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Monoclonal Antibodies Against Glucagon-Producing Alpha Cells in Pancreas Convert These Cells to Insulin-Producing Beta Cells in Animal Models; Approach May Lead to Treatment for Both Type 1 and Type 2 Diabetes

Blocking cell receptors for glucagon, the counter-hormone to insulin, cured mouse models of diabetes by converting glucagon-producing cells into insulin producers instead, a team led by University of Texas (UT) Southwestern (UTSW) researchers reports in a new study. The findings, published online on March 2, 2021 in PNAS, could offer a new way to treat both Type 1 and Type 2 diabetes in people. The open-access article is titled “Glucagon Blockade Restores Functional β-cell Mass in Type 1 Diabetic Mice and Enhances Function of Human Islets.” More than 34 million Americans have diabetes, a disease characterized by a loss of beta cells in the pancreas. Beta cells produce insulin, a hormone necessary for cells to absorb and use glucose, a type of sugar that circulates in the blood and serves as cellular fuel. In Type 2 diabetes, the body’s tissues develop insulin resistance, prompting beta cells to die from exhaustion from secreting excess insulin to allow cells to take in glucose. In Type 1 diabetes, which affects about 10 percent of the diabetic population, beta cells die from an autoimmune attack. Both kinds of diabetes lead to severely elevated blood sugar levels that eventually can cause a host of possible complications, including loss of limbs and eyesight, kidney damage, diabetic coma, and death. Most treatments for diabetes focus on insulin, but its counterpart--the hormone glucagon that is produced by alpha cells in the pancreas--has received comparatively little attention, says study leader May-Yun Wang (photo) (, PhD, Assistant Professor of Internal Medicine at UTSW. Glucagon binds to receptors on cells in the liver, prompting this organ to secrete glucose.

CytoDyn’s Phase 3 Trial of Leronlimab (Vyrologix™) Demonstrates 24% Reduction in Mortality and Faster Hospital Discharge for Mechanically Ventilated Critically Ill COVID-19 Patients; Webcast Monday

On March 05, 2021, 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, reported that the Phase 3 trial of leronlimab for the treatment of severe-to-critical patients with COVID-19 demonstrated continued safety, substantial improvement in survival rate, and faster hospital discharge in critically ill COVID-19 patients. The trial’s data has been reported to the U.S. Food and Drug Administration (FDA), the U.K.’s Medicines & Healthcare product Regulatory Agency (MHRA) and Health Canada (HC), and the company is in discussions with each to determine the best path forward for approval of leronlimab for treatment of COVID-19 in critically ill populations. A manuscript of the trial’s data is being prepared and will be submitted for publication in one or more major medical journals. Highlights from the trial’s data for this critically ill population include the following:
--Survival Benefit: There was a 24% reduction in all-cause mortality (primary endpoint of the study) in the leronlimab arm versus the placebo arm of the study.
--Shortened Time to Recovery: The average length of hospital stay was reduced by 6 days for patients who received leronlimab with "commonly used COVID-19 treatments,” also referred to as “Standard of Care” or “SoC,” compared to placebo patients who received SoC only, with a statistically significant p-value of 0.005.
--Discharged Alive: In addition, patients who received leronlimab demonstrated an improved probability of "discharged alive" at Day 28 (28% versus 11%), a 166% better rate than in the placebo group.

Advance In “Optical Tweezers” May Boost Biomedical Research

Much like the Jedis in Star Wars use “the force” to control objects from a distance, scientists can use light or “optical force” to move very small particles. The inventors of this ground-breaking laser technology, known as “optical tweezers,” were awarded the 2018 Nobel Prize in Physics. Optical tweezers are used in biology, medicine, and materials science to assemble and manipulate nanoparticles such as gold atoms. However, the technology relies on a difference in the refractive properties of the trapped particle and the surrounding environment. Now scientists have discovered a new technique that allows them to manipulate particles that have the same refractive properties as the background environment, overcoming a fundamental technical challenge. The study “Optical Tweezers Beyond Refractive Index Mismatch Using Highly Doped Upconversion Nanoparticles” was published online on February 18, 2021 in Nature Nanotechnology ( "This breakthrough has huge potential, particularly in fields such as medicine," says leading co-author Dr. Fan Wang from the University of Technology Sydney (UTS). "The ability to push, pull, and measure the forces of microscopic objects inside cells, such as strands of DNA or intracellular enzymes, could lead to advances in understanding and treating many different diseases such as diabetes or cancer. Traditional mechanical micro-probes used to manipulate cells are invasive, and the positioning resolution is low. They can only measure things like the stiffness of a cell membrane, not the force of molecular motor proteins inside a cell," he says. The research team developed a unique method to control the refractive properties and luminescence of nanoparticles by doping nanocrystals with rare-earth metal ions.

Huntington's Disease May Be Driven by Slowed Protein-Building Machinery in Cells; New Study Shows That Mutant Huntingtin Protein Slows Ribosomes

In 1993, scientists discovered that a single mutated gene, HTT, caused Huntington's disease, raising high hopes for a quick cure. Yet today, there's still no approved treatment. One difficulty has been a limited understanding of how the mutant huntingtin protein sets off brain cell death, says neuroscientist Srinivasa Subramaniam, PhD, of Scripps Research, Florida. In a new study published online on March 5, 2021 in Nature Communications, Dr. Subramaniam's group has shown that the mutated huntingtin protein slows brain cells' protein-building machines, called ribosomes. "The ribosome has to keep moving along to build the proteins, but in Huntington's disease, the ribosome is slowed," Dr. Subramaniam says. "The difference may be two-, three-, four-fold slower. That makes all the difference." The open-access Nature Communications article is titled “"Mutant Huntingtin Stalls Ribosomes and Represses Protein Synthesis in a Cellular Model of Huntington Disease” ( Cells contain millions of ribosomes each, all whirring along and using genetic information to assemble amino acids and make proteins. Impairment of their activity is ultimately devastating for the cell, Dr. Subramaniam says. "It's not possible for the cell to stay alive without protein production," he says. The team's discoveries were made possible by recent advancements in gene translation tracking technologies, Dr. Subramaniam says. The results suggest a new route for development of therapeutics, and have implications for multiple neurodegenerative diseases in which ribosome stalling appears to play a role.

Proteomics Analysis Identifies Potential Drug Targets for Aggressive Human Cancers

Researchers at Baylor College of Medicine have shown that analysis of the proteomics, or all the protein data, from aggressive human cancers is a useful approach to identify potential novel therapeutic targets. The scientists reported their findings in an article published online on February 24, 2021 in Oncogene (, the identification of "proteomic signatures" that are associated with clinical measures of aggressive disease for each of the seven cancer types studied. Some signatures were shared between different types of cancer and included cellular pathways of altered metabolism. Importantly, experimental results provided proof-of-concept that their proteomics analysis approach is a valuable strategy to identify potential therapeutic targets. The Oncogene article is titled “Mass-Spectrometry-Based Proteomic Correlates of Grade and Stage Reveal Pathways and Kinases Associated With Aggressive Human Cancers.” "There are two notable aspects of this study. One is that we explored the proteomic landscape of cancer looking for proteins that were expressed in association with aggressive forms of cancer," said co-corresponding author Chad Creighton (photo), PhD, Professor of Medicine and Co-Director of Cancer Bioinformatics at the Dan L. Duncan Comprehensive Cancer Center at Baylor. "We analyzed protein data that included tens of thousands of proteins from about 800 tumors including seven different cancer types--breast, colon, lung, renal, ovarian, uterine, and pediatric glioma--made available by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets."

Novel Drug May Prevent Alzheimer’s Disease by Modulating, Rather Than Inhibiting, Key Enzyme (γ-Secretase) Involved in Amyloid Plaque Formation; Drug Proves Successful and Safe in Animal Models

Amyloid plaques are pathological hallmarks of Alzheimer's disease (AD)--clumps of misfolded proteins that accumulate in the brain, disrupting and killing neurons and resulting in the progressive cognitive impairment that is characteristic of the widespread neurological disorder. In a new study, published online on March 2, 2021 in the Journal of Experimental Medicine (JEM) (, researchers at University of California (UC) San Diego School of Medicine, Massachusetts General Hospital, and elsewhere have identified a new drug that could prevent AD by modulating, rather than inhibiting, a key enzyme involved in forming amyloid plaques. The open-access article is titled “Preclinical Validation of a Potent γ-Secretase Modulator for Alzheimer’s Disease Prevention.” In studies using rodents and monkeys, the researchers report that the drug was found to be safe and effective, paving the way for possible clinical trials in humans. "Alzheimer's disease is an extraordinarily complex and multi-faceted condition that has, so far, defied effective treatment, let alone prevention," said senior author Steven L. Wagner, PhD, Professor in the Department of Neurosciences at UC San Diego School of Medicine. "Our findings suggest a potential therapy that might prevent one of the key elements of AD." Amyloid plaques are composed of small protein fragments called amyloid beta (Aβ) peptides. These peptides are generated by enzymes called β-secretase and γ-secretase, which sequentially cleave a protein called amyloid precursor protein on the surfaces of neurons to release Aβ fragments of varying lengths. Some of these fragments, such as Aβ42, are particularly prone to forming plaques, and their production is elevated in patients with mutations predisposing them to early-onset AD.

Immunotherapy Drug Delays Onset of Type 1 Diabetes in At-Risk Group

More than five years after receiving an experimental immunotherapy drug, 50% of a group of people at high risk of developing Type 1 diabetes remained disease-free compared with 22% of those who received a placebo, according to a new trial overseen by Yale School of Medicine researchers. And those who developed diabetes did so on average about five years after receiving the new drug, called teplizumab, compared with 27 months for those who received the placebo. The study, which was done in collaboration with researchers from Indiana University, was published online on March 3, 2021 in Science Translational Medicine ( The open-access article is titled “Teplizumab Improves and Stabilizes Beta Cell Function in Antibody-Positive High-Risk Individuals.” "If approved for use, this will be the first drug to delay or prevent Type 1 diabetes," said Kevan Herold, MD, the C.N.H. Long Professor of Immunobiology and of Medicine (Endocrinology) at Yale School of Medicine and co-senior author of the paper. The drug, developed by biotechnology company Provention, has been awarded breakthrough status by the U.S. Food and Drug Administration and could be approved for general use by summer, Dr.Herold said. In the trial, an analysis of the 76 subjects showed reduced levels of damage caused by T cells in response to the drug and improved functioning of insulin-producing beta cells in those who received teplizumab. The subjects in the trial had a median age of 13 years and relatives with Type 1 diabetes. The new study is the result of 30 years of work by Dr. Herold's lab to find new treatments for Type 1 diabetes. The findings are a follow-up to another clinical study organized by TrialNet, an international coalition dedicated to the study of the disease.

Research Reveals Mechanism by Which Bacteria May Defeat Drugs That Fight Cystic Fibrosis

University of Montana (UM) researchers and their partners have discovered a strategy used by bacteria to defeat antibiotics and other drugs used to combat infections afflicting people with cystic fibrosis. The research was published online on February 23, 2021 in Cell Reports. The open-access paper is titled "P. aeruginosa Aggregates in Cystic-Fibrosis Sputum Produce Exopolysaccharides That Likely Impede Current Therapies." Cystic fibrosis is a life-threatening disease that causes persistent lung infections and limits a person's ability to breathe over time. A common strain of bacteria, Pseudomonas aeruginosa, often thrives in the lungs of people with cystic fibrosis, as well as in wounds from burns or diabetic ulcers. Once a P. aeruginosa infection is established, it can be incredibly difficult to cure, despite repeated courses of antibiotics. Laura Jennings (photo), PhD, a Research Assistant Professor in UM's Division of Biological Sciences and an affiliate with the University's Center for Translational Medicine, said her research, conducted with colleagues, showed that the stubborn germs living in the lungs of cystic fibrosis patients create a self-produced carbohydrate slime. And this slime makes the bacteria more resistant to the antibiotics prescribed by doctors, as well as drugs that reduce the thickness of mucus. "We found the first direct evidence that these carbohydrates are produced at the sites of infection," Dr. Jennings said. "We showed that one of the carbohydrates, called Pel, sticks to extracellular DNA, which is abundant in the thick mucus secretions prominent in cystic fibrosis lungs.”

New Tools May Identify COVID Patients at Highest Risk of Mechanical Ventilation and of Death; May Permit Better Allocation of Scarce Resources

Two novel calculators for predicting which patients admitted to the hospital with COVID-19 are at greatest risk of requiring mechanical ventilation or of in-hospital death have been developed and validated by Massachusetts General Hospital (MGH). In a study published in the March 2021 issue The Lancet's EClinicalMedicine (, researchers describe how these models could enable clinicians to better stratify risk in COVID-infected patients to optimize care and resource utilization in hospitals faced with ICU capacity constraints. The open-access article is titled “Estimating Risk of Mechanical Ventilation and In-Hospital Mortality Among Adult COVID-19 patients Admitted to Mass General Brigham: The VICE and DICE Scores.” "Information that can accurately predict severity of the clinical course at the time of hospital admission has been limited," says senior author Rajeev Malhotra, MD, a cardiologist at MGH and investigator in the MGH Cardiovascular Research Center. "Using a combination of past medical history, vital signs, and laboratory results at the time of patient admission, we developed models that can differentiate between risk for mechanical ventilation and risk for in-hospital mortality. While other studies have focused on 30-day hospital outcomes, we followed all COVID-19 patients to the end of their hospital course because a significant number are hospitalized well beyond 30 days." The research team compiled this clinical information from 1,042 patients confirmed with COVID-19 who were admitted to five hospitals in the Mass General Brigham health care system during the first three months of the pandemic.

Dynamic Light Scattering (DLS) Technique May Help Elucidate Mysteries of Exosomes

Despite great progress in understanding various cellular mechanisms over the last decades, many of mysteries remain. Such is the case for exosomes, small cell-released vesicles that can contain various molecules, including RNAs, DNA, proteins, and lipids. The roles of exosomes are believed to be quite varied and important, both for normal bodily functions and also in the spreading of diseases like cancer. However, exosomes are so small that studying them is challenging and typically calls for costly and time-consuming techniques, such as electron microscopy (EM). To tackle this difficulty, a team of undergraduate students from Daegu Gyeongbuk Institute of Science and Technology (DGIST), Korea, explored a different and promising method for analyzing exosomes. In their study, which was published in PLOS One (, the students focused on dynamic light scattering (DLS), a laser-based technique that can be used to easily determine statistical parameters about the sizes of a large number of vesicles. What was admirable, according to Professor Jung-Ah Cho (corresponding author of the study), was that "the undergraduate students independently conducted the whole study under DGIST's Undergraduate Group Research Program with no external help." The open-access PLOS One article is titled “The Characterization of Exosomes from Fibrosarcoma Cell and the Useful Usage of Dynamic Light Scattering (DLS) for Their Evaluation.” First, the students compared the exosomes of two types of cancer cells: a well-studied breast cancer cell line and a mouse fibrosarcoma cell line. The exosomes secreted by cancer cells of the latter type had rarely been studied before.

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