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August 30th, 2017

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 (www.visitasilomar.com). 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.

Study of Worm Infection Reveals Cross-Talk in Lymph Nodes

Lymph nodes are small, kidney-shaped organs found throughout the body. Full of immune cells, the lymph nodes’ function is to clear out foreign objects and support the immune system. Lymph nodes communicate with the tissues and with each other through the lymphatic vessels, which carry fluids and objects from the tissues and back out to the bloodstream. Normally, lymphatic vessels grow during the embryo stage, but also in adults during wound healing, cancer, and inflammation. But the exact mechanism of this "lymphangiogenesis" is yet unknown. Ecole Polytechnique Fédérale de Lausanne (EPFL) scientists have now identified the molecules that signal the growth of lymphatic vessels during worm infections. The work was published on August 28, 2017 in Nature Communications. The open-access article is titled “Interactions Between Fibroblastic Reticular Cells and B Cells Promote Mesenteric Lymph Node Lymphangiogenesis.” The lymphatic vessels drain pathogens from tissues to the collecting lymph nodes, where immune responses begin. These vessels also allow lymphocytes and dendritic cells --which expose pathogen material to trigger the immune system -- to flow in and out of the lymph nodes. Because of this, lymphangiogenesis is important for immune responses against infections. But recent studies have shown that lymphangiogenesis can also regulate immune responses during inflammation. This connection between inflammation and lymphangiogenesis is key in our understanding of the adaptive immune response, which is the slower but more specialized wave against infections and involves T and B cells. The lab of Dr. Nicola Harris at EPFL looked at the mesenteric lymph node, which collects fluids and material from the intestine of mice. The research, led by Dr.

Microbes Compete for Nutrients, Affect Metabolism & Development in Mice

"Gut bacteria get to use a lot of our food before we do," says Dr. Federico Rey, a Professor of Bacteriology at the University of Wisconsin-Madison. Then we get their leftovers -- or their waste. The problem, says Dr. Rey, is that if our microbiome overindulges, we might not have access to the nutrients we need. That's the suggestion from new research conducted by Dr. Rey's group that shows mice that harbor high levels of microbes that eat choline are deprived of this essential nutrient. Compared to mice without choline-hungry bacteria, the choline-starved mice had an increased susceptibility to metabolic diseases and gave birth to pups with biochemical alterations in the brain and that exhibited more anxious behaviors. The study was published online on July 31, 2017 in Cell Host & Microbe. UW-Madison Professor of Bacteriology Daniel Amador-Noguez and researchers from Harvard University also contributed to the work. The article is titled “Metabolic , Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption.” Epigenetic regulation -- the decorating of genes with chemical groups that control how much they are expressed -- appears to underlie the effects of gut bacteria that consume too much choline. Choline contributes to the pool of resources that cells use to make these modifications to DNA, and with less choline available, the cell's ability to modify and regulate genes can be impaired. Tissues from the liver to the brain had altered epigenetic patterns in mice with high levels of choline-eating microbes. "Epigenetic modifications change how genes are expressed," explains Kym Romano, a graduate student in Dr. Rey's group and one of the lead authors of the new research.

August 27th

Half-Way Milestone Reached in Development of Kinase Chemogenomic Set

The Structural Genomics Consortium at the University of North Carolina at Chapel Hill (SGC-UNC), in partnership with the DiscoverX Corporation, has reached the milestone halfway point in its development of the Kinase Chemogenomic Set, a potent group of inhibitors which allow deeper exploration of the human kinome, a family of enzymes critical to understanding human disease and developing new therapies. By building this selective set of compounds and making it freely available, UNC-Chapel Hill and its partners are offering the scientific community a better understanding of the roles the kinome plays in human disease and the ability to collaborate on the discovery and advancement of new therapies. The kinome, made up of enzymes called kinases, provides a tremendous opportunity for drug discovery. While more than 30 kinase inhibitors have been approved for the treatment of disease, the kinome has been largely unexplored until SGC-UNC, DiscoverX, and other SGC partner companies embarked on this project. "Through our collaboration with DiscoverX, we screened a large set of compounds that we call Published Kinase Inhibitor Set 2, and these results allowed us to reach the halfway point in constructing the KCGS" said Dr. David Drewry, a Research Associate Professor at the UNC Eshelman School of Pharmacy and SGC-UNC principal investigator who is leading the project to develop the Kinase Chemogenomic Set. "To mark this milestone and in keeping with our mission of open science, we are releasing these results into the public domain. We sincerely thank all of our co-author partners whose vision, generosity and hard work makes the construction of this set possible." A publication describing the team's strategy and progress toward achieving a comprehensive KCGS was posted online in PLOS ONE on August 2, 2017.

New Research on Fragile X Syndrome Reinforces Importance of Early Detection

Fragile X syndrome--the most common heritable cause of autism spectrum disorder--is something of a phantom. It interferes with the production of a protein critical to synapse formation during a brief period in early development when the brain is optimizing its ability to process sensory input. Then it dials way down...leaving behind permanent changes in neural circuit structure that can cause low IQ, learning disabilities, and hypersensitivity, along with other symptoms characteristic of ASD. This picture of the basic nature of Fragile X has been reinforced by a series of studies reported in a paper titled "Fragile X Mental Retardation Protein Requirements in Activity Dependent Critical Period Neural Circuit Refinement" published in the August 7,2017 issue of Current Biology. The article is titled “Fragile X Mental Retardation Protein Requirements in Activity-Dependent Critical Period Neural Circuit Refinement.” The research was conducted by a team of researchers in the Broadie Laboratory at Vanderbilt University--Kendal Broadie, Stevenson Professor of Neurobiology, postdoctoral fellow Dr. Caleb Doll, and graduate student Dominic Vita--who employed a battery of state-of-the-art techniques to document the effects that the lack of a critical protein caused by the syndrome, called the Fragile X Mental Retardation Protein (FMRP), has on the development of the brain and nervous system of the Drosophila disease model."Our research confirms that the Fragile X protein is essential for refining the brain's ability to process sensory information. The brains of individuals with the syndrome look perfectly normal. They can walk, talk, and chew gum, just not at peak performance," Dr. Broadie said.