Newswise — ROCKVILLE, MD – As concern continues to grow concerning the novel coronavirus, COVID-19, so does the opportunity for misinformation to spread as the public searches for reliable information on infection and means of protection. COVID-19 has been detected in more than 60 locations internationally thus far, including the United States. Following a recent meeting of biophysicists from around the world, the leadership of the Biophysical Society (BPS) believe that it is important for the media and elected officials to endeavor to share data-driven, evidence-based responses to the COVID-19 pandemic. “Biophysics has been critical to understanding the mechanics of how the molecules of life are made and how complex systems in our bodies, including the immune system, work,” said Catherine Royer, president of BPS. “Currently, BPS member biophysicists around the world are helping lead the effort to fight this virus by understanding how it works on a molecular level.” While this virus outbreak continues to evolve, Royer urges the public to use basic hygiene precautions to protect themselves from illness, including COVID-19. For the latest information and developments on the outbreak in your country, the BPS recommends Centers for Disease Control (CDC) and the World Health Organization (WHO) websites.
Newswise — COLUMBUS, Ohio – Young children from low-income homes whose mothers reported frequent use of toxic chemicals such as household cleaners were more likely to show delays in language development by age 2, a new study found. In addition, the children scored lower on a test of cognitive development. These developmental delays were evident even when the researchers took into account factors such as the education and income of mothers, which are also linked to their children’s language and cognitive skills. The findings provide additional evidence of the need for pediatricians and other health care providers to counsel parents of young children to restrict their use of toxic household chemicals, said Hui Jiang, lead author of the study and senior research associate at The Ohio State University. “We found that a significant percentage of mothers with young children may commonly expose their children to toxic household chemicals, possibly because they are unaware that such materials may be harmful,” said Jiang, who is with Ohio State’s Crane Center for Early Childhood Research and Policy. The study was published online recently in the journal Clinical Pediatrics. The researchers used data on 190 families from the Kids in Columbus Study, a Crane Center research project that followed children born into low-income families in Columbus for five years after birth. When they first started the study, mothers were asked about their use of household chemicals such as floor and toilet cleaners and solvents during pregnancy. They were asked again when their child was 14 to 23 months old. Mothers also reported whether they had mold in the home, their use of pesticides, and neighborhood pollution sources. Children’s language development was measured when they were between 14 and 23 months old and again when they were 20 to 25 months old. The researchers used a standardized test that examines children’s understanding and expression of language – for example, recognition of objects and people, following directions, and naming objects and pictures. Findings showed that neighborhood pollution, mold in the house and pesticide use were not significantly linked to child outcomes. But the more household chemicals mothers reported using regularly after childbirth, the lower the child language and cognitive outcomes at 2 years of age. There was no link between chemical use during pregnancy and child outcomes, possibly because mothers reported using significantly fewer chemicals during pregnancy. Exposure to toxic chemicals was reported by about 20 percent of mothers during pregnancy, but that increased to 30 percent when their children were between 1 and 2 years old. Mothers also reported using more household chemicals after childbirth. “A lot of mothers seem to know to limit exposure to toxic chemicals during pregnancy, but once their child is born, they may think it is no longer a problem,” Jiang said. But research has shown these early years of a child’s life are key in many ways, said Laura Justice, co-author of the study and professor of educational psychology at Ohio State. “When kids reach about 2 years old, that is a peak time for brain development,” said Justice, who is executive director of The Crane Center. “If the use of toxic chemicals is interfering with that development, that could lead to problems with language and cognitive growth.” While many mothers may use household cleaners and other toxic chemicals when their children are young, low-income mothers may face particular challenges, Jiang said. For example, they often live in smaller apartments where it may be more difficult to keep children away from chemicals, particularly while they are cleaning. Jiang noted that this study simply analyzed the relationship between mothers’ use of toxic chemicals and later child development and as such can’t prove that chemical use caused the developmental delays. “Future studies are need to more carefully examine the mechanisms through which household toxicants may disrupt early language development,” she said. The findings do show that pediatricians need to emphasize that pregnancy is not the only time for mothers to be concerned about chemical use, Justice said. “Parents need to understand the delicacy of brain development in the first several years of life and their children’s susceptibility to chemical exposure,” she said. Other co-authors were Kelly Purtell and Randi Bates, both of Ohio State.
Newswise — Researchers at the Johns Hopkins Kimmel Cancer Center have made significant progress toward development of a simple, noninvasive liquid biopsy test that detects prostate cancer from RNA and other specific metabolic chemicals in the urine. A description of their findings appears in the Feb. 28 issue of the journal Scientific Reports. The investigators emphasize that this is a proof-of-principle study for the urine test, and it must be validated in additional, larger studies before it is ready for clinical use. The researchers used RNA deep-sequencing and mass spectrometry to identify a previously unknown profile of RNAs and dietary byproducts, known as metabolites, among 126 patients and healthy, normal people. The cohort included 64 patients with prostate cancer, 31 with benign prostatic hyperplasia and prostatitis diseases, and 31 healthy people with none of these conditions. RNA alone was not sufficient to positively identify the cancer, but addition of a group of disease-specific metabolites provided separation of cancer from other diseases and healthy people. “A simple and noninvasive urine test for prostate cancer would be a significant step forward in diagnosis. Tissue biopsies are invasive and notoriously difficult because they often miss cancer cells, and existing tests, such as PSA (prostate-specific antigen) elevation, are not very helpful in identifying cancer,” says Ranjan Perera, Ph.D., the study’s senior author. Perera is also the director of the Center for RNA Biology at Johns Hopkins All Children's Hospital, a senior scientist at the Johns Hopkins All Children’s Cancer & Blood Disorders Institute and the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research, and an associate professor of oncology at the Johns Hopkins University School of Medicine and Johns Hopkins Kimmel Cancer Center member. “We discovered cancer-specific changes in urinary RNAs and metabolites that — if confirmed in a larger, separate group of patients — will allow us to develop a urinary test for prostate cancer in the future,” says Bongyong Lee, Ph.D., the study’s first author and a senior scientist at the Cancer & Blood Disorders Institute. Perera and Lee are available for media interviews about the study. For more information or to schedule an interview, contact the Johns Hopkins Kimmel Cancer Center Office of Public Affairs at 410-955-1287, firstname.lastname@example.org or email@example.com. In addition to Perera, Lee and other Johns Hopkins investigators, the study was performed with collaborators at AdventHealth, the University of Florida, the Sanford Burnham Prebys Medical Discovery Institute and the Shanghai Second Medical Institute. The research was supported by the National Institutes of Health (NIH) grant NCI 5P30CA030199 (SBP), P30 CA006973 (JHU SKCCC), the Florida Department of Health, Bankhead-Coley Cancer Research Program 5BC08 and the International Prostate Cancer Foundation, Southeast Center for Integrated Metabolomics-NIH grant #U24 DK097209. Photo credit: Adobe Stock
McMaster University Associate professor Andrew McArthur, left, and PhD candidate Jalees Nasir are authors of the study and members of the Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences at McMaster University. Photo courtesy McMaster University Newswise — Hamilton, ON (February 28, 2020) – McMaster University researchers have developed a tool to share with the international health sciences community which can help determine how the virus that causes COVID-19 is spreading and whether it is evolving. Simply put, the tool is a set of molecular ‘fishing hooks’ to isolate the virus, SARS-CoV-2, from biological samples. This allows laboratory researchers to gain insight into the properties of the isolated virus by then using technology called next-generation sequencing. The details were published on Preprints.org. “You wouldn’t use this technology to diagnose the patient, but you could use it to track how the virus evolves over time, how it transmits between people, how well it survives outside the body, and to find answers to other questions,” said principal investigator Andrew McArthur, associate professor of biochemistry and biomedical sciences, and a member of the Michael G. DeGroote Institute for Infectious Disease Research (IIDR) at McMaster. “Our tool, partnered with next-generation sequencing, can help scientists understand, for example, if the virus has evolved between patient A and patient B.” McArthur points out that the standard technique to isolate the virus involves culturing it in cells in contained labs by trained specialists. The McMaster tool gives a faster, safer, easier and less-expensive alternative, he said. “Not every municipality or country will have specialized labs and researchers, not to mention that culturing a virus is dangerous,” he said. “This tool removes some of these barriers and allows for more widespread testing and analyses.” First author Jalees Nasir, a PhD candidate in biochemistry and biomedical sciences at McMaster, has been working with McMaster and Sunnybrook Health Sciences Centre researchers to develop a bait capture tool that can specifically isolate respiratory viruses. When news recently broke of COVID-19, Nasir knew he could develop a “sequence recipe” to help researchers to isolate the novel virus more easily. “When you have samples from a patient, for example, it can consist of a combination of virus, bacteria and human material, but you’re really only interested in the virus,” Nasir said. “It’s almost like a fishing expedition. We are designing baits that we can throw into the sample as hooks and pull out the virus from that mixture.” The decision was made to release the sequences publicly without the normal practice of peer-review or clinical evaluation to ensure this tool was available to all quickly, recognizing the urgency of the situation, said McArthur. The research team plans to collaborate with Sunnybrook for further testing, but also hopes other scientists can quickly perform their own validation. McArthur added that a postdoctoral fellow in his lab, David Speicher, is currently communicating details of the technology to the international clinical epidemiology community. “Since we’re dealing with an outbreak, there was no value in us doing a traditional academic study and the experiments,” said McArthur. “We designed this tool and are releasing it for use by others. “In part, we’re relying on our track record of knowing what we are doing, but we’re also relying on people who have the virus samples in hand being able to do the validation experiment so that it’s reliable.” The research was funded by the Comprehensive Antibiotic Resistance Database at McMaster.
‘BRAIN SURFING’: ULTRASOUND WAVES FOCUSED ON PREFRONTAL CORTEX ELEVATE MOOD, CHANGE BRAIN CONNECTIVITY
Joseph L Sanguinetti, Stuart Hameroff, Ezra E Smith, Tomokazu Sato, Chris MW Daft, William J Tyler, John JB Allen (2020) Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans Frontiers in Human Neuroscience Newswise — A team of researchers at the University of Arizona has found that low-intensity ultrasound waves directed at a particular region of the brain’s prefrontal cortex in healthy subjects can elevate mood, and decrease connectivity in a brain network that has been shown to be hyperactive in psychiatric disorders. The method uses transcranial focused ultrasound (‘tFUS’), a painless, non-invasive technique to modulate brain function comparable to transcranial magnetic stimulation (‘TMS’), and transcranial direct current stimulation (‘tDCS’). This study shows, for the first time, a correlation between tFUS-induced mood enhancement, and reorganization of brain circuits. Commonly used for medical imaging, ultrasound consists of mechanical vibrations in the range of ‘megahertz’, a million waves per second, well above human auditory threshold at 20 thousand waves per second. The waves echo off internal body surfaces including unborn babies to provide dynamic anatomical images. Low intensity ultrasound has also long been used as a therapy, e.g. to reduce pain, inflammation and peripheral nerve dysfunction all over the body. Regarding the brain, ultrasound is attenuated by the skull, but passes through sufficiently to focus on specific brain regions at desired depths. At low intensities,, tFUS has been shown to be safe, and able to modulate brain activity, behavior and human mental states. In the present study, researchers aimed tFUS at the right ventrolateral pre-frontal cortex, specifically the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. For example increased activity there correlates with reduced negative emotional experience. In a randomized placebo-controlled double blind study, 51 healthy student volunteers (27 female, 24 male, mean age 19.7 years) received 30 seconds of either tFUS at 500 kilohertz (0.5 megahertz), or placebo exposure, by a transducer held to the scalp over the temporal window, aimed at rIFG. Subjects completed mood surveys before, and up until 30 minutes after tFUS, and results showed that, compared to those receiving placebo, mood scores (‘Global Affect’) for subjects receiving tFUS were significantly higher 20 and 30 minutes later and, anecdotally, up to one hour. In a second experiment in healthy volunteers, tFUS mood-elevating effects were replicated, and functional magnetic resonance imaging (fMRI) done before and 20 minutes after tFUS aimed at rIFG. Results showed decreased functional connectivity between rIFG and a number of cortical areas, and decreased connectivity within the default mode network (DMN), a circuit involved in self-referential thinking, mind-wandering and worrying. The mechanisms by which tFUS acts in the brain to alter mental states and neuronal connectivity are unknown, as is that by which TMS and tDCS act, and how mental states arise in the brain at all. At the cellular level, ultrasound has been proposed to act on membranes, receptors, extra-cellular matrix and intra-neuronal cytoskeletal microtubules. With known resonances in megahertz, microtubules play prominent roles in synaptic plasticity, and have been theoretically proposed as a substrate for consciousness. Decreasing connectivity within DMN suggests the possibility of less self-referential thinking, such as worrying or rumination, and may correlate with being more ‘in the moment’. Indeed a temporary reduction in this network could be particularly useful and lead to longer term neural plasticity if combined with reinforcing therapy, like mindfulness meditation or other modalities Lead author Jay Sanguinetti commented: "We're not trying to stimulate neurons to fire, nor simply activate pleasure areas, but to modulate plasticity and enable brain circuits to ‘re-tune’ toward being more mindful ‘in the moment’. tFUS as well as unfocused transcranial ultrasound (‘TUS’) are safe, painless, relatively inexpensive, and extremely promising for a variety of mental and cognitive disorders including traumatic brain injury, Alzheimer’s disease, depression, Parkinson’s, chronic pain and addiction.
Newswise — Doctors who use drugs that target antibiotic-resistant bacteria as a first-line defense against pneumonia should probably reconsider this approach, according to a new study of more than 88,000 veterans hospitalized with the disease. The study, conducted by University of Utah Health and VA Salt Lake City Health Care System researchers, found that pneumonia patients given these medications in the first few days after hospitalization fared no better than those receiving standard medical care for the condition. “Sometimes in our eagerness to improve outcomes, particularly among critically ill patients, we, as doctors, may be overly broad in our initial treatments. This appears to be true with pneumonia, where we found no benefit associated with use of the so-called ‘big gun’ antibiotics as an initial treatment to cover resistant organisms, even among those patients who are at high risk for these types of infections.” says Matthew Samore, M.D., the study’s senior author, a U of U Health professor of medicine, and Director of the Informatics Decision Enhancement and Analytic Sciences Center at the VA Salt Lake City Health Care System. The study, one of the largest ever to examine trends of antibiotic use in the treatment of pneumonia, appears in JAMA Internal Medicine. Pneumonia is the eighth leading cause of death in the United States, accounting for more than 1 million hospitalizations and about 50,000 deaths each year. It can be caused by viruses, fungi, and bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA), which can cause a rare but hard-to-treat form of pneumonia. Unfortunately, determining whether MRSA or other pathogens are responsible for any particular case of pneumonia is difficult. That’s because testing sputum (mucus) samples for the cause of pneumonia is often inaccurate, and collecting lung tissue samples can be invasive and risky, especially in patients who are extremely ill. So, doctors often have to rely on their best judgment to deduce what treatment might work until if and when definitive test results are available, says Barbara Jones, M.D., the study’s lead author, a U of U Health assistant professor of internal medicine, and career development awardee of VA Health Research & Development Service. To determine how this decision-making process affects patient care, Samore, Jones, and colleagues retrospectively examined the medical records of 88,605 pneumonia patients, ages 62 to 81, who were admitted to VA Medical Centers nationwide between 2008 and 2013. The researchers tracked whether these patients were initially treated with standard antibiotic therapy for pneumonia—such as cerftriaxone and azithromycin—or two types of anti-MRSA care: standard therapy plus vancomycin (an antibiotic,) vancomycin without standard therapy. The researchers observed that as doctors became more aware of and concerned about MRSA infection in the lungs, they became more likely to use anti-MRSA therapies as an initial treatment, despite the fact that MRSA only accounts for about 2% of pneumonia cases. In fact, use rose from about 20% of patients in 2008 to nearly half of them in 2013. As a result, many of the patients who were treated with anti-MRSA antibiotics probably didn’t need them. The researchers found no discernable benefit of anti-MRSA treatment in addition to standard treatment. In fact, anti-MRSA treatment was associated with a 40 % higher risk of dying within 30 days of discharge, perhaps due to the potentially severe side effects of vancomycin including increased incidence of kidney failure and secondary infections. However, further study is needed to fully determine the underlying causes of this increased risk, according to the researchers. “Our study calls into question the strategy of broad empiric antibiotic coverage that has previously been promoted by pneumonia practice guidelines,” Jones says. “We’re not saying that it’s never appropriate to use anti-MRSA therapy for treating pneumonia. But in the absence of better tests to identify MRSA as a potential pathogen causing the disease, using anti-MRSA therapies does not seem to offer any advantage over standard treatment therapy. “Under these circumstances,” she adds, “it may be safer for patients if physicians to stick to standard antibiotic treatments for a couple of days to see how patients are doing rather than leaping into anti-MRSA therapy right off the bat.”
Plaque HD® Toothpaste Identifies Plaque So That It Can Be Removed With Directed Brushing. In This Trial, All Randomized Subjects Were Given The Same Brushing Protocol And Received A 30-Day Supply Of Toothpaste Containing Either Plaque HD® Or An Identical Non-Plaque Identifying Placebo Toothpaste. Newswise — For decades, researchers have suggested a link between oral health and inflammatory diseases affecting the entire body — in particular, heart attacks and strokes. Inflammation is intimately involved in the pathogenesis of atherosclerosis and is accurately measured by high sensitivity C-reactive protein (hs-CRP), a sensitive marker for future risks of heart attacks and strokes. Researchers from Florida Atlantic University’s Schmidt College of Medicine, Marshfield Clinic Research Institute, and the University of Wisconsin School of Medicine and Public Health, collaborated on a randomized trial titled, “Correlation between Oral Health and Systemic Inflammation” (COHESION), to further explore whether Plaque HD®, a plaque identifying toothpaste, reduces hs-CRP. Results of the randomized pilot trial, published online ahead of print in the American Journal of Medicine, showed that Plaque HD® produced a statistically significant reduction in hs-CRP among those with elevations at baseline. Plaque HD® is the first toothpaste that identifies plaque so that it can be removed with directed brushing. In addition, the product’s proprietary formulation contains unique combinations and concentrations of cleaning agents that weaken the core of the plaque structure to help the subject visualize and more effectively remove the plaque. In this trial, all randomized subjects were given the same brushing protocol and received a 30-day supply of toothpaste containing either Plaque HD® or an identical non-plaque identifying placebo toothpaste. To assess hs-CRP, levels were measured by Quest Diagnostics using an enzyme linked immunosorbent assay. “The current findings are similar to those from our previous pilot trial,” said Charles H. Hennekens, M.D., Dr.P.H., senior author, first Sir Richard Doll Professor, and senior academic advisor in FAU’s Schmidt College of Medicine. “Whether this plaque-identifying toothpaste decreases heart attacks or strokes requires a large-scale randomized trial of sufficient size and duration. These results provide a stronger rationale to conduct such trials. If positive, the results of these trials would have significant potential clinical and public health implications.” Based on these findings, Hennekens and colleagues at FAU and the University of Wisconsin School of Medicine and Public Health are drafting an investigator-initiated research grant proposal to the National Institutes of Health (NIH). Their proposed randomized trial will test whether Plaque HD® reduces progression of atherosclerosis in the coronary and carotid arteries, for which systemic inflammation is an important precursor. A report from the United States Centers for Disease Control and Prevention found that 47.2 percent of American adults aged 30 years and older have some form of periodontal disease, a pathological inflammatory condition of the gums and tissues surrounding the teeth. Periodontal disease increases with age affecting more than 70 percent of adults 65 years and older. Prior research has suggested that periodontal disease may be connected to variety of other diseases, including heart disease and stroke and other inflammatory diseases such as rheumatoid arthritis. Inflammation throughout the body may be a crucial link between periodontal and other systemic diseases. Further, two years ago, the prestigious New England Journal of Medicine ranked the original manuscript published in 1997 by Hennekens and colleagues on aspirin, inflammation and cardiovascular disease, as their most influential original report of the last 20 years. Those randomized data derived from the landmark Physician’s Health Study, in which Hennekens was the founding principal investigator, and suggested that hs-CRP predicted future heart attacks and strokes. Co-authors of this randomized pilot trial are Amit Acharya, Ph.D., Marshfield Clinic Research Center and the University of Wisconsin School of Medicine and Public Health; Ingrid Glurich, Ph.D, Marshfield Clinic Research Center; and Scott Hetzel, M.S., KyungMann Kim, Ph.D., Matthew C. Tattersall, D.O., F.A.C.C.; and David L. DeMets, Ph.D., all with the University of Wisconsin School of Medicine and Public Health. - FAU -
© MPG/ Massih Media Synaptic Glutamate Receptors. When The Neurotransmitter Glutamate (Red) Binds To The Receptors Of The So-Called NMDA-Type (Blue), These Receptors Open And Sodium And Calcium Ions (Yellow, Green) Flow Into The Cell. The Result Is An Improved Information Transfer At The Synapse. Newswise — If the immune system attacks its own body, it can often have devastating consequences: autoantibodies bind to the body’s structures, triggering functional disorders. The receptors for glutamate, a neurotransmitter, can also become the target of autoantibodies. Researchers at the Max Planck Institute of Experimental Medicine in Göttingen have been investigating the circumstances under which autoantibodies for a particular glutamate receptor - known as the NMDA receptor - are formed, and their effects in the brain. The researchers have discovered that the level of these autoantibodies in the blood can fluctuate considerably over a person’s lifetime - independent of health conditions - and increases with age. Chronic stress can, however, drive up the concentration of these autoantibodies in the blood even in early life. According to the researchers, when the antibodies are able to enter the brain to act on NMDA receptors, people suffer less depression and anxiety. These autoantibodies are clearly acting as the body’s own antidepressants. Glutamate receptors sit in the nerve cell membrane and bind to glutamate, a neurotransmitter. The NMDA receptor is a receptor type essential for learning and memory. Up to 20 percent of the population have antibodies against this receptor in their blood. Usually, the blood-brain barrier prevents these antibodies crossing from the blood into the brain. Only if this barrier is damaged can the antibodies have any greater effect. If the antibodies bind to NMDA receptors in the brain, these are then removed from the nerve cell membrane (‘internalized’). This disrupts the signalling to neighbouring cells. If an inflammation is present in the brain, for example, due to a viral infection, the presence of these autoantibodies can lead to a so-called ‘anti-NMDAR-encephalitis’: an illness brought to the public’s attention by the 2016 film ‘Brain on Fire’. The effect of these NMDA receptor autoantibodies can typically influence the symptoms of the underlying encephalitis, contributing to epileptic seizures, impaired movement, psychosis and loss of cognitive function. Autoantibody levels increase with age In a new study, Hannelore Ehrenreich and her colleagues from the Max Planck Institute of Experimental Medicine in Göttingen have discovered that the concentration of these autoantibodies in the blood of mice and humans can fluctuate considerably over time. However, the level rises with age, as the body is continually exposed to factors which stimulate the immune system, and with it, autoantibody production. One of these factors is stress. According to the researchers, chronically stressed mice show a higher level of NMDA receptor autoantibodies in their blood compared to their non-stressed conspecifics. Ehrenreich and her team also analysed the concentration of antibodies in the blood of young migrants. “People who are subjected to high stress in their lives have a greater probability of carrying NMDA receptor autoantibodies in their blood, even at a young age,” says Ehrenreich. These are like a ticking time bomb in the body. “If an infection or some other factor appears which weakens the blood-brain barrier, the autoantibodies enter the brain and can cause epileptic seizures or other neurological disorders,” says Ehrenreich. A good example would be Knut, the famous Berlin polar bear. Positive effect of antibodies However, the researchers’ recent study has for the first time indicated that the autoantibodies can also play a positive role in the brain. Mice with a more permeable blood-brain barrier and NMDA receptor autoantibodies in the brain were significantly more mobile and less depressed during times of chronic stress than their conspecifics with an intact blood-brain barrier. An analysis of a large patient database revealed that people with NMDA autoantibodies and a permeable blood-brain barrier also suffered significantly less depression and anxiety. The NMDA autoantibody obviously plays a role in the brain similar to ketamine, an antidepressant that also acts on NMDA receptors. “The effect of these autoantibodies - whether they contribute to the symptoms of an encephalitis or inhibit depression - is evidently determined not only by their level in the brain, but also by any underlying condition, in particular the presence or absence of inflammation,” explains Ehrenreich.
Newswise — Northfield, IL — Recognizing a need for evidence-based recommendations to guide molecular testing in the management of patients with cancer, the College of American Pathologists (CAP) and three collaborating societies are developing a clinical guideline for testing DNA mismatch repair (MMR) and microsatellite instability (MSI) status in patients with a range of cancer types. Today, the groups open the public comment period for the guideline “MMR and MSI Testing in Patients Being Considered for Checkpoint Inhibitor Therapy.” All stakeholders—including pathologists who refer and perform molecular testing, oncologists, laboratory personnel, and allied health professionals—should provide feedback on the draft recommendations before March 13 to ensure final recommendations are clinically practical. “This guideline is the first to address testing based more on the methodology status of a biomarker and less on the cancer type or tumor origin,” explains guideline developer, pathologist Russell Broaddus, MD, PhD, FCAP. “As we’ve learned more about patient response to checkpoint inhibitor therapy, we’ve seen that patients whose cancers had high levels of MSI or defective MMR would respond well, specifically to a checkpoint inhibitor drug such as pembrolizumab.” Dr. Broaddus chairs the panel of experts representing the societies collaborating on the guideline: the American Society of Clinical Oncology (ASCO), the Association for Molecular Pathology (AMP), and Fight Colorectal Cancer (Fight CRC). The panel will consider all comments garnered during the comment period prior to finalizing the recommendations and submitting the guideline for publication. “For patients, knowing your MSI status is extremely important prior to selecting a treatment,” according to experts at Fight CRC. “Many patients with MSI-high tumors have had a positive response to immunotherapy treatments, also known as immune-checkpoint therapies.” And while the FDA approved a drug for patients with MSI-high or MMR-deficient tumor status, regardless of cancer type, it did not detail how to test for that status. This new CAP guideline aims to fill that gap and provide oncologists, pathologists, and laboratories of all sizes with evidence-based recommendations to efficiently deploy specific assays and accurately identify patients eligible for treatment. In particular, the panel developing the guideline sought evidence to answer these questions: Which test modality best predicts DNA MMR? Does cancer type matter when choosing a testing modality? Does MMR by immunohistochemistry, MSI by polymerase chain reaction, or MSI by next generation sequencing results predict improved clinical outcomes in patients treated with checkpoint inhibitors? Does tumor mutation burden predict improved clinical outcomes in patients treated with checkpoint inhibitors? As drafted, the guideline includes six recommendations and three “good practice statements” that impact testing for patients with colorectal, endometrial, gastroesophageal and small bowel, and other types of cancer. In addition, the recommendations provide guidance on the role of tumor mutational burden in MMR testing and the evaluation of Lynch Syndrome. To read and comment on the draft guideline, visit cap.org until March 13, 2020. About the College of American Pathologists As the world's largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. For more information, read the CAP Annual Report at cap.org.
New research shows how rapid SUMOylation of cell surface cardiac sodium channels causes late sodium current in response to hypoxia, a challenge that confronts many people with heart disease. This discovery offers new targets for therapeutics to prevent late current and arrhythmia associated with heart attacks, chronic heart failure and other life-threatening low oxygen cardiac conditions. Newswise — Irvine, Calif. February 18, 2020 – Low oxygen levels in the heart have long been known to produce life-threatening arrhythmias, even sudden death. Until now, it was not clear how. New findings, in a study led by Steve A. N. Goldstein, MD, PhD, vice chancellor for Health Affairs at the University of California, Irvine, and distinguished professor in the UCI School of Medicine Departments of Pediatrics and Physiology & Biophysics, reveal the underlying mechanism for this dangerous heart disorder. “Our research shows that within seconds, at low levels of oxygen (hypoxia), a protein called small ubiquitin-like modifier (SUMO) is linked to the inside of the sodium channels which are responsible for starting each heartbeat,” said Goldstein. “And, while SUMOylated channels open as they should to start the heartbeat, they re-open when they should be closed. The result is abnormal sodium currents that predispose to dangerous cardiac rhythms.” Titled, “Hypoxia produces pro-arrhythmic late sodium current in cardiac myocytes by SUMOylation of NaV1.5 channels,” the study was published today in Cell Reports. Lead author, Leigh D. Plant, PhD, assistant professor at the Bouvé College of Health Sciences, Department of Pharmaceutical Sciences at Northeastern University, was a former post-doctoral fellow with Dr. Goldstein. Every heartbeat begins when sodium channels open and ions to rush into heart cells—this starts the action potential that causes the heart muscle to contract. When functioning normally, the sodium channels close quickly after opening and stay closed. Thereafter, potassium channels open, ions leave the heart cells, and the action potential ends in a timely fashion, so the muscle can relax in preparation for the next beat. If sodium channels re-open and produce late sodium currents, as observed in this study with low oxygen levels, the action potential is prolonged and new electrical activity can begin before the heart has recovered risking dangerous, disorganized rhythms. Fifteen years ago, the Goldstein group reported SUMO regulation of ion channels at the surface of cells, an unexpected finding since the SUMO pathway had been thought to operate solely to control gene expression in the nucleus. “This new research shows how rapid SUMOylation of cell surface cardiac sodium channels causes late sodium current in response to hypoxia, a challenge that confronts many people with heart disease,” said Goldstein. “Previously, the danger of late sodium current was recognized in patients with rare, inherited mutations of sodium channels that cause cardiac Long QT syndrome, and to result from a common polymorphism in the channel we identified in a subset of babies with sudden infant death syndrome (SIDS).” The information, gained through the current study, offers new targets for therapeutics to prevent late current and arrhythmia associated with heart attacks, chronic heart failure and other life-threatening low oxygen cardiac conditions. This study was funded by National Institutes of Health. About UCI Health Affairs UCI Health Affairs comprises the schools, institutes, and centers in the Susan and Henry Samueli College of Health Sciences and an academic health system, UCI Health. The college unites the disciplines of medicine, nursing, pharmacy and pharmaceutical sciences, and population and public health to advance a transformative educational and healthcare delivery model that is patient-centered, science-based, transdisciplinary, and team-delivered. About the UCI School of Medicine Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and master’s students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu. Photo Credit: UCI School of Medicine