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ASEMV 2017—EV-Associated Tissue Factor Key to New Assay That May Predict Risk of Venous Thromboembolism in Cancer

On Tuesday morning, Rienk Nieuland, PhD, a principal investigator of the Academic Medical Centre of the University of Amsterdam, presented a possible new approach to predicting the risk of venous thromboembolism (VTE) in cancer patients. He noted that VTE is effectively treated by prophylactic anticoagulation, but that because anticoagulation increases the bleeding risk, prophylactic treatment of all cancer patients is not desirable. Hence, there is a need to identify cancer patients at high risk of VTE in whom the benefits of thromboprophylaxis may outweight the risks. In describing his group’s work to meet this need, he first noted that saliva contains EVs exposing the protein tissue factor (TF). When we lick a wound, this brings together coagulation factors (blood) and TF (saliva), thereby promoting the clotting of blood. He added that blood from healthy humans does not contain EVs exposing TF, but that circulating EVs exposing TF are encountered during surgery and in several pathologic conditions, including sepsis and cancer. Dr. Nieuwand’s group developed a plasma clotting test (Fibrinogen Generation Test, FGT) in which the clotting time depends on the presence of endogenous EV-associated TF. The ability of the FGT to identify cancer patients at high risk of VTE was determined in a multicenter prospective cohort study. Dr. Nieuwand reported that the results were promising, particularly with regard to pancreatic cancer, and may provide clinically useful information, either as a stand-alone biomarker or when combined with other biomarkers and/or clinical prediction scores for VTE. The American Society for Exosomes and Microvesicles (ASEMV) 2017 Annual Meeting was held October 8-12 at the Asilomar Conference Grounds in Pacific Grove, California.

ASEMV 2017—Morphine-Mediated Potentiation of HIV-Associated Neurological Disorder (HAND)

On Monday morning, October 9, Shilpu Buch, PhD, Professor and Vice-Chair for Research, Director of the Nebraska Center for Substance Abuse Research, Nebraska Medical Center, University of Nebraska, presented on “Exosomal miRNA-Mediated Loss of Pericyte Coverage at the Blood-Brain Barrier: Implications for Morphine-Mediated Potentiation of HIV-Associated Neurological Disorder (HAND).” Dr. Buch began by noting that both in vitro and in vivo studies have shown that morphine potentiates the neurodegenerative effecs of HIV on the central nervous system (CNS). BBB breach by toxic stimuli is associated with the transmigration of monocytes and leukocyts into the brain, she said. Dr. Buch reported that three cell types are key to the blood-brain barrier (BBB). These are endothelial cells, astrocytes, and pericytes. She said that astrocyte-pericyte cross-talk is critical to BBB integrity. She said that pericytes regulate the BBB and that morphine reduces pericyte coverage of the BBB, resulting in cognitive impairment ant neuroinflammation. The underlying mechanism(s) by which morphine-exposed astrocytes regulate pericytes at the BBB, remains unknown. Previously, her group had identified a wide array of microRNAs (miRs) that are dysregulated in the CNS of SIV-infected, morphine-dependent macaques. In addition, her group has shown in vitro thatEVs released from morphine- and HIV-protein-Tat-exposed astrocytes can shuttle miRNAs, which, in turn, are taken up by neurons, leading to neuronal dysfunction. Here, Dr. Buch reported on the results of her group’s current study to examine the roles of miRs released from morphine-exposed astrocytes in mediating the loss of pericytes at the BBB.

ASEMV 2017—Gliomas Are Focus of Multiple Presentations

The American Society for Exosomes and Microvesicles (ASEMV) 2017 Annual Meeting was held October 8-12 at the Asilomar Conference Grounds in Pacific Grove, California. The event was attended by 180 scientists from around the United States and world. In the last talk on Tuesday, evening, Michael Olin, PhD, Assistant Professor in the Department of Pediatrics, Division of Hematology/Oncology, University of Minnesota, presented his group’s work on the identification of a peptide that activates a pathway that opposes the CD200 immune inhibition pathway induced by exosomes released by cancer cells, particularly glioblastoma (GBM) cells. Dr. Olin has shown that parenteral injection of the peptide and tumor lysate reduces or eliminates glioma in dogs with natural gliomas. Dr. Olin and colleagues have recently founded a company (OX2 Therapeutics, dedicated to bringing this therapeutic peptide to the clinic, hopefully within a year. Earlier on Tuesday evening, Xandra Breakefield, PhD, Professor of Neurology, Harvard Medical School; Geneticist, Massachusetts General Hospital, began by emphasizing the grim nature of glioblastoma multiforme which is fatal (15-month average lifespan after diagnosis) and for which there has been no change in treatment in 20 years. Dr. Breakefield noted that glioma-secreted extracellular vesicles (EVs) are taken up by microglia cells which typically constitute 30%-40% of the tumor microenvironment. She noted that normally microglia act as sentinels in the brain, actively sensing the milieu and performing “warrior” and “nurturer” functions as needed. The genes controlling this important sensory role have been termed the microglia “sensome.” Dr.

18-Year-Old Harvard Freshman Electrifies Scientists on Second Day of American Society for Exosomes and Microvesicles (ASEMV) 2017 Annual Meeting in Asilomar, California

On Monday, October 9, Indrani Das, an 18-year-old freshman at Harvard, electrified a crowd of 200 established scientists at the ASEMV 2017 Annual Meeting with the description of her exosome research that won the Regeneron 2017 United States Science Talent Search Grand Prize of $250,000 (this is the nation's oldest and most prestigious science and math competition for high school seniors--previous sponsors of the Talent Search were Westinghouse and Intel) (photo shows Indrani on the day her prize was awarded). Comments heard after Indrani’s Asilomar presentation included “brilliant,” “powerful,” “incredible.” Her winning project was titled “Exosomal MicroRNA-124s: Novel Translational Reactive Astrocyte Repair in Vitro.” Indrani’s early interest in neurodegenerative diseases and brain injury therapy had provided the impetus for her four-year high school study of exosomes as she had learned that these vesicles can pass through the blood-brain barrier and might perhaps be used to provide therapeutic cargo to sites of brain injury. She knew that stroke, traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease all cause the behavior of glial cells to change dramatically, in particular to cause a phenomenon called reactive astrogliosis. Healthy astrocytes take up glutamate, an essential excitatory neurotransmitter, from their surroundings, but, in reactive astrogliosis, this process breaks down and glutamate accumulates in the extracellular space where it can damage surrounding neurons. In fact, neurons die when exposed to the medium that reactive astrocytes are grown in. Indrani knew that the excitatory amino acid transporter EAAT2 is one of the major glutamate transporters expressed predominantly in astrocytes and is responsible for 90% of total glutamate uptake.

ASEMV 2017 Meeting on Exosomes & Microvesicles Opens in California

With almost 200 attendees from around the USA and world, the seventh annual American Society for Exosomes and Microvesicles (ASEMV 2017) meeting opened on Sunday, October 8, at the naturally spectacular Asilomar Conference Grounds in Pacific Grove, California. Opening remarks by Michael Graner, PhD, University of Colorado Denver, briefly outlined the history of the ASEMV meetings from the early days when just a few were working on exosomes to the present time when exosome studies are being carried out in almost every conceivable area of biology. Dr. Graner emphasized that the recurrent theme of the ASEMV meetings over the years has been “awesome science,” and he expected this year to be the same. He then introduced the evening’s three speakers: Dr. Takahiro Ochiya, Chief, Division of Molecular and Cellular Medicine, National Cancer Center, Tokyo, Japan; Dr. Christie D. Fowler, Department of Neurobiology and Behavior, University of California-Irvine; and Dr. Janos Zempleni, Department of Nutrition and Health Science, University of Nebraska-Lincoln. Dr. Ochiya spoke on “Extracellular Vesicles As a Novel Therapeutic Target for Cancer Metastasis.” Dr. Fowler spoke on “Extracellular MicroRNAs Released During Nicotine Self-Administration.” Dr. Zempleni spoke on the “Delivery and Alterations of Microbial Signals by Bovine Milk Exosomes in Non-Bovine Species.” Details of these talks will be described in an upcoming article in BioQuick News. This year’s meeting was organized by ASEMV President Dr. Stephen J.

Scientists Sequence Genome of Taiwan Pit Viper and Examine Role of Genetic Drift in Venom Evolution

A bite from a pit viper, locally known in Taiwan and Okinawa as habu, can cause permanent disability and even death. Yet, much about its venom remains an enigma. Highly variable in composition, even between littermates, this toxic cocktail keeps changing over generations. A recent study published online on September 27, 2017 in Genome Biology and Evolution sheds light on the evolution of snake venoms. For the first time, researchers have sequenced a habu genome, that of the Taiwan habu (Protobothrops mucrosquamatus), and compared it to that of its sister species, the Sakishima habu (Protobothrops elegans). The article is titled “Population Genomic Analysis of a Pitviper Reveals Microevolutionary Forces Underlying Venom Chemistry.” More than 50 instances of snake bites were recorded in the past year on Okinawa alone, prefectural government figures show. Globally, snake bites cause between 81,000 and 138,000 mortalities per year, according to the World Health Organization. In developing countries and rural areas with high exposure to venomous species and scant medical resources, snake bites can be especially devastating. For such places, creating effective antivenom can be a matter of life or death. "For many years it was known that snake venoms evolve very rapidly, and the most common explanation for this has been natural selection," said Dr. Alexander Mikheyev, senior author on the paper and head of the Ecology and Evolution Unit at the Okinawa Institute of Science and Technology (OIST), "but there are reasons to suspect that this might not be the only evolutionary force at work."

Nobel Prize in Chemistry 2017 Awarded for Cryo-Electron Microscopy

We may soon have detailed images of life’s complex machineries at atomic resolution. The Nobel Prize in Chemistry 2017 has been awarded to three European-born scientists: Jacques Dubochet, Joachim Frank, and Richard Henderson; for the development of cryo-electron microscopy, which both simplifies and improves the imaging of biomolecules. This method has moved biochemistry into a new era. A picture can be a key to understanding. Scientific breakthroughs often build upon the successful visualization of objects invisible to the human eye. However, biochemical maps have long been filled with blank spaces because the available technology has had difficulty generating images of much of life’s molecular machinery. Cryo-electron microscopy changes all of this. Researchers can now freeze biomolecules mid-movement and visualize processes they have never previously seen, which is decisive for both the basic understanding of life’s chemistry and for the development of pharmaceuticals. Electron microscopes were long believed to only be suitable for imaging dead matter, because the powerful electron beam destroys biological material. But in 1990, Richard Henderson succeeded in using an electron microscope to generate a three-dimensional image of a protein at atomic resolution. This breakthrough proved the technology’s potential. Joachim Frank made the technology generally applicable. Between 1975 and 1986, he developed an image-processing method in which the electron microscope’s fuzzy two-dimensional images are analyzed and merged to reveal a sharp three-dimensional structure. Jacques Dubochet added water to electron microscopy. Liquid water evaporates in the electron microscope’s vacuum, which makes the biomolecules collapse.

Study Finds Non-Protein-Coding Fusion Genes Are Frequent in Breast Cancer

A fusion gene occurs when a chromosomal break brings two separate genes together into a new functioning gene. So far, the research has focused on protein-coding fusion genes. However, human genes consist not only of protein-coding components, but also of components that lack this ability. The latter have not attracted any interest so far, argues Dr. Carlos Rovira (photo), cancer researcher and Associate Professor of Oncology at Lund University in Sweden. "We study genes that lack the ability to produce proteins, and we were very surprised to discover that this type of study has not been done before - the 'non-coding' components of fusion genes have never been analyzed globally in this context. This means that previous analyses have ruled out important genetic components, and that fusion gene data should be re-analyzed to possibly find more markers and potential targets for cancer treatment", says Dr. Rovira, who has been researching breast cancer for many years. "In our study, we discovered a new class of fusion genes that primarily affect the activity of microRNA. These genes are small and often located inside larger protein-coding genes, but they are very short and lack the code required to control protein production. It has already been shown that microRNAs are important for the development of cancer, but the relationship between them and fusion genes was previously unexplored." Fusion genes are commonly found in patients with leukemia and soft tissue cancers, and are of great value in terms of diagnosis and treatment. They have also been used for many years for targeted cancer treatment. The new work was reported online on October 5, 2017 in Nature Communications.

Mystery of BRCA1 Breast Cancer Risk Gene Solved, 20 Years After Its Discovery; Interaction With BARD1 Is Key

More than 20 years after scientists revealed that mutations in the BRCA1 gene predispose women to breast cancer, Yale scientists have pinpointed the molecular mechanism that allows those mutations to wreak their havoc. The findings, reported online on October 4, 2017 in Nature, will not only help researchers design drugs to combat breast and ovarian cancers, but also help identify women who are at high risk of developing them, the authors say. The Nature article is titled “BRCA1–BARD1 Promotes RAD51-Mediated Homologous DNA Pairing.” "There have been about 14,000 papers written about BRCA1, and you would think we already know everything about the gene, but we don't," said senior author Dr. Patrick Sung, Professor of Molecular Biophysics and Biochemistry and of Therapeutic Radiology and member of the Yale Cancer Center. The discovery of BRCA1's role in DNA repair and suppression of tumors was the first evidence that the risk of cancer could be inherited. It was originally thought that mutations in BRCA1 and the related BRCA2 gene might account for 7% to 8% of breast and ovarian cancers, Dr. Sung said. However, the cancer risk is likely much higher because in many cancer cases the expression of the BRCA genes is silenced even though no mutation can be found, he added. Dr. Sung and colleagues showed in their Nature paper that the interaction of BRCA1 with its partner BARD1 is necessary to recruit the exact genetic sequence needed to repair breaks in DNA caused by endogenous stress and environmental insults such as radiation exposure. "Defining the mechanism of the BRCA-dependent DNA repair pathway will help scientists design drugs to kill cancer cells more efficiently," Dr. Sung said.

Gene Therapy Halts Progression of Cerebral Adrenoleukodystrophy (ALD) in Clinical Trial; Impact Has Been “Phenomenal” Physician States

In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD) -- a neurodegenerative disease that typically claims young boys' lives within 10 years of diagnosis -- effectively stabilized the disease's progression in 88 percent of patients, researchers from the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Massachusetts General Hospital report today. According to their results, published online on October 4, 2017 in the New England Journal of Medicine, 15 of 17 patients had stable neurologic functioning more than two years on average after receiving the gene therapy, which was administered in a clinical trial sponsored by bluebird bio. It is one of the largest gene therapy trials targeting a single-gene disease to be published to date. The NEJM article is titled “Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.” "Although we need to continue to follow the patients to determine the long-term outcome of the gene therapy, so far it has effectively arrested the progress of cerebral adrenoleukodystrophy in these young boys," says David A. Williams, MD, Chief Scientific Officer and Senior Vice-President for Research at Boston Children's Hospital and President of Dana-Farber/Boston Children's Cancer and Blood Disorders Center and the lead author of the study. "This is a devastating disease, and we are all quite grateful that the patients and their families chose to participate in the trial." The treatment leverages Bluebird Bio's proprietary Lenti-D gene therapy to deliver the functional gene to patients' stem cells in the laboratory. "The clinical experience with Lenti-D demonstrates the potential for gene therapy to benefit patients with CALD," said David Davidson, MD, Chief Medical Officer of Bluebird Bio.

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