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Archive - Mar 2017

March 25th

“Bench to Bedside to Bench—And Back Again”

In the era of genome sequencing, it's time to update the old "bench-to-bedside" shorthand for how basic research discoveries inform clinical practice, researchers from The Jackson Laboratory (JAX), the National Human Genome Research Institute (NHGRI), and institutions across the U.S. declare in a Leading Edge commentary published in the March 23, 2017 issue of Cell. The article is titled “Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.” "Interactions between basic and clinical researchers should be more like a 'virtuous cycle' of bench to bedside and back again," says JAX Professor Carol Bult, Ph.D., senior author of the commentary. "New technologies to determine the function of genetic variants, together with new ways to share data, mean it's now possible for basic and clinical scientists to build upon each other's work. The goal is to accelerate insights into the genetic causes of disease and the development of new treatments." Genome sequencing technologies are generating massive quantities of patient data, revealing many new genetic variants. The challenge, says commentary first author Teri Manolio, M.D., Ph.D., Director of the NHGRI Division of Genomic Medicine, "is in mining all these data for genes and variants of high clinical relevance." In April 2016, NHGRI convened a meeting of leading researchers from 26 institutions to explore ways to build better collaborations between basic scientists and clinical genomicists, in order to link genetic variants with disease causation. The Cell commentary outlines the group's recommendations, which include promoting data sharing and prioritizing clinically relevant genes for functional studies.

Astrocytes Play Role in Workings of Biological Clock

Until recently, work on biological clocks that dictate daily fluctuations in most body functions, including core body temperature and alertness, focused on neurons, those electrically excitable cells that are the divas of the central nervous system. Asked to define the body's master clock, biologists would say it is two small spheres -- the suprachiasmatic nuclei, or SCN -- in the brain that consist of 20,000 neurons. The scientists likely wouldn't even mention the 6,000 astroglia mixed in with the neurons, said Erik Herzog, Ph.D., a neuroscientist in Arts & Sciences at Washington University in St. Louis. In a March 23, 2017 advance online publication from Current Biology (“Astrocytes Regulate Daily Rhythms in the Suprachiasmatic Nucleus and Behavior”), Dr. Herzog and his collaborators show that the astroglia help to set the pace of the SCN to schedule a mouse's day. The astroglia, or astrocytes, were passed over in silence partly because they weren't considered to be important. Often called "support cells," they were supposed to be gap fillers or place holders. Their Latin name, after all, means "starry glue." Then two things happened. Scientists discovered that almost all the cells in the body keep time, with a few exceptions such as stem cells. And they also began to realize that the astrocytes do a lot more than they had thought. Among other things, astrocytes secrete and slurp neurotransmitters and help neurons form strengthened synapses to consolidate what we've learned. In fact, scientists began to speak of the tripartite synapse, emphasizing the role of an astrocyte in the communication between two neurons. So, for a neuroscientist like Dr. Herzog, the obvious question was: What were the astrocytes doing in the SCN? Were they keeping time?

Study Shows Potential of Stem Cell Therapy to Repair Lung Damage

A new study has found that stem cell therapy can reduce lung inflammation in an animal model of chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Although still at a pre-clinical stage, these findings have important potential implications for the future treatment of patients. The findings were presented in Estoril, Portugal on March 25, 2017 at the European Respiratory Society's Lung Science Conference. Lung damage caused by chronic inflammation in conditions such as COPD and cystic fibrosis, leads to reduced lung function and eventually respiratory failure. Mesenchymal stem cell (MSC) therapy is currently being investigated as a promising therapeutic approach for a number of incurable, degenerative lung diseases. However, there is still limited data on the short and long-term effects of administering stem cell therapy in chronic respiratory disease. The new research investigated the effectiveness of MSC therapy in a mouse model of chronic inflammatory lung disease, which reflects some of the essential features of diseases such as COPD and cystic fibrosis. Researchers delivered stem cells intravenously to ?-ENaC overexpressing mice at 4 and 6 weeks of age, before collecting sample tissue and cells from the lungs at 8 weeks. The scientists compared these findings to those of a control group that did not receive the MSC therapy. The results showed that inflammation was significantly reduced in the group receiving MSC therapy. Cells counts for both monocytic cells and neutrophils, both signs of inflammation, were significantly reduced after MSC therapy. Analysis of lung tissue revealed a reduction in the mean linear intercept and other measures of lung destruction in MSC treated mice.

March 24th

Exosome-Based Test May Enable Earlier Detection of Transplant Rejection

Approximately 30,000 organ transplants occur in the United States each year. However, between 20 and 50 percent—depending on the organ type—of the transplanted organs fail within five years, most often because the recipient’s immune system attacks, or “rejects,” the donated organ. Researchers at the Perelman School of Medicine at the University of Pennsylvania (Penn) have discovered a method that appears to provide earlier warning of organ transplant rejection compared to standard methods, and requires only a exosome-based blood test rather than a more invasive and painful needle biopsy. This new method is detailed in a study published online on March 20, 2017 in the Journal of Clinical Investigation. The open-access article is titled “ Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue.” If the validity of the new approach for detecting transplant rejection is confirmed in further studies, it could enable doctors to keep transplant recipients healthier and their transplants working longer. A better biomarker would allow doctors to reverse rejection episodes in many of these cases using immunosuppressive drugs. “There is a critical need for a biomarker that will work across the entire field of transplantation and will allow us to detect rejection and intervene much sooner than we are currently able to,” said lead author Prashanth Vallabhajosyula, M.D., an Assistant Professor of Cardiovascular Surgery at Perelman. “We think our proposed biomarker platform could fulfill that need.” In principle, when doctors are able to detect rejection episodes earlier and intervene more effectively, transplant recipients also will be able to use lower maintenance doses of immunosuppressive drugs when rejection is not occurring.

New Device for Exosome-Based Non-Invasive Approach to Diagnosing & Tracking Prostate Cancer

Technology being developed at Washington State University (WSU) provides a non-invasive approach for diagnosing prostate cancer and tracking the disease’s progression. The innovative filter-like device isolates prostate cancer indicators from other cellular information in blood and urine. It could enable doctors to determine how cancer patients are responding to different treatments without needing to perform invasive biopsies. The WSU research team fitted a mat of tiny glass springs with specially designed biomarkers that attract the fatty droplets (exosomes) of proteins and RNA that tumor cells shed into body fluids. The exosomes can contain genetic information that can be analyzed to determine a cancer’s molecular composition, even how far it has advanced. “It may be possible to predict which drugs would be most effective in treating a patient’s cancer,” said WSU Chemistry Professor Clifford Berkman, who led the design of the biomarkers. “More broadly, this technology could be expanded to other types of cancers and diseases.” Writing in Springer’s Journal of Materials Science (online on February 16, 2017), Dr. Berkman, Parissa Ziaei, a Ph.D. student in the WSU Interdisciplinary Materials Science and Engineering Program, and Grant Norton, Ph.D., Professor of Mechanical and Materials Engineering at WSU, said their capture technique is more efficient than previous approaches at isolating prostate tumor exosomes from other bits and pieces of cellular information. The researchers are working on designs for a version of their filter-like device for use in a clinical setting.

Exosome Role in TB Is Focused on by Expert on World Tuberculosis Day

In the time it takes to read this article, half a dozen people will have died from tuberculosis (TB). It is a cruel and persistent killer, claiming 1.8 million lives each year, an estimated 200,000 of which are children, according to the World Health Organization (WHO). Considering the gravity of those numbers, it’s even more alarming to know that many cases go unreported. “Tuberculosis is the most prevalent infectious disease that the world has seen, based on the number of people infected and the number of resulting fatalities,” said Jeff Schorey (photo), Ph.D., George B. Craig Jr. Professor in the Department of Biological Sciences at the University of Notre Dame, in a Notre Dame press release issued on World Tuberculosis Day, March 24, 2017. “It is the single leading cause of death by an infectious organism.” World Tuberculosis Day marks the official discovery of Mycobacterium tuberculosis by Dr. Robert Koch on March 24, 1882. But the infectious disease is considered to date back thousands of years. It causes death worldwide, primarily affecting low- and middle-income countries. Pulmonary TB can spread with a cough, infecting anyone in the vicinity. Patients require access to first-line drugs and face a six-month regimen of multiple antibiotics. An incomplete course of antibiotics poses an increased risk for developing multi-drug-resistant TB. “What you need for any infectious disease is a vaccine,” Dr. Schorey said. “In the absence of that, you need dependable and effective drugs with minimal side-effects, if at all. You also need reliable diagnostics to determine who needs to be treated.” Research plays a vital role in the fight to end the tuberculosis epidemic. Dr.

Electrical "Switch" in Brain's Capillary Network Monitors Activity and Controls Blood Flow

All it takes is the flip of a protein "switch" within the tiny wire-like capillaries of the brain to increase the blood flow that ensures optimal brain function. New research has uncovered that capillaries have the capacity to both sense brain activity and generate an electrical vasodilatory signal to evoke blood flow and direct nutrients to nourish hard-working neurons. These findings were reported online on March 20, 2017 in Nature Neuroscience. The article is titled “Capillary K+-Sensing Initiates Retrograde Hyperpolarization to Increase Local Cerebral Blood Flow.” When there is an increase in brain activity, there is an increase in blood flow, says Thomas Longden, Ph.D., Assistant Professor of Pharmacology at the Larner College of Medicine at the University of Vermont and first author of the study. "The area of the brain covered by the capillaries--the smallest blood vessels in the body -- vastly surpasses the area covered by arterioles. This ideally positions them for monitoring neuronal activity and controlling blood flow." Understanding the mechanisms that precisely direct cerebrovascular blood flow to satisfy the brain's ever-changing energy needs has, to date, eluded scientists. Neurons consume an enormous amount of the body's energy supplies--approximately 20 percent--yet lack their own reserves, so are reliant on blood to deliver nutrients. Previously, capillaries were thought to be passive tubes and the arterioles were thought to be the source of action. Now, Dr. Longden and colleagues have discovered that capillaries actively control blood flow by acting like a series of wires, transmitting electrical signals to direct blood to the areas that need it most.

Brain Scans May Help Clinicians Choose Psychotherapy or Medication Treatment for Depression

Researchers from Emory University in Georgia have found that specific patterns of activity on brain scans may help clinicians identify whether psychotherapy or antidepressant medication is more likely to help individual patients recover from depression. The study, called PReDICT, randomly assigned patients to 12 weeks of treatment with one of two antidepressant medications or with cognitive behavioral therapy (CBT). At the start of the study, patients underwent a functional MRI brain scan, which was then analyzed to see whether the outcome from CBT or medication depended on the state of the brain prior to starting treatment. The study results were published online on March 24, 2017 as two papers in the American Journal of Psychiatry. The articles were titled “Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study,” and “Functional Connectivity of the Subcallosal Cingulate Cortex and Differential Outcomes to Treatment with Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder.” The MRI scans identified that the degree of functional connectivity between an important emotion processing center (the subcallosal cingulate cortex) and three other areas of the brain was associated with the treatment outcomes. Specifically, patients with positive connectivity between the brain regions were significantly more likely to achieve remission with CBT, whereas patients with negative or absent connectivity were more likely to remit with antidepressant medication. "All depressions are not equal and like different types of cancer, different types of depression will require specific treatments.

Gene Locus (PTPRD) Variant Discovered Associated with Tau Pathology in Brain; PTPRD Variant Associated with Susceptibility to Neurofibrillary Tangles (NFTs)

Investigators at Rush University Medical Center in Chicago and the Brigham and Women's Hospital in Boston have reported the discovery of a new gene that is associated with susceptibility to a common form of brain pathology called Tau (image of Tau protein) that accumulates in several different conditions, including Alzheimer's disease, certain forms of dementia, and Parkinsonian syndromes, as well as chronic traumatic encephalopathy that occurs with repeated head injuries. Published online on March 21, 2017 in Molecular Psychiatry, the manuscript describes the identification and validation of a genetic variant within the protein tyrosine phosphatase receptor-type delta (PTPRD) gene. The article is titled “Susceptibility to Neurofibrillary Tangles: Role of the PTPRD Locus and Limited Pleiotropy with Other Neuropathologies.” "Aging leads to the accumulation of many different pathologies in the brain," said Co-Principal Investigator Dr. David Bennett who directs the Alzheimer Disease Center at Rush. "One of the most common forms of pathology is the neurofibrillary tangle (NFT) that was at the center of our study," he said. "The NFT is thought to be more closely related to memory decline than other forms of aging-related pathologies, but there are still very few genes that have been implicated in the accumulation of this key feature of Alzheimer's disease and other brain diseases." Using autopsies from 909 individuals participating in studies of aging based at Rush University, the team of investigators assessed the human genome for evidence that a genetic variant could affect NFT. Lead author Dr. Lori Chibnik of Brigham and Women's Hospital said that "the variant that we discovered is common: most people have one or two copies of the version of the gene that is linked to accumulating more pathology as you get older.

Vogelstein-Led Study at Johns Hopkins Shows That Random DNA Copying Mistakes Account for Two-Thirds (66%) of Cancer, More Than Environmental Factors (29%) and Family History (5%) Combined; Findings Emphasize Urgent Need for Earlier Detection Methods

Johns Hopkins Kimmel Cancer Center scientists report data from a new study providing evidence that random, unpredictable DNA copying “mistakes” account for nearly two-thirds of the mutations that cause cancer. Their research is grounded on a novel mathematical model based on DNA sequencing and epidemiologic data from around the world. “It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer. But it is not as well-known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes,” says Cristian Tomasetti, Ph.D., Assistant Professor of Biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health. “These copying mistakes are a potent source of cancer mutations that historically have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes.” “We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations. However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed,” says Bert Vogelstein (photo), M.D., Co-Director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center. Dr. Tomasetti and Dr. Vogelstein conducted the new study , which is described in an open-access report published in the March 24, 2017 issue of Science.