Newswise — The heart’s ability to beat normally over a lifetime is predicated on the synchronized work of proteins embedded in the cells of the heart muscle. Like a fleet of molecular motors that get turned on and off, these proteins cause the heart cells to contract, then force them to relax, beat after life-sustaining beat. Now a study led by researchers at Harvard Medical School, Brigham and Women’s Hospital and the University of Oxford shows that when too many of the heart’s molecular motor units get switched on and too few remain off, the heart muscle begins to contract excessively and fails to relax normally, leading to its gradual overexertion, thickening and failure. Results of the work, published Jan. 27 in Circulation, reveal that this balancing act is an evolutionary mechanism conserved across species to regulate heart muscle contraction by controlling the activity of a protein called myosin, the main contractile protein of the heart muscle. The findings—based on experiments with human, mouse and squirrel heart cells—also demonstrate that when this mechanism goes awry it sets off a molecular cascade that leads to cardiac muscle over-exertion and culminates in the development of hypertrophic cardiomyopathy (HCM), the most common genetic disease of the heart and a leading cause of sudden cardiac death in young people and athletes. “Our findings offer a unifying explanation for the heart muscle pathology seen in hypertrophic cardiomyopathy that leads to heart muscle dysfunction and, eventually, causes the most common clinical manifestations of the condition,” said senior author Christine Seidman, professor of genetics in the Blavatnik Institute at Harvard Medical School, a cardiologist at Brigham and Women’s Hospital and a Howard Hughes Medical Institute Investigator. Importantly, the experiments showed that treatment with an experimental small-molecule drug restored the balance of myosin arrangements and normalized the contraction and relaxation of both human and mouse cardiac cells that carried the two most common gene mutations responsible for nearly half of all HCM cases worldwide. If confirmed in further experiments, the results can inform the design of therapies that halt disease progression and prevent complications. “Correcting the underlying molecular defect and normalizing the function of heart muscle cells could transform treatment options, which are currently limited to alleviating symptoms and preventing worst-case scenarios such as life-threatening rhythm disturbances and heart failure,” said study first author Christopher Toepfer, who performed the work as a postdoctoral researcher in Seidman’s lab and is now a joint fellow in the Radcliffe Department of Medicine at the University of Oxford. Some of the current therapies used for HCM include medications to relieve symptoms, surgery to shave the enlarged heart muscle or the implantation of cardioverter defibrillators that shock the heart back into rhythm if its electrical activity ceases or goes haywire. None of these therapies address the underlying cause of the disease. Imbalance in the motor fleet Myosin initiates contraction by cross-linking with other proteins to propel the cell into motion. In the current study, the researchers traced the epicenter of mischief down to an imbalance in the ratio of myosin molecule arrangements inside heart cells. Cells containing HCM mutations had too many molecules ready to spring into action and too few myosin molecules idling standby, resulting in stronger contractions and poor relaxation of the cells. An earlier study by the same team found that under normal conditions, the ratio between “on” and “off” myosin molecules in mouse heart cells is around 2-to-3. However, the new study shows that this ratio is off balance in heart cells that harbor HCM mutations, with disproportionately more molecules in active versus inactive states. In an initial set of experiments, the investigators analyzed heart cells obtained from a breed of hibernating squirrel as a model to reflect extremes in physiologic demands during normal activity and hibernation. Cells obtained from squirrels in hibernation—when their heart rate slows down to about six beats per minute—contained 10 percent more “off” myosin molecules than the heart cells of active squirrels, whose heart rate averages 340 beats per minute. “We believe this is one example of nature’s elegant way of conserving cardiac muscle energy in mammals during dormancy and periods of deficient resources,” Toepfer said. Next, researchers looked at cardiac muscle cells from mice harboring the two most common gene defects seen in HCM. As expected, these cells had altered ratios of “on” and “off” myosin reserves. The researchers also analyzed myosin ratios in two types of human heart cells: Stem cell-derived human heart cells engineered in the lab to carry HCM mutations and cells obtained from the excised cardiac muscle tissue of patients with HCM. Both had out-of-balance ratios in their active and inactive myosin molecules. Further experiments showed that this imbalance perturbed the cells’ normal contraction and relaxation cycle. Cells harboring HCM mutations contained too many “on” myosin molecules and contracted more forcefully but relaxed poorly. In the process, the study showed, these cells gobbled up excessive amounts of ATP, the cellular fuel that sustains the work of each cell in our body. And because oxygen is necessary for ATP production, the mutated cells also devoured more oxygen than normal cells, the study showed. To sustain their energy demands, these cells turned to breaking down sugar molecules and fatty acids, which is a sign of altered metabolism, the researchers said. “Taken together, our findings map out the molecular mechanisms that give rise to the cardinal features of the disease,” Seidman said. “They can help explain how chronically overexerted heart cells with high energy consumption in a state of metabolic stress can, over time, lead to a thickened heart muscle that contracts and relaxes abnormally and eventually becomes prone to arrhythmias, dysfunction and failure.”Restoring balance Treating both mouse and human heart cells with an experimental small-molecule drug restored the myosin ratios to levels comparable to those in heart cells free of HCM mutations. The treatment also normalized contraction and relaxation of the cells and lowered oxygen consumption to normal levels. The drug, currently in human trials, restored myosin ratios even in tissue obtained from the hearts of patients with HCM. The compound is being developed by a biotech company; two of the company’s co-founders are authors on the study. The company provided research support for the study. In a final step, the researchers looked at patient outcomes obtained from a database containing medical information and clinical histories of people diagnosed with HCM caused by various gene mutations. Comparing their molecular findings from the laboratory against patient outcomes, the scientists observed that the presence of genetic variants that distorted myosin ratios in heart cells also predicted the severity of symptoms and likelihood of poor outcomes, such as arrhythmias and heart failure, among the subset of people that carried these very genetic variants. What this means, the researchers said, is that clinicians who identify patients harboring gene variants that disrupt normal myosin arrangements in their heart muscle could better predict these patients’ risk of adverse clinical course. “This information can help physicians stratify risk and tailor follow-ups and treatment accordingly,” Seidman said. Other investigators on the research included Amanda Garfinkel, Gabriela Venturini, Hiroko Wakimoto, Giuliana Repetti, Lorenzo Alamo, Arun Sharma, Radhika Agarwal, Jourdan Ewoldt, Paige Cloonan, Justin Letendre, Mingyue Lun, Iacopo Olivotto, Steven Colan, Euan Ashley, Daniel Jacoby, Michelle Michels, Charles Redwood, Hugh Watkins, Sharlene Day, James Staples, Raúl Padrón, Anant Chopra, Christopher Chen, Carolyn Ho, Alexandre Pereira and Jonathan Seidman. The work was supported by the Wellcome Trust (grant 206466/Z/17/Z), Sarnoff Cardiovascular Research Foundation, National Science Foundation (cooperative agreement EEC-1647837), MyoKardia, Italian Ministry of Health (grant RF-2013-02356787 NET-2011-02347173), American Heart Association, A. Alfred Taubman Medical Research Institute, British Heart Foundation (grant RG/12/16/29939), British Heart Foundation Centre of Research Excellence, Leducq Foundation, National Institutes of Health (grants 1P50HL112349, 1U01HL117006, HL11572784, U01HL098166, 5R01HL080494 and 5R01HL084553), São Paulo Research Foundation (2017/20593-7) and Howard Hughes Medical Institute. Relevant disclosures: Researchers Christine Seidman and Jonathan Seidman are founders and own shares in MyoKardia, a company developing therapies that target the heart muscle, including the chemical compound used in the experiments.
Newswise — The NYU Langone Transplant Institute on Monday became the first center in the United States to transplant a heart using a novel method in which, after the heart has stopped beating and death has been declared, surgeons place the organ donor on cardiopulmonary bypass and blood is circulated through the body. This enables transplant surgeons to assess a heart for transplant while mitigating potential injury to all organs. It also holds the promise of significantly increasing the number of heart transplants from donors who have died from cardiac arrest as opposed to the typical donation after brain death. The procedure was performed by a team of cardiothoracic surgeons, anesthesiologists, intensivists, nurses, perfusionists, and others from the Transplant Institute, in collaboration with LiveOnNY, the organ procurement organization. It is the first in an ongoing research study to evaluate the feasibility and safety of the protocol. “This groundbreaking transplant procedure is the culmination of nearly two years of hard work to ensure all the ethical, logistical, and regulatory needs and requirements were met,” says Nader Moazami, MD, professor of cardiothoracic surgery and Surgical Director of Heart Transplantation & Mechanical Circulatory Support at NYU Langone. Other transplant centers in the country have recently launched clinical trials to study Donation after Circulatory Death, or DCD, using a device which circulates warm, oxygenated blood through the heart after it has been removed from the body. NYU Langone’s innovative protocol uses the standard cardiopulmonary bypass used in cardiac surgery to reestablish circulation while the heart is still in the body. “We’re thrilled with the success of this first transplant surgery, which has promise to increase not only heart donation rates, but other lifesaving organs as well,” says Zachary N. Kon, MD, associate professor of cardiothoracic surgery and Surgical Director of Lung Transplantation at NYU Langone. “One of the advantages of this novel method is that it gives all organs the potential benefit of restoring perfusion prior to procurement.” While transplant centers across the country have made great strides to address organ shortages, the demand still far exceeds the supply. According to the Organ Procurement and Transplantation Network, there were 3,399 heart transplants in 2018, with 3,800 patient remaining on the wait list, resulting in 314 deaths and 330 becoming too sick for transplantation. Most heart donations in the United States are from patients who are declared brain dead; experts hypothesize that the widespread dissemination of controlled DCD could increase the donor pool by as much as 20 percent. NYU Langone developed the new protocol in collaboration with LiveOnNY, New York City’s organ procurement organization. “This quantum leap forward in American transplantation is a game changer for those desperately awaiting heart transplants by expanding the pool of suitable donors,” says Amy L. Friedman, MD, Executive Vice President and Chief Medical Officer at LiveOnNY, which helped NYU Langone identify the organ donor. “It resulted from the generosity and commitment of this one donor and their loved ones who honored the donor’s wish to save the lives of others.” Drs. Kon and Moazami are co-authors on an article published January 8 in the American Journal of Transplantation, investigating the ethical and logistical concerns for establishing controlled DCD heart transplantation in the United States. They collaborated with colleagues in NYU Langone’s Division of Medical Ethics, Brendan Parent, JD, adjunct instructor in the Department of Population Health, and Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics in the Department of Population Health, among others. “The NYU Langone Transplant Institute is constantly seeking to drive discovery and innovation in the field of transplantation, to help all those waiting for a lifesaving organ,” says Robert Montgomery, MD, DPhil, Professor of Surgery and Director of the NYU Langone Transplant Institute. “This is an exciting advancement that will likely have a major impact on transplantation rates in this country.”
Newswise — What keeps most infectious disease researchers up at night aren’t infamous viruses like Ebola. Instead, influenza, commonly known as the flu, continues to be a clear and present danger to humanity. “Influenza is a huge problem, as the virus sickens or kills millions of people each year,” says David Markovitz, M.D., professor of internal medicine in the division of infectious diseases at Michigan Medicine. “A new pandemic along the lines of the 1918 Spanish flu has the potential to kill millions here and abroad.” To that end, he and an extensive team of collaborators have worked for years on broad-spectrum antiviral drugs developed from, of all things, banana plants. In a new paper published in the Proceedings of the National Academy of Sciences, Markovitz, first author Evelyn Coves-Datson, a M.D., Ph.D. student, Akira Ono, Ph.D., professor of microbiology and immunology and their team have shown that an engineered compound based on a banana lectin, a protein called H84T, has real potential for clinical use against influenza. In their experiments, more than 80% of mice exposed to a form of influenza that is typically fatal were able to survive the disease after receiving an injection of the protein, even up to 72 hours after exposure. The team also provides early evidence that the compound is safe. A downside of naturally occurring banana lectin—which can cause inflammation by inappropriately activating the immune system—wasn’t present in mice given H84T. Furthermore, because H84T is a protein, there was concern that the body would recognize it as foreign and develop antibodies against it, thereby neutralizing it or causing harm. The team found that while mice did develop antibodies against H84T, they didn’t appear to be adversely affected by them. The compound works because it targets a sugar called high mannose, which is present on the outside of certain viruses but not on most healthy cells. “We were able to show that H84T blocks the ability of the influenza virus to fuse with structures termed endosomes in the human cell, a key step in infection,” he explains. Doing so disabled their ability to replicate and wreak havoc. Amazingly, this mechanism of action, binding of high mannose sugars on the surface of viruses, means that H84T is effective not only against influenza, but also against Ebola, HIV, measles, MERS, a new deadly viral illness that was first reported in Saudi Arabia in 2012, SARS and all other coronaviruses tested. Even more promising is that the compound works where Tamiflu (oseltamivir), the current standard therapy for severe flu, has failed. “We’ve also shown that there may be a synergistic effect between H84T and Tamiflu,” says Markovitz. His team hopes to do more research with the compound in humans in the hopes of getting it to market. “We envision the government potentially stockpiling it in the event of a pandemic.” However, he says, “there are many difficulties to commercialization. Pharmaceutical economics do not seem to favor the development of antivirals or antibacterials for one-time usage, which is a huge problem.” This paper also included the following U-M researchers: Steven King, Maureen Legendre, Auroni Gupta, Susana Chan and Emily Gitlin. Paper cited: “A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo,” Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.191515211
Newswise — Virtual Reality during chemotherapy has been shown to improve breast cancer patients’ quality of life during the most stressful treatments, according to a recent study. Breast cancer is, to date, the most frequent oncological disease worldwide, and has an impact both from a physical and psychological point of view. Receiving a breast cancer diagnosis is a challenge, a trauma that causes severe stress from the moment of diagnosis, with frequent manifestations of anxiety and depression. The advances made by oncology and medical treatments, such as the new chemotherapy drugs, allow today to reach a survival that touches 90%. Although modern cancer treatments have partially reduced the side effects on health and quality of life, these therapies are experienced with considerable suffering by women and these can sometimes develop conditioned responses to treatments (such as anticipatory anxiety), reducing compliance of women with treatment (frequent requests for dose reduction or treatment interruption) and, consequently, the effectiveness of the drugs themselves, and therefore survival. In recent years, several psychological interventions have been implemented breast cancer patients during the various stages of treatment, starting from diagnosis, to hospitalization and during chemotherapy infusions. Among the psychological interventions supported by technological tools, the first study implemented in Italy aimed at evaluating the efficacy of Virtual Reality during chemotherapy treatments has just released its results. The study was published in the international journal: Journal of Cellular Physiology. The study, which saw the participation of an international team of researchers affiliated with the Sbarro Health Research Organization in Philadelphia, the Sapienza University of Rome, the Pascale Institute of Naples, and the University of Siena, Italy. The study was coordinated by the psycho-oncologist Andrea Chirico, researcher at the Sapienza, and the internationally renowned Oncologist Antonio Giordano, M.D., Ph.D., founder and Director of the Sbarro Health Research Organization. Several psychological tests designed to accurately measure stress and mood before and after chemotherapy treatment were administered to 94 women who underwent chemotherapy treatments for breast cancer at the Pascale Institute in Naples. During chemotherapy a group of women wore a Virtual Reality headset and were immersed in an alternative reality, the second group of women was subjected to music therapy, the control group did not receive any supportive treatment during chemotherapy, which is the current standard at the oncology department. The results showed that the group of women subjected to virtual reality was able to benefit from the treatment with a substantial lowering of anxiety levels, while the group of women who did not receive any supportive treatment, anxiety increased and mood also deteriorated significantly after chemotherapy. The highly realistic Virtual Environment is a deserted island where women were able to freely interact with the setting, also undertaking some activities such as walking in the forest, doing yoga, observing animals, swimming, etc ... "This represents the first Italian scientific result in terms of the use of virtual reality during chemotherapy," says Giordano. "We must pave the way for scientific studies that can replicate our results to understand the true potential of these tools," adds Chirico. Among the authors of the study, Michelino de Laurentiis, Director of the Department of Breast Cancer, Principal Investigator for the Pascale Institute claims that, “after these important results, agreeing with the CEO Attilio Bianchi and Prof. Gerardo Botti, Scientific Director of the Pascale Institute, we are planning a new department of breast medical oncology with HI TECH chairs equipped with virtual reality to ensure that all of our patients could have a better and unique quality of care in Italy.” About the Sbarro Health Research Organization The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org
Credit: Columbia University Irving Medical Center (Kuo Lab) A new study suggests that patients with essential tremor have unusual brain waves in the cerebellum that cause the tremors (the same brain waves in mice produce tremor). The left image show a cerebellar electroencephalogram (EEG) in a control subject; the right image shows the additional brain waves in a patient. Highest intensity is colored in red, lowest intensity in blue. Newswise — NEW YORK, NY (Jan. 15, 2020)—The source of essential tremor—a movement disorder that causes involuntary trembling of the hands, arms, and head—has been enigmatic, impeding the development of effective treatments for a condition that affects 4% of people over 40. Now a new study from Columbia University Irving Medical Center and NewYork-Presbyterian suggests the tremors are caused by overactive brain waves at the base of the brain, raising the possibility of treating the disorder with neuromodulation to calm the oscillations. “Past studies have identified changes in brain structure in people with essential tremor, but we didn’t know how those changes caused tremors,” says Sheng-Han Kuo, MD, the study’s senior author and assistant professor of neurology at Columbia University Vagelos College of Physicians and Surgeons. “This study pins down how those structural changes affect brain activity to drive tremor.” The study was published online today in Science Translational Medicine. About Essential Tremor Essential tremor is the most common movement disorder in the United States, affecting about 10 million Americans (approximately eight times as many people as Parkinson’s disease). The condition causes involuntary, rhythmic trembling, usually in the hands, and is exacerbated during such activities as buttoning a shirt or using utensils. Although essential tremor is not life-threatening, it can severely impact quality of life. Some beta blockers and anti-epileptic drugs can reduce symptoms, but they carry side effects, such as fatigue and shortness of breath. They also don’t work very well in essential tremor patients, which Kuo says isn’t surprising since the cause of the condition hasn’t been well understood. Tremor Patients Have Excessive Brain Activity in the Cerebellum The researchers have previously identified structural changes in the cerebellum of essential tremor patients and used a new cerebellar encephalogram (EEG) technique to search for unusual brain waves in this part of the brain. Among 20 essential tremor patients examined with cerebellar EEG, most had strong oscillations (between 4 and 12 Hz) in the cerebellum that were not found in any of the 20 control subjects. Patients with more severe tremors had stronger oscillations. Oscillations First Found in Mice The researchers first discovered the cerebellar oscillations in mice that had developed tremors closely resembling those seen in essential tremor patients. The tremors could be turned on and off by stimulating certain neurons in the mouse brain, alternately suppressing and unleashing the oscillations. “These results established a causal relationship between the brain oscillations and tremor, which cannot be directly tested in patients,” says Kuo, who is also an assistant attending neurologist at NewYork-Presbyterian/Columbia University Irving Medical Center. Excessive Oscillations Stem from Extra Synapses In previous studies of postmortem brain tissue from essential tremor patients, the Columbia team discovered that patients with essential tremor had an abnormally high number of synapses, or connections, between two types of nerve cells in the brain’s cerebellum—climbing fibers and Purkinje cells. In the current study, again using postmortem brain tissue, the researchers found that the formation of these synapses appears to be influenced by a protein called glutamate receptor delta 2 (GluRẟ2). “When this protein is underexpressed, any excess synapses that form between climbing fibers and Purkinje cells are not eliminated, resulting in too many neuronal connections,” says Kuo. When the team reduced expression of GluRẟ2 in mice, the animals developed tremors similar to those seen in humans. Restoring GluRẟ2 function suppressed the tremors, proving that the protein plays a key role in essential tremor. Potential for New Treatments The study opens several new possibilities for treatment of essential tremor, Kuo says. “Using cerebellar EEG as a guide, we may be able to use neuromodulation techniques such as tDCS or TMS (transcranial direct-current stimulation or transcranial magnetic stimulation) to reduce tremor, or even drugs to reduce transmission between the climbing fibers and Purkinje cells.” Kuo is also working to develop medications that increase GluRẟ2 expression in the brain, which may reduce tremor. +++ The study is titled “Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology.” The other contributors are Ming-Kai Pan (National Taiwan University Hospital, Taipei City, Taiwan), Yong-Shi Li (Columbia University Irving Medical Center, New York, NY), Shi-Bing Wong (CUIMC and Taipei Tzu Chi Hospital, Tzu Chi Medical Foundation, New Taipei City, Taiwan), Chun-Lun Ni (CUIMC), Yi-Mei Wang (National Taiwan University Hospital), Wen-Chuan (National Taiwan University Hospital), Liang-Yin Lu (National Taiwan University Hospital), Jye-Chang Lee (National Taiwan University Hospital), Etty P. Cortes (CUIMC), Jean-Paul G. Vonsatte (CUIMC), Qian Sun (Columbia and Case Western Reserve University, Cleveland, OH), Elan D. Louis (Yale University, New Haven, CT), and Phyllis L. Faust (CUIMC). The research was supported by the National Institutes of Health (grants K08NS083738, R01NS104423, R01NS086736, R01NS073872, R01NS085136, R01NS088257, R01NS04289, and R21NS077094), Parkinson’s Foundation, International Essential Tremor Foundation, National Institute of Environmental Health Sciences, Ministry of Science and Technology in Taiwan, and National Taiwan University Hospital, and a Louis V. Gerstner Jr. Scholar Award. The authors declare that they have no financial or other conflicts of interest.
Credit: UC San Diego Health Sciences Artistic representation of changes in mouse brain networks with alcohol dependence. The left side represents control individuals with numerous networks and small sets of connected brain regions indicated by lines. The right side represents individual mice with a history of alcohol dependence, depicting a small set of only three brain networks with a high number of connections. Novel imaging technologies produce first whole-brain atlas at single-cell resolution, revealing how alcohol addiction - and abstinence - change neural physiology and affect previously unsuspected regions of the brain. Newswise — Employing advanced technologies that allow whole brain imaging at single-cell resolution, researchers at University of California San Diego School of Medicine report that in an alcohol-dependent mouse model, the rodent brain’s functional architecture is substantially remodeled. But when deprived of alcohol, the mice displayed increased coordinated brain activity and reduced modularity compared to nondrinker or casual drinker mice.The findings, published in the January 14, 2020 online issue of PNAS, also identified several previously unsuspected regions of the brain relevant to alcohol consumption, providing new research targets for better understanding and treatment of alcohol dependence in humans.“The neuroscience of addiction has made tremendous progress, but the focus has always been on a limited number of brain circuits and neurotransmitters, primarily dopaminergic neurons, the amygdala and the prefrontal cortex,” said senior author Olivier George, PhD, associate professor in the Department of Psychiatry at UC San Diego School of Medicine.“Research groups have been fighting for years about whether ‘their’ brain circuit is the key to addiction. Our results confirm these regions are important, but the fact that we see such a massive remodeling of the functional brain architecture was a real shock. It’s like studying the solar system and then discovering that there is an entire universe behind it. It shows that if you really want to understand the neurobiological mechanisms leading to addiction, you can’t just look at a handful of brain regions, you need to look at the entire brain, you need to take a step back and consider the whole organ.”George said the findings further undermine the idea that addiction is simply a psychological condition or consequence of lifestyle. “You would be surprised at how prevalent this view remains,” he said. “The brain-wide remodeling of the functional architecture observed here is not ‘normal.’ It is not observed in a naïve animal. It is not observed in an animal that drinks recreationally. It is only observed in animals with a history of alcohol dependence and it is massive. Such a decrease in brain modularity has been observed in numerous brain disorders, including Alzheimer’s disease, traumatic brain injury and seizure disorders.”Brain modularity is the theory that there are functionally specialized regions in the brain responsible for different, specific cognitive processes. For example, the frontal lobes of the human brain are involved in executive functions, such as reasoning and planning, while the fusiform face area located in the lower rear of the brain is involved in recognizing faces. Reduced modularity, said George, likely interferes with “normal neuronal activity and information processing and contributes to cognitive impairment, emotional distress and intense craving observed in mice during abstinence from alcohol.”Due to the format of the testing, George said it was not clear if the reduced modularity was permanent. “So far, we only know that it lasts at least one week into abstinence. We have not tested longer durations of abstinence, but it’s one of our goals.”George and colleagues used multiple new and emerging imaging technologies to create their whole-brain atlas of mouse brains, capable of being viewed at the level of single cells. The result was a first, they said, providing unprecedented data and insights.“This new approach allows us to explore an entirely new universe. It can answer so many questions. What I am most interested in now is figuring out how early these brain changes start and how long do they last for. This would be critical to understanding when the switch to addiction happens and when does your brain come back to normal, if it ever does. We are also very interested in comparing the brain network of alcohol dependence with other drugs, such as cocaine, nicotine and methamphetamines.”The imaging approach cannot yet be used with human brains, which are far larger and more complex. “I don’t think that it is possible to do it in humans now, the technology is just not there,” said George. “But when I started doing this research 15 years ago, this technique didn’t exist at all and I never ever imagined it would be possible, so who knows what the future will bring.”Co-authors include: Adam Kimbrough, UC San Diego; Daniel J. Lurie and Mark D’Esposito, UC Berkeley; Andres Collazo, California Institute of Technology; and Max Kreifeldt, Harpreet Sidhu, Giovana Camila Macedo and Candice Contet, The Scripps Research Institute.Funding for this research came, in part, from the National Institutes of Health (grants AA006420, AA026081, AA022977, AA026685, AA024198, NS79698, AA027301, and AA007456), the Pearson Center for Alcoholism and Addiction Research and the Arnold and Mabel Beckman Foundation.
Credit: Kim Allison, MD, FCAP Updated CAP/ASCO guideline offers specific recommendations for handling and reporting breast cancer testing cases that indicate low estrogen receptor expression. Accurate endocrine receptor testing is critical to optimal treatment plans Newswise — Northfield, Ill. and Alexandria, Va.— The updated guideline for estrogen and progesterone receptor (ER/PgR) testing in breast cancer, published jointly today by the College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO), reaffirms much of the original guidance and has more specific recommendations for handling and reporting cases with low ER expression. Globally, more than 1 million women are diagnosed annually with breast cancer, and receptor testing conducted on their biopsies typically shows that approximately eight in 10 of these women have ER-positive breast cancer. Well-performed tests are essential to identify those patients who could benefit from endocrine therapy. And more broadly, hormone receptor status can be valuable for tumor classification and other factors that inform treatment. In a notable change, cases with 1-10% of cells staining for ER expression will now be reported as ER-low positive. Pathology reports for these cases should include a recommended comment that acknowledges the more limited data on endocrine responsiveness in this group. Also in such cases, pathologists should report the status of internal controls, with a special comment for specimens that lack internal positive controls. The new guideline also recommends that laboratories establish specific standard operating procedures to ensure the validity of ER-low positive (1-10%) or ER negative (0 or <1%) results and their interpretation. Correlation of ER staining with the histologic features, and attention to other standard quality control measures, is also recommended, including additional steps to assess unusual or discordant results. The utility of PgR testing continues to be largely prognostic in the ER-positive invasive cancer population, but testing using similar principles to ER testing is still recommended for invasive cancers. The updated guideline also more clearly recommends that ER be tested in cases of newly diagnosed DCIS (without invasion) to help estimate potential benefit of endocrine therapy to reduce the risk of a future breast cancer event. But, specifically, PgR testing in DCIS is optional. “Like the original guideline, invasive cancers with 1-100% ER staining are considered positive and eligible for endocrine therapy,” Kimberly Allison, MD, FCAP, pathologist and project co-chair explained. “But this update focuses on better assessment of cases with lower levels of ER expression. We wanted to establish guidance to help ensure that the results from hormone receptor testing in women diagnosed with breast cancer are as accurate as possible. This will give physicians and patients more information to guide them when making treatment decisions.” “The critical point for clinicians is that they need to be aware of and able to discuss with patients the implications of ER-low positive test results,” explained Antonio Wolff, MD, FACP, FASCO, an oncologist representing ASCO and project co-chair. “We now have more standardized recommendations for these cases.” Likewise, patients should be aware of their test results and should be encouraged to discuss decisions to use endocrine therapy with their clinical care team. The update to this pivotal evidence-based guideline is available today in an early online release from the Archives of Pathology & Laboratory Medicine and Journal of Clinical Oncology. In addition, CAP- and ASCO-developed resources to help clinicians implement the guideline are available at no charge via the society’s websites.
Newswise — SAN FRANCISCO, Calif. — Jan. 13, 2020 — A survey conducted by The Harris Poll has uncovered key gaps in American’s knowledge of eye health, and what they don’t know is putting them at risk of vision loss. With the number of people affected by potentially blinding eye diseases expected to double in the years ahead1, it’s critical that people better understand eye health. As the new year begins and people rededicate themselves to their health, the American Academy of Ophthalmology is urging Americans to get smart about eye health in 2020. This survey was conducted online by The Harris Poll on behalf of the American Academy of Ophthalmology in August 2019 among more than 3,500 U.S. adults age 18 and older. Here are some of the key findings: While 81% of adults say they are knowledgeable about eye/vision health, less than 1 in 5 (19%) were able to correctly identify the three main causes of blindness in the U.S., which are glaucoma, age-related macular degeneration (AMD) and diabetic eye disease. Less than half (47%) are aware that vision loss and blindness does not affect all people equally. Only around one-third of adults (37%) know you do not always experience symptoms before you lose vision to eye diseases. Less than half (47%) are aware your brain can make it difficult to know if you are losing your vision by adapting to vision loss. “Far too often, we witness the consequences of patients entering the ophthalmologist’s office too late to avoid severe vision loss,” said Anne L. Coleman, M.D., Ph.D., president of the American Academy of Ophthalmology. “In 2020, we want all Americans to have clear vision when it comes to eye health. That starts with educating yourself about eye diseases and visiting an ophthalmologist.” Ophthalmologists are medical and surgical physicians trained to recognize all the potential threats to vision, which is why the Academy recommends that healthy adults see an ophthalmologist for a comprehensive, baseline eye exam by age 40 and have their eyes checked every year or two at age 65 or older. The impacts of vision loss are also underappreciated. Another key finding showed that people are unaware that vision loss can also amplify the adverse effects of other chronic illnesses. Although the majority of adults (57%) are aware that vision loss in adults increases the risk for injury or death, only 1 in 4 (24%) know that vision loss in adults is associated with psychological problems such as social isolation and depression. Study after study has shown that people fear vision loss more than they fear cancer, stroke, heart disease and other serious health problems. What this new study shows is that Americans are scared about an issue they know very little about. The year 2020, with all its symbolism with clear vision, is the year to change that. For ophthalmologist-reviewed information about eye diseases and treatments, eye health news, and tools to locate an ophthalmologist, visit AAO.org/EyeSmart. EyeCare America® Can Help If you are concerned about the cost of the exam, the American Academy of Ophthalmology’s EyeCare America® program may be able to help. This national public service program provides eye care through volunteer ophthalmologists for eligible seniors 65 and older; and those at increased risk for eye disease. To see if you or your loved ones are eligible, visit www.aao.org/eyecareamerica. About the Survey This survey was conducted online within the U.S. by The Harris Poll on behalf of the American Academy of Ophthalmology among 3,512 U.S. adults ages 18 and over between August 8 and 27, 2019. Data by race/ethnicity were weighted where necessary by gender, age, region, income, education, household size, marital status, employment, and specific eye conditions of interest to bring them into line with their actual proportions in the population. The data for each race/ethnicity group was then combined into a grand total to reflect the proportions of each race/ethnicity within the U.S. adult population. Propensity score weighting was also used to adjust for respondents’ propensity to be online. For additional details about the survey results, please contact Lindsey.Bailys@gcihealth.com. About the American Academy of Ophthalmology The American Academy of Ophthalmology is the world’s largest association of eye physicians and surgeons. A global community of 32,000 medical doctors, we protect sight and empower lives by setting the standards for ophthalmic education and advocating for our patients and the public. We innovate to advance our profession and to ensure the delivery of the highest-quality eye care. Our EyeSmart® program provides the public with the most trusted information about eye health. For more information, visit aao.org.
Credit: Mark Cornelison | UK Photo University of Kentucky researchers (from left) Matthew Gentry, Haining Zhu and Lisha Kuang co-authored a study that shows a class of antibiotics could be a promising therapy for frontotemporal dementia. Newswise — LEXINGTON, Ky. (Jan. 10, 2020) — Researchers at the University of Kentucky’s College of Medicine have found that a class of antibiotics called aminoglycosides could be a promising treatment for frontotemporal dementia. Results of their proof of concept study, which was a collaborative effort between UK’s Department of Molecular and Cellular Biochemistry and the University of California San Francisco’s Department of Pathology, were recently published in the journal, Human Molecular Genetics. Frontotemporal dementia is the second-most common dementia after Alzheimer’s disease and the most common type of early onset dementia. It typically begins between ages 40 and 65 and affects the frontal and temporal lobes of the brain, which leads to behavior changes, difficulty speaking and writing, and memory deterioration. A subgroup of patients with frontotemporal dementia have a specific genetic mutation that prevents brain cells from making a protein called progranulin. Although progranulin is not widely understood, its absence is linked to the disease. A group led by Haining Zhu, a professor in UK’s Department of Molecular and Cellular Biochemistry, discovered that after aminoglycoside antibiotics were added to neuronal cells with this mutation, the cells started making the full-length progranulin protein by skipping the mutation. “These patients’ brain cells have a mutation that prevents progranulin from being made. The team found that by adding a small antibiotic molecule to the cells, they could ‘trick’ the cellular machinery into making it,” said Matthew Gentry, a co-author of the study and the Antonio S. Turco Endowed Professor in the Department of Molecular and Cellular Biochemistry. The researchers found two specific aminoglycoside antibiotics - Gentamicin and G418 - were both effective in fixing the mutation and making the functional progranulin protein. After adding Gentamicin or G418 molecules to the affected cells, the progranulin protein level was recovered up to about 50 to 60%. These results could be promising to drug development. Currently, there are no effective therapies for any type of dementia. After this preclinical proof of concept study, the next step is to study the antibiotics’ effects on mice with the mutation that causes frontotemporal dementia, Zhu says. Another focus is to possibly develop new compounds from Gentamicin and G418 that could be safer and more effective. Although Gentamicin is an FDA-approved medication, its clinical usage is limited as it is associated with a number of adverse side effects. “If we can get the right resources and physician to work with, we could potentially repurpose this drug. This is an early stage of the study, but it provides an important proof of concept that these aminoglycoside antibiotics or their derivatives can be a therapeutic avenue for frontotemporal dementia,” said Zhu.
Credit: Alicia Ortega, MS Newswise — For adult patients with brainstem high-grade gliomas — one of the rarest and deadliest forms of brain cancer — surgically removing the entire tumor may add many months or potentially years of survival beyond that offered by radiation and chemotherapy, according to results of a medical records study led by researchers at the Johns Hopkins Kimmel Cancer Center. The investigators point out that survival for these tumors has remained poor, with a median survival length of eight months after diagnosis in people who only receive a biopsy. However, if total surgical removal is an option for patients, the data in the records studied suggest it could boost this number to a median of 16 months or more. “Knowing what these surgeries can do could help neurosurgeons, neuro-oncologists and patients have a better sense of what to expect so we can move forward toward better standardized care for these rare and critical tumors,” says study leader Debraj Mukherjee, M.D., M.P.H., assistant professor of neurosurgery at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. The findings were reported online Oct. 16 in the Journal of Neuro-Oncology. Every year, about 10,000 patients in the U.S. are diagnosed with high-grade gliomas, aggressive cancers that arise from a brain cell type called glia, which form the “scaffolding” of the organ. Only a small fraction of these cancers form in the brainstem, a core structure critical for nearly all functions necessary for life, such as heart rate, breathing and consciousness. Because of the vital nature of this region, brainstem high-grade gliomas have traditionally been treated only by chemotherapy and radiation. However, in recent years, Johns Hopkins and several other academic medical centers around the world have been able to safely access tumors through so-called “brainstem safe entry zones,” making surgery possible for previously inoperable tumors. Consequently, a growing number of patients have opted for partial or total removal of their tumors, according to the researchers. But because gliomas are rare, and the availability of surgical treatment relatively recent, it has been difficult to compare treatments, and unclear what kind of survival benefit surgery confers. To find out, Mukherjee, along with Johns Hopkins Kimmel Cancer Center postdoctoral fellow Adham M. Khalafallah, M.D., M.B.B.Ch., and their colleagues used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Result (SEER) database, an extensive collection of information on cancer patients gleaned from registries in 19 geographic regions that cover about 35% of the U.S. population. A search of this database, covering a time span from 1973 to 2015, turned up 103 patients with brainstem high-grade gliomas who underwent either a biopsy (15%) or some surgical intervention (85%) for their tumors. Of those who had surgery, about 19% underwent total surgical removal. Beyond information on interventions, SEER records included a wealth of other data on these patients, including age, race, marital status, size of their tumor, how far it had spread, if postoperative radiation treatment was done and length of survival after diagnosis. When the researchers analyzed this information, they found significantly longer survival in patients who had surgery. Compared with the median survival length of eight months after diagnosis in patients who had just a biopsy, those who had a partial resection survived about 11 months, and those who had a gross total resection survived about 16 months. In a fraction of patients who had other factors associated with longer survival, such as younger age and marital status, median survival with a total resection was up to four times higher than patients who only had biopsies. In the future, Mukherjee adds, it might be possible to boost survival even further by identifying biomarkers that could help personalize which treatments might benefit patients most. Other Johns Hopkins researchers who participated in this study include Joshua Doyle, Wuyang Yang, Yi Sun and Chetan Bettegowda.