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Archive - Jul 2020

Date

July 21st

Four Studies by Students/Fellow in Professor Lorraine O’Driscoll’s Laboratory at Trinity College Dublin Are Presented at International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22)

Professor Lorraine O’Driscoll (photo), PhD, is Professor in Pharmacology and Irish Research Council Advanced Laureate at the School of Pharmacy and Pharmaceutical Sciences, and the Trinity Biomedical Sciences Institute of Trinity College Dublin in Ireland. Dr. O’Driscoll (https://pharmacy.tcd.ie/staff/odriscoll-cv.php?uname=lodrisc) (https://www.tcd.ie/research/profiles/?profile=lodrisc) is also the Coordinator and Principal Investigator of the TRAIN-EV Program (http://train-ev.eu/), which provides training to 15 PhD students in extracellular vesicles (EVs) for benefit in health and disease. Dr. O’Driscoll’s research group focuses on diagnostic, prognostic, and predictive biomarkers; discovering new therapeutic targets; cancer cells’ communication via extracellular vesicles (EVs), as well as the potential uses of EVs from mesenchymal stem cells (MSCs) in regenerative medicine and improving infant milk formula (IMF) by understand milk EVs. Three of Dr. O’Driscoll’s PhD students and one of her post-doctoral research fellows are presenting posters at the International Society for Extracellular Vesicles (ISEV) Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/). These four posters focus on EV release in triple-negative breast cancer, EV release inhibition in prostate cancer, analysis of EVs from drug-resistant and drug-sensitive cancer cells as potential predictive biomarkers in liquid biopsy, and optimizing methods for the separation and characterization of EVs from skim milk and infant milk formula. PhD student Niamh McNamee presented a poster (PF08.02) titled “Inhibition of Extracellular Vesicles in Triple-Negative Breast Cancer.” In her introduction, Ms. McNamee noted that triple-negative breast cancer (TNBC) is the most aggressive from of breast cancer.

Exosomes That Are Both Antigen-Specific & Carry a Selected Gene-Regulating miRNA Act at the Immune Synapse to Induce APC-Derived Secondary Suppressive Exosomes, A Unique Approach That May Have Treatment Applications in Cancer, Autoimmunity, & Allergy

At the International Society for Extracellular Vesicles 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Philip Askenase, MD, presented a poster (PT09.16) titled “Unique Dual Targeting Antigen-Specific and Delivered Chosen-Gene-Specific Regulating Primary Exosomes Acting at the Immune Synapse to Induce APC-Derived Secondary Effector T Cell Suppressive Exosomes.” Dr. Askenase is Professor of Medicine (Clinical Immunology) at the Yale University School of Medicine in the Section of Rheumatology and Clinical Immunology, and former Chief of Allergy & Clinical Immunology at the Yale University School of Medicine. In the ISEV poster, Dr. Askenase and colleagues report identification of a multi-exosome-APC (antigen-presenting cell) circuit that may be applicable far beyond the skin immunity these scientists study in mice. The researchers show results indicating they have been able to induce therapeutic exosomes that both specifically target a particular antigen on acceptor cells like APCs due to antibody light chains bound to the surface of the exosomes, and also target specific gene functions of the acceptor cells, due to delivery, in the exosome’s cargo, of a selected microRNA (miRNA). This dual antigen-specific (via the surface-bound antibody light chains) and gene-specific (via the exosome-associated selected miRNA) therapy may have applications in the treatment of cancer, autoimmunity, and allergy. In order to demonstrate this capability experimentally, Dr.

Second of Four Featured Abstract at ISEV 2020 Virtual Annual Meeting (July 20-22) Describes Initial Results of Efforts to Develop Reference Intervals for Extracellular Vesicles (EVs) in Human Plasma by Flow Cytometry

On Monday, June 20, in the second of four Featured Abstracts being presented by junior investigators during the ISEV 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Bo Li (photo), PhD, from the Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China (People’s Republic), presented her group’s abstract (FA04) “Towards Reference Intervals of Extracellular Vesicles in Human Plasma by Flow Cytometry.” In her introduction, Dr. Li noted that, although flow cytometers with submicrometer sensitivity can characterize single extracellular vesicles (EVs) in clinical samples, there is no consensus about the concentrations of EVs in plasma from healthy humans. To determine cut-off values for diagnoses, reference intervals of EVs in plasma are needed, Dr. Li asserted. To establish such reference intervals, Dr. Li said there are four requirements. First, a significant number of healthy donors should be included. Secondly, the presence of non-EV particles, residual platelets, lipoproteins, and hemolysis should be quantified. Thirdly, a clinically applicable protocol to avoid swarm detection should be established in advance. And lastly, flow cytometry signals should be in SI units. Dr. Li said that the long-term aim of this study is to determine reference intervals of EV concentrations in human plasma within known dynamic ranges of the detectors. In the experimental work to establish a clinical reference, Dr. Li and colleagues first collected blood from 224 healthy volunteers and prepared platelet-free plasma. Then, they performed quality-control measurements including residual platelet count, serum index, and lipid spectrum. They also determined that a protocol of 31-fold to 10(3) dilution is safe to prevent swarm detection in plasma from healthy donors.

First of Four Featured Abstracts at ISEV 2020 Virtual Annual Meeting (July 20-July 22) Focuses on How Ral-GTPases Promote Metastasis by Controlling Biogenesis & Organotropism of Exosomes; Breast Cancer Metastasis to Lung Is Subject of Study

On Monday, June 20), in the first of four Featured Abstracts being presented by junior investigators during the ISEV 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Shima Ghoroghi (photo), from Dr. Jacky Goetz’s Laboratory for Tumor Mechanics (http://www.goetzlab.com/team/), University of Strasbourg, France, delivered abstract FA01 “Ral-GTPases Promote Metastasis by Controlling Biogenesis and Organotropism of Exosomes.” Ms. Ghoroghi joined Dr. Goetz’s group as a PhD student in 2016 to study the role of Ral-GTPases in the secretion of exosomes by tumor cells during metastasis under close supervision of Dr. Vincent Hyenne, a specialist in exosomes. In her introduction, Ms. Ghoroghi noted that exosomes are small vesicles of endosomal origin, composed of different biomolecules including RNA, lipids, and proteins, which can be taken up by distant cells and deliver a functional message. Many studies have shown that exosomes play a major role in tumor progression by mediating the communication between tumors cells and their microenvironment. The main goals of Ms. Ghoroghi’s PhD project consist in dissecting the mechanisms of exosome secretion influenced by Ral-GTPases and understanding the importance of these exosomes in metastasis. During her PhD studies, Ms. Ghoroghi found that Ral-GTPases are central molecules linking the mechanisms of exosome secretion to their capacity to disseminate and induce pre-metastatic niches. She provided a detailed dissection of the impact of the Ral-GTPases on exosome secretion levels and content. She also showed that Ral-GTPases control exosome secretion by acting on the endosomal secretion pathway through the phospholipase D1 (PLD1), which also promotes exosome secretion.

International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22) Opens with Record 1,600 Attendees from Over 50 Countries

The International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), with 1,600 virtual attendees from over 50 countries around the world, and offering ~600 presentations of various types (Plenary Addresses, “Hot Topic” Panel Sessions, Featured Abstracts, Oral Abstract Talks, Poster Chats, & Education Sessions), both live-streamed and on-demand, opened on Monday, July 20, with welcoming remarks by Alissa Weaver, MD, PhD Professor & Chair, Cell & Developmental Biology, Vanderbilt University School of Medicine, and Lucia Languino, PhD, Professor, Cancer Biology, Thomas Jefferson University, Philadelphia, the two ISEV International Organizing Committee (IOC) Co-Chairs, and by Ken Witwer, PhD, Associate Professor, Molecular and Comparative Pathobiology, Johns Hopkins, and ISEV Executive Chair for Science & Meetings. These warm words were followed by the meeting’s first live-streamed plenary address on the “The Mystery of EV Biogenesis—Past, Present, and Future,” presented by Phyllis Hanson, MD, PhD, Chair of Biological Chemistry at the University of Michigan. Dr. Hanson is a world-leading expert on the organization of cellular membranes. She studies how proteins interact with each other, and with membranes, to influence membrane trafficking and cellular organelles, and the way in which these interactions influence neurodegenerative diseases such as Alzheimer's disease. Dr. Hanson was introduced by her former colleague Dr. Weaver and Dr. Hanson’s address was followed by a 15-minute Q&A session moderated by Dr. Languino.

SECOND PLENARY ADDRESS FOCUSES ON "EVs IN NEUROLOGICAL DISEASES"

July 17th

Specific T-Cell Immunity to SARS-CoV-2 Revealed in Recovered COVID-19 and SARS Patients, and in Uninfected Controls; Results Published in Nature

Singapore scientists have uncovered SARS-CoV-2-specific T-cell immunity in recovered COVID-19 and SARS patients, and in uninfected individuals. The study by scientists from Duke-NUS Medical School, in close collaboration with the National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore General Hospital (SGH) and National Centre for Infectious Diseases (NCID) was published online on July 15, 2020 as an accelerated preview article in Nature. The findings suggest infection and exposure to coronaviruses induces long-lasting memory T-cells, which could help in the management of the current pandemic and in vaccine development against COVID-19. The open-access Nature article is titled “SARS-CoV-2-Specific T Cell Immunity in Cases of COVID-19 and SARS, and Uninfected Controls.” The team tested subjects who had recovered from COVID-19 and found the presence of SARS-CoV-2-specific T-cells in all of them, which suggests that T-cells play an important role in this infection. Importantly, the team showed that patients who recovered from SARS 17 years ago after the 2003 outbreak, still possess virus-specific memory T-cells and displayed cross-immunity to SARS-CoV-2. "Our team also tested uninfected healthy individuals and found SARS-CoV-2-specific T-cells in more than 50 percent of them. This could be due to cross-reactive immunity obtained from exposure to other coronaviruses, such as those causing the common cold, or presently unknown animal coronaviruses. It is important to understand if this could explain why some individuals are able to better control the infection," said Professor Antonio Bertoletti, MD, from Duke-NUS' Emerging Infectious Diseases (EID) program, who is the corresponding author of this study.

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: PLENARY SPEAKERS

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 five plenary speakers who are acknowledged leaders in the field of extracellular vesicles (EVs). They are Alain Brisson, currently Emeritus Professor at the University of Bordeaux, in the team Extracellular Vesicles & Membrane Repair in CNRS unit CBMN; Hollis Cline, PhD, the Hahn Professor of Neuroscience and Co-Chair of the Department of Neuroscience at Scripps Research in La Jolla, California; Phylis Hanson, MD, PhD, the Minor J. Coon Collegiate Professor of Biological Chemistry and Chair of Biological Chemistry at the University of Michigan; Eduardo Marban, MD, PhD, Founding Director, Cedars-Sinai Heart Institute; and Shannon Stott, PhD, Assistant Professor, Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Associate Member, Broad Institute. Additional information on each of the ISEV 2020 plenary speakers is provided below.

ALAINE BRISSON, PHD

Largest Study of Prostate Cancer Genomics in US Men of African Ancestry Highlights Importance of Including Under-Represented Groups in Genetic/Health Studies That Are Often Focused on Those of European Ancestry ; Results Will Inform RESPOND Study

Black men in the United States are known to suffer disproportionately from prostate cancer, but few studies have investigated whether genetic differences in prostate tumors could have anything to do with these health disparities. Now, in the largest study of its kind to date, researchers from Boston University School of Medicine (BUSM), UC San Francisco (UCSF), and Northwestern University have identified genes that are more frequently altered in prostate tumors from men of African ancestry compared to other racial groups, though the reasons for these differences are not yet known, the authors say. None of the individual tumor genetic differences that were identified are likely to explain significant differences in health outcomes or to prevent Black Americans from benefiting from a new generation of precision prostate cancer therapies, the authors say, as long as the therapies are applied equitably. The newly identified gene variants could potentially lead to precision prostate cancer therapies specifically focused on men of African ancestry, but this is not yet clear. The results will inform broader efforts by the National Cancer Institute's RESPOND African American Prostate Cancer study (https://www.respondstudy.org/) to link gene variants to health outcomes in an even larger cohort of Black patients nationwide. Despite declines in mortality related to cancer in the U.S., disparities by race have persisted. One in every six Black Americans will be diagnosed with prostate cancer in their lifetime, and these men are twice as likely to die from the disease as men of other races. But it is not yet clear to researchers whether differences in prostate cancer genetics contribute to these health disparities in addition to the social and environmental inequities known to drive poorer health outcomes across the board.

July 17th

Three COVID-19 Clinical Trials of Regeneron’s Antibody Cocktail REGN-COV2 Move Forward at University of Wisconsin-Madison School of Medicine & Public Health

The University of Wisconsin (UW) School of Medicine and Public Health and UW Health will conduct three clinical trials to test a new treatment and preventative for COVID-19, in collaboration with Regeneron Pharmaceuticals. The school will use its companion health system UW Health as a trial site to evaluate an “antibody cocktail,” dubbed REGN-COV2, created by the Tarrytown, New York-based pharmaceutical company. To create REGN-COV2, Regeneron scientists selected virus-neutralizing antibodies produced from mice that have been genetically modified to simulate a human immune system, as well as antibodies identified from humans who have recovered from COVID-19, according to Regeneron. The experimental antibodies interact with the receptor binding domain (RBD) of the SARS-CoV-2 virus’s spike (S) protein and block viral interaction with human angiotensin-converting enzyme 2 (ACE2), which is the cell-surface protein the virus docks with during infection. The three trials include: an adaptive Phase 1, 2, and 3 randomized, double-blinded, placebo-controlled study to evaluate the safety and efficacy in hospitalized patients with COVID-19; an adaptive Phase 1, 2, and 3 randomized, double-blinded, placebo-controlled study to evaluate the safety and efficacy in non-hospitalized patients with COVID-19; and a Phase 3 randomized, double-blinded, placebo-controlled study to evaluate the ability of REGN-COV2 to prevent an infection of the virus that causes COVID-19 in people who have been exposed to someone in their household with the disease. UW Health is one of approximately 100 trial sites for REGN-COV2 in the United States. Recruitment will begin immediately with a goal of enrolling 30 to 50 people per trial at the UW Health site.

All of Us Research Program at University of Wisconsin-Madison Joins Fight Against COVID-19

Those who have enrolled in the All of Us Research Program at the University of Wisconsin‒Madison and UW Health (https://allofus.wisc.edu/), now have the potential to directly impact the national fight against the COVID-19 pandemic. The National Institutes of Health (NIH), which oversees the nationwide program, recently announced that it is leveraging its diverse All of Us participant base to seek new insights into COVID-19 through antibody testing, a survey on the pandemic’s mental and physical impacts, and analysis of electronic health record information provided by participants. UW‒Madison, which is part of a Wisconsin consortium that includes Gundersen Health System, Marshfield Clinic, and the Medical College of Wisconsin, has actively enrolled individuals in the Madison and Milwaukee areas since All of Us launched in May 2018. UW Health is a key partner for recruitment and enrollment efforts in Madison. “This is an exciting opportunity for our participants to have a direct impact on COVID-19 research, watching how their participation in this historic effort is truly making a difference,” said Elizabeth Burnside, MD, Co-Principal Investigator, All of Us at UW‒Madison, and a UW Health physician. “This focused initiative could be especially important for members of communities that are often under-represented in health research and who may question the overall and personal benefit of research participation.” To date, more than 271,000 people nationwide have participated in the All of Us Program and more than 50% of them represent racial and ethnic minorities.