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Archive - Mar 24, 2017

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.

NAD+ “Booster” Could Have Significant Anti-Aging Effects

Researchers at the University of New South Wales (UNSW) in Australia have made a discovery that could lead to a revolutionary drug that actually reverses aging, improves DNA repair, and could even help NASA get its astronauts to Mars. In a paper published in Science on March 23, 2017, the team identifies a critical step in the molecular process that allows cells to repair damaged DNA. The article is titled “A Conserved NAD+ Binding Pocket That Regulates Protein-Protein Interactions During Aging.” The scientists’ experiments in mice suggest a treatment is possible for DNA damage from aging and radiation. It is so promising it has attracted the attention of NASA, which believes the treatment can help its Mars mission. While our cells have an innate capability to repair DNA damage - which happens every time we go out into the sun, for example - their ability to do this declines as we age. The scientists determined that the metabolite NAD+, which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. Treating mice with a NAD+ precursor, or "booster," called NMN improved their cells' ability to repair DNA damage caused by radiation exposure or old age. "The cells of the old mice were indistinguishable from the young mice, after just one week of treatment," said lead author Professor David Sinclair of UNSW School of Medical Sciences and Harvard Medical School. Human trials of NMN therapy will begin within six months. "This is the closest we are to a safe and effective anti-aging drug that's perhaps only three to five years away from being on the market if the trials go well," says Dr. Sinclair, who maintains a lab at UNSW in Sydney.