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News Article | February 15, 2017
Site: www.eurekalert.org

BOSTON - (February 14, 2017) - Joslin Diabetes Center will take part in two clinical trials this year to test artificial pancreas systems designed to automatically monitor and regulate blood glucose levels in people with type 1 diabetes, which would replace traditional methods of managing the disease such as testing blood glucose levels by finger stick or using continuous glucose monitoring systems with separate, non-integrated delivery of insulin by either injections or a pump. Lori Laffel, MD, MPH, Chief of the Pediatric, Adolescent, and Young Adult Section at Joslin Diabetes Center, is Principal Investigator at the Joslin site for the trials, which are among four major research efforts being funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) to test and refine artificial pancreas systems. If successful, the trials could lead to applications for regulatory approval for use of the devices by people with type 1 diabetes, helping to improve glucose control and reduce the burden of diabetes self-management. Joslin is a site for the International Diabetes Closed-Loop Trial being led by the University of Virginia in Charlottesville (UVA). The trial will provide clinical results of an automated insulin delivery system that features a reconfigured smartphone running advanced algorithms that link wirelessly to a continuous glucose monitor and an insulin pump that the patient wears, as well as a remote-monitoring site, aimed at keeping blood glucose levels in range. In addition, Joslin will be a site for a trial later this year that will compare a hybrid model of an artificial pancreas approved in September 2016 by the U.S. Food and Drug Administration to a next-generation system. One hundred adolescents and young adults (ages 14-30) will test each system for three months during the trial, which will be led by the International Diabetes Center in Minneapolis and the Schneider Medical Center in Israel. "We are entering an era of exceptional opportunity for patients living with type 1 diabetes, with regard to improving glycemic control and enhancing the quality of life for our patients," said Dr. Laffel. "We are very pleased at Joslin to contribute to advancing this initiative through our participation in this important research." The trials are funded under NIH grant numbers DK108483 and DK108611. Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is an independent, non-profit institution affiliated with Harvard Medical School, and one of only 11 NIH-designated Diabetes Research Centers in the U.S. For more information, please visit http://www. .


News Article | January 27, 2017
Site: www.medicalnewstoday.com

When a cell is dividing, two identical structures, called centrosomes, move to opposite sides of the cell to help separate its chromosomes into the new cells. More than 100 years ago, scientists observed that cancer cells often have more than two centrosomes, but they couldn't untangle whether the extra structures were a result of the cancer - or part of its cause. Now, biologists at Johns Hopkins have solved that conundrum, finding that extra centrosomes can single-handedly promote tumor formation in mice. Beyond revealing more about cancer initiation, the researchers believe that their mice represent a model for cancer research that more closely mimics the traits of human cancer than previously available strains. "Mouse models of cancer are usually produced by altering a single gene or a combination of genes known to fuel a particular type of cancer," says Andrew Holland, Ph.D., assistant professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and member of the Johns Hopkins Kimmel Cancer Center. "That often produces tumors in which every cell is genetically similar. But human tumors contain lots of variety, which may explain why they often don't respond to drugs the same way mice do." Michelle Levine, a Ph.D. candidate and the primary researcher on the project, adds, "Extra centrosomes generate genetic diversity in the mice, which creates tumors much more similar to human tumors." A summary of Holland's group's findings appears online in the journal Developmental Cell. During cell division, centrosomes help properly distribute chromosomes. When chromosome distribution goes wrong, each new cell inherits either too many or too few chromosomes. Holland says the condition, called aneuploidy, can be found in more than 90 percent of solid tumors in humans, suggesting a causal link. But, until now, there hadn't been a way to test how extra centrosomes contribute to aneuploidy and tumor formation. Previous experiments in lab-grown cells showed that elevated levels of the protein Plk4 caused an increase in centrosome numbers. Holland's team wanted to see if the same would happen in mice genetically engineered to produce extra Plk4, but the researchers knew that aneuploidy would be lethal during the delicate process of embryonic development. They engineered mice that would only produce extra Plk4 after being given the antibiotic doxycycline and waited until the mice were a month old to give them their first dose in their drinking water. After a month of doxycycline treatment, the researchers assessed the number of centrosomes in the mouse tissues. As suspected, they found many instances of excess centrosomes - in the skin, spleen, intestine, thymus, liver, pancreas and stomach. When they assessed chromosome numbers in cells from the skin and spleen, they found that up to one-third of them were aneuploid, indicating that the extra centrosomes were contributing to improper chromosome distribution. Holland says: "Faulty chromosome distribution causes an imbalance in how many copies of each gene a cell inherits. It also increases the chances of chromosomes being broken and subsequently swapping parts with each other. "Human cancers usually develop over decades," he says. "Some initial error - extra centrosomes, in this case - weakens the faithfulness with which chromosomes are duplicated and passed on to daughter cells. Then, every cell division is a chance for a cancer-promoting mutation to occur. Eventually, enough of these accumulate in a given tissue, and a tumor forms." Strikingly, half of the mice with high Plk4 levels developed cancer within nine to 18 months - when they were middle-aged - while none of the normal mice did. And each case of cancer originated in a tissue with elevated centrosome numbers, specifically the thymus, spleen and skin. "The evidence strongly suggests that it was extra centrosomes, not some unknown function of Plk4, that caused these tumors to form," says Holland. "First, we performed an experiment where we only increased levels of Plk4 for one month. In this case, extra centrosomes persisted after the excessive levels of Plk4 had declined, and the mice still developed tumors over a year later. Second, nearly every tissue in their bodies experienced high levels of Plk4, but it was only in those with extra centrosomes that we saw tumors form." Holland notes that not every tissue with extra centrosomes formed tumors - for example, the intestine. "While extra centrosomes can be sufficient to initiate tumor formation, they are not able to do so in every tissue," he says. "We don't yet know why this is, but we hope to address this in future studies." Additionally, some tissues, like the lungs and kidney, didn't make extra centrosomes, even though their levels of Plk4 were high. These tissues also failed to form tumors. Levine explains that extra centrosomes form only in dividing cells. The lungs and kidneys are relatively stable in an adult mouse, she says, so even though they did show high levels of Plk4, cells were not dividing frequently, and there was less centrosome multiplication. "That said, cells in the liver, pancreas and stomach showed high numbers of centrosomes but low rates of cell division, so there are probably unique things about each tissue that also contribute to the differences," she adds. Levine suggests that other mice could be genetically engineered to make extra centrosomes specifically in some of the tissues that didn't make them in this study. Ultimately, she thinks mice with extra centrosomes will become an invaluable tool for studying how cancer begins and how it can be defeated. Other authors of the report include Julia Moyett and James Lu of the Johns Hopkins University School of Medicine; Bjorn Bakker, Diana Spierings, Peter Lansdorp and Floris Foijer of the University of Groningen; Bram Boeckx and Diether Lambrechts of the Vesalius Research Center; Benjamin Vitre of the University of Montpellier; and Don Cleveland of the Ludwig Institute for Cancer Research. This work was supported by grants from Pew-Stewart Scholar Award, the Kimmel Cancer Center, a Johns Hopkins University School of Medicine Innovation Award, the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK09086), the National Institute of General Medical Sciences (GM 114119, GM 29513), the American Cancer Society (RSG-16-156-01-CCG), the Dutch Cancer Society (2012-RUG-5549) and the European Research Council (ROOTS-Grant Agreement 294740). Article: Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals, Andrew J. Holland et al., Developmental Cell, doi: 10.1016/j.devcel.2016.12.022, published 26 January 2017.


News Article | February 16, 2017
Site: www.eurekalert.org

DALLAS - Feb. 16, 2017 - A component of an enzyme family linked to DNA repair, stress responses, and cancer also plays a role in enhancing or inhibiting major cellular activities under physiological conditions, new research shows. The UT Southwestern Medical Center research focused on PARP-1, a member of the PARP enzyme family. Short for poly (ADP-ribose) polymerase, PARP became the focus of attention in 2014 with approval of the first PARP inhibitor drug to treat advanced ovarian cancer associated with mutant BRCA DNA repair genes. The drug, Lynparza or olaparib, blocks nuclear PARP enzymes, inhibiting DNA repair even further and causing genome instability that kills the cancer cells. In two related studies published in Molecular Cell, UT Southwestern scientists describe how PARP-1 can act at a molecular level under physiological conditions to reduce the formation of fat cell precursors and to help maintain the unique ability of embryonic stem cells to self-renew and become any of a variety of different cell types. One of the studies is published online today; the earlier study posted Jan. 19. PARP-1's role in these cellular processes occurs during gene transcription, when DNA is copied into messenger RNA molecules, which can then be used as a template to produce new proteins. Researchers already knew about PARP's role in DNA damage-related diseases like cancer, said Dr. W. Lee Kraus, senior author of both UTSW studies and Professor of Obstetrics and Gynecology, and Pharmacology at UT Southwestern. Dr. Kraus also directs the Cecil H. and Ida Green Center for Reproductive Biology Sciences and holds the Cecil H. and Ida Green Distinguished Chair in Reproductive Biology Sciences. These findings take the field in a new direction, Dr. Kraus said. "Our research shows that PARP-1 also plays a role in normal physiological processes and normal cellular functions. It's an important component of the cellular machinery that senses and responds to the environment," he said. While studies in mouse models show PARP-1 is not essential for life, it becomes important when an organism needs to adapt to changing environmental or physiological cues, such as developmental processes or altered diet, Dr. Kraus said. Understanding how PARP-1 works could one day help researchers find ways to target the protein to treat metabolic disorders or obesity, he said. The two new UT Southwestern studies outline for the first time the exact molecular mechanisms of PARP-1's roles in inhibiting the formation of fat cell precursors and in maintaining stem cells. Here are the key findings: Dr. Ziying Liu, a former graduate student and current postdoctoral researcher, was lead author of the study released today. Co-first authors of the earlier study were Dr. Xin Luo, a former graduate student and current data scientist, and Keun Woo Ryu, a graduate student. Other authors contributing to one or both studies were Dr. Dae-Seok Kim, Dr. Rebecca Gupte, and Dr. Bryan Gibson, postdoctoral researchers; Tulip Nandu, computational biologist; Dr. Yonghao Yu, Assistant Professor of Biochemistry and a Virginia Murchison Linthicum Scholar in Medical Research; and Dr. Rana Gupta, Assistant Professor of Internal Medicine. Researchers from the Perelman School of Medicine at the University of Pennsylvania also contributed. The study was supported by funding from the National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases, the Department of Defense Breast Cancer Research Program, the American Heart Association, the Welch Foundation, and the Cecil H. and Ida Green Center for Reproductive Biology Sciences. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. To automatically receive news releases from UT&bsp;Southwestern via email, subscribe at http://www.


News Article | February 28, 2017
Site: www.eurekalert.org

Teens and young adults with type 2 diabetes develop kidney, nerve, and eye diseases - as well as some risk factors for heart disease - more often than their peers with type 1 diabetes in the years shortly after diagnosis. The results are the latest findings of the SEARCH for Diabetes in Youth study, published Feb. 28 in the Journal of the American Medical Association. Funded by the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC), SEARCH researchers examined how quickly and often youth developed signs of kidney, nerve and eye diseases, among the most common complications of diabetes. They also measured several risk factors for heart disease. Participants had diabetes an average of under eight years at the end of the study. Though youth with type 2 diabetes showed signs of complications more often in nearly every measure than their peers with type 1, many youth in both groups developed complications. "There's often the assumption that young people don't develop complications from diabetes, but that's just not true. We saw that young people with diabetes are developing signs of major complications in the prime of their lives," said Dr. Barbara Linder, a study author and senior advisor for childhood diabetes research within the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "Particularly for youth with type 2, this research demonstrates the clear need to learn how to reduce or delay the debilitating complications of diabetes, itself a huge challenge for young people to manage." SEARCH examined 1,746 youth with type 1 diabetes (averaging about 18 years old) and 272 with type 2 diabetes (average age about 22) between 2002-2015. All were diagnosed before age 20. Youth were identified at five clinical centers - Kaiser Permanente Southern California in Pasadena, University of Colorado in Denver, Cincinnati Children's Hospital Medical Center, University of North Carolina at Chapel Hill, and Seattle Children's Hospital. Wake Forest University in Winston-Salem, North Carolina, served as coordinating center. The researchers looked at factors including glucose control, body mass index, waist-to-height ratio and blood pressure, but no factor could explain why people with type 2 developed more complications than counterparts with type 1. By about age 21, about 1/3 of participants with type 1 diabetes and about 3/4 of participants with type 2 had at least one complication from diabetes or were at high risk for a complication. "This study highlights the need for early monitoring for development of complications among young people with diabetes," said Dr. Sharon Saydah, senior scientist at CDC and an author on the paper. "If young people can delay onset of these complications from diabetes by even a few years, that can ease their burden and lengthen their lives." Type 1 diabetes typically develops in young people. In type 1, the body does not make insulin, a hormone needed to live. In type 2 diabetes, the body does not make enough insulin or does not use insulin well. In the past, type 2 diabetes was extremely rare in youth, but occurrences have risen alongside the obesity epidemic. Find health information on diabetes at https:/ . About the CDC: CDC works 24/7 saving lives and protecting people from health threats to have a more secure nation. Whether these threats are chronic or acute, manmade or natural, human error or deliberate attack, global or domestic, CDC is the U.S. health protection agency. The NIDDK, part of the NIH, conducts and supports basic and clinical research and research training on some of the most common, severe, and disabling conditions affecting Americans. The Institute's research interests include: diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. For more information, visit http://www. . About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .


News Article | February 15, 2017
Site: www.prweb.com

A novel interventional radiology technique for weight loss is safe and well tolerated in morbidly obese individuals, according to a new study appearing in the online edition of Radiology. Though the results are preliminary, the technique has the potential to be a new weapon in the war on obesity. Obesity—defined as a body mass index (BMI), or measure of body fat based on weight and height, of 30 or more—is a major public health problem that affects more than one-third of Americans, according to the National Institute of Diabetes and Digestive and Kidney Diseases. Obese people face an increased risk of diabetes, stroke, heart attack and other major health issues. Traditional approaches like a low-calorie diet, behavior modification, exercise and medication have shown limited effectiveness. One of the more successful interventions has been bariatric surgery, but its invasiveness can result in significant complications. Trans-arterial embolization of the gastric fundus, also known as bariatric embolization, has emerged in recent years as another potential weight-loss tool. The technique itself has been used for decades to stop bleeding in the gastric artery, but the idea of using it to treat obesity arose more recently based on observations of hormonal changes in patients who underwent bariatric surgery. “A number of research papers in the 1990s found signs of hormonal changes after bariatric surgery,” said the study’s lead author, Clifford R. Weiss, M.D., from the Johns Hopkins University School of Medicine in Baltimore. “In particular, there was a pretty rapid reduction in ghrelin, the most potent hunger-stimulating hormone we know. The hormone is produced in an area of the stomach called the fundus, which is fed primarily by the left gastric artery.” In bariatric embolization, very small, bead-like particles are introduced into the left gastric artery, using imaging guidance and minimally invasive techniques. Once in place, they obstruct the circulation of blood, leading to ischemia and a reduction in ghrelin production. Researchers at the Johns Hopkins University School of Medicine have developed and studied the technique for weight loss over the last 10 to 12 years, Dr. Weiss said. This phase of the study (June 2014 to August 2015) included results from the first five patients, four of whom were women. Prior to intervention, the patients were morbidly obese, with a mean BMI of 43.8. Using fluoroscopic guidance, interventional radiologists were able to embolize the left gastric artery in all five patients with 300- to 500-micrometer beads. The patients experienced an average weight loss of 5.9 percent at one month and 9.0 percent at three months. Serum ghrelin levels dropped 17.5 percent, on average, at three months. There was a trend toward improvement in quality-of-life parameters. There were no major adverse events in the study group. Dr. Weiss, along with co-principal investigator, Aravind Arepally, M.D., from Piedmont Healthcare, used embolic beads that were approximately 10 times larger than the beads used in the preclinical studies, as smaller beads are thought to increase the risk of gastric ulceration. However, performing gastric artery embolization with smaller beads may produce a greater reduction in ghrelin, so future studies may be needed to examine the clinical benefits of smaller-caliber spheres. “These are very promising and exciting results,” Dr. Weiss said. “I think this paper and the additional data we’re compiling show that bariatric embolization is very well tolerated by patients, and there are signs that it could have medium- and long-term efficacy for weight loss.” Dr. Weiss and colleagues will complete the study in the fall and have all the data collected by the end of the year. They can then do a more definitive study on efficacy, Dr. Weiss said, with a larger number of patients and a focus on the long-term results. Dr. Weiss emphasized that bariatric embolization is not intended to be a first-line treatment for obesity or a replacement for bariatric surgery. “Obesity is a complicated disease that takes many different therapies to treat, including psychological counseling, diet, medication and, in extreme cases, surgery,” he said. “If we can provide one more piece to the armamentarium, that would be an exciting next step in the treatment of obese patients.” “Clinical Safety of Bariatric Arterial Embolization: Preliminary Results of the BEAT Obesity Trial.” Collaborating with Dr. Weiss were Olaguoke Akinwande, M.D., Kaylan Paudel, M.D., Lawrence J. Cheskin, M.D., Brian Holly, M.D., Kelvin Hong, M.D., Aaron M. Fischman, M.D., Rahul S. Patel, M.D., Eun J. Shin, M.D., Kimberley E. Steele, M.D., Ph.D., Timothy H. Moran, M.D., Kristen Kaiser, Amie Park, B.S., David M. Shade, J.D., and Dara L. Kraitchman, V.M.D., Ph.D. Radiology is edited by Herbert Y. Kressel, M.D., Harvard Medical School, Boston, Mass., and owned and published by the Radiological Society of North America, Inc. (http://radiology.rsna.org/) RSNA is an association of 54,000 radiologists, radiation oncologists, medical physicists and related scientists promoting excellence in patient care and health care delivery through education, research and technologic innovation. The Society is based in Oak Brook, Ill. (RSNA.org)


News Article | February 16, 2017
Site: www.eurekalert.org

DALLAS - Feb. 16, 2017 - Researchers at UT Southwestern Medical Center, working with a California biotech firm, have developed a potential drug to treat polycystic kidney disease - an incurable genetic disease that often leads to end-stage kidney failure. The drug, now called RGLS4326, is in preclinical animal testing at San Diego-based Regulus Therapeutics Inc. An investigational new drug filing to pave the way for human clinical trials is expected later this year, said Dr. Vishal Patel, Assistant Professor of Internal Medicine at UT Southwestern. Dr. Patel is senior author of a study describing research that led to the drug's development, published online today in Nature Communications. Affecting about 600,000 people in the U.S., autosomal dominant polycystic kidney disease (ADPKD) causes numerous fluid-filled cysts to form in the kidney. An affected kidney, normally the size of a human fist, sometimes grows as large as a football. As their numbers and sizes increase, these cysts eventually interfere with the kidney's ability to filter blood and remove bodily waste. The cysts can quietly grow for decades until symptoms appear such as blood in the urine, Dr. Patel said. About half of those affected with ADPKD suffer kidney failure by age 60, according to the National Kidney Foundation. "There isn't a single drug on the U.S. market right now to treat the disease," Dr. Patel said. "Once your kidneys fail, your only option for survival is to get a transplant or start dialysis." In 2009, Dr. Patel began searching for microRNAs that might underlie progression of ADPKD. MicroRNAs - or MiRs for short - are tiny RNA fragments that interfere with normal gene expression. Proof that such RNA fragments even existed came in the early 1990s; their presence in humans was first reported in 2000. Those discoveries led to a groundswell of interest in developing drugs to treat diseases caused by microRNAs, Dr. Patel said - in part because the process can be straightforward once the problem-causing fragment is identified. "Because miRs are so small, drugs can easily be designed against them. And since we know the nucleotide sequence of every known microRNA, all that is required is to prepare an anti-miR with a sequence that is exactly the opposite of the miR's," he said. In this study, researchers in Dr. Patel's lab focused on microRNA cluster 17~92 following identification of potential miR targets. A National Institutes of Health grant funded the UTSW research. In 2013, Dr. Patel and fellow researchers reported in Proceedings of the National Academy of Sciences that this microRNA cluster indeed appeared to promote kidney cyst growth. Using four mouse models, the researchers next studied whether inhibiting this microRNA could slow cyst growth and thus delay ADPKD progression. They found that genetically deleting microRNA-17~92 slowed cyst growth and more than doubled the life spans of some mice tested. Based on that finding, Dr. Patel's lab collaborated with Regulus Therapeutics to test an anti-microRNA-17 drug. The test drug slowed the growth of kidney cysts in two mouse models and in cell cultures of human kidney cysts, the study showed. In the Nature Communications study, UTSW researchers also reported how miR-17 causes cyst proliferation: the molecule essentially reprograms the metabolism of kidney cells so that cellular structures called mitochondria use less nutrients, freeing up resources to instead make cell parts that become cysts. MiR-17 accomplishes this by repressing a protein involved in making RNA called peroxisome proliferator-activated receptor alpha (PPARα), the researchers found. Other UT Southwestern researchers included lead author Dr. Sachin Hajarnis, a research scientist; Dr. Ronak Lakhia, Instructor in Internal Medicine; Matanel Yheskel and Andrea Flaten, research technicians; Darren Williams, former research associate; Dr. Shanrong Zhang, research engineer; Joshua Johnson, an M.D./Ph.D. student; Dr. William Holland and Dr. Christine Kusminski, Assistant Professors of Internal Medicine; and Dr. Philipp Scherer, Professor of Internal Medicine and Cell Biology, who holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research. Also contributing to the study were researchers from the University of Minnesota Medical School, the Mayo Clinic School of Medicine, the University of Montreal, the University of Kansas, and Regulus Therapeutics. Funding was provided by the National Institutes of Health (NIH) and the PKD Foundation. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under Award Number R01DK102572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. UT Southwestern and Regulus Therapeutics have applied for a patent for treatment of polycystic kidney disease with miR-17 inhibitors. In addition, Dr. Patel's laboratory has a sponsored research agreement with Regulus, and Dr. Patel serves as a consultant for Regulus. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.


News Article | February 15, 2017
Site: www.eurekalert.org

A form of RNA released from fat cells into the blood may help to regulate other tissues. BOSTON - (February 15, 2017) - Fat cells are not simply big blobs of lipid quietly standingby in the body--instead, they send out hormones and other signaling proteins that affect many types of tissues. Scientists at Joslin Diabetes Center now have identified a route by which fat also can deliver a form of small RNAs called microRNAs that helps to regulate other organs. "This mechanism may offer the potential to develop an entirely new therapeutic approach," says C. Ronald Kahn, M.D., Joslin's chief academic officer, Mary K. Iacocca Professor of Medicine at Harvard Medical School and senior author of a paper on the research published today in the journal Nature. The research suggests the possibility, Kahn explains, of developing gene therapy treatments using fat cells that aid in treating metabolic diseases, cancer or other conditions in the liver or other organs. Working in mice and with human cells, he and his colleagues studied the role of microRNAs, a form of small RNAs that are not translated into proteins but can regulate other RNAS that produce protein. They are made by all cells in the body, and it is known that some of these microRNAs may be released from the originating cell into the blood. However, exactly what they do once they enter the bloodstream has been debated. The Joslin scientists focused on microRNAs from fat cells that are released into the blood via tiny sacks called "exosomes". The researchers began with a mouse model that was genetically modified so that its fat cells could not create microRNAs. The Joslin researchers then showed that in these mice which do not make microRNAs in fat, the total population of microRNAs circulating in exosomes dropped significantly. This decrease in circulating miRNAs could be restored when the investigators transplanted normal fat into these mice, a result indicating that many of the microRNAs in circulation were coming from fat. Next, the scientists studied people with two forms of lipodystrophy--a condition in which fat is lost or genetically not present. In both groups of people, they found that levels of microRNAs circulating in exosomes were lower than normal. This suggested that these microRNAs generated by fat might aid in diagnostics for metabolic conditions such as obesity, type 2 diabetes and fatty liver disease, Kahn says. But were these microRNAs also crossing into other tissues and regulating genes there, so that they might potentially be used for therapeutics? The Joslin researchers followed up on this question by looking at a gene whose expression in the mouse liver increases in lipodystrophy. They discovered that this gene expression could be modified by microRNA in exosomes released by fat. They also showed that the mice that couldn't produce microRNAs in fat cells didn't produce that type of microRNA at all. "But if you put back that missing microRNA in exosomes, it does regulate the gene," Kahn says. "So fat is using this as a way to send a signal to the liver." Next, the scientists made a mouse model with fat cells engineered to make a certain microRNA that is found in humans, but not mice, and showed that these human microRNAs could also regulate their target in the livers of the mice and that this was do to these circulating exosomal microRNAs. "We showed in mice that these circulating microRNAs in exosomes can regulate gene expression, at least in liver and perhaps in other tissues," Kahn sums up. His team is now looking to see if this microRNA mechanism also works in other tissues such as muscle and brain cells. Additionally, the scientists will investigate ways the mechanism might be applied in gene therapy. Fat is easy to access, a major advantage for gene therapy, Kahn points out. "We could take out a patient's subcutaneous fat with a simple needle biopsy, modify the fat cells to make the microRNAs that we want, put the cells back into the patient, and then hope to get regulation of genes that the patient is not regulating normally," he suggests. This approach for gene therapy to treat fatty liver disease, for example, might prove both safer and more effective than reengineering cells in the liver itself. "We think it also might be useful for non-metabolic diseases, such as cancer of the liver," Kahn says. Lead author on the Nature paper is Thomas Thomou. Other Joslin contributors include Jonathan Dreyfuss, Masahiro Konishi, Masaji Sakaguchi, Tata Nageswara Rao and Jonathon Winnay. Marcelo Mori of the Federal University of São Paolo in São Paolo, Brazil; Christian Wolfrum of ETH Zurich in Zurich, Switzerland; Steven Grinspoon of Massachusetts General Hospital in Boston; and Phillip Gorden of the National Institute of Diabetes and Digestive and Kidney Diseases also are co-authors. Lead funding was from the National Institutes of Health. Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is an independent, non-profit institution affiliated with Harvard Medical School, and one of only 11 NIH-designated Diabetes Research Centers in the U.S. For more information, visit http://www. or follow @joslindiabetes


News Article | February 16, 2017
Site: www.eurekalert.org

(New York, NY - February 16, 2017) --Mount Sinai researchers have created a novel model that shows the step-by-step progression from normal blood cells to leukemia and its precursor diseases, creating replicas of the stages of the disease to test the efficacy of therapeutic interventions at each stage, according to a study to be published in Cell Stem Cell. This research marked the first time scientists have been able to transplant leukemia from humans to a test tube and then into mice for study, a landmark feat that will allow for valuable research to help find therapies for blood cancer patients in the future. "The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before," said Eirini P. Papapetrou, MD, PhD, Associate Professor of Oncological Sciences, Medicine, Hematology, and Medical Oncology at the Icahn School of Medicine at Mount Sinai. "These findings provide a framework to aid investigation into disease mechanisms, drug responses, and the cellular and molecular events driving leukemia progression." Scientists used CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat), a new, cutting-edge genome editing technology, to convert blood cells from patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) to particular stem cells (called induced pluripotent stem cells) that can mimic all stages of disease progression, from a healthy state to pre-malignancy and finally full-blown leukemia. Though scientists believe that cancer develops through a step-by-step process by which a normal cell transforms to a fully malignant cell through intermediate stages, recreating the steps was challenging with previous tools. Scientists were able to manipulate the leukemia in a test tube environment, both by genetically modifying the disease-ridden stem cells at certain stages to revert to a pre-cancerous state, and by altering them so they would either progress to a severe or mild form of MDS. The ability to manipulate the leukemia to regress or progress will allow future researchers to test therapies that may be most potent at a particular stage, thus saving or extending a patient's life. Memorial Sloan Kettering Cancer Center was a valuable collaborator in this research. The lab of Michael G. Kharas, PhD, performed some of the mouse transplantation experiments in the study. "We are encouraged by the discovery that it was possible to generate potent engraftable leukemia derived from AML induced pluripotent stem cells," said Dr. Kharas, the co-corresponding author. "This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression." The progression model created through this research could also be used to develop models for more complex cancers, including solid tumors, the researchers said. The research was funded by grants from the National Institutes of Health from the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases (R01HL121570 and R00DK087923); the Damon Runyon Cancer Research Foundation, the Edward P. Evans Foundation, the Ellison Medical Foundation, the Henry and Marilyn Taub Foundation, the Babich Family Foundation and Alex's Lemonade Stand Foundation. The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community-based facilities to tertiary and quaternary care. The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is on the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals." For more information, visit http://www. or find Mount Sinai on Facebook, Twitter and YouTube.


News Article | January 28, 2017
Site: www.techtimes.com

Researchers from The Scripps Research Institute have pinpointed a specific hormone in the brain that appears to be responsible for triggering fat burn in the gut. Serotonin has been established before as a driving factor for fat loss. However, it wasn't clear how exactly the neurotransmitter was able to influence fat reduction. To find out, Supriya Srinivasan and colleagues carried out experiments on Caenorhabditis elegans. Commonly used as a model organism in biological applications, the roundworm has a simpler metabolic system than people but features a brain capable of producing a lot of the same signaling molecules that a human brain does. As such, many researchers believe that results involving C. elegans may have potential relevance to humans. For a study published in the journal Nature Communications, the researchers erased certain genes in C. elegans to determine if it was possible to disrupt the path between serotonin in the brain and fat burning. Testing genes one after the other, they were able to zero in on a gene that codes for FLP-7, a neuropeptide hormone. According to the researchers, FLP-7 was actually identified as a muscle contraction-triggering peptide when applied to pig intestines. Back then, it was believed that the hormone connected the brain to the gut but it was not specifically linked to fat metabolism. After identifying FLP-7 as a fat-burning trigger, the researchers moved on to determining if it has a direct connection to levels of serotonin in the brain. Lavinia Palamiuc, the study's first author, led this part of the study by tagging FLP-7 using fluorescent red protein, allowing for the peptide to be viewed within C. elegans. Based on their observation, the researchers saw that FLP-7 was released by brain neurons responding to elevated levels of serotonin. The neuropeptide hormone then entered the circulatory system and started the fat-burning process within the gut. "That was a big moment for us," said Srinivasan. And understandably so, as this is the first time that researchers discovered a brain hormone that selectively and particularly spurs the fat-burning process without affecting food intake. While increasing levels of serotonin have a massive effect on food intake, reproductive behavior, and movement, increasing levels of FLP-7 did not have any obvious side effects, noted the researchers. Based on observations, the researchers simply continued functioning as usual while burning more fat. According to Srinivasan, this finding may encourage studies in the future to focus on how levels of FLP-7 can be regulated without resulting in side effects typically experienced when levels of serotonin are manipulated. Supported by grants from the NIH's Office of Research Infrastructure Programs and National Institute of Diabetes and Digestive and Kidney Diseases, the current study also included work from Tallie Noble, Megan Vaughan, Emily Witham, and Harkaranveer Ratanpal. For those interested in losing body fat, another study offers another tip: what time you eat your dinner may have a hand in how you burn off fat. According to the study, consuming meals within a smaller time frame in a day may boost weight loss abilities by increasing the body's capacity to consume proteins and burn fat. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


News Article | March 3, 2017
Site: www.techtimes.com

A new potential drug that could treat polycystic kidney disease was found. The disease is incurable, and it often happens to lead to end-stage kidney failure. The study, published in Nature Communications, on Feb. 16, was conducted by researchers at the UT Southwestern Medical Center, who collaborated with a California-based biotech company. The new medicine that could potentially cure polycystic kidney disease is called RGLS4326, and it is currently in preclinical animal testing. According to assistant professor Vishal Patel, senior author of the study, an investigational drug associated with this finding should be available later in 2017. The disease manifests through an abnormal growth of the kidney due to cysts filled with fluid, which keep growing in size until they eventually prevent the organ for serving its functions. Due to this, the kidney loses its capacity to remove bodily waste and filter blood. According to the researchers, the patients can have this disease for decades until the first symptoms show up, such as blood in the urine. At the moment, there is no available drug on the market to treat this disease, and the only two available options once the kidney reaches failure are dialysis or a transplant. Back in 2009, Dr. Patel started to look for microRNAs (MiRs) that could provide a better understanding on the disease. These MiRs are very small pieces of RNA that can interfere with normal gene expression. Researchers discovered the role of MiRs back in the 1990's, and the scientific interest in finding a viable drug to treat diseases caused by these small RNA fragments increased rapidly. The reason for this scientific interest is that, once the fragment is found, the rest of the scientific process can evolve rapidly. Because of the fragments' small dimensions, researchers can easily create drugs to annihilate their actions. Once the researchers identify the RNA fragment, the only thing left to do is preparing an anti-MiR with the very opposite sequence. As part of a 2013 research, the scientists focused their efforts on finding MiR clusters in the attempt to identify potential viable targets. As a result to that research they published a paper with a potential RNA sequence that they found promoted kidney cyst growth, called the 17~92 sequence. In the current study, the researchers employed mouse models, in which they inhibited the microRNA sequence, finding that the genetic deletion of the 17~92 sequence slowed cyst growth. Additionally, the lifespan of the tested mice increased more than twice its initial value. "In support of this conclusion, we show that genetic deletion of miR-17∼92 attenuates disease progression in ADPKD mouse models irrespective of the mutated gene, the type of mutation (null or hypomorphic) or the dynamics of cyst growth (rapidly fatal, aggressive but long-lived or slowly progressing)," noted the study. Polycystic kidney disease is a genetic disorder that affects approximately 600,000 people in the United States, about half of those affected with the disease experience kidney failure by the age of 60. The cysts cause high blood pressure, as well as problems with blood vessels in the heart and brain, according to the National Institute of Diabetes and Digestive and Kidney Diseases. For the patients who are currently suffering from this disease, it is highly recommended to regulate a healthy diet, in order to have control on blood pressure. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

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