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December 22nd, 2020

Stability of Ebola Virus Nucleocapsid Studied Via Supercomputer Simulations to Identify Possible Targets of Therapeutic Attack

In the midst of a global pandemic with COVID-19, it's hard to appreciate how lucky those outside of Africa have been to avoid the deadly Ebola virus disease. It incapacitates its victims soon after infection with massive vomiting or diarrhea, leading to death from fluid loss in about 50 percent of the afflicted. The Ebola virus transmits only through bodily fluids, marking a key difference from the COVID-19 virus and one that has helped contain Ebola's spread. Ebola outbreaks continue to flare up in West Africa, although a vaccine developed in December 2019 and improvements in care and containment have helped keep Ebola in check. Supercomputer simulations by a University of Delaware team that included an undergraduate supported by the XSEDE (Extreme Science and Engineering Discovery Environment) EMPOWER program are adding to the mix and helping to crack the defenses of Ebola's coiled genetic material. This new research could help lead to breakthroughs in treatment and improved vaccines for Ebola and other deadly viral diseases such as COVID-19. "Our main findings are related to the stability of the Ebola nucleocapsid," said Juan R. Perilla, PhD, an Assistant Professor in the Department of Chemistry and Biochemistry at the University of Delaware. Dr. Perilla co-authored a new study published in online on October 20, 2020 in the AIP Journal of Chemistry Physics. It focused on the nucleocapsid, a protein shell that protects against the body's defenses the genetic material Ebola uses to replicate itself. The open-access article is titled "Molecular Determinants of Ebola Nucleocapsid Stability from Molecular Dynamics Simulations.” "What we've found is that the Ebola virus has evolved to regulate the stability of the nucleocapsid by forming electrostatic interactions with its RNA, its genetic material," Dr.

December 21st

Codiak’s Novel Engineered Exosome Therapeutic Candidate (ExoIL-12) Being Investigated in Phase 1 Clinical Trial As Single Agent for Treatment of Early-Stage Cutaneous T Cell Lymphoma (CTCL) and, Potentially, Other Cancers

On December 21, 2020, Codiak BioSciences, Inc. (NASDAQ: CDAK), a clinical-stage company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, today announced the December 21, 2020 online publication of a new manuscript, “Exosome Surface Display of IL-12 Results In Tumor-Retained Pharmacology With Superior Potency and Limited Systemic Exposure Compared to Recombinant IL-12,” in Molecular Cancer Therapeutics (https://mct.aacrjournals.org/content/early/2020/12/18/1535-7163.MCT-20-0484), a journal of the American Association for Cancer Research. exoIL-12 is a novel engineered exosome therapeutic candidate currently being investigated in a Phase 1 clinical trial as a single agent for the treatment of early-stage cutaneous T cell lymphoma (CTCL) and potentially other cancers. This publication details the findings from the preclinical development program and highlights the potential of exoIL-12 to inhibit tumor growth by facilitating potent local pharmacology, precisely quantified doses, undetectable systemic exposure, and the robust generation of systemic anti-tumor immunity superior to that of recombinant IL-12 (rIL-12).“We believe exoIL-12 represents a potentially first-in-class approach for a number of cancers that have previously shown clinical responses to IL-12, a potent anti-tumor cytokine for which prior development has been limited due to unwanted systemic exposure and related toxicity,” said Sriram Sathyanarayanan, PhD, Senior Vice President, Preclinical Research, Codiak.

December 18th

Artificial SARS-CoV-2-Like Particles Very Sensitive to Warmer Temperatures, Study Suggests; Particle Exterior Degrades in 30 Minutes on Surfaces at 93 F; Little Effect Seen at 71 F; Surface Humidity Effect Appears Negligible

Winter is coming in the northern hemisphere and public health officials are asking how the seasonal shift will impact the spread of SARS-CoV-2, the virus that causes COVID-19. A new study (https://pubmed.ncbi.nlm.nih.gov/33272571/) tested how temperatures and humidity affect the structure of individual SARS-CoV-2 virus-like particles on surfaces. University of Utah scientists and colleagues found that just moderate temperature increases broke down the virus' structure, while humidity had very little impact. In order to remain infectious, the SARS-CoV-2 membrane needs a specific web of proteins arranged in a particular order. When that structure falls apart, it becomes less infectious. The study findings suggest that as temperatures begin to drop, particles on surfaces will remain infectious longer. This is the first study to analyze the mechanics of the virus on an individual particle level, but the findings agree with large-scale observations of other coronaviruses that appear to infect more people during the winter months. "You would expect that temperature makes a huge difference, and that's what we saw. To the point where the packaging of the virus was completely destroyed by even moderate temperature increases," said Michael Vershinin, PhD, Assistant Professor at the University of Utah and co-senior author of the paper. "What's surprising is how little heat was needed to break them down--surfaces that are warm to the touch, but not hot. The packaging of this virus is very sensitive to temperature." The paper (https://pubmed.ncbi.nlm.nih.gov/33272571/) reporting these temperature results was published online on November 28, 2020, in the journal Biochemical Biophysical Research Communications.

December 17th

Physician/Molecular Geneticist Richard A. Gatti Honored with Lifetime Achievement Award for Decades of Service to Those with the Rare Genetic Disease Ataxia-Telangiectasia (A-T) and Their Families

As one of the highlights of the 2018* biennial Ataxia-Telangiectasia (A-T)** Clinical Research Conference, held this year in Naples, Italy (November 29-December 1), a lifetime achievement award was presented to UCLA Professor-in-Residence of Genetics Richard A. Gatti (photo), MD, who for over 40 years has continuously advanced the world’s scientific understanding of this rare, but devastating neurodegenerative disease, largely of children (see additional pics from event at end). In addition to his own numerous scientific achievements in the area of A-T, Dr. Gatti has stimulated hundreds of graduate students to pursue further studies of A-T and he has inspired numerous scientific colleagues to work as hard as they can to better understand this disease and to bring us ever closer to possible treatments and even an eventual cure. And Dr. Gatti, not only carries out scientific research at the highest level, but he sees and treats A-T patients and their families, so he is never far from the ultimate driving motivation of trying to do his best to help real patients and families who are struggling with an extremely difficult disease. Approximately 120 A-T experts from around the world attended the three-day conference in Naples, which was held at the University of Naples Federico II, right on the shore of the Bay of Naples, and with the daunting vista of Mount Vesuvius standing spectacularly right across the Bay. After a very full day of scientific sessions on Saturday, almost all the conference attendees boarded the evening buses that would take them high into the hills of Naples for the wonderful award dinner for Dr. Gatti, which featured spectacular vistas of the beautiful lights and waters of historic Naples.

December 16th

Scientists Map Network of Over 100 SARS-Cov-2’s Helper Proteins Inside Human Cells; One (TMEM41B) Is Absolutely Required by Four Tested Coronaviruses, As Well As by Three Deadly Flaviruses—Yellow Fever, West Nile, and Zika

As all viruses, SARS-CoV-2 is in the grey zone between a chemical and a living being. Its biological machinery is too scant to propagate on its own, and instead the virus hijacks proteins of the host to generate new copies of itself. Scientists hope that by developing drugs that disrupt such proteins, it might become possible to deal a fatal blow to the virus. Now a new study (titled “Genome-Scale Identification of SARS-Cov-2 and Pan-Coronavirus Host Factor Networks”) maps out this intricate network of helpers for SARS-CoV-2 and three other coronaviruses that cause the common cold. The results identify over a hundred human proteins without which these viruses cannot replicate inside the cells and cause disease.Among them is a protein that stands out because it is an absolute requirement for infection by the four coronaviruses. Moreover, it is also needed by viruses from an entirely different family, flaviviruses, including those that cause yellow fever, West Nile, and Zika disease, according to results of a second study (titled “TMEM41B Is a Pan-Flavivirus Host Factor”). “The fact that this protein is important to multiple different viruses makes it a promising and high-priority target for drug development efforts,” says Charles M. Rice, PhD, Professor of Virology at Rockefeller University, who co-led the studies with John Poirier, PhD, Assistant Professor, Medicine, at New York University. Both studies were published in Cell. The TMEM41B article was published online on December 8, 2020, and the Genome-Scale Identification article was published online on December 9, 2020. Once it has entered a host cell, SARS-CoV-2 co-opts hundreds of molecules to make copies of the viral RNA and wrap them up as thousands of new viruses.

Potentially Useful Existing Drugs Suggested After GWAS Identification of Five Genes Associated with Most Severe Form of COVID-19; Work Called “Stunning Realization of the Promise of Human Genetics to Help Understand Critical Illness”

Existing drugs that could be repurposed to treat COVID-19 have been identified in a study highlighting genes linked to severe forms of the disease. Genes involved in antiviral immunity and lung inflammation have been pinpointed in the research, led by a scientist from the Roslin Institute of Scotland’s University of Edinburgh. The breakthrough should help doctors understand how COVID -19 damages lungs at a molecular level, and points towards existing drugs that could be effective against severe illness. Scientists studied the DNA of 2,700 patients in 208 intensive care units (ICUs) in the UK. Researchers from the GenOMICC (Genetics of Mortality in Critical Care) consortium--a global collaboration to study genetics in critical illness—used genome-wide association studies (GWAS) to compare the genetic information of COVID -19 patients in ICU with samples provided by healthy volunteers from other studies. The scientists found key differences in five genes--known as IFNAR2, TYK2, OAS1, DPP9, and CCR2--which may underlie why some people become severely sick with COVID -19, while others are not affected, or only moderately affected. Scientists were then able to predict the effect of drug treatments on patients, because some variations of the identified genes are known to respond in a similar way to particular drugs. For example, the scientists showed that a reduction in the activity of the TYK2 gene protects against COVID-19. A class of anti-inflammatory drugs called JAK inhibitors, which includes the drug baricitinib, produces this effect. The researchers also discovered that a boost in the activity of the gene INFAR2 could create protection, because it is likely to mimic the effect of treatment with interferon—a protein released by cells of the immune system to defend against viruses.

Researchers Expose Power of Histone Modifier Enzyme (DOT1L) on Key Immune Cells

Communication, serendipity, and a histone modifier enzyme called DOT1L (disruptor of telomeric silencing 1-like) have all combined to produce some exciting findings on the immune system's B cells and T cells by two groups of Monash Biomedicine Discovery Institute (BDI) (Australia) scientists. The new results could result in further studies into a target for asthma and allergies, and fundamental work exploring the formation of immunity itself. Two papers on DOT1L by teams led by BDI’s Professor Colby Zaph and Associate Professor Kim Good-Jacobson--whose labs are next door to each other--were both published online on December 16, 2020 in Cell Reports. Dr. Zaph’s article is titled “The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells During Infection and Inflammation" (https://www.cell.com/cell-reports/pdf/S2211-1247(20)31494-7.pdf). Dr. Good-Jacobson’s article is titled “The Histone Methyltransferase DOT1L Is Essential for Humoral Immune Responses” (https://www.cell.com/cell-reports/pdf/S2211-1247(20)31493-5.pdf). Professor Zaph and colleagues found that the DOT1L enzyme was critical in controlling how T cells (white blood cells critical for immunity to infections) (image) make the choice to develop into distinct subsets. T cells have the ability to adopt a variety of fates that depend on the type of infection they face. Type 1 T cells (Th1) for example are critical for clearing viral infections, while type 2 T cells (Th2) are required for immunity to worm parasites. Critically, dysregulated Th1 cells can cause diseases such as inflammatory bowel disease, diabetes, and arthritis, and uncontrolled Th2 cell responses can lead to asthma and allergies.

December 15th

Immune Cell (Treg) That Drives Breast Cancer Could Be Useful Target In Novel Immunotherapies

Breast cancer is the most common cancer in women worldwide, but many immunotherapies have had limited success in treating aggressive forms of the disease. "A deeper understanding of the immunobiology of breast cancer is critical to the success in harnessing immunotherapeutic approaches to improve breast cancer survival," said Paula Bos (photo), PhD, member of the Cancer Biology research program at he Virginia Commonwealth University (VCU) Massey Cancer Center and Assistant Professor in the Department of Pathology at the VCU School of Medicine. New research findings from Dr. Bos, published online in the December 8, 2020 issue of Cell Reports, identified a type of immune cells that acts as a major driver of breast cancer growth by preventing the accumulation of a specific protein that induces anti-tumor responses. This new knowledge could be utilized for the development of novel immunotherapeutic approaches to treat the disease. The article is titled “Regulatory T Cells Support Breast Cancer Progression by Opposing IFN-γ-Dependent Functional Reprogramming of Myeloid Cells.” Regulatory T cells (Treg cells) are a special class of immune cells that possess a unique ability to suppress the function of other immune cells. This function serves to protect the organism from overreacting to certain molecules created within the body; however, in many cases it subdues the immune system's ability to attack cancer cells. Therefore, Treg cells are often abundant in solid tumors, particularly breast cancers, and are commonly associated with worse outcomes. In previous research, Dr. Bos demonstrated that targeting Treg cells in breast cancer models significantly reduced tumor growth and metastasis; however, it remained unclear on a molecular level why this tumor reduction was happening.

Two Analyses of Dallas Heart Study Data Yield New Insights on Depression

In analyses of Dallas Heart Study Data, researchers at the University of Texas (UT) Southwestern (UTSW) have found links between inflammation, menopause, and depressive disorder and published their findings in two articles. One article (https://www.psychiatrist.com/JCP/article/Pages/association-between-glyca...), published recently in the Journal of Clinical Psychiatry, shows a link between an inflammatory molecule (GlycA) in the blood and a person’s likelihood of depressive symptoms. This open-action article is titled “An Association Between the Inflammatory Biomarker GlycA and Depressive Symptom Severity.” The other article (https://www.maturitas.org/article/S0378-5122(20)30384-4/fulltext), published online on September 30, 2021 in the journal Maturitas, indicates which symptoms of menopause are most predictive of depression. This article is titled “Association of Menopause Symptoms with Depressive Symptom Severity in a Diverse Community-Based Sample.” Both studies are based on data from the Dallas Heart Study (DHS) (https://www.utsouthwestern.edu/research/translational-medicine/doing-res...), which, since 2000, has tracked the health of thousands of participants with the goal of improving the diagnosis, prevention, and treatment of heart disease. “The DHS dataset is an extraordinary resource at UT Southwestern,” says Sherwood Brown (photo) (https://profiles.utsouthwestern.edu/profile/10878/sherwood-brown.html?&s...), MD, PhD, senior author of both depression papers and Professor of Psychiatry and Vice Chair for Clinical Research at UTSW. In the first two years of the study, more than 6,000 residents of Dallas County completed a detailed medical survey; 3,500 of them, aged 30 to 65, provided blood samples and underwent imaging studies.

Compound Derived from Thunder God Vine Could Help Pancreatic Cancer Patients; Triptolide Appears to Attack “Super Enhancers” in Pancreatic Cancer DNA

The results of a pre-clinical study led by researchers at the Translational Genomics Research Institute (TGen), a Phoenix-based affiliate of California’s City of Hope, suggest how a compound derived from the thunder god vine (photo)--an herb used in China for centuries to treat joint pain, swelling and fever--is able to kill cancer cells and potentially improve clinical outcomes for patients with pancreatic cancer. The medicinal plant's key ingredient, triptolide, is the basis of a water-soluble prodrug called Minnelide, which appears to attack pancreatic cancer cells and the cocoon of stroma surrounding the tumor that shields it from the body's immune system. Investigators recently published their study results online on November 9, 2020 in Oncogenesis. The open-access article (https://www.nature.com/articles/s41389-020-00285-9) is titled “Triptolide Targets Super-Enhancer Networks in Pancreatic Cancer Cells and Cancer-Associated Fibroblasts.” The study found that the compound's mechanism of action is the ability of triptolide (Minnelide) to disrupt what are known as super-enhancers, strings of DNA needed to maintain the genetic stability of pancreatic cancer cells and the cancer-associated-fibroblasts that help make up the stroma surrounding the cancer. "The cancer cells rely on super-enhancers for their growth and survival," said Haiyong Han, PhD, a Professor in TGen's Molecular Medicine Division and one of the study's senior authors. "We found that, by disrupting these super-enhancers, triptolide not only attacks the cancer cells, but also the stroma, which helps accelerate cancer cell death.