeth Thomas Professor of Medicine, Microbiology, and Immunology and Director of the Immunotherapy Program at UNC Lineberger. "Now we may have a new approach to make CAR T cells work in solid tumors, which we think could be a game-changer for therapies aimed at an appreciable number of cancers." Dr. Serody is the paper's corresponding author and Nuo Xu, PhD, formerly a graduate student at UNC Lineberger and UNC School of Medicine, is the first author.

Data from Moderna COVID-19 Vaccine Trial Reported in December 30 NEJM Article; Data Shows 94.1 Percent Efficacy for mRNA-1273 Vaccine Candidate

A peer-reviewed paper published online on December 30, 2020 in The New England Journal of Medicine provides data from the much-anticipated COVE study, which evaluated mRNA-1273, a vaccine candidate against COVID-19 manufactured by Moderna, Inc. Results from the primary analysis of the study, which will continue for two years, provide evidence that the vaccine can prevent symptomatic infection. Among the more than 30,000 participants randomized to receive the vaccine or a placebo, 11 of those in the vaccine group developed symptomatic COVID-19 compared to 185 participants who received the placebo, demonstrating 94.1 percent efficacy in preventing symptomatic COVID-19. Cases of severe COVID-19 occurred only in participants who received the placebo. Brigham and Women's Hospital served as a site for the trial as part of the COVID-19 Prevention Network (CoVPN), funded by the National Institutes of Health. In addition, Lindsey Baden, MD, an infectious diseases specialist at the Brigham and an expert in vaccine development for viral diseases, served as Co-Principal Investigator for the study and lead author of the paper. The open-access NEJM article is titled "Efficacy and Safety of mRNA-1273 SARS-CoV-2 Vaccine.” "Our work continues. Over the next months, we'll have increasing amounts of data to better define how this vaccine works, but the results so far show a 94.1 percent efficacy. These numbers are compelling," said Dr. Baden. "And, importantly, the data suggest protection from severe illness, indicating that the vaccine could have an impact on preventing hospitalizations and deaths, at least in the first several months post-vaccination."

December 30th

Researchers in Spain Suggest COVID-19 Infection of Oxygen-Sensing Carotid Body May Be Cause of “Silent Hypoxemia” Observed in Many COVID-19 Patients; Carotid Body Activators Might Prove Useful in Treatment, If Hypothesis Confirmed

One of the physiopathological characteristics of COVID-19 that has most baffled the scientific and medical community is what is known as "silent hypoxemia" or "happy hypoxia." Patients suffering this phenomenon, the causes of which are still unknown, have severe pneumonia with markedly decreased arterial blood oxygen levels (known as hypoxemia). However, they do not report dyspnea (subjective feeling of shortness of breath) or increased breathing rates, which are usually characteristic symptoms of people with hypoxemia from pneumonia or any other cause. Patients with "silent hypoxemia" often suffer a sudden imbalance, reaching a critical state that can be fatal. Normally, individuals (healthy or sick) with hypoxemia report a feeling of shortness of breath and a higher breathing rate, thus increasing the body's uptake of oxygen. This reflex mechanism depends on the carotid body. This small organ, located on either side of the neck next to the carotid artery, detects the drop in blood oxygen and sends signals to the brain to stimulate the respiratory center. A group of researchers from the Seville Institute of Biomedicine - IBiS/University Hospitals Virgen del Rocío y Macarena/CSIC/University of Seville, led by Dr. Javier Villadiego, Dr. Juan José Toledo-Aral, and Dr. José López-Barneo, specialists in the physiopathological study of the carotid body, have suggested in the journal Function, that "silent hypoxemia" in COVID-19 cases could be caused by this organ (carotid body) being infected by the coronavirus (SARS-CoV-2).