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Archive - Jul 2020

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July 8th

Forkhead Box Protein 01 (Fox01) Is Key Transcription Factor Regulating Abnormal Heart Growth; Fox01 Binds Widely Throughout Genome in Mouse Model of Cardiac Hypertrophy, Activating Broad Array of Genes in Heart Cells & Stimulating Growth Signaling

The human heart is like a sponge, able to expand and grow, increasing its capacity to take up blood. In theory, an enlarged heart can also squeeze out more blood, with more power, than an average-sized heart. But in reality, for most people, this growth--known as cardiac hypertrophy--is abnormal and signals trouble. Cardiac hypertrophy is brought on by various factors, high blood pressure in particular. Existing treatments only delay the inevitable--that the spongy heart muscle becomes thicker and stiffer over time, culminating in heart failure, in which the heart can no longer contract strongly enough to pump blood through the body. A greater understanding of the molecular mechanisms driving abnormal heart growth promises to turn this around, however, and in new work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) cast fresh light on a key molecular regulator in the heart known as FoxO1 (forkhead bozx protein 01). In an article published online on July 9, 2020 in Circulation, the Temple scientists are the first to show that the transcription factor FoxO1 attaches to and activates a wide array of genes in heart cells, leading to widespread increases in growth signaling, specifically within the heart. The article is titled “Genomic Binding Patterns of Forkhead Box Protein O1 Reveal Its Unique Role in Cardiac Hypertrophy.” "FoxO1 is a major transcription factor that regulates genes involved in metabolism and growth," said Jessica Pfleger (photo), PhD, Instructor in the Center for Translational Medicine at LKSOM and lead author of the new study.

Gall Fly Outmaneuvers Goldenrod Host Plant in Ongoing Competition for Survival

Over time, goldenrod plants and the gall flies that feed on them have been one-upping each other in an ongoing competition for survival. Now, a team of researchers has discovered that by detecting the plants' chemical defenses, the insects may have taken the lead. According to John Tooker, PhD, Professor of Entomology in the Department of Entomology at Penn State, this complex scenario begins when a female gall fly (Eurosta solidaginis) lays its eggs in the leaf bud of a goldenrod plant (Solidago altissima). This action forces the plant to produce a tumor-like growth, called a gall. This gall, he said, provides the fly larvae with a source of nutrition and safety from predators and the environment, but decreases the plants' ability to reproduce. "Our previous research showed that goldenrod plants have evolved to 'eavesdrop' on the sexual communications of their gall fly herbivores -- specifically, the sex pheromones used by males to attract females," he said. "Our new research, suggests that the plants respond to this 'intelligence' by strengthening, also known as 'priming,' chemical defenses to prevent females from laying eggs and inducing gall formation." Eric Yip, PhD, postdoctoral scholar in the Department of Entomology, Penn State, explained that this plant-insect dynamic is similar to the reversals of fortune that occur in the "Spy vs. Spy" comic strip, only the characters are a plant and an insect rather than a pair of cartoon drawings. To investigate the effects of priming, the researchers, in their new study, exposed almost 300 goldenrod plants comprising 11 genetic types--or genotypes--to male gall flies that varied in age, from one to four weeks old, as well as a control in which the plants were not exposed to flies.

International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting, Including Exosomes, July 20-22: Plenary Speakers, Panel Sessions, Oral Abstract Talks, Poster Chats, & Educational Sessions; FOCUS: PANEL SESSIONS

The International Society for ExtracellularVesicles (ISEV) AnnualMeeting (ISEV2020), Including #Exosomes, Is Now VIRTUAL (July 20-22); and will feature over 600 Discussions (Plenary Addresses, Panel Sessions, Oral Abstract Talks, Poster Chats, & Educational Sessions). The program can viewed here (https://www.isev.org/mpage/2020Program) and registration can be done here (https://www.isev.org/mpage/2020Registration). As eminent Yale professor Philip Askenase, MD, has said, “Exosomes are a sensational biological discovery and they seem to be involved in nearly all biological and clinical processes.” Please attend the virtual ISEV 2020 meeting to learn more about these fascinating and immensely important tiny particles. The 2020 virtual meeting will feature four live panel sessions which will offer presentations by experts in the field, followed by moderated half-hour Q&A/panel discussions. The topics of the four panel discussions are “EV Heterogeneity,” “EVs in Liquid Biopsy (Diagnostics/Biomarkers),” “Extracellular RNA,” and “In Vivo Approaches to Understanding EV Function.” Details on these four panel discussion sessions and the speakers who will be presenting are given below.

PANEL 1--EV HETEROGENEITY

July 8th

Dark Matter of Genome Is Focus of Enlightening Presentation During AACR 2020 Virtual Meeting June 22-24

[This article was written for BioQuick News by Michael A. Goldman, PhD, Professor & Former Chair, Biology, San Francisco State University (SFSU) (https://faculty.sfsu.edu/~goldman/). Dr. Goldman has written Op-Ed pieces or letters for the Los Angeles Times, the Wall Street Journal, the Sacramento Bee, the San Francisco Chronicle and the New York Times, as well as a variety of technical articles, including ones appearing in Science and Nature Genetics. He has been Associate Editor for Chromosome Research and a contributing editor to Bio-IT World. Dr. Goldman believes that the public learns much about science and bioethics from fiction, and he reviews novels addressing various aspects of genetic science and its implications, in publications such as Nature, Science, Nature Genetics, and the San Francisco Chronicle. Dr. Goldman can be contacted at goldman@sfsu.edu. This article is copyrighted by Michael A. Goldman. BioQuick News is grateful to Dr, Goldman for this excellent contribution.] ARTICLE BY DR. MICHAEL A. GOLDMAN: Genome projects just seem to nucleate around Washington University in St. Louis. If it isn't the genome, it's the Pangenome or the Epigenome. Dr. Ting Wang (https://www.genome.wustl.edu/people/ting-wang/), of the Department of Genetics and McDonnel Genome Institute at Washington University, has been involved in all of them. He currently directs the NIH 4D Nucleome Network Data Coordination Integration Center (http://dcic.4dnucleome.org/) and the NIEHS Environmental Epigenomics Data Center, and his laboratory hosts the WashU Epigenome Browser (https://epigenomegateway.wustl.edu/). Dr. Wang's own research isn't as pedestrian as you might think.

RNA Is Key in Helping Stem Cells Know What to Become; Polycomb Repressive Complex 2 (PRC2) Requires RNA Binding for Chromatin Localization in Human Pluripotent Stem Cells and for Defining Cellular State, Paper from Nobelist Cech & Rinn Labs Asserts

Look deep inside our cells, and you'll find that each has an identical genome--a complete set of genes that provides the instructions for our cells' form and function. But if each blueprint is identical, why does an eye cell look and act differently than a skin cell or a brain cell? How does a stem cell--the raw material with which our organ and tissue cells are made--know what to become? In a study published online on July 6, 2020 in Nature Genetics (https://www.nature.com/articles/s41588-020-0662-x), University of Colorado-Boulder (CU Boulder) researchers come one step closer to answering that fundamental question, concluding that the molecular messenger RNA (ribonucleic acid) plays an indispensable role in cell differentiation, serving as a bridge between our genes and the so-called "epigenetic" machinery that turns them on and off. When that bridge is missing or flawed, the researchers report in their article, a stem cell on the path to becoming a heart cell never learns how to beat. The article is titled “RNA Is Essential for PRC2 Chromatin Occupancy and Function in Human Pluripotent Stem Cells.” The paper comes at a time when pharmaceutical companies are taking unprecedented interest in RNA. And, while the research is young, it could ultimately inform development of new RNA-targeted therapies, from cancer treatments to therapies for cardiac abnormalities. "All genes are not expressed all the time in all cells. Instead, each tissue type has its own epigenetic program that determines which genes get turned on or off at any moment," said co-senior author Thomas Cech (photo) (https://en.wikipedia.org/wiki/Thomas_Cech), PhD, a Nobel laureate and Distinguished Professor of Biochemistry. "We determined in great detail that RNA is a master regulator of this epigenetic silencing and that in the absence of RNA, this system cannot work. It is critical for life."

Experimental Drug (Tofersen from Biogen) Shows Early Promise Against Rare Inherited Form of ALS Caused by Mutations in Superoxide Dismutase 1 (SOD1)

An experimental drug for a rare, inherited form of amyotrophic lateral sclerosis (ALS) (Lou Gehrig’s disease) has shown promise in a phase 1/phase 2 clinical trial conducted at Washington University School of Medicine in St. Louis, Massachusetts General Hospital in Boston, and other sites around the world and sponsored by the pharmaceutical company Biogen Inc. The trial indicated that the experimental drug, known as tofersen, shows evidence of safety that warrants further investigation and lowers levels of a disease-causing protein in people with a type of amyotrophic lateral sclerosis, or ALS, caused by mutations in the gene SOD1 (superoxide dismutase 1). The results of the study, published on July 9, 2020 in the New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2003715), have led to the launch of a phase 3 clinical trial to further evaluate the safety and efficacy of tofersen, The NEJM article is titled "Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS." "ALS is a devastating, incurable illness," said principal investigator Timothy M. Miller (Photo, Credit: Huy Mach), MD, PhD, the David Clayson Professor of Neurology at Washington University and Director of the ALS Center at the School of Medicine. "While this investigational drug is aimed at only a small percentage of people with ALS, the same approach--blocking the production of specific proteins at the root of the illness--may help people with other forms of the illness. "This trial indicated that tofersen shows evidence of safety that warrants further investigation and that the dose we used lowers clinical markers of disease. There are even some signs that it slowed clinical progression of ALS, although the study was not designed to evaluate effectiveness at treating the disease, so we can't say anything definitive.

Hormone (GDF15) Being Studied As Possible Treatment for Obesity Is Risk Factor for Sepsis, New Study Shows; Inhibitor of GDF15 May Be Useful As Complementary Treatment for Sepsis

A group of scientists from the Instituto Gulbenkian de Ciência (IGC) (https://gulbenkian.pt/ciencia/) in Portugal, led by Luís Moita, PhD, discovered that a hormone that is being studied as a treatment for obesity reduces the resistance to infection caused by bacteria and is a risk factor for sepsis. The work, developed in collaboration among researchers from Portugal, France, Germany, and South Korea, was published online on June 2, 2020 in PNAS. The open-access article is titled “CXCL5-Mediated Recruitment of Neutrophils into the Peritoneal Cavity of Gdf15-Deficient Mice Protects Against Abdominal Sepsis” (https://www.pnas.org/content/117/22/12281). Sepsis is a potentially fatal illness, that derives from a deregulated response of the organism to an infection, leading to organ malfunction. A study recently published in the scientific journal The Lancet (https://www.sciencedirect.com/science/article/abs/pii/S0140673618306962), estimated that, in 2017, sepsis affected 49 million people and 11 million people worldwide have died. With the aim of expanding knowledge about this disease, Dr. Moita’s team at IGC investigated whether the hormone known as GDF15 (growth and differentiation factor 15) could play a role in sepsis. This hormone is currently being widely studied by several laboratories and pharmaceutical companies as a treatment for obesity. “We’ve discovered a critical effect of GDF15 on infection, which is relevant because this hormone increases in many common diseases, like obesity, [and] pulmonary and cardiovascular diseases”, explains Dr. Moita.

July 7th

Under Oxidative Stress from Hydrogen Peroxide (H2O2), Defensive Clp Proteins of E. coli Ensure That Iron Pools Remain Sufficient for Reactivation of Key Oxidized Metalloenzymes

Researchers at the University of Illinois, Urbana-Champaign, have shown that, during oxidative stress from hydrogen peroxide (H2O2), Clp proteins in E. coli act to ensure that cellular pools of iron remain adequate and accessible for the reactivation of oxidized metalloenzymes. This system countervails the simultaneous drive to sequester iron, which can react with H2O2 and cause DNA damage. The researchers concluded that E. coli cells are able to strike a careful balance, diminishing iron pools enough to protect the cell’s DNA (from hydroxyl radicals that are produced when iron reacts with H2O2), but keeping the iron pools substantial enough so that critical iron-dependent enzymes can be repaired. The results were published online on June 29, 2020 in the Journal of Bacteriology. The article is titled “During Oxidative Stress the Clp Proteins of Escherichia coli Ensure That Iron Pools Remain Sufficient to Reactivate Oxidized Metalloenzymes.” The authors are first author Ananya Sen (photo), Yidan Zhou, and Professor James A. Imlay, from the Department of Microbiology at the University of Illinois, Urbana-Champaign. The authors noted that “H2O2 is formed in natural environments by both biotic and abiotic processes. It easily enters the cytoplasms of microorganisms, where it can disrupt growth by inactivating iron-dependent enzymes. It also reacts with the intracellular iron pool, generating hydroxyl radicals that can lethally damage DNA.” Consequently, the authors said that bacteria have developed various mechanisms to combat the potential damage that can be caused by H2O2. Bacteria possess H2O2-responsive transcription factors that control defensive regulons (sets of related genes that are activated together). These defensive regulons typically code for catalases and peroxidases that scavenge H2O2.

CytoDyn’s Leronlimab Prevents Transmission of SHIV in Macaque Study; Results of Preclinical Study Presented Tuesday, July 7, in Oral Presentation at the 23rd International AIDS Conference (AIDS 2020)

On July 7, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with potential clinical indications for HIV, COVID-19, cancer, GvHD (graft versus host disease), and NASH (non-alcoholic steato-hepatitis), announced the results from a preclinical macaque study evaluating leronlimab as pre-exposure prophylaxis (PrEP) to prevent sexual HIV transmission. The study evaluated the impact of a macaque-equivalent dose of either 350 mg (once weekly) or 700 mg (bi-monthly) leronlimab on acquisition of infection in a total of 18 animals, and found that the equivalent 700 mg bi-monthly leronlimab dose completely prevented rectal transmission of Simian-Human Immunodeficiency Virus (SHIV) in macaques. These results were presented today in an oral presentation titled “CCR5 Antibody Blockade Protects Rhesus Macaques from Rectal SHIV Acquisition" at the 23rd International AIDS Conference (AIDS 2020) (https://www.aids2020.org/). “The results reported here in the preclinical macaque model of HIV sexual transmission support leronlimab as a possible PrEP (pre-exposure prophylaxis) agent at a time when long-acting human HIV PrEP options are limited,” said Jonah Sacha, PhD, Professor at Oregon Health & Science University (OHSU), and the study’s lead investigator. “We are eager to build upon these preclinical results describing leronlimab’s utility in HIV prevention by initiating clinical studies for leronlimab as a PrEP treatment. Current PrEP options require a continued daily dosing regimen in order to be effective and are inherently difficult to maintain in the long-term,” said Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn, which has developed leronlimab.

Novavax Announces $1.6 Billion Funding from Operation Warp Speed to Support Late-Stage Clinical Development, Pivotal Phase 3 Clinical Trial to Support Licensure, Large-Scale Manufacturing & Production of 100 Million Vaccine Doses Starting in Late 2020

On June 7, 2020, Novavax, Inc. (Nasdaq: NVAX) (https://novavax.com/), a late-stage biotechnology company developing next-generation vaccines for serious infectious diseases, announced that it has been selected to participate in Operation Warp Speed (OWS), a U.S. government program that aims to begin delivering millions of doses of a safe, effective vaccine for COVID-19 in 2021. Novavax has been awarded $1.6 billion by the federal government to complete late-stage clinical development, including a pivotal Phase 3 clinical trial; establish large-scale manufacturing; and deliver 100 million doses of NVX CoV2373, Novavax’ COVID-19 vaccine candidate, as early as late 2020. NVX CoV2373 consists of a stable, prefusion protein made using its proprietary nanoparticle technology and includes Novavax’ proprietary Matrix M™ adjuvant. “The pandemic has caused an unprecedented public health crisis, making it more important than ever that industry, government, and funding entities join forces to defeat the novel coronavirus together. We are honored to partner with Operation Warp Speed to move our vaccine candidate forward with extraordinary urgency in the quest to provide vital protection to our nation’s population,” said Stanley C. Erck, MBA, President and Chief Executive Officer of Novavax. “We are grateful to the U.S. government for its confidence in our technology platform, and are working tirelessly to develop and produce a vaccine for this global health crisis.” Under terms of the agreement, Novavax will demonstrate it can rapidly stand up large-scale manufacturing and transition into ongoing production, including the capability to stockpile and distribute large quantities of NVX-CoV2373 when needed.