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February 17th, 2020

Novel Formulation Permits Use of Toxin from Rattlesnake Venom to Treat Chronic Pain

Crotoxin, extracted from the venom of the South American rattlesnake Crotalus durissus terrificus, has been studied for almost a century for its analgesic, anti-inflammatory, and antitumor activities and as an even more powerful muscle paralyzer than botulinum toxin. However, the toxicity of crotoxin limits its medicinal use. A new study, published online on November 20, 2019, by Brazilian researchers in the journal Toxins, shows that crotoxin's therapeutic effects can be enhanced and its toxicity reduced when it is encapsulated in nanostructured SBA-15 silica, a material originally developed for use in vaccine formulations. The open-access Toxins article is titled “Crotoxin Conjugated to SBA-15 Nanostructured Mesoporous Silica Induces Long-Last Analgesic Effect in the Neuropathic Pain Model in Mice. The study was conducted under the aegis of Brazil's National Science and Technology Institute (INCT) on Toxins, one of the INCTs supported by FAPESP (São Paulo Research Foundation) in São Paulo State in partnership with the National Council for Scientific and Technological Development (CNPq), an agency of the Brazilian government. The INCT's principal investigator is Osvaldo Augusto Sant'Anna, PhD. The study was part of the doctoral research of Morena Brazil Sant'Anna, whose thesis advisor is Gisele Picolo, PhD. Dr. Picolo herself was the principal investigator for a project on the same topic. Researchers Flavia Souza Ribeiro Lopes and Louise Faggionato Kimura participated in the study, which was performed at Butantan Institute in São Paulo. Dr.

HIF-2α Is Pivotal for Progression of Clear Cell Renal Cell Carcinomas (ccRCC) and Can Be Disabled by New Experimental Drug, PT2385

An experimental drug already shown to be safe and to help some patients with clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer, effectively disables its molecular target. The finding from a team of researchers at the UT Southwestern Medical Center’s Kidney Cancer Program, was published in the February 14, 2020 issue of Clinical Cancer Research, reveals a weakness in this cancer that could be further exploited with other targeted treatments in the future. The article is titled “HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.” Approximately 70,000 new cases of ccRCC are diagnosed every year in the U.S. The five-year life expectancy after diagnosis is low compared with other cancers, at about 10-12 percent. Unlike many other forms of cancer, ccRCC doesn’t respond to chemotherapy or conventional radiation. When study lead author James Brugarolas, MD, PhD, Professor of Internal Medicine (Hematology/Oncology) and Director of the Kidney Cancer Program at UT Southwestern, began his career two decades ago, only one medication was approved to treat this cancer. There are now over a dozen approved drugs for ccRCC; however, says Dr. Brugarolas, each offers only a modest effect on survival and comes with a host of side effects. Searching for better pharmaceuticals to fight this cancer, researchers at the Kidney Cancer Program focused on a protein known as hypoxia-inducible factor 2α (HIF-2α), which investigators at UTSW first discovered and described in the late 1990s. HIF-2α is a target of a tumor suppressor protein called von Hippel-Lindau (VHL) protein that’s characteristically inactivated in most cases of ccRCC.

February 16th

Precision Medicine World Conference (PMWC 2020) Ends Last of Three Full-Day Sessions on Friday, January 24, in California's Silicon Valley

Friday, January 24, was the third and last day of the Precision Medicine World Conference 2020 (PMWC 2020) in California’s Silicon Valley, with seven parallel tracks of talks focusing on different aspects of precision medicine. The tracks were Emerging Therapeutics; AI and Data Intelligence; Diagnostics in Clinical Practice; Molecular Profiling—From Research to Clinic; Health Data, Microbiome, and Patient Education; Showcase 1; and Showcase 2. The first five tracks consisted of leaders in the field discussing the latest advances, sometimes in individual presentations and sometimes in panel discussions. The two Showcase tracks gave new companies the opportunity to present their work in crisp 15-minute talks. This year’s PMWC, the 11th annual PMWC conference in Silicon Valley, and the 17th PMWC meeting overall, including smaller, more regional meetings, was the largest annual meeting ever, with over 2,300 attendees from around the world and over 400 presentations given over the full three days. The conference took place in the Santa Clara Convention Center in the heart of California’s Silicon Valley. The theme of this year’s conference was “How Do We Accelerate Precision Medicine and Deliver on Its Proses?” This year’s conference was co-hosted by UCSF, Stanford Health Care/Stanford Medicine, the University of Michigan, the University of Pittsburgh, and Duke Health. Sponsors of the conference included Illumina, Agendia, Bio-Rad, QIAGEN, RubAdaptive, Agilent, Caprion, GO, Google Cloud, Gritstone, Karius, Molecular Health, RubrYc, Oncocyte, Siemens Healthineers, Sophia, Thermo-Fisher Scientific, Quanterix, and Tabula Rasa HealthCare. Neary 100 companies were exhibitors at the meeting.

Precision Medicine World Conference (PMWC 2020) Continues on Second Day of Three Full-Day Sessions on Thursday, January 23, in California's Silicon Valley

Thursday, January 23, was the second full day of the Precision Medicine World Conference 2020 (PMWC 2020) in California’s Silicon Valley, and consisted of seven parallel tracks of talks focusing on different aspects of precision medicine. The tracks were Emerging Therapeutics; AI and Data Intelligence; Diagnostics in Clinical Practice; Molecular Profiling—From Research to Clinic; Health Data, Microbiome, and Patient Education; Showcase 1; and Showcase 2. The first five tracks consisted of leaders in the field discussing the latest advances, sometimes in individual presentations and sometimes in panel discussions. The two Showcase tracks gave new companies the opportunity to present their work in crisp 15-minute talks. This year’s PMWC, the 11th annual PMWC conference in Silicon Valley, and the 17th PMWC meeting overall, including smaller, more regional meetings, was the largest annual meeting ever, with over 2,300 attendees from around the world and over 400 presentations given over the full three days. The meeting took place in the Santa Clara Convention Center in the heart of California’s Silicon Valley. The theme of this year’s conference was “How Do We Accelerate Precision Medicine and Deliver on Its Promises?” This year’s conference was co-hosted by UCSF, Stanford Health Care/Stanford Medicine, the University of Michigan, the University of Pittsburgh, and Duke Health. Sponsors of the conference included Illumina, Agendia, Bio-Rad, QIAGEN, RubAdaptive, Agilent, Caprion, GO, Google Cloud, Gritstone, Karius, Molecular Health, RubrYc, Oncocyte, Siemens Healthineers, Sophia, Thermo-Fisher Scientific, Quanterix, and Tabula Rasa HealthCare. Nearly 100 companies were exhibitors at the meeting.

February 15th

Precision Medicine World Conference (PMWC 2020) Opened First of Three Full-Day Sessions on Wednesday, January 22, in California’s Silicon Valley

On Wednesday, January 22, the full meeting of the Precision Medicine World Conference 2020 (PMWC 2020) opened in California’s Silicon Valley, with seven parallel tracks of talks focusing on different aspects of precision medicine (https://www.pmwcintl.com/). The tracks were Emerging Therapeutics; AI and Data Intelligence; Diagnostics in Clinical Practice; Molecular Profiling—From Research to Clinic; Health Data, Microbiome, and Patient Education; Showcase 1; and Showcase 2. The first five tracks consisted of leaders in the field discussing the latest advances, sometimes in individual presentations and sometimes in panel discussions. The two Showcase tracks gave new companies the opportunity to present their work in crisp 15-minute talks. This year’s PMWC, the 11th annual PMWC conference in Silicon Valley, and the 17th PMWC meeting overall, including small, more regional meetings, was the largest annual meeting ever, with over 2,300 attendees from around the world and over 400 presentations given over the full three days. The meeting took place in the Santa Clara Convention Center in the heart of California’s Silicon Valley. The theme of this year’s conference was “How Do We Accelerate Precision Medicine and Deliver on Its Promises?” This year’s conference was co-hosted by UCSF, Stanford Health Care/Stanford Medicine, the University of Michigan, the University of Pittsburgh, and Duke Health. Sponsors of the conference included Illumina, Agendia, Bio-Rad, QIAGEN, RubAdaptive, Agilent, Caprion, GO, Google Cloud, Gritstone, Karius, Molecular Health, RubrYc, Oncocyte, Siemens Healthineers, Sophia, Thermo-Fisher Scientific, Quanterix, and Tabula Rasa HealthCare. Nearly 100 companies were exhibitors at the meeting.

February 8th

Combination of Cryo-EM and Mass Spec Reveals New Insights into Post-Translational Modifications (PTMs) of Tau Protein; PTMs Mediate Structural Diversity of Toxic Tau Protein in Various Tauopathies Such As Alzheimer’s Disease

The tau protein has long been implicated in Alzheimer's disease and a host of other debilitating brain diseases. But scientists have struggled to understand exactly how tau converts from its normal, functional form into a misfolded, harmful one. Now, researchers at Columbia University's Zuckerman Institute and the Mayo Clinic in Florida, together with colleagues at Emory University and Arizona State University, have used cutting-edge technologies to see tau in unprecedented detail. By analyzing brain tissue from patients, this research team has revealed that modifications to the tau protein may influence the different ways it can misfold in a person's brain cells. These differences are closely linked to the type of neurodegenerative disease that will develop -- and how quickly that disease will spread throughout the brain. The study, published online on February 6, 2020 in Cell, employed two complementary techniques to map the structure of tau and decipher the effects of additional molecules, called post-translational modifications (PTMs), on its surface. These new structural insights could accelerate the fight against neurodegenerative diseases, by helping researchers identify new biomarkers that detect these disorders before symptoms arise and design new drugs that target specific PTMs, preventing the onset of disease before it wreaks havoc on the brain. The Cell article is titled “"Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains." "Tau has long been a protein of significant interest due to its prevalence in disease," said Anthony Fitzpatrick, PhD, a Principal Investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute, who led the study.

February 6th

Mayo Researchers Discover Way to Prime Cancer Tumors for Immunotherapy

A cancer tumor's ability to mutate allows it to escape from chemotherapy and other attempts to kill it. So, encouraging mutations would not seem to be a logical path for cancer researchers. Yet a Mayo Clinic team and their collaborators took that counterintuitive approach and discovered that, while it created resistance to chemotherapy, it also made tumors sensitive to immunotherapy. They also found that this approach worked successfully across tumor types and individual patient genomes. Their findings, involving mouse models and human cells, were published online on February 7, 2020 in Nature Communications. The open-access article is titled “APOBEC3B-Mediated Corruption of the Tumor Cell Immunopeptidome Induces Heteroclitic Neoepitopes for Cancer Immunotherapy.” The international team of researchers based in Rochester, Minnesota and London, and led by Richard Vile (photo), PhD, a Mayo Clinic Professor of Pediatric Oncology, studied models of both pediatric brain tumors and melanoma. They found that, in mice, high levels of the protein APOBEC3B drove a high rate of tumor mutations. Yet, at the same time, these levels of APOBEC3B also sensitized cells to treatment with immune checkpoint blockade, a major mechanism of immunotherapy. "When you put that in the context of vaccine therapy, the mutations generate neoepitopes, a type of peptide that is a prime target for killer T cells," says Dr. Vile. "So that, combined with the checkpoint blockade, make for a potential cross-tumor therapy." The results showed a high rate of cures in subcutaneous melanoma and brain tumor models, and effectiveness no matter the tumor type or location. The results also showed that an individualized approach for each patient is not required.

Breakthrough in Study of Age-Related Macular Degeneration (AMD), the Most Common Cause of Blindness: Complement System-Activating Protein (FHR4) Shown to Be Closely Linked to AMD; Finding May Enable Both Risk Assessment & Treatment

An international team of scientists has identified a protein that is strongly linked to the commonest cause of blindness in developed countries when its levels are raised in the blood. The discovery is a major step forward in the understanding of age-related macular degeneration (AMD), which affects 1.5 million people in the UK alone. The study, carried out by a team from the Universities of Manchester, Cardiff, London, and Nijmegen, and Manchester Foundation NHS Trust was published online on February 7, 2020 in Nature Communications. The open-access article is titled “"Increased Circulating Levels of Factor H Related Protein 4 Are Strongly Associated with Age-Related Macular Degeneration." The protein, Factor H-Related Protein 4 (FHR4), was found by the team to be present at higher levels in the blood of patients with AMD compared to individuals of a similar age without the disease. The findings were confirmed in 484 patient and 522 control samples from two independent collections across Europe. Analyses of eyes donated for research after life also revealed the Factor FHR4 protein was present in the AMD-affected parts of the eye. FHR4 was shown by the team to activate part of the immune system -called the complement system; over-activation of the complement system was already known to be a major causal factor of AMD. FHR4 is one of a group of proteins that regulate the complement system and the genes encoding these proteins are tightly clustered on chromosome 1, the largest human chromosome. When the team investigated a set of genetic variants across the human genome, they found that genetic variants in this region on chromosome 1 determined the levels of FHR4 in the blood. And they found that the same genetic variants were associated with AMD.

February 6th

Yale Researchers Find That Ubiquitous Cellular Protein, Polycystin 2, When Unmutated, Plays Lead Role In Cell Survival; When Mutated, It Can Cause Polycystic Kidney Disease (PKD)

The protein known as polycystin 2 is present in every cell in the body, but, until now, scientists knew little about its purpose. Yale researchers; together with colleagues at the University of Illinois at Urbana, the Washington University School of Medicine in St. Louis, and Heidelberg University; have discovered that it protects against cell death, making it a potential target for therapies to treat a variety of diseases of the liver and kidneys, as well as for brain aneurysms, heart disease, and cancer. Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant transient receptor potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. The new research on polycystin 2 was reported online on January 15, 2020 in Scientific Reports. The open-access article is titled “Polycystin 2 Is Increased in Disease to Protect Against Stress-Induced Cell Death.” There are over 6 million protein species in the human body, and scientists are still learning the key roles these proteins play. In the case of polycystin 2, researchers had almost exclusively focused on the protein’s role in polycystic kidney disease (PKD), specifically autosomal dominant PKD (AD-PKD), from which the protein draws its name. When polycystin 2 is mutated, it triggers the disease, which is characterized particularly by the development of large, fluid-filled cysts in the kidney, causing renal failure that necessitates a kidney transplant. “No one knew any function for this protein other than when it was mutated,” said Barbara Ehrlich (at left in photo), PhD, Yale Professor of Pharmacology and of Cellular and Molecular Physiology, who co-led the study with graduate student Allison Brill (at right in photo), 2020 Yale Graduate School of Arts & Sciences (GSAS).

Unprecedented Analyses of More Than 2,600 Whole Genome Sequences from 38 Different Tumor Types Results in 21 Studies Published Simultaneously in Nature Journals; One Suggests Many Cancer Mutations Occur Years Before the Cancer Develops

In a virtually unprecedented event, 21 open-access research papers arising from the monumental efforts of the ICGC/TCGA consortium on whole genome sequencing and integrative analysis of cancer have been published simultaneously online on February 5, 2020, in the following journals published by Nature: Nature Communications (8), Nature (6), Nature Genetics (5), Nature Biotechnology (1), and Communications Biology (1). The work is based on an international collaboration of over 1,300 scientists and clinicians from 37 countries known as the Pan-Cancer Analysis of Whole Genomes (PCAWG). The effort involved analysis of more than 2,600 genomes of 38 different tumor types, creating a huge resource of primary cancer genomes. The flagship paper is titled “Pan-Cancer Analysis of Whole Genomes.” In this BioQuick post, another one of the 21 articles (“The Evolutionary History of 2,658 Cancers”) is described. The the titles and links for all 21 articles are provided following description of the Evolutionary History article. In addition, related articles, including editorials and a News & Views article are provided at the end. Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI) and the Francis Crick Institute in the UK have analyzed the whole genomes of over 2r,600 tumors from 38 different cancer types to determine the chronology of genomic changes during cancer development. Cancer occurs as part of a lifelong process in which our genome changes over time. As we age, our cells cannot maintain the integrity of the genome after cell division without making some errors (mutations). This process can be accelerated by various genetic predispositions and environmental factors, such as smoking. Over our lifetimes, these mutations build up and cells may be mis-programmed, leading to cancer.