National Institute of Arthritis and Musculoskeletal and Skin Disease

Bel Air South, MD, United States

National Institute of Arthritis and Musculoskeletal and Skin Disease

Bel Air South, MD, United States
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News Article | June 29, 2017
Site: www.eurekalert.org

Cancer hides in plain sight of the immune system. The body's natural tumor surveillance programs should be able to detect and attack rogue cancer cells when they arise, and yet when cancer thrives, it does so because these defense systems have failed. A team of investigators led by Niroshana Anandasabapathy, MD, PhD, at Brigham and Women's Hospital have uncovered a critical strategy that some cancers may be using to cloak themselves - they find evidence of this genetic program across 30 human cancers of the peripheral tissue, including melanoma skin cancer. Their results are published June 29 in Cell. "Our study reveals a new immunotherapy target and provides an evolutionary basis for why the immune system may fail to detect cancers arising in tissues," said corresponding author Anandasabapathy, of BWH's Department of Dermatology. "The genetic program we report on helps the immune system balance itself. Parts of this program prevent the immune system from destroying healthy organs or tissues, but might also leave a blind spot for detecting and fighting cancer." The authors studied immune mononuclear phagocytes - a group of disparate cells that act as the "Pac man" of the immune system. When these cells detect foreign invaders and dying normal tissues, they devour or engulf their components. These cells then present these components on their surface teach T cells to maintain tolerance to healthy tissues, or to fight infections and pathogens. Despite differences in function, all immune mononuclear phagocytes found in the skin- (a peripheral tissue like lung and gut) share a common set of genetic programming, which is further enhanced when they enter the tissue. This program is conserved in fetal and adult development, and across species. And, the research team reports, is co-opted by multiple human cancers of tissue. The team finds that this program is prompted by an "instructive cue" from interferon gamma - a molecule that plays a critical role in regulating immunity. The authors find IFN-gamma for mononuclear phagocytes in development but that IFN-gamma and tissue immune signatures are much higher in skin cancer than in healthy skin. Having an immune response measured by IFN-gamma and tissue signatures correlated with improved metastatic melanoma survival outcomes, making these signatures potential biomarkers for cancer survival. The authors reasoned such a program might contain key molecules that help the immune system reduce inflammation, but that might also leave a blind spot to cancer detection. One of the key genes the researchers detected is suppressor of cytokine signaling 2 (SOCS2). When this gene was turned off in a mouse model, the immune system was able to robustly detect and reject cancer in models of melanoma and thymoma (cancer of the thymus). They also observed improved vaccination responses, and heightened auto-inflammation suggesting this gene normally dampens auto-inflammatory responses and contracts protective immunity. "Our research suggests that these cancers are co-opting tissue-specific immune development to escape detection, but we see that turning off SOCS2 unmasks them," said Anandasabapathy. "This sheds new light on our understanding of how the immune system is programed to see cancers and also points the way toward new therapeutic targets for treating cancers that have these signatures." This project was made possible through open collaborations between researchers from BWH, Princeton University, Rockefeller University, the Icahn School of Medicine at Mount Sinai, and the Broad Institute of MIT and Harvard. This work was supported by a 5T32AR007098, Dermatology Training Grant; the DFCI Wong Family Award for Translational Cancer Research; a T32GM07739 MSTP Grant; the Searle Scholars Program; the Beckman Young Investigator Program;the NIH New Innovator Award DP2OD020839; the Melanoma Research Alliance- BWH Department of Dermatology combined grant; the Cancer Research Institute; the Klarman Family Foundation; the National Institute of Arthritis and Musculoskeletal and Skin Disease R01AR070234 and K23 AR063461. Aviv Regev is on the SAB for ThermoFisher Scientific, Syros Pharmaceuticals and Driver Group. James Krueger is a consultant for Biogen. Levi Garraway was a consultant for Foundation Medicine, Novartis, Boehringer Ingelheim, Eli Lilly; an equity holder in Foundation Medicine; and a member of the Scientific Advisory Board at Warp Drive. Garraway also received grant support from Novartis. He is now an employee of Eli Lilly and Company. Paper cited: Nirschl CJ et al. "IFN-gamma-dependent tissue immune homeostasis is co-opted in the tumor microenvironment" Cell DOI: 10.1016/j.cell.2017.06.016 Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits and nearly 46,000 inpatient stays, is the largest birthing center in Massachusetts and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 3,000 researchers, including physician-investigators and renowned biomedical scientists and faculty supported by nearly $666 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.


News Article | May 9, 2017
Site: www.eurekalert.org

BOSTON -- Researchers from Hebrew Senior Life's Institute for Aging Research have discovered that foot pain - particularly severe foot pain - correlates to a higher incidence of recurrent falls. This finding also extends to those diagnosed with planus foot posture (flat feet), indicating that both foot pain and foot posture may play a role in falls among older adults. Using data from the Framingham Foot study, researchers found that foot pain and foot posture were not associated with any one fall; however, in the case of multiple falls, foot pain and foot posture were often a factor. These findings were published today in the journal Gerontology. "We know that having more than one fall can be of concern. Many don't think of feet as the culprit. However, higher odds of recurrent falls were seen for those with foot pain, especially severe foot pain, as well as those with planus foot posture, indicating that both foot pain and foot posture may play a role in falls," said Marian Hannan, Co -Director of the Musculoskeletal Research Center at the Institute for Aging Research and Associate Professor of Public Health, Harvard School of Public Health. "This is important because falls are a serious problem for older adults. They are a leading cause of hospitalization and often lead to a loss of independence, a decrease in quality of life, and sometimes death. With this new knowledge we hope to find more solutions to lessen the risk of falls in older adults," said Lead author Arunima Awale, Research Associate at Hebrew Senior Life's Institute for Aging Research. More than 30 percent of individuals over the age of 65 fall at least once a year. This figure increases to over 40% for persons aged 75 years or older. As a result of this study, scientists are hopeful that by lessening the instance of foot pain in older adults they can significantly reduce hospitalizations and loss of independence for American seniors. This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Disease and National Institute of Aging (grant number AR047853); and the National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195). About the Institute for Aging Research Scientists at the Institute for Aging Research seek to transform the human experience of aging by conducting research that will ensure a life of health, dignity and productivity into advanced age. The Institute carries out rigorous studies that discover the mechanisms of age-related disease and disability; lead to the prevention, treatment and cure of disease; advance the standard of care for older people; and inform public decision-making. The Aging Brain Center within IFAR studies cognitive aging and conditions affecting brain health. Hebrew SeniorLife, an affiliate of Harvard Medical School, is a national senior services leader uniquely dedicated to rethinking, researching and redefining the possibilities of aging. Founded in Boston in 1903, the nonprofit, non-sectarian organization today provides communities and health care for seniors, research into aging, and education for geriatric care providers. For more information about Hebrew SeniorLife, visit http://www. , follow us on Twitter @H_SeniorLife, like us on Facebook or read our blog.


News Article | November 7, 2016
Site: www.eurekalert.org

Scientists at Duke Health and Zhejiang Chinese Medical University have developed a strategy to stop the uncontrollable itch caused by urushiol, the oily sap common to poison ivy, poison sumac, poison oak and even mango trees. The team found that by blocking an immune system protein in the skin with an antibody, they could halt the processes that tell the brain the skin is itchy. The research was done in mice and is described in the Nov. 7 Proceedings of the National Academy of Sciences. They hope their model could lead to potential treatments for people who are allergic to poison ivy -- an estimated 80 percent of the population. For most people, contact with poisonous plants is painful but not life-threatening. Still, there are significant health care costs associated with more than 10 million people in the U.S. affected each year, said senior author Sven-Eric Jordt, Ph.D., associate professor of anesthesiology at Duke. "Poison ivy rash is the most common allergic reaction in the U.S., and studies have shown that higher levels of carbon dioxide in the atmosphere are creating a proliferation of poison ivy throughout the U.S. -- even in places where it wasn't growing before," Jordt said. "When you consider doctor visits, the costs of the drugs that are prescribed and the lost time at work or at school, the societal costs are quite large." Some symptoms of the fiery, blistering rash can be alleviated with antihistamines and steroids. But in recent years, scientists have determined that the most severe itching doesn't go away with antihistamines, because it arises from a different source, Jordt said. Jordt and collaborators determined the itch is triggered by interleukin 33 (IL-33), a protein in the skin involved in immune response. All people have IL-33 in their skin, but the protein is elevated in people who have eczema and psoriasis, Jordt said. The protein is known for inducing inflammation, but these new experiments show the protein also acts directly on the nerve fibers in the skin, exciting them and telling the brain that the skin is severely itchy. The researchers used an antibody to block IL-33 and found that it not only reduced inflammation, but also cut down scratching in mice with poison ivy rashes. An antibody that counteracts human IL-33 is currently being evaluated in humans through a Phase 1 clinical trial to determine its safety and potential side effects. In an additional approach tested in the mouse experiments, the researchers also found they could also alleviate itch by blocking a receptor for IL-33, called ST2. "There could be translational significance here," Jordt said. "So our next step will be to look at human skin to see if we see the same activity and the same pathways. We will also look at anti-inflammatory drugs that are already approved to see if they have the potential to alleviate itch." In addition to Jordt, study authors include Boyi Liu; Yan Tai; Satyanarayana Achanta; Melanie M. Kaelberer; Ana I. Caceres; Xiaomei Shao; and Jianqiao Fang. The research was supported by the Duke Anesthesiology DREAM Innovation Grant (2015-DIG LIU), Zhejiang Chinese Medical University Start-Up Funding (722223A08301/ 001/004), the National Natural Science Foundation of China (81603676) and three National Institutes of Health -- the National Center for Advancing Translational Sciences (UL1 TR001117), the National Institute of Environmental Health Sciences (R01 ES015056, U01 ES015674) and the National Institute of Arthritis and Musculoskeletal and Skin Disease (R21 AR070554). The authors declare no conflicts of interest.


Bulken-Hoover J.D.,National Institute of Arthritis and Musculoskeletal and Skin Disease | Bulken-Hoover J.D.,U.S. Army | Jackson W.M.,National Institute of Arthritis and Musculoskeletal and Skin Disease | Ji Y.,National Institute of Arthritis and Musculoskeletal and Skin Disease | And 5 more authors.
Molecular Biotechnology | Year: 2012

Peripheral nerve damage frequently accompanies musculoskeletal trauma and repair of these nerves could be enhanced by the targeted application of neurotrophic factors (NTFs), which are typically expressed by endogenous cells that support nerve regeneration. Injured muscle tissues express NTFs to promote reinnervation as the tissue regenerates, but the source of these factors from within the muscles is not fully understood. We have previously identified a population of mesenchymal progenitor cells (MPCs) in traumatized muscle tissue with properties that support tissue regeneration, and our hypothesis was that MPCs also secrete the NTFs that are associated with muscle tissue reinnervation. We determined that MPCs express genes associated with neurogenic function and measured the protein-level expression of specific NTFs with known functions to support nerve regeneration. We also demonstrated the effectiveness of a neurotrophic induction protocol to enhance the expression of the NTFs, which suggests that the expression of these factors may be modulated by the cellular environment. Finally, neurotrophic induction affected the expression of cell surface markers and proliferation rate of the MPCs. Our findings indicate that traumatized muscle-derived MPCs may be useful as a therapeutic cell type to enhance peripheral nerve regeneration following musculoskeletal injury. © Springer Science+Business Media, LLC 2011.

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