BreakThrough Digest Medical News |
- Neuron loss in schizophrenia and depression could be prevented with an antioxidant
- Breakthrough in battle against leukemia
- New monoclonal antibody developed that can target proteins inside cancer cells
- Sleep discovery could lead to therapies that improve memory
- Clot-busting drug as effective as angioplasty
| Neuron loss in schizophrenia and depression could be prevented with an antioxidant Posted: 12 Mar 2013 09:00 PM PDT Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia and depression. In schizophrenia, deficits have been particularly well-described for a subtype of GABA neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical for proper cognitive and emotional functioning.
It now appears that parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that may emerge commonly in development, particularly in the context of psychiatric disorders like schizophrenia or bipolar disorder, where compromised mitochondrial function plays a role. parvalbumin neurons may be protected from this effect by N-acetylcysteine, also known as Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of acetaminophen (Tylenol) overdose, reports a new study in the current issue of Biological Psychiatry. Dr. Kim Do and collaborators, from the Center for Psychiatric Neurosciences of Lausanne University in Switzerland, have worked many years on the hypothesis that one of the causes of schizophrenia is related to vulnerability genes/factors leading to oxidative stress. These oxidative stresses can be due to infections, inflammations, traumas or psychosocial stress occurring during typical brain development, meaning that at-risk subjects are particularly exposed during childhood and adolescence, but not once they reach adulthood. Their study was performed with mice deficient in glutathione, a molecule essential for cellular protection against oxidations, leaving their neurons more exposed to the deleterious effects of oxidative stress. Under those conditions, they found that the parvalbumin neurons were impaired in the brains of mice that were stressed when they were young. These impairments persisted through their life. Interestingly, the same stresses applied to adults had no effect on their parvalbumin neurons. Most strikingly, mice treated with the antioxidant N-acetylcysteine, from before birth and onwards, were fully protected against these negative consequences on parvalbumin neurons. “These data highlight the need to develop novel therapeutic approaches based on antioxidant compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects,” said Do. “To give an antioxidant from childhood on to carriers of a genetic vulnerability for schizophrenia could reduce the risk of emergence of the disease.” “This study raises the possibility that GABA neuronal deficits in psychiatric disorder may be preventable using a drug, N-acetylcysteine, which is quite safe to administer to humans,” added Dr. John Krystal, Editor of Biological Psychiatry. ### The article is “Early-Life Insults Impair Parvalbumin Interneurons via Oxidative Stress: Reversal by N-Acetylcysteine” by Jan-Harry Cabungcal, Pascal Steullet, Rudolf Kraftsik, Michel Cuenod, and Kim Q. Do (doi: 10.1016/j.biopsych.2012.09.020). The article appears in Biological Psychiatry, Volume 73, Issue 6 (March 15, 2013), published by Elsevier. Notes for Editors Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno. Journalists wishing to interview the authors may contact Kim Do at 41-21-643-65-65 or kim.do@chuv.ch. The authors’ affiliations, and disclosures of financial and conflicts of interests are available in the article. John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here. About Biological Psychiatry Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders. The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged. Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 5th out of 129 Psychiatry titles and 16th out of 243 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2011 Impact Factor score for Biological Psychiatry is 8.283. About Elsevier Elsevier is a world-leading provider of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier’s online solutions include ScienceDirect, Scopus, Reaxys, ClinicalKey and Mosby’s Nursing Suite, which enhance the productivity of science and health professionals, and the SciVal suite and MEDai’s Pinpoint Review, which help research and health care institutions deliver better outcomes more cost-effectively. A global business headquartered in Amsterdam, Elsevier employs 7,000 people worldwide. The company is part of Reed Elsevier Group PLC, a world-leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange). Contact: Rhiannon Bugno |
| Breakthrough in battle against leukemia Posted: 12 Mar 2013 09:00 PM PDT Scientists at Griffith University’s Institute for Glycomics and The Saban Research Institute of Children’s Hospital Los Angeles have discovered a critical weakness in leukaemic cells, which may pave the way to new treatments.
The research team has demonstrated that leukaemic cells can be eradicated by removing a carbohydrate modification displayed on the cell’s surface. Director of Griffith University’s Institute for Glycomics, Professor Mark von Itzstein is the Australian team leader. He said the discovery is an important advance against leukaemia, a cancer of malignant white blood cells that multiply uncontrollably. Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. “We have found that the leukaemic cell has an altered cell surface carbohydrate decoration compared to normal cells and this also conveys resistance to drug treatment,” Professor von Itzstein said. “We have now shown that with the removal of this carbohydrate alteration the cells die.” Professors Nora Heisterkamp and John Groffen, leaders of the US-based team, Professor von Itzstein and their colleagues have published their research findings in the latest edition of the internationally acclaimed Journal of Experimental Medicine. Professor von Itzstein said the research could lead to new ways to fight the disease, particularly where it has become treatment resistant. “Up until 40 years ago, only one child in five survived ALL”, but advances in chemotherapy have changed that outcome and now nearly 80 percent of children with ALL will be cured,” Professor von Itzstein said. “For the remaining 20 percent, however, the disease returns necessitating additional rounds of intensive chemotherapy. Unfortunately, most relapsed patients die within one year because their cancer cells are resistant to chemotherapy. “In the future, we hope that this novel, structural approach to treating ALL may offer an effective treatment option for children battling drug-resistant forms of the disease.” Professor von Itzstein said the discovery had been made possible only through a unique sharing of research expertise. “These results are the culmination of an international collaboration that commenced only a few years ago when Professor Groffen spent study leave in the Institute for Glycomics on Griffith’s Gold Coast Campus,” Professor von Itzstein said. “It has been a wonderful opportunity to combine the US team’s internationally acclaimed expertise in leukaemia with our own expertise in carbohydrate science. “By exploiting this ‘Achilles heel’ in these leukaemic cells, our collaborative research efforts are now focused on the development of a new type of drug therapy that targets this carbohydrate modification.” Patron of the Institute for Glycomics Leukaemia project in Australia, Air Chief Marshal Angus Houston AC, AFC (Ret’d), said he was delighted with this latest advance. “These new findings provide the groundwork for a new fight against this terrible disease,” he said. ### About Griffith University’s Institute for Glycomics:
Based at Griffith University’s Gold Coast Campus, research at the Institute for Glycomics involves the study of the carbohydrates and carbohydrate-recognising proteins in various biological systems, and the design of novel drugs and vaccines to treat or prevent clinically important diseases���. This approach presents an exciting therapeutic platform for the control of a wide-range of medical conditions such as a variety of cancers, infectious diseases, inflammation and immune disorders. The Institute is the only one of its kind in Australia and only one of six in the world. Contact: Helen Wright |
| New monoclonal antibody developed that can target proteins inside cancer cells Posted: 12 Mar 2013 09:00 PM PDT Researchers have discovered a unique monoclonal antibody that can effectively reach inside a cancer cell, a key goal for these important anticancer agents, since most proteins that cause cancer or are associated with cancer are buried inside cancer cells���. Scientists from Memorial Sloan-Kettering Cancer Center and Eureka Therapeutics have collaborated to create the new human monoclonal antibody, which targets a protein associated with many types of cancer and is of great interest to cancer researchers.
Unlike other human therapeutic monoclonal antibodies, which can target only proteins that remain on the outside of cancer cells, the new monoclonal antibody, called ESK1, targets a protein that resides on the inside of the cell. ESK1 is directed at a protein called WT1, which is overexpressed in a range of leukemias and other cancers including myeloma and breast, ovarian, and colorectal cancers. WT1 is a high priority target for cancer drugs because it is an oncogenic protein, meaning that it supports the formation of cancer. In addition, it is found in few healthy cells, so there are less likely to be side effects from drugs that target it. “This is a new approach for attacking WT1, an important cancer target, with an antibody therapy. This is something that was previously not possible,” said David A. Scheinberg, MD, PhD, Chair of the Sloan-Kettering Institute’s Molecular Pharmacology and Chemistry Program and an inventor of the antibody. “There has not been a way to make small molecule drugs that can inhibit WT1 function. Our research shows that you can use a monoclonal antibody to recognize a cancer-associated protein inside a cell, and it will destroy the cell.” The first studies of the antibody are showing promise in preclinical research as a treatment for leukemia as reported March 13, 2013, in Science Translational Medicine. “ESK1 represents a paradigm change for the field of human monoclonal antibody therapeutics,” said Cheng Liu, PhD, President and Chief Executive Officer of Eureka Therapeutics. “This research suggests that human antibody therapy is no longer limited to targeting proteins present outside cancer cells, but can now target proteins within the cancer cell itself.” ESK1 was engineered to mimic the functions of a T cell receptor, a key component of the immune system. T cells have a receptor system that is designed to recognize proteins that are inside the cell. As proteins inside the cell get broken down as part of regular cellular processes, molecules known as HLA molecules carry fragments of those proteins ? known as peptides ? to the surface. When T cells recognize certain peptides as abnormal, the T cell kills the diseased cell. In the current study, the investigators showed that ESK1 alone was able to recognize WT1 peptides and kill cancer cells in the test tube and also in mouse models for two different types of human leukemia. “We were surprised that the antibody worked so well on its own,” said Dr. Scheinberg, senior author of the paper. “We had originally expected that we might need to use the antibody as a carrier to deliver a drug or a radioactive therapy to kill the cancer cells, but this was not necessary.” Additional studies must be done in the laboratory before ESK1 is ready to be tested in patients. But the monoclonal antibody was engineered to be fully human, which should speed the time it takes to move the drug into the clinic. Researchers expect that the first clinical trials, for leukemia, could begin in about a year. The antibody was developed under a collaborative effort between Memorial Sloan-Kettering and Eureka, which have jointly filed for patent protection���. ### This work was supported by grants from the Leukemia and Lymphoma Society, the National Cancer Institute, the Sloan-Kettering Institute’s Experimental Therapeutics Center and Technology Development Fund, the Commonwealth Foundation for Cancer Research, the Tudor and Glades Foundations, the Merker Fund, the Lymphoma Foundation, and the Mesothelioma Applied Research Foundation. About Memorial Sloan-Kettering Cancer Center Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to http://www.mskcc.org. About Eureka Therapeutics Eureka Therapeutics is a privately held biotechnology company located in the San Francisco Bay Area, focused on the discovery of fully-human antibody drugs for the treatment of cancer. Utilizing its antibody drug discovery and engineering technologies, Eureka is advancing safe and effective therapies for targeting previously inaccessible cancer antigens. The company has built an early stage pipeline of innovative drugs, with the most advanced candidate at pre-clinical stage in collaboration with Memorial Sloan-Kettering Cancer Center. For more information about Eureka Therapeutics, please visit: http://www.eurekainc.com. Contact: Caitlin Hool |
| Sleep discovery could lead to therapies that improve memory Posted: 10 Mar 2013 09:00 PM PDT A team of sleep researchers led by UC Riverside psychologist Sara C. Mednick has confirmed the mechanism that enables the brain to consolidate memory and found that a commonly prescribed sleep aid enhances the process. Those discoveries could lead to new sleep therapies that will improve memory for aging adults and those with dementia, Alzheimer’s and schizophrenia.
The groundbreaking research appears in a paper, “The Critical Role of Sleep Spindles in Hippocampal-Dependent Memory: A Pharmacology Study,” published in the Journal of Neuroscience. Earlier research found a correlation between sleep spindles ? bursts of brain activity that last for a second or less during a specific stage of sleep ? and consolidation of memories that depend on the hippocampus. The hippocampus, part of the cerebral cortex, is important in the consolidation of information from short-term to long-term memory, and spatial navigation. The hippocampus is one of the first regions of the brain damaged by Alzheimer’s disease. Mednick and her research team demonstrated, for the first time, the critical role that sleep spindles play in consolidating memory in the hippocampus, and they showed that pharmaceuticals could significantly improve that process, far more than sleep alone. In addition to Mednick the research team includes: Elizabeth A. McDevitt, UC San Diego; James K. Walsh, VA San Diego Healthcare System, La Jolla, Calif; Erin Wamsley, St. Luke’s Hospital, St. Louis, Mo.; Martin Paulus, Stanford University; Jennifer C. Kanady, Harvard Medical School; and Sean P.A. Drummond, UC Berkeley. “We found that a very common sleep drug can be used to increase verbal memory,” said Mednick, the lead author of the paper that outlines results of two studies conducted over five years with a $651,999 research grant from the National Institutes of Health. “This is the first study to show you can manipulate sleep to improve memory. It suggests sleep drugs could be a powerful tool to tailor sleep to particular memory disorders���.” A total of 49 men and women between the ages of 18 and 39 who were normal sleepers were given varying doses of zolpidem (Ambien) or sodium oxybate (Xyrem), and a placebo, allowing several days between doses to allow the pharmaceuticals to leave their bodies. Researchers monitored their sleep, measured sleepiness and mood after napping, and used several tests to evaluate their memory. The researchers found that zolpidem significantly increased the density of sleep spindles and improved verbal memory consolidation. “(P)harmacologically enhancing sleep spindles in healthy adults produces exceptional memory performance beyond that seen with sleep alone or sleep with the comparison drug (sodium oxybate),” the sleep researchers wrote. “? The results set the stage for targeted treatment of memory impairments as well as the possibility of exceptional memory improvement above that of a normal sleep period.” Mednick said one of the next steps in this line of research is to determine which component of the physical response to Ambien ? the amnesia associated with the drug, or something related to a specific aspect of sleep ? is responsible for increasing the density of sleep spindles and the resulting consolidation of memory. She also hopes to study the impact of zolpidem on older adults, who experience poor declarative memory and also decreased sleep spindles. Individuals with Alzheimer’s, dementia and schizophrenia also experience decreases in sleep spindles. “Could we find a dose response, for example, the more Ambien, the more benefit?” she asked. Sleep is a very new field of research and its importance is generally not taught in medical schools, Mednick said. “We know very little about it,” said Mednick, who began studying sleep in the early 2000s with research into how naps benefit perceptual learning. “We do know that it affects behavior, and we know that sleep is integral to a lot of disorders with memory problems. We need to integrate sleep into medical diagnoses and treatment strategies. This research opens up a lot of possibilities.” Contact: Bettye Miller |
| Clot-busting drug as effective as angioplasty Posted: 10 Mar 2013 09:00 PM PDT A clot-busting therapy may benefit some heart attack patients who cannot have immediate angioplasty, according to research presented today at the American College of Cardiology’s 62nd Annual Scientific Session.
“Drug therapy before transfer is at least as effective as [angioplasty], and an urgent catheterization was avoided in two-thirds of patients,” said Frans Van de Werf, MD, PhD, professor of cardiology at University of Leuven, Belgium, and the study’s lead investigator. “It gives [clinicians] time to consider other options, such as [coronary artery bypass graft] and medical therapy.” The Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial included 1,915 patients from 15 countries. All had ST-elevation myocardial infarction (STEMI), a type of heart attack caused by a blood clot completely blocking one of the heart’s arteries. Patients were first seen in community hospitals or by emergency medical personnel. In these settings, immediate angioplasty?the preferred first-line treatment for STEMI?was not possible until patients were transferred to a major medical center. Before transfer, subjects were randomized to either angioplasty?also called PCI, or percutaneous coronary intervention?immediately after arrival or to drug therapy with tenecteplase plus enoxaparine, clopidogrel and aspirin before arrival. When patients on tenecteplase reached a medical center, about one-third needed urgent angioplasty. The other two-thirds did not. They received an angiogram an average of 17 hours after arrival. Based on the results of the angiogram, patients received either PCI or coronary artery bypass graft surgery under non-urgent circumstances. The primary endpoint was a composite of all-cause mortality, shock, congestive heart failure and subsequent heart attack within 30 days. Results were similar between the immediate PCI group and the tenecteplase group (14.3 vs. 12.4 percent, p=0.211). There were no differences in cardiac-specific mortality or cardiac rehospitalization. Patients receiving tenecteplase were more likely to have normal blood flow on an angiogram, compared with the PCI-only group (58 vs. 21 percent). They were less likely than the PCI-only group to have an angiogram show complete blockage of an artery (16 vs. 59 percent). More tenecteplase patients than PCI-only patients eventually underwent coronary artery bypass graft surgery. During the course of the trial, researchers halved the dose of tenecteplase in people ages 75 and older to minimize cranial bleeding, a common complication of clot-busting therapy. The incidence of such bleeding in the total study population was 0.5 percent after the dose reduction. “We offer this pharmaceutical strategy with timely coronary angiography as an alternative to primary PCI,” Dr. Van de Werf said. “We believe that it may be helpful in some early-presenting patients for whom immediate PCI is not possible.” ### The study was funded by Boehringer Ingelheim. Dr. Van de Werf’s institution, the University of Leuven, received a grant from Boehringer Ingelheim to conduct the STREAM trial, as well as funding for a study of dabigatran in patients with a mechanical heart valve. The ACC’s Annual Scientific Session brings together cardiologists and cardiovascular specialists from around the world each year to share the newest discoveries in treatment and prevention. Follow @ACCMediaCenter and #ACC13 for the latest news from the meeting. The American College of Cardiology is a nonprofit medical society comprised of 43,000 physicians, surgeons, nurses, physician assistants, pharmacists and practice managers. The College is dedicated to transforming cardiovascular care, improving heart health and advancing quality improvement, patient-centered care, payment innovation and professionalism. The ACC also leads the formulation of important cardiovascular health policy, standards and guidelines. It bestows credentials upon cardiovascular specialists, provides professional education, supports and disseminates cardiovascular research, and operates national registries to measure and promote quality care. For more information, visit cardiosource.org. This study will be simultaneously published online in the New England Journal of Medicine at the time of presentation. Dr. Van de Werf will be available to the media on Sunday, March 10, at 12:30 p.m., in Moscone Center, South, Room 300. Dr. Van de Werf will present “The STREAM Trial” on Sunday, March 10, at 10:45 a.m., in Moscone Center, South, Esplanade Ballroom. Contact: Beth Casteel |
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