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Archive - Aug 2017

August 31st

Variants in Fetal Genome Associated with Risk of Preeclampsia in Mother

For the first time, a relationship has been found between fetal genes and the risk of preeclampsia in the mother. Norwegian researchers, including a team from the Norwegian University of Science and Technology (NTNU), figure prominently in the international group that presented the discovery in Nature Genetics, first published online earlier this summer, on June 19, 2017. The article is titled “Variants in the Fetal Genome Near FLT1 Are Associated with Risk Of Preeclampsia.” Preeclampsia affects approximately 3 per cent of births in Norway; worldwide, that number is estimated to be about 5 per cent. In the vast majority of cases, the mother has mild symptoms, typically high blood pressure. Nevertheless, preeclampsia is one of the leading causes of death in both mothers and babies around the time of birth, and sometimes the only way to treat it is to deliver the baby, even prematurely. "For the first time ever, we have discovered a fetal gene that increases the risk of preeclampsia," says Dr. Ann-Charlotte Iversen at the Department of Clinical and Molecular Medicine at NTNU. She says there has not been much research on the role of fetal genes in triggering the illness. Preeclampsia usually begins with a problem in the placenta, which is mainly composed of fetal cells. For that reason, it makes sense that fetal cells might have a hand in causing the illness, Dr. Iversen said, even though it is the mother's symptoms during the last part of the pregnancy that lead to the diagnosis. Dr. Iversen is head of a research group at NTNU's Centre of Molecular Inflammation Research (CEMIR).

FDA Approval of Novartis’ Kymriah Brings First Gene Therapy to United States; CAR T-Cell Therapy Approved to Treat Certain Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia (ALL)

On August 30, 2017, the U.S. Food and Drug Administration issued a historic action making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases. The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, MD. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.” Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

August 30th

Rare Genetic Variant in CX3CR1 Gene for Microglia Receptor May Contribute to Risk of Schizophrenia and Autism

Huntington's disease, cystic fibrosis, and muscular dystrophy are each diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy – if you have the mutation, then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism. "Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism," says Osaka University Professor Toshihide Yamashita, one of the authors of the study. "Microglia contribute to the structure and function of synapse connectivities." Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. Such mutations have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders. Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7,000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction. "Rare variants alter gene function, but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause," said Dr. Yamashita, who added the alanine-to-threonine substitution was a rare variant. The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

University of Buffalo Pharmacy Professor Awarded $1.5 Million to Silence Exosome-Mediated Chatter Among Cancer Cells

With the support of a new $1.58 million grant from the National Institutes of Health (NIH), University at Buffalo researchers aim to develop a targeted treatment to prevent communication between cancer cells. By developing biomaterials that target exosomes – lipid vesicles secreted by many cells that act as a courier between them – the researchers will deliver anti-cancer drugs to alter the pathogenic messages being delivered. Exosomes, once thought of as the cell’s garbage disposal, have the ability to transport genetic information, allowing them to reprogram cells and alter their function. When secreted by a cancer cell into the circulatory system, exosomes may carry genetic material that enhances the spread of cancer to surrounding tissue and other parts of the body. “Reprograming these exosomes may disarm the dangerous package that they carry, potentially preventing tumor growth and spread to distant sites or organs,” says Juliane Nguyen (photo), PharmD, PhD, Principal Investigator and Assistant Professor in the Department of Pharmaceutical Sciences in the School of Pharmacy and Pharmaceutical Sciences. The announcement was made in a UB press release dated August 28, 2017 and authored by Marcene Robinson. “This will lay the foundation for the development of novel drug carriers for treating diseases in which exosomes are pathological. More specifically, these new carriers have the potential to prevent metastasis in cancer patients.” Currently, there are no therapeutic strategies capable of disrupting the pathogenic communication facilitated by exosomes. The four-year grant is provided through the NIH’s National Institute of Biomedical Imaging and Bioengineering.

Some Women with History of Pre-Eclampsia Have Significantly Lower Risk for Breast Cancer

Researchers have demonstrated that women with a history of pre-eclampsia, a pregnancy complication characterized by high blood pressure, have as much as a 90% decrease in breast cancer risk if they carry a specific common gene variant. Further studies are now underway to determine the mechanism of this protection in an effort to develop new breast cancer prevention strategies for all women. The study was published online on August 18, 2017 in Cancer Causes & Control. The open-access article is titled "Functional IGF1R Variant Predicts Breast Cancer Risk in Women with Preeclampsia in California Teachers Study.” The research, directed by lead author Mark Powell, MD, MPH, and Buck Institute Professor Christopher Benz, MD, was carried out in the large California Teachers Study. Women with pre-eclampsia were found to have a 74% lower risk of the most common type of breast cancer (hormone receptor positive) if they carried two T alleles of a variant of the insulin-like growth factor receptor gene when compared to women carrying no T alleles. This decrease in risk increased to 90% if the pregnancy with preeclampsia occurred before the age of 30. "We are thrilled to work with researchers from our Scientific Advisory Board on this exciting project with the potential for developing a new approach to prevention. This very much fits with our goal of reducing the risk of breast cancer," said Rose Barlow, Executive Director of Zero Breast Cancer, which administered the study with funding from the Avon Foundation for Women. "This research could contribute to understanding the key impact of pregnancy on breast cancer risk, and may help explain why some women are protected while others are not," said Dr. Powell, who is a visiting scientist at the Buck Institute and is Director of the Breast Cancer Prevention Project. Dr.

August 29th

DroNc-Seq, A Technology That Merges Single-Nucleus RNA Sequencing with Microfluidics, Brings Massively Parallel Measurement to Gene Expression Studies in Complex Tissues

Last year, Broad Institute researchers described a single-nucleus RNA sequencing method called sNuc-Seq. This system enabled researchers to study the gene expression profiles of difficult-to-isolate cell types, as well as cells from archived tissues. Now, a Broad-led team has overcome a key stumbling block to sNuc-Seq's widespread use: i.e., scale. In a paper published online on August 28, 2017 in Nature Methods, postdoctoral fellows Dr. Naomi Habib, Dr. Inbal Avraham-Davidi, and Dr. Anindita Basu; core institute members Dr. Feng Zhang and Dr. Aviv Regev; and their colleagues reveal DroNc-Seq, a single-cell expression profiling technique that merges sNuc-Seq with microfluidics, allowing massively parallel measurement of gene expression in structurally-complicated tissues. The article is titled “Massively Parallel Single-Nucleus RNA-Seq with DroNc-Seq.” Researchers struggled in the past to study expression in neurons and other cells from complex tissues, like the brain, at the single-cell level. This was because the procedures for isolating the cells affected their RNA content and did not always accurately capture the true proportions of the cell types present in a sample. Moreover, the procedures did not work for frozen archived tissues. sNuc-Seq bypassed those problems by using individual nuclei extracted from cells as a starting point instead. sNuc-Seq, however, is a low-throughput technology, using 96- or 384-well plates to collect and run samples. To scale the method up to the level needed in order to efficiently study thousands of nuclei at a time, the team turned to microfluidics. Their inspiration was: Drop-Seq, a single-cell RNA-seq (scRNAseq) technique that encapsulates single cells together with DNA barcoded-beads in microdroplets to greatly accelerate expression-profiling experiments and reduce cost.

New NAS Member from Hawaii Reveals How Animals Select Good Microbes, Reject Harmful Ones

Margaret McFall-Ngai, Professor and Director of the Pacific Biosciences Research Center (PBRC), School of Ocean and Earth Science and Technology, at the University of Hawai'i (UH) at Mānoa, is the only woman at UH who is a member of the National Academy of Sciences (NAS). In her inaugural article published this week (August 28 – Seoptember 1) in PNAS commemorating her induction into one of the country's most distinguished scientific groups, she and a team of researchers reveal a newly discovered mechanism by which organisms select beneficial microbes and reject harmful ones. The internal microbial communities, or consortia, of mammals, such as humans, are complex in that they require many bacterial types for healthy function. Tissues in the respiratory system, the Fallopian tubes, and the Eustachian tubes are lined with cilia--microscopic hair-like structures that extend out from the surface of many animal cells. A central role attributed to these ciliated tissues is to effectively clear out toxic molecules and undesirable microbes; in work performed largely by Dr. Janna Nawroth (now at Emulate, Inc., Boston) and co-led by Dr. McFall-Ngai and Dr. Eva Kanso, a mathematical modeler at the University of Southern California (USC), these ciliated tissues are shown to also selectively recruit beneficial microbes, called symbionts. "A few years ago, when the biomedical community discovered that all of these surfaces of mammals have a rich co-evolved microbial consortium, a microbiome, that promotes the health of those systems, the question became: how do they do it--that is, by what mechanisms do they select the good microbes and reject the harmful ones?" explained Dr. McFall-Ngai. The ciliated tissues of most animals are inaccessible to observation and study.

August 28th

Novartis Anti-Inflammatory Drug (IL-1ß Inhibitor) Reduces Risk of Cardiovascular Disease and Perhaps Even of Lung Cancer in Patients with Previous Heart Attack and Atherosclerosis

On August 27, 2017, Novartis revealed primary data from CANTOS, a Phase III study evaluating quarterly injections of ACZ885 (canakinumab) in people with a prior heart attack and inflammatory atherosclerosis as measured by high-sensitivity C-reactive protein (hsCRP) levels of >=2mg/L, a known marker of inflammation. Trial participants received either placebo or one of three doses of ACZ885 in combination with current standard of care therapies, with 91% of them taking lipid-lowering statins. The study showed that ACZ885 led to a statistically significant 15% reduction in the risk of major adverse cardiovascular events (MACE), a composite of non-fatal heart attack, non-fatal stroke, and cardiovascular death, compared to placebo (p-value 0.021). This benefit was sustained throughout the duration of the study (median follow up 3.7 years) and was largely consistent across key pre-specified baseline sub groups. The study met the primary endpoint in cardiovascular risk reduction with the 150 mg dose of ACZ885; the 300 mg dose showed similar benefits and the 50 mg dose was less efficacious. The study findings in cardiovascular risk reduction were presented on August 27, 2017 at the European Society of Cardiology (ESC) Congress and published simultaneously in The New England Journal of Medicine. The NEJM article is titled “Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.” The details of the additional CANTOS lung cancer findings were also presented at ESC and simultaneously published in The Lancet.

Invitation to ASEMV 2017 Annual Meeting (Exosomes & Microvesicles) in Asilomar, California (October 8-12)

The American Society for Exosomes and Microvesicles (ASEMV) is inviting interested scientists to the ASEMV 2017 meeting, to be held October 8-12, 2017 at the Asilomar Conference Center in California. This center is located on the Monterrey peninsula, just south of San Francisco ( The meeting will cover the full breadth of the exosome field, from basic cell biology to clinical applications, and follow the ASEMV tradition of inclusion and diversity as participants learn about the latest advances in the field. ASEMV 2017 is a forum for learning the latest discoveries in the field of exosomes, microvesicles, and extracellular RNAs. Over the course of four days at the Asilomar Conference Center, ASEMV 2017 will offer presentations from leading scientists and young researchers. Topics will span the breadth of the extracellular vesicle/RNA field, including the basic sciences, disease research, translation efforts, and clinical applications. Talks will be presented in multiple sessions, beginning at 7 pm on Sunday, October 8, 2017, and concluding at 4 pm on Thursday, October 12, 2017. Poster sessions will run throughout the meeting, with ample time to get to know your colleagues in the field and explore the many opportunities in this rapidly expanding field. Please see the links below.

Symptom Severity in Neuropsychiatric Disorder (Functional Neurological Disorder) Associated with Structural Changes Within Brain Network

An imaging study by Massachusetts General Hospital (MGH) investigators has identified differences in key brain structures of individuals whose physical or mental health has been most seriously impaired by a common, but poorly understood, condition called functional neurological disorder (FND). In their report published online on August 26, 2017 in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP), the research team describes reductions in the size of a portion of the insula in FND patients with the most severe physical symptoms and relative volume increases in the amygdala among those most affected by mental health symptoms. The article is titled “Corticolimbic Structural Alterations Linked to Health Status and Trait Anxiety in Functional Neurological Disorder.” "The brain regions implicated in this structural neuroimaging study are areas involved in the integration of emotion processing, sensory-motor, and cognitive functions, which may help us understand why patients with functional neurological disorder exhibit such a mix of symptoms," says David Perez, MD, MMSc, of the MGH Departments of Neurology and Psychiatry, the lead and corresponding author of the report. "While this is a treatable condition, many patients remain symptomatic for years, and the prognosis varies from patient to patient. Advancing our understanding of the pathophysiology of FND is the first step in beginning to develop better treatments." One of the most common conditions bringing patients to neurologists, FND involves a constellation of neurologic symptoms - including weakness, tremors, walking difficulties, convulsions, pain, and fatigue - not explained by traditional neurologic diagnoses. This condition has also been called conversion disorder, reflecting one theory that patients were converting emotional distress into physical symptoms, but Dr.