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July 5th, 2020

Label-Free Sensing of MCT1 and CD147 in Surface of Glioma-Derived Exosomes May Be Used for Tracking Metabolic Reprogramming and Malignant Progression in Glioma; Study Suggests Inhibitors of MCT1 & CD147 May Be Effective In Treating Gliomas

Researchers at the City University of Hong have demonstrated that malignant glioma cells release large numbers of exosomes containing high levels of MCT1 (monocarboxylate transporter 1) and its ancillary protein CD147 (cluster of differentiation 147). High levels of these two proteins are known to occur in malignant glioma and are associated with the tumor’s reprogramming to glycolysis (Warburg effect) as a rapid source of energy in a hypoxic environment. The authors showed that malignant glioma cells (GMs) release tremendous numbers of exosomes (nanovesicles of 30 nm to 200 nm in size), which promote tumor progression by the transport of pro-oncogenic molecules to neighboring cells. In their study, the authors found that hypoxia-induced malignant GMs strongly enhanced MCT1 and CD147 expression, playing a crucial role in promoting calcium-dependent exosome release. The hypoxic-GMs-derived exosomes contained significantly high levels of MCT1 and CD147, which could be quantitatively detected by noninvasive localized surface plasmon resonance (LSPR) and atomic force microscopy (AFM) biosensors, demonstrating that MCT1 and CD147 could be used as precise surrogate biomarkers for tracking parent GMs’ metabolic reprogramming and malignant progression as liquid biopsies. These new results were published on June 26, 2020 in Science Advances. The open-access article is titled “Label-Free Sensing of Exosomal MCT1 And CD147 for Tracking Metabolic Reprogramming and Malignant Progression in Glioma.” In the introduction to this article, the authors noted that glioma is the most common type of brain cancer and that it originates predominantly from neuroglial stem cells.

July 4th

Protective Antibodies Identified for Rare, Polio-Like Disease in Children

Researchers at Vanderbilt University Medical Center, Purdue University and the University of Wisconsin-Madison have isolated human monoclonal antibodies that potentially can prevent a rare, but devastating, polio-like illness in children linked to a respiratory viral infection. The results have been published as the cover story of the July 3, 2020 issue of Science Immunology, and the article is titled “Human Antibodies Neutralize Enterovirus D68 and Protect Against Infection and Paralytic Disease.” The illness, called acute flaccid myelitis (AFM), causes sudden weakness in the arms and legs following a fever or respiratory illness. More than 600 cases have been identified since the U.S. Centers for Disease Control and Prevention (CDC) began tracking the disease in 2014. There is no specific treatment for AFM, which tends to strike in the late summer or early fall, and which has been associated with some deaths. However, the disease has recently been linked to a group of respiratory viruses called enterovirus D68 (EV-D68). Researchers at the Vanderbilt Vaccine Center isolated antibody-producing blood cells from the blood of children who had previously been infected by EV-D68. By fusing the blood cells to fast-growing myeloma cells, the researchers were able to generate a panel of monoclonal antibodies that potently neutralized the virus in laboratory studies. Colleagues at Purdue determined the structure of the antibodies, which shed light on how they specifically recognize and bind to EV-D68. One of the antibodies protected mice from respiratory and neurologic disease when given either before or after infection by the enterovirus.

CytoDyn Announces Execution of Exclusive Agreement with American Regent for Distribution and Supply of Leronlimab for Treatment of COVID-19 in United States, Pending Trial Results & FDA Approval

On July 3, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced that it has signed an exclusive Distribution and Supply Agreement with American Regent, Inc. (“American Regent”) (https://www.americanregent.com/) for the distribution of leronlimab for the treatment of COVID-19 in the United States. Under the terms of the agreement, CytoDyn will supply leronlimab for the treatment of COVID-19 for distribution by American Regent and receive quarterly payments based on a profit-sharing arrangement. “Having this distribution agreement in place ahead of the readout from CytoDyn’s COVID-19 clinical trials further emphasizes CytoDyn’s commitment to making leronlimab immediately available to patients based on the successful completion of its ongoing clinical trials,” said Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn. “We are particularly happy to be partnering with a company with the proven expertise, unparalleled commercial reach, and stellar reputation of American Regent.” “American Regent is looking forward to partnering with CytoDyn to provide COVID-19 patients rapid and efficient access to a potentially life-saving drug,” said Mr. Harsher Singh, American Regent’s Vice President and Chief Commercial Officer. CytoDyn is currently enrolling a Phase 2b/3 clinical trial for 390 severe and critically ill COVID-19 patients, which is a randomized, placebo-controlled trial with 2:1 ratio (active drug to placebo ratio). CytoDyn has also completed its enrollment of a Phase 2 randomized clinical trial with 75 patients in the mild-to-moderate COVID-19 population. CytoDyn has been granted more than sixty emergency Investigational New Drug (eIND) authorizations by the U.S.

CytoDyn CEO on DrBeen Webcast July 4, 2020 (9 pm EDT) (YouTube & FB) to Discuss with Mobeen Syed, MD, the Many Potential Opportunities for Anti-CCR5 Monoclonal Antibody Leronlimab, Including Treatment of COVID-19, HIV, & Triple-Negative Breast Cancer

CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, has announced that Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn will be interviewed on the DrBeen webcast hosted by Mobeen Syed, MD, on Saturday, July 4, 2020 at 9:00 pm EDT (6 pm PDT, 7 pm MDT, and 8 pm CDT). The interview will be available simultaneously on two channels:

YouTube - DrBeen Medical Lectures
Link: https://www.youtube.com/c/USMLEOnline

Facebook: DrBeen Medical
Link: https://m.facebook.com/drbeenmedical

CYTODYN & CORONAVIRUS DISEASE 2019(COVID-19): CytoDyn has met its 75-patient enrollment target in its Phase 2 clinical trial for COVID-19, a randomized clinical trial for mild-to-moderate COVID-19 population in the U.S. and enrollment continues in CytoDyn’s Phase 2b/3 randomized clinical trial for severe and critically ill COVID-19 population in several hospitals throughout the country. SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

July 3rd

Gene Mutations That Cause Familial Mediterranean Fever (FMF) May Convey Resistance to Bubonic Plague; FMF Mutations in Gene for Inflammation Protein Pyrin Associated with Plague Resistance

Researchers have discovered that Mediterranean populations may be more susceptible to an autoinflammatory disease because of evolutionary pressure to survive the bubonic plague. The study, carried out by scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, determined that specific genomic variants that cause a disease called familial Mediterranean fever (FMF) may also confer increased resilience to the plague. The researchers suggest that because of this potential advantage, FMF-causing genomic variants have been positively selected for in Mediterranean populations over centuries. The findings were published online on June 29, 2020 in Nature Immunology. The article is titled “Ancient Familial Mediterranean Fever Mutations in Human Pyrin and Resistance to Yersinia pestis.” Over centuries, a biological arms race has been fought between humans and microbial pathogens. This evolutionary battle is between the human immune system and microorganisms trying to invade our bodies. Microbes affect the human genome in many ways. For example, they can influence some of the genomic variation that accumulates in human populations over time. "In this era of a new pandemic, understanding the interplay between microbes and humans is ever critical," said Dr. Dan Kastner, MD, PhD, NHGRI Scientific Director and a co-author on the paper. “We can witness evolution playing out before our very eyes.” One such microbe is Yersinia pestis, the bacterial agent responsible for a series of well-documented bubonic plague (https://www.cdc.gov/plague/faq/index.html) epidemics that led to over 50 million deaths.

Some Animals Can, Indeed, Sense Coming Earthquakes Ahead of Time, New Study Suggests; Future Work Will Pursue Development of Early-Warning Systems Harnessing This “Sixth Sense” of Animals

Even today, nobody can reliably predict when and where an earthquake will occur. However, eyewitnesses have repeatedly reported that animals behave unusually before an earthquake. In an international cooperation project, researchers from the Max Planck Institute of Animal Behavior in Konstanz/Radolfzell and the Cluster of Excellence Centre for the Advanced Study of Collective Behaviour at the University of Konstanz, have investigated whether cows, sheep, and dogs can actually detect early signs of earthquakes. To do so, they attached sensors to the animals in an earthquake-prone area in Northern Italy and recorded their movements over several months. The movement data show that the animals were unusually restless in the hours before the earthquakes. The closer the animals were to the epicenter of the impending quake, the earlier they started behaving unusually. The movement profiles of different animal species in different regions could therefore provide clues with respect to the place and time of an impending earthquake. You may watch a video about the research project in campus.kn, the online magazine of the University of Konstanz: https://www.campus.uni-konstanz.de/en/science/the-sixth-sense-of-animals.... Please see details of the new research below. The results were published online on June 3, 2020 in Ethology. The open-access article is titled ““Potential Short-Term Earthquake Forecasting by Farm-Animal Monitoring” (https://onlinelibrary.wiley.com/doi/full/10.1111/eth.13078). Experts disagree about whether earthquakes can be exactly predicted. Nevertheless, animals seem to sense the impending danger hours in advance. For example, there are reports that wild animals leave their sleeping and nesting places immediately before strong quakes and that pets become restless.

July 2nd

RNA Structures Revealed by the Thousands Using Lead (Pb+2) Sequencing Approach

Researchers from Bochum and Münster in Germany have developed a new method to determine the structures of all RNA molecules in a bacterial cell at once. In the past, this had to be done individually for each molecule. Besides their exact composition, their structure is crucial for the function of the RNAs. The team describes the new high-throughput structure mapping method, termed Lead-Seq for lead (Pb) sequencing in an article published online on May 28, 2020 in Nucleic Acids Research. The article is titled “Lead-Seq: Transcriptome-Wide Structure Probing in Vivo Using Lead (II) Ions.” Christian Twittenhoff, Vivian Brandenburg (at right in photo), Francesco Righetti, PhD, and Professor Franz Narberhaus (at left in photo), PhD, from the Chair of Microbial Biology at Ruhr-Universität Bochum (RUB) collaborated with the Bioinformatics Group headed by Professor Axel Mosig, PhD, at RUB and the team led by Professor Petra Dersch, PhD, at the University of Münster, previously from the Helmholtz Centre for Infection Research in Braunschweig. In all living cells, genetic information is stored in double-stranded DNA and transcribed into single-stranded RNA, which then serves as a blueprint for proteins. However, RNA is not only a linear copy of the genetic information, but often folds into complex structures. The combination of single-stranded and partially folded double-stranded regions is of central importance for the function and stability of RNAs. "If we want to learn something about RNAs, we must also understand their structure," says Professor Narberhaus. With lead sequencing, the authors present a method that facilitates the simultaneous analysis of all RNA structures in a bacterial cell.

CAR-T Cells Recognize & Attack Human and Mouse Solid-Tumor Cancer Cells in Vitro; CAR-T Cell Therapy Has Previously Shown Effectiveness Against Blood Cancers, But Not Against Solid Tumors; Current Approach Targets Glycosylated Peptides on Solid Tumors

A method known as CAR-T (chimeric antigen receptor T cells) therapy (https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell) has been used successfully in patients with blood cancers such as lymphoma and leukemia. The approach modifies a patient's own T-cells by adding a piece of an antibody that recognizes unique features on the surface of cancer cells. The potency of adoptive T cell therapies targeting the cell surface antigen CD19 has been demonstrated in hematopoietic cancers. In a new study, researchers report that they have dramatically broadened the potential targets of this approach--their engineered T-cells attack a variety of solid-tumor cancer cells from humans and mice. Heretofore, CAR-T therapy had not demonstrated effectiveness against solid tumors. The researchers, led by a team from the University of Illinois at Urbana-Champaign, and including scientists from the University of Chicago and the University of Copenhagen, reported their findings online on June 30, 2020 in the Proceedings of the National Academy of Sciences (https://www.pnas.org/content/117/26/15148). The article is titled "Structure-Guided Engineering of the Affinity and Specificity of CARs Against Tn-Glycopeptides." [Editor’s Note: Tn antigen refers to the monosaccharide structure N-acetylgalactosamine (GalNAc) linked to serine or threonine by a glycosidic bond (https://en.wikipedia.org/wiki/Tn_antigen)] "Cancer cells express on their surface certain proteins that arise because of different kinds of mutations," said Preeti Sharma, PhD, a postdoctoral researcher at the University of Illinois at Urbana-Champaign who led the research, together with Biochemistry Professor David Kranz (http://mcb.illinois.edu/faculty/profile/d-kranz/), PhD, a member of the Cancer Center at Illinois and an affiliate of the Carl R.

Engineers Develop Novel Method to Produce NO2 Gaseous Messenger Molecule at Precise Locations in Body; Approach Could Illuminate NO2’s Roles in Neural, Circulatory, & Immune Systems; Work Described As “Milestone in Bioelectronics”

Nitric oxide (NO2) is an important signaling molecule in the body, with a role in building nervous system connections that contribute to learning and memory. It also functions as a messenger in the cardiovascular and immune systems. But it has been difficult for researchers to study exactly what its role is in these systems and how it functions. Because it is a gas, there has been no practical way to direct it to specific individual cells in order to observe its effects. Now, a team of scientists and engineers at MIT, and elsewhere, has found a way of generating the gas at precisely targeted locations inside the body, potentially opening new lines of research on this essential molecule’s effects. The findings were published online on June 29, 2020 reported in Nature Nanotechnology, in a paper by MIT Professors Polina Anikeeva (photo), PhD, Karthish Manthiram, PhD, and Yoel Fink, PhD; graduate student Jimin Park; postdoc Kyoungsuk Jin, PhD; and 10 others at MIT, and in Taiwan, Japan, and Israel. The article is titled “In Situ Electrochemical Generation of Nitric Oxide for Neuronal Modulation.” “It’s a very important compound,” Dr. Anikeeva says. But figuring out the relationships between the delivery of nitric oxide to particular cells and synapses, and the resulting higher-level effects on the learning process has been difficult. So far, most studies have resorted to looking at systemic effects, by knocking out genes responsible for the production of enzymes the body uses to produce nitric oxide where it’s needed as a messenger. But that approach, Dr. Anikeeva says, is “very brute force.

Certain Bacteria Are Circumventing Plant Defenses, Causing Foodborne Illnesses; Salmonella Can Enter Plants by Opening the Stomates in Plant Leaves

As the world wrestles with the coronavirus (COVID-19) pandemic, which arose after the virus jumped from an animal species to the human species, University of Delaware researchers are learning about new ways other pathogens are jumping from plants to people. Opportunistic bacteria--Salmonella, Listeria, and E. coli, for example--often piggy-back on raw vegetables, poultry, beef, and other foods to gain entry into a human host, causing millions of food-borne illnesses each year. But University of Delaware researchers Harsh Bais, PhD, and Kali Kniel, PhD, and their collaborators now have found that wild strains of Salmonella can circumvent a plant's immune defense system, getting into the leaves of lettuce by opening up the plant's tiny breathing pores called stomates (image). The plant shows no symptoms of this invasion and once inside the plant, the pathogens cannot just be washed off. Stomates are little kidney-shaped openings on leaves that open and close naturally and are regulated by circadian rhythm. They open to allow the plant to cool off and breathe. They close when they detect threats from drought or plant bacterial pathogens. Some pathogens can barge into a closed stomate using brute force, Dr. Bais said. Fungi can do that, for example. Bacteria don't have the enzymes needed to do that, so they look for openings--in roots or through stomates, he said. Plant bacterial pathogens have found a way to reopen those closed stomates and gain entry to the plant's internal workings, Dr. Bais said. But now, in research published online on April3, 2020 in Frontiers in Microbiology (https://www.frontiersin.org/articles/10.3389/fmicb.2020.00500/full), Dr. Bais and Dr. Kniel have shown that some strains of the human pathogen salmonella have developed a way to reopen closed stomates, too.