Scientists pinpoint mechanism that leads to steroid diabetes

first_imgReviewed by Kate Anderton, B.Sc. (Editor)Jan 25 2019Patients undergoing long-term treatment with steroids may suffer from metabolic side effects. Researchers at the Helmholtz Zentrum München and the Ludwig Maximilians University of Munich (LMU), partners in the German Center for Diabetes Research (DZD), have now pinpointed a mechanism that leads to so-called steroid diabetes. Their findings have been published in Nature Communications.”Glucocorticoids such as cortisone have been used to treat inflammatory diseases such as asthma or rheumatism for many decades, and they are the most commonly prescribed anti-inflammatory drugs,” explains Prof. Henriette Uhlenhaut, Group Leader at the Institute for Diabetes and Obesity (IDO) at the Helmholtz Zentrum München and the Gene Center of the LMU. “They are also frequently used in autoimmune diseases, organ transplantations and cancer. It is estimated that between one and three percent of the Western population are currently receiving these drugs – which corresponds to more than one million Germans alone.”Related StoriesIt is okay for women with lupus to get pregnant with proper care, says new studyChaos in the house and asthma in children – the connectionSugary drinks linked to cancer finds studyHowever, although glucocorticoids are prescribed for a wide range of conditions, their use is limited by the various side effects – including unwanted metabolic effects – that can occur during treatment. Once the glucocorticoids bind to their receptor inside the cell, the receptor starts switching numerous genes on and off. “These include various metabolic genes, which can consequently cause so-called steroid diabetes,” Henriette Uhlenhaut explains.In the current study, her team – together with colleagues from the Max Delbrück Center for Molecular Medicine in Berlin, the Salk Institute in San Diego and the University of Freiburg – set out to identify the exact sequence of events that occurs once the steroids bind their receptor.”What struck us most was the E47 transcription factor, which – along with the glucocorticoid receptor – is responsible for the changes in gene expression, particularly in liver cells,” explains Charlotte Hemmer, a doctoral candidate at the IDO and first author of the current study. “We were able to identify the underlying pathway by conducting genome-wide analyses and genetic studies.”In order to corroborate their findings, the scientists then proceeded to examine a preclinical model lacking the E47 gene. “The loss of E47 actually protected against the negative impact of glucocorticoids, while an intact E47 gene led to metabolic changes such as high blood sugar, elevated blood fat levels or a fatty liver as a response to steroid treatment,” Charlotte Hemmer adds.Since the components of the newly discovered mechanism are also conserved in humans, Henriette Uhlenhaut and her team, along with their clinical cooperation partners, would now like to find out whether their results can be translated to human studies. “If this is the case, it could open up new opportunities for therapeutic intervention and the use of safer immuno-suppressants in order to combat the side effects of steroid therapy.”​ Source: read more

Researchers study reason for burden of HLBS disorders in south rural communities

first_imgReviewed by James Ives, M.Psych. (Editor)May 23 2019People born in rural communities in the South, especially in southern Appalachia and the Mississippi Delta, may live shorter and less healthy lives than their counterparts elsewhere in the country, in part due to a high burden of heart, lung, blood and sleep disorders (HLBS). Within the same Southern regions, however, there are counties with very low risk of disease that have profiles of economic disadvantages, race/ethnicity, and rurality similar to those considered high risk.In an effort to understand why certain factors amplify risk in some rural counties and what renders some communities more resilient, researchers will be studying 4,000 multi-ethnic participants from 10 of the low-income rural counties in Kentucky, Alabama, Mississippi and Louisiana recruited into a new longitudinal cohort study. The Risk Underlying Rural Areas Longitudinal Study (RURAL) will allow researchers to learn what causes the burden of HLBS disorders in these communities and how to alleviate them.This multi-site prospective cohort study will be coordinated by Boston University School of Medicine’s Vasan Ramachandran, MD, FAHA, FACC, principal investigator and Boston University director of the renowned Framingham Heart Study, with which he has been affiliated for more than 20 years. Over fifty investigators at 16 institutions will participate in this six-year, $21.4 million study funded by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.Using a self-contained mobile examination unit, ‘a research center on wheels,’ a transdisciplinary team will conduct an approximately four-hour detailed baseline examination on the study participants. Familial, lifestyle and behavioral factors, along with medical history including risk for HLBS disorders will be recorded. Environmental and economic factors also will be studied and standard and novel risk factors for HLBS disorders will be assayed. Investigators will use smart phones and wearable activity monitors in order to help collect health and lifestyle information of the participants. The rural health challenge in the South does not spare any race or ethnicity. These high risk and economically disadvantaged rural communities are vulnerable to clusters of multiple health problems. We aim to understand the rural health challenges in the South and share our findings with and offer health education to these rural communities.”Vasan Ramachandran, Boston University School of Medicine Stephanie Boone, PhD, MPH, University of Louisville (Kentucky); Stephanie Broyles, PhD, LSU’s Pennington Biomedical Research Center; Ervin Fox, MD, MPH, University of Mississippi Medical Center; Suzanne Judd, PhD, University of Alabama at Birmingham and Paul Targonski, MD, PhD, University of Virginia at Charlottesville will play a central role in participant recruitment, retention, follow-up, data collection, return of results, community engagement and education.Source: Boston University School of Medicinelast_img read more

Research findings lead to new clinical trial for people with myelofibrosis

first_imgRelated StoriesOlympus launches next-generation X Line objectives for clinical, research applicationsScientists develop universal FACS-based approach to heterogenous cell sorting, propelling organoid researchOlympus Europe and Cytosurge join hands to accelerate drug development, single cell researchThe researchers worked to establish whether blocking the nuclear cytoplasmic transport process would slow the growth of myelofibrosis cells. To accomplish this, they generated a type of mouse with a specific mutation that leads to symptoms very similar to those experienced by myelofibrosis patients. When these mice were treated with the newly tested drug selinexor they responded just as well as those treated with ruxolitinib, and importantly, selinexor actually appeared to reduce the percentage of malignant cells.Based on these findings, the researchers designed a new clinical trial to study the effectiveness of selinexor in people with myelofibrosis. The clinical trial of selinexor in the treatment of relapsed/refractory myelofibrosis is now open at HCI. The researchers aim to enroll at least 24 patients who will receive the treatment in a setting that will allow for rigorous examination of any clinical benefit and monitoring of side effects. If this early trial indicates positive outcomes for patients, more extensive studies involving additional sites and more patients will be planned. Our results opened a new window for therapeutic intervention. By wonderful coincidence, selinexor, an inhibitor of this specific mechanism, is in clinical trials for certain blood cancers and now will be tested specifically in myelofibrosis patients.” Reviewed by James Ives, M.Psych. (Editor)Jun 20 2019Researchers at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) discovered in laboratory studies that an experimental drug called selinexor may block a crucial survival pathway exploited by myelofibrosis cells. Their study was published in Clinical Cancer Research, a journal of the American Association of Cancer Research. Based on these findings, they designed a clinical trial now open at HCI to examine this drug’s effectiveness in patients with myelofibrosis (National Clinical Trial 03627403)Myelofibrosis is a rare cancer that prevents the bone marrow from making healthy blood cells. Life expectancy varies, but most patients will not live beyond five years after the diagnosis. HCI treats about 25 newly diagnosed myelofibrosis patients a year.Srinivas Tantravahi, MBBS, MRCP, a physician-scientist at HCI and assistant professor of medicine at the U of U, takes care of patients with myelofibrosis, and says it is a very debilitating disease. “Essentially, it’s a bone marrow failure. The patient will experience severe symptoms including enlargement of the spleen, anemia, pain in the belly, fatigue, and a very poor quality of life,” says Tantravahi, who was part of the study team. “A stem cell transplant can potentially cure the disease, but most patients diagnosed with myelofibrosis are older or not healthy enough to undergo the weeks-long procedure.”A drug called ruxolitinib is the current primary treatment for myelofibrosis patients who are not healthy enough to receive a stem cell transplant. This drug can decrease spleen size, improve symptoms and improve quality of life, but it does not typically reduce the percentage of malignant cells. The lack of available therapies for myelofibrosis patients motivated the research team at HCI to look for new avenues for treatment. “Ruxolitinib is a fine drug, but its effects are mostly short-lived. And, until now, there were no other options for patients who aren’t healthy enough for a stem cell transplant,” said Dongqing Yan, PhD, a research associate in the Deininger/O’Hare Lab at HCI and lead author on the study.The team discovered myelofibrosis cells are highly sensitive to blockade a cellular process called nuclear-cytoplasmic transport.Anthony Pomicter, MS, manager of the Deininger/O’Hare lab explains: Source:Huntsman Cancer Institute The ability to advance a study like this from bench to bedside – from first discovery in a laboratory setting to first in the world clinical trial – is a credit to the unique environment at HCI. Myelofibrosis is a rare cancer, and it makes life miserable for those affected. It is extremely important that HCI and other institutions continue to push the discovery effort in all types of cancer, including rare diseases like myelofibrosis, so can we bring better treatment options to our patients.”Michael Deininger, MD, PhD, HCI senior director of transdisciplinary research and professor of medicine at the U of U, and senior author on the studylast_img read more