News Article | November 2, 2016
Researchers at the National Institutes of Health (NIH) have developed a new, less invasive way to perform transcatheter aortic valve replacement (TAVR), a procedure widely used to treat aortic valve stenosis, a lethal heart condition. The new approach, called transcaval access, will make TAVR more available to high risk patients, especially women, whose femoral arteries are too small or diseased to withstand the standard procedure. The Journal of the American College of Cardiology published the findings. Aortic valve stenosis involves the narrowing of the heart's aortic valve which reduces blood flow through the heart. For about 85 percent of patients with this condition, doctors typically perform TAVR through the femoral artery in the leg. But for the other 15 percent, doctors must find a different access route. The most common alternative routes are through the chest, which requires surgery and are associated with significantly more complications. Transcaval access, which can be performed in awake patients, involves electrifying a small wire so that it crosses between neighboring blood vessels in the abdomen. The technique calls for making large holes in both the abdominal aorta and the inferior vena cava, which physicians previously considered dangerous because of the risk of fatal bleeding. The new method was developed by researchers at the National, Heart, Lung and Blood Institute (NHLBI) and tested in a trial on 100 patients at 20 hospitals across the United States. Researchers said it proved successful in 99 of the patients. "This is a seminal study," said the lead author, cardiologist Adam B. Greenbaum, M.D., co-director of the Henry Ford Hospital Center for Structural Heart Disease, Detroit. "It challenged conventional wisdom, objecting to the idea of safe passage between the vena cava and the aorta. More important, it is the first of many non-surgical minimally-invasive tissue-crossing, or so-called transmural catheter procedures developed at NIH that can be applied to diverse fields of medicine." Robert J. Lederman, M.D., a senior investigator in NHLBI's Division of Intramural Research who led the study, said researchers developed the method to address a specific clinical need, even though they knew it would be a challenging proposition for most surgeons and physicians to accept. The proposed and counterintuitive mechanism of action is that bleeding from the aorta spontaneously decompresses into a corresponding hole the physician makes in the vein, because the surrounding area behind the peritoneum has higher pressure than the vein. The results of the research, which were independently confirmed by a committee of outside cardiologists, show the procedure not only has a high success rate, but also an acceptable rate of bleeding and vascular complications, particularly in the high risk patients studied. The study builds on the access technique that Lederman's NHLBI team developed and first tested in animals in 2012 and first applied with Henry Ford physicians to help patients in 2013. NHLBI and its collaborators are now working to find ways to train more specialists to perform the procedure. The study will also be presented on Monday, October 31 at the Transcatheter Cardiovascular Therapeutics conference in Washington, D.C. Co-authors include researchers from Henry Ford Hospital; Emory University, Atlanta; Oklahoma Heart Institute, Tulsa; Lexington Medical Center, West Columbia, South Carolina; and Oschner Medical Center, New Orleans.
News Article | November 21, 2016
Researchers from North Carolina State University and the National Institutes of Health (NIH) have developed a method that stops allergic reactions by removing a key receptor from mast cells and basophils. Their work has implications for the treatment of skin allergies and asthma. Allergic reactions are driven by mast cells and basophils - types of inflammatory cells found in tissues and the bloodstream, respectively, that function as part of our immune system. When you come into contact with an allergen - ragweed, for example - immunoglobulin E (IgE) specific to that allergen acts through its receptor on the mast cell, stimulating the mast cells and basophils to release mediators, such as histamine, that trigger an allergic response. Currently, most allergy treatments focus on either stopping the effects of histamine and other mediators or on dampening the body's overall immune response by use of steroids. Unfortunately neither approach is totally effective, and in the case of dampening the immune response, can have significant drawbacks. Glenn Cruse, formerly of the NIH, current assistant professor of immunology at NC State and corresponding author of a paper describing the work, along with NIH colleague and co-author Dean Metcalfe, wanted to try and block the allergic reaction at its source. Cruse and Metcalfe looked at a gene called MS4A2, which is only expressed in mast cells and basophils, and is responsible for forming the IgE receptor on the mast cell. The researchers utilized a technique known as exon skipping, a form of RNA splicing, to eliminate the portion of one of the IgE receptor gene's mRNA that is essential to making a protein which places the IgE receptor on the mast cell surface. The cell's DNA remains unaffected. When the exon targeting therapy is stopped, the protein blocked by exon skipping is made again. Cruse and Metcalfe tested their therapy on mast cells in vitro - where it eliminated activation of mast cells by allergen - and against allergic dermatitis in vivo, using a mouse model. Their results in vivo showed a marked reduction in the allergic dermatitis response in the mice. "Asthma and allergic diseases affect up to 20 percent of people in developed countries, and their prevalence is increasing," says Cruse. "By eliminating the expression of the IgE receptor on the surface of mast cells, we have identified an innovative and targeted approach with the potential to treat allergic inflammation in millions of patients worldwide. "Due to the specificity of our approach for mast cells and basophils, it should have significant advantages over current therapies. However, it is important to note that while our findings are very promising, we are still in the early stages of developing this therapeutic approach." The research appears in Proceedings of the National Academy of Sciences. Funding was provided by the NIH Division of Intramural Research of NIAID and NHLBI. Note to editors: An abstract of the paper follows "Exon skipping of FcεRIβ eliminates expression of the high affinity IgE receptor in mast cells with therapeutic potential for allergy" Authors: Glenn Cruse, North Carolina State University and National Institutes of Health;, Tomoki Fukuyama, Greer K. Arthur, Wolfgang Bäumer, North Carolina State University; Yuzhi Yin, Avanti Desai, Michael A. Beaven and Dean D. Metcalfe, National Institutes of Health Published: Proceedings of the National Academy of Sciences Abstract: Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high affinity IgE receptor (FcεRIβ) to eliminate surface high affinity IgE receptor (FcεRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FcεRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of FcεRIβ is a potential approach for mast cell-specific treatment of allergic diseases.
News Article | February 16, 2017
A mutation that impacts changes in the shape of an essential viral protein may influence the infectivity of West Nile and other viruses in the flavivirus family, according to a new study in PLOS Pathogens. Flaviviruses are responsible for many diseases of global health importance, including West Nile, dengue, and Zika fevers. However, many of these diseases have no effective vaccines or treatments. Some researchers, including Leslie Goo of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, Maryland, hope that a better understanding of how flaviviruses interact with the immune system's antibodies could enable better prevention and treatment. In the new study, Goo led a research team in carrying out a series of experiments to test the effects of different mutations in a flavivirus protein called envelope (E) protein, which plays a major role in infection. Using E protein from West Nile, they identified a mutation called T198F that makes E protein more sensitive to inhibition with antibodies. E protein is known to change shape in a process known as "viral breathing," which alternately hides and exposes certain parts of the protein. Further experiments revealed that T198F occurs in a part of E protein that regulates viral breathing, resulting in exposure of another, otherwise poorly accessible part of the protein. The scientists introduced the T198F mutation into different flaviviruses and found that, in West Nile and dengue, but not in Zika, it did indeed increase accessibility of a relatively hidden protein region, making this region more vulnerable to antibodies. When introduced into mice, West Nile virus containing this mutation reduced infectivity and disease severity. Further research is needed to better understand E protein viral breathing behavior, as well as how it impacts flavivirus infection in mice and, possibly, humans. The resulting knowledge could help pave the way to new vaccines and antiviral drugs. In your coverage please use this URL to provide access to the freely available article in PLOS Pathogens: http://dx. Citation: Goo L, VanBlargan LA, Dowd KA, Diamond MS, Pierson TC (2017) A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis. PLoS Pathog 13(2): e1006178. doi:10.1371/journal.ppat.1006178 Funding: This work was supported by grants from the Burroughs Wellcome Fund (MSD) and the National Institutes of Health (R01 AI073755) (MSD), and by the National Institute of Allergy and Infectious Diseases Division of Intramural Research (TCP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
News Article | November 22, 2016
The parasite that causes river blindness infects about 37 million people in parts of Africa and Latin America, causing blindness and other major eye and skin diseases in about 5 million of them. A study from Washington University School of Medicine in St. Louis sheds light on the genetic makeup of the parasite, a step toward the goal of eradication. The study appears Nov. 21 in the journal Nature Microbiology, along with a companion paper also focused on the genetics of the parasite. "In West Africa, there are two separate strains of this parasite based on geographic areas -- the savanna strain and the forest strain," said senior author Makedonka Mitreva, PhD, an associate professor of medicine. "The severity of the disease caused by each strain is very different. The savanna strains are much more virulent and have been associated with higher rates of blindness. The forest strains cause a mild skin disease. That's why we wanted to see how they differ genetically." The parasite is a roundworm called Onchocerca volvulus and is carried by black flies that thrive near rivers and streams. Large-scale efforts to control the disease have been underway for decades, with mass drug-administration programs beginning in the 1970s in West Africa and in Central Africa and Central and South America in the early 1990s. The drug ivermectin remains the first-line treatment to target the parasite. The drug's discoverers were honored with the Nobel Prize in Physiology or Medicine just last year. With this treatment success combined with insect-control programs to reduce black fly populations, the World Health Organization (WHO) has set a goal of eliminating the river blindness parasite by 2025. But after several decades of exposure to ivermectin, these parasites are beginning to show resistance. "We want to understand the origin of this resistance," said Mitreva, who also is an assistant director of The McDonnell Genome Institute at Washington University. "Are these parasites evolving to survive the treatment, or are the surviving worms actually new strains that have been introduced due to migration of the black flies or of the parasite itself?" To find out, Mitreva and her colleagues studied samples of the roundworms that have been stored since the early 1990s, before large-scale ivermectin treatment programs began. They also are sequencing present-day strains for comparison. The current study reports data only from the historical samples. "We worked hard to find samples of the parasite that had not been exposed to the drug because we needed to establish an ancestral baseline," Mitreva said. "The current worm populations and their genomes have been strongly shaped by 30 years of massive drug-administration programs. So you can't just collect worm samples from these parts of the world today and sequence them. We had to look back in time." The new study included 27 roundworm samples taken in the early 1990s from four distinct regions -- West African forest, West African savanna, Uganda and Ecuador. According to Mitreva, the Uganda strains, collected in central Africa, could not be classified as either the forest or savanna strain. Similarly, the strains from Ecuador, in South America, were also very different from the African strains. Mitreva and her colleagues showed gene movement between the savanna and forest strains, but only in one direction. Genes from the savanna strain have flowed into the forest strain but not vice versa. This is due to differences in climate and the versatility of the black flies that carry the parasite. "Black flies in the savanna region are known to survive in the forest region," Mitreva said. "They can fly longer distances and live in the forest environment. But the forest black flies can't survive in the savanna." The new study also included the complete genome sequence of a type of bacteria living in the parasite that the worm relies on for survival. Past evidence suggested that the more bacteria living in the parasites, the more severe the infection. But Mitreva said the current study does not support that observation. The investigators also are sequencing the same bacteria from present-day strains to see what, if anything, may have changed about them over the past three decades. In general, Mitreva said, large-scale control efforts -- including mass treatment with ivermectin and the use of insecticides to reduce black fly populations -- have been very effective over the past 30 years. But since pockets of drug resistance are showing up, she said studies such as this one are important if the WHO's goal of eliminating the parasite by 2025 is to be met. This work was supported by the National Institutes of Health (NIH), grant numbers U54HG003079 and R01AI081803; the Bill & Melinda Gates Foundation, grant number OPP GH 1083853; and by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID). Choi YJ, Tyagi R, McNulty SN, Rosa BA, Ozersky P, Martin J, Hallsworth-Pepin K, Unnasch TR, Norice CT, Nutman TB, Weil GJ, Fischer PU, Mitreva M. Genomic diversity in Onchocerca volvulus and its Wolbachia endosymbiont. Nature Microbiology. Nov. 21, 2016. Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
News Article | December 6, 2016
NEW YORK, Dec. 06, 2016 (GLOBE NEWSWIRE) -- Dr. Michael Irwin, Director and Cousins Distinguished Professor of Psychiatry at UCLA Medical Center, has been selected to join the Physician Board at the American Health Council. He will be sharing his knowledge and expertise in the areas of Neuropsychiatry, Psychiatry, and Psychoneuroimmunology. A photo accompanying this announcement is available at http://www.globenewswire.com/NewsRoom/AttachmentNg/d330d72a-0ea3-4752-844f-fd3d59a8468d Dr. Irwin has been active in the healthcare industry for the past 35 years. He obtained his MD from the University of California, San Diego, in 1981, and completed his Residency at the UCLA School of Medicine in 1985. Dr. Irwin’s strong interest in behavioral health led him to his current profession. His day-to-day responsibilities include research regarding how inflammation can affect depression and the regulation of the immune system and oversight of a staff of 50 and a junior staff of 5 direct reports. He is also responsible for over $5 million worth of NIH funding. Dr. Irwin attributes his success to luck and opportunity, hard work, being intuitive, attending and working for an excellent school, and the amazing support of his family. Among his many accomplishments, he is most proud of those that he has mentored and trained and their great success. He has been published in over 340 research articles, 2 books, and several yearly lectures. His long-term goals include establish primary care models for the underserved. Dr. Irwin’s many awards and honors include the Early Career Award, American Psychosomatic Society (1991); President, Psychoneuroimmunology Research Society (2001); Member, National Advisory Council, Center for Complementary and Alternative Medicine (2001-2004); President, Academy of Behavioral Medicine Research (2003); Outstanding Faculty Research Mentor Award, UCLA School of Medicine (2005); Norman Cousins Research Award, Psychoneuroimmunology Research Society (2007); Chair, Blue Ribbon Intramural Research Strategic Planning Panel, NCCAM (2008); Distinguished Fellow, American Psychiatric Association (2008); Secretary Treasurer, American Psychosomatic Society (2008-2010); Lauda Wellness Award (2009); President-Elect/President, American Psychosomatic Society (2010-2011); Best Research Prize, European Society of Integrative Medicine (2014); and Chairperson, IH Centers for Scientific Review, Mechanisms of Emotion, Stress and Health Study Section (2014-2016). Dr. Irwin has received funding awards from the National Institute of Aging, National Cancer Institute, National Heart Lung and Blood Disorders Institute, National Institute of Alcoholism and Alcohol Abuse, National Institute of Arthritis and Musculoskeletal Disorders, National Institute of Drug Abuse, National Center for Complementary and Alternative Medicine (NCCAM), and the National Institute of Mental Health. Charitable organizations he is involved with include UCLA, Cornell University, and University of Pennsylvania. Dr. Irwin is proud to have had his research on Meditation published in the Los Angeles Times.
Ward E.,Intramural Research |
Desantis C.,Surveillance and Health Services Research |
Robbins A.,Surveillance and Health Services Research |
Kohler B.,North American Association of Central Cancer Registries |
Jemal A.,Surveillance and Health Services Research
CA Cancer Journal for Clinicians | Year: 2014
In this article, the American Cancer Society provides estimates of the number of new cancer cases and deaths for children and adolescents in the United States and summarizes the most recent and comprehensive data on cancer incidence, mortality, and survival from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries (which are reported in detail for the first time here and include high-quality data from 45 states and the District of Columbia, covering 90% of the US population). In 2014, an estimated 15,780 new cases of cancer will be diagnosed and 1960 deaths from cancer will occur among children and adolescents aged birth to 19 years. The annual incidence rate of cancer in children and adolescents is 186.6 per 1 million children aged birth to 19 years. Approximately 1 in 285 children will be diagnosed with cancer before age 20 years, and approximately 1 in 530 young adults between the ages of 20 and 39 years is a childhood cancer survivor. It is therefore likely that most pediatric and primary care practices will be involved in the diagnosis, treatment, and follow-up of young patients and survivors. In addition to cancer statistics, this article will provide an overview of risk factors, symptoms, treatment, and long-term and late effects for common pediatric cancers. © 2014 American Cancer Society, Inc.
Jemal A.,Surveillance Research |
Bray F.,International Agency for Research on Cancer |
Center M.M.,Surveillance Research |
Ferlay J.,International Agency for Research on Cancer |
And 2 more authors.
CA Cancer Journal for Clinicians | Year: 2011
The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally. ©2011 American Cancer Society, Inc.
Siegel R.,Surveillance Research |
Ward E.,Intramural Research |
Brawley O.,American Cancer Society |
Jemal A.,Surveillance Research
CA Cancer Journal for Clinicians | Year: 2011
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,596,670 new cancer cases and 571,950 deaths from cancer are projected to occur in the United States in 2011. Overall cancer incidence rates were stable in men in the most recent time period after decreasing by 1.9% per year from 2001 to 2005; in women, incidence rates have been declining by 0.6% annually since 1998. Overall cancer death rates decreased in all racial/ethnic groups in both men and women from 1998 through 2007, with the exception of American Indian/Alaska Native women, in whom rates were stable. African American and Hispanic men showed the largest annual decreases in cancer death rates during this time period (2.6% and 2.5%, respectively). Lung cancer death rates showed a significant decline in women after continuously increasing since the 1930s. The reduction in the overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 898,000 deaths from cancer. However, this progress has not benefitted all segments of the population equally; cancer death rates for individuals with the least education are more than twice those of the most educated. The elimination of educational and racial disparities could potentially have avoided about 37% (60,370) of the premature cancer deaths among individuals aged 25 to 64 years in 2007 alone. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population with an emphasis on those groups in the lowest socioeconomic bracket. © 2011 American Cancer Society, Inc.
Siegel R.L.,Intramural Research |
Ward E.M.,Intramural Research |
Jemal A.,Intramural Research
Cancer Epidemiology Biomarkers and Prevention | Year: 2012
Background: Results from case-control studies outside the United States have been conflicted about the efficacy of colonoscopy for reducing cancer risk in the right colon. To contribute to this discourse from an alternative perspective, we analyzed high-quality surveillance data to report on recent trends in populationbased colorectal cancer incidence rates by tumor location in the United States. Methods: Data from cancer registries in the Surveillance, Epidemiology, and End Results Program were analyzed to examine colorectal cancer incidence trends from 1992 through 2008 among individuals aged ≥50 years (n = 267,072). Joinpoint regression analysis was used to quantify annual percent change in agestandardized rates by tumor location and disease stage. Results: Incidence rates for right-sided colon tumors decreased annually by 2.6% (95% CI: 2.0-3.2) since 1999 in men and 2.3% (CI: 1.6-3.0) since 2000 in women, after remaining stable during the previous seven/eight years. Incidence rates for left-sided tumors were generally decreasing from 1992 to 2008 in both sexes. Beginning in 1999/2000, substantial, almost identical annual declines occurred for late-stage disease in both the right and left colon: 3.9% (CI: 3.1-4.8) and 4.2% (CI: 3.5-4.9), respectively, in men; and 3.3% (CI: 2.5-4.1) and 3.3% (CI: 2.8-3.8) in women. Conclusion: Large declines in the incidence of right-sided colon tumors among individuals 50 years and older began around 2000. Impact: Increased colonoscopy utilization during the past decademayhave contributed to a reduction in risk for cancers in both the right and left colorectum in the United States. ©2012 AACR.
Steenland K.,Emory University |
Ward E.,Intramural Research
CA Cancer Journal for Clinicians | Year: 2014
Silica has been known to cause silicosis for centuries, and evidence that silica causes lung cancer has accumulated over the last several decades. This article highlights 3 important developments in understanding the health effects of silica and preventing illness and death from silica exposure at work. First, recent epidemiologic studies have provided new information about silica and lung cancer. This includes detailed exposure-response data, thereby enabling the quantitative risk assessment needed for regulation. New studies have also shown that excess lung mortality occurs in silica-exposed workers who do not have silicosis and who do not smoke. Second, the US Occupational Safety and Health Administration has recently proposed a new rule lowering the permissible occupational limit for silica. There are approximately 2 million US workers currently exposed to silica. Risk assessments estimate that lowering occupational exposure limits from the current to the proposed standard will reduce silicosis and lung cancer mortality to approximately one-half of the rates predicted under the current standard. Third, low-dose computed tomography scanning has now been proven to be an effective screening method for lung cancer. For clinicians, asking about occupational history to determine if silica exposure has occurred is recommended. If such exposure has occurred, extra attention might be given to the early detection of silicosis and lung cancer, as well as extra emphasis on quitting smoking. CA Cancer J Clin 2014;64:63-69. © 2013 American Cancer Society, Inc. © 2013 American Cancer Society, Inc.