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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 | December 20, 2016
Site: www.eurekalert.org

DALLAS - Dec. 20, 2016 - UT Southwestern Medical Center researchers have invented a transistor-like threshold sensor that can illuminate cancer tissue, helping surgeons more accurately distinguish cancerous from normal tissue. In this latest study, researchers were able to demonstrate the ability of the nanosensor to illuminate tumor tissue in multiple mouse models. The study is published in Nature Biomedical Engineering. "We synthesized an imaging probe that stays dark in normal tissues but switches on like a light bulb when it reaches solid tumors. The purpose is to allow surgeons to see tumors better during surgery," said senior author Dr. Jinming Gao, Professor of Oncology, Pharmacology and Otolaryngology with the Harold C. Simmons Comprehensive Cancer Center. The nanosensor amplifies pH signals in tumor cells to more accurately distinguish them from normal cells. "Cancer is a very diverse set of diseases, but it does have some universal features. Tumors do not have the same pH as normal tissue. Tumors are acidic, and they secrete acids into the surrounding tissue. It's a very consistent difference and was discovered in the 1920's," said Dr. Baran Sumer, Associate Professor of Otolaryngology, and co-senior author of the study. The researchers hope the improved surgical technology can eventually benefit cancer patients in multiple ways. "This new digital nanosensor-guided surgery potentially has several advantages for patients, including more accurate removal of tumors, and greater preservation of functional normal tissues," said Dr. Sumer. "These advantages can improve both survival and quality of life." For example, this technology may help cancer patients who face side effects such as incontinence after rectal cancer surgery. "The new technology also can potentially assist radiologists by helping them to reduce false rates in imaging, and assist cancer researchers with non-invasive monitoring of drug responses," said Dr. Gao. According to the National Cancer Institute, there are 15.5 million cancer survivors in the U.S., representing 4.8 percent of the population. The number of cancer survivors is projected to increase by 31 percent, to 20.3 million, by 2026. Dr. Sumer and Dr. Gao were joined in this study by Dr. Gang Huang, Instructor of Pharmacology; Dr. Xian-Jin Xie, Professor of Clinical Sciences; Dr. Rolf Brekken, Professor of Surgery and Pharmacology and an Effie Marie Cain Research Scholar; and Dr. Xiankai Sun, Director of Cyclotron and Radiochemistry Program in Department of Radiology and Advanced Imaging Research Center, Associate Professor of Radiology, and holder of the Dr. Jack Krohmer Professorship in Radiation Physics; Dr. Joel Thibodeaux, Assistant Professor of Pathology and Director of Cytopathology, Parkland Memorial Hospital. Additional UT Southwestern researchers who contributed to the study include: Dr. Tian Zhao, Dr. Xinpeng Ma, Mr. Yang Li, Dr. Zhiqiang Lin, Dr. Min Luo, Dr. Yiguang Wang, Mr. Shunchun Yang and Ms. Zhiqun Zeng in the Harold C. Simmons Comprehensive Cancer Center; and Dr. Saleh Ramezani in the Department of Radiology. Dr. Gao and Dr. Sumer are scientific co-founders of OncoNano Medicine, Inc. The authors declare competing financial interests in the full-text of the Nature Biomedical Engineering article. UT Southwestern Medical Center has licensed the technology to OncoNano Medicine and has a financial interest in the research described in the article. Funding for the project includes grants from the Cancer Prevention and Research Institute of Texas. Dr. Gao and Dr. Sumer are investigators for two Academic Research grants and OncoNano Medicine was the recipient of a CPRIT Product Development Research grant. Research reported in this press release was supported by the National Cancer Institute under Award Number R01 CA192221 and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 47 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. 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 Southwestern via email, subscribe at http://www.


News Article | December 20, 2016
Site: www.eurekalert.org

DALLAS - Dec. 20, 2016 - A new way to fight multidrug-resistant bacteria by blinding them rather than killing them proved highly effective in a model of burn injuries, UT Southwestern Medical Center research shows. "In the United States, there are more than 1 million burn injuries and 100,000 hospitalizations annually. Up to 75 percent of the mortality in burn patients is associated with infections, which are particularly common in patients who suffer extensive burns -- those that cover 40 percent or more of the body," said Dr. Steven Wolf, Section Chief for Burns and Professor of Surgery at UT Southwestern Medical Center. Dr. Wolf, one of three senior authors of the study published today in Scientific Reports, is also a former Director of the Burn Center at the U.S. Army Institute of Surgical Research in San Antonio, Texas. "Rather than killing the bacteria, we blinded them so they could not find the places where they normally stick to the host (body's) cells. If bacteria cannot bind, they cannot grow," said Dr. Wolf, who is also Surgery's Vice Chair for Research and holder of the Golden Charity Guild Charles R. Baxter, M.D. Chair. The study done in rats targeted one of the most lethal pathogens: multidrug-resistant Pseudomonas aeruginosa, which is found in approximately 33 percent of all burn cases and in 59 percent of extensive burns. The researchers showed that topical application of an engineered adhesion inhibitor molecule - Multivalent Adhesion Molecule 7, or MAM7 - substantially decreased the bacterial levels in wounds in the first 24 hours after administration and prevented the spread of the infection to adjacent tissue for three more days. In addition, the experimental molecule aided wound healing and maintained normal inflammatory responses to the burn, the researchers report. "Antibiotic-resistant bacteria are an increasingly prevalent problem in the clinic and hospital, so new ways to prevent and treat infections are direly needed. Antibiotics work by killing bacteria, which places microbes under extreme pressure to develop antibiotic resistance," said co-senior author Dr. Kim Orth, Professor of Molecular Biology and Biochemistry at UT Southwestern. "Our approach doesn't target bacterial survival; rather it targets the microbes' ability to damage the host - its virulence. There is no reason for the bacteria to become resistant to this approach. Being unable to bind to wounded tissue is an inconvenience, and the bacteria move on," Dr. Orth said. She compared the situation to the search for parking at a shopping mall. "If all the parking spaces are filled, then the bacteria have no place to park," said Dr. Orth, a Howard Hughes Medical Institute Investigator who also holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research at UT Southwestern. The experimental molecule was developed in the Orth laboratory and grew out of the postdoctoral research project of the study's third senior author, Dr. Anne-Marie Krachler, now with the McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth). When working at UT Southwestern, Dr. Krachler studied a group of adhesion molecules called adhesins that are created by bacteria to bind, or stick to cells in an early and crucial step in causing infection. Although most adhesins are specific to various pathogens, members of the adhesion family she identified - Multivalent Adhesion Molecules, including MAM7 - are used by most gram-negative bacteria, including the type used in this burn study. In one UTSW experiment, Dr. Krachler detached MAM7 from the bacteria that produce it and showed that the lack of MAM7 made the bacteria much less able to cause infection. In 2013, Dr. Orth gave a UT Southwestern President's Lecture describing the molecular activity of MAM7. Dr. Wolf was in attendance, and approached Dr. Orth about a collaboration to test the efficacy of MAM7 using a fluorescent strain of antibiotic-resistant bacteria in a live animal model. That led to the multiyear effort to develop the recombinant MAM7 inhibitor attached to a scaffold made of bacteria-sized polymer microbeads that was used in this study. UT Southwestern has an international patent application filed on the molecule. "We attached lots of copies of MAM7 to the microbeads. In this study, we found that topically applied MAM7-coupled microbeads reach the cells' binding sites first and - for at least four days in this experiment - stay there, without hindering wound healing. The MAM7 adhesion inhibitors remain on the wounds and prevent the bacteria from binding to the tissue," Dr. Orth said. In addition to burns, Dr. Krachler said, this strategy could work against diabetic ulcers and surgical wounds that can become infected. "What's exciting about MAM7 is that the agent is so broad-spectrum. Most bacteria have their own specific type of adhesion molecules. For instance Vibrio uses one kind and Salmonella uses a different one and multidrug-resistant bacteria another, but almost all of them want to park in the same place. "Antibiotics are amazing drugs, and they have saved countless lives since their discovery more than 80 years ago. But there is a challenge - the challenge of antibiotic resistance that has made many antibiotics ineffective. A material that targets virulence instead of killing bacteria could be a way to treat infections that are resistant to antibiotics," she said. "This is a trial in rats. A future goal is to use this strategy in patients." Following the success of this proof-of-concept study, additional steps include testing whether the anti-adhesion strategy might also block infection of bacteria that can cause lethal infections during surgery, Dr. Orth said. UT Southwestern co-authors include: lead author Dr. Ryan Huebinger, Assistant Professor of Surgery; Dr. Marcela de Souza Santos, a postdoctoral researcher in Molecular Biology; Dr. Deborah Carlson, Assistant Professor of Surgery and Pediatrics; and Dr. Juquan Song, Assistant Professor of Surgery. Researchers at the University of Birmingham, United Kingdom, also participated. The research received support from the Biotechnology and Biological Sciences Research Council in the United Kingdom; the National Institutes of Health; Once Upon a Time...; the Welch Foundation; the Howard Hughes Medical Institute; the Golden Charity Guild Charles R. Baxter Chair in Burn Surgery, which provided additional research funding; and the Burroughs Welcome Fund. The U.S. Army Institute for Surgical Research provided the bioluminescent strain of P. aeruginosa used in this study. 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 Southwestern via email, subscribe at http://www.


News Article | October 31, 2016
Site: www.eurekalert.org

DALLAS - October 31, 2016 - Normal, healthy heart muscle is well-supplied with oxygen-rich blood. But UT Southwestern Medical Center cardiologists have been able to regenerate heart muscle by placing mice in an extremely low-oxygen environment. Researchers with the Hamon Center for Regenerative Science and Medicine gradually lowered the oxygen in the air breathed by mice until it was at 7 percent - about the concentration of oxygen at the top of Mt. Everest. After two weeks in the low-oxygen environment, the heart muscle cells - called cardiomyocytes - were dividing and growing. Under normal circumstances cardiomyocytes do not divide in adult mammals. The findings, published in Nature, build upon years of work that began with the discovery that the hearts of newborn mammals have the ability to regenerate, similar to the way skin has the ability to repair itself after a cut. But this ability of heart muscle to regenerate is quickly lost in the following weeks as the animal ages and cardiomyocytes are bathed in the oxygen-rich environment of the beating heart, causing damage to the cells. "The adult human heart is not capable of any meaningful repair following a heart attack, which is why heart attacks have such a devastating impact," said Dr. Hesham Sadek, Associate Professor of Internal Medicine and with the Hamon Center. "Though counterintuitive, we've shown that severely lowering oxygen exposure can sidestep damage to cells caused by oxygen and turn cell division back on, leading to heart regrowth." In the current study, researchers lowered the oxygen level from the normal 21 percent to 7 percent over a period of weeks, then monitored the mass and function of the heart. They demonstrated that reduction in oxygen leads to both an increase in cardiomyocytes and improved heart function. The researchers had tried a 10 percent oxygen environment, but there was no heart regrowth in the 10 percent oxygen environment. To avoid oxygen damage to cells, oxygen levels needed to be very low, a situation referred to as hypoxia. "This work shows that hypoxia equivalent to the summit of Mt. Everest can actually reverse heart disease, and that is extraordinary," said Dr. Benjamin Levine, Professor of Internal Medicine who holds the Distinguished Professorship in Exercise Sciences, and who directs the Institute of Exercise and Environmental Medicine at Texas Health Presbyterian Hospital Dallas, a joint program of UT Southwestern and Texas Health Resources. "In theory, creating a low-oxygen environment could lead to repair not only of heart muscle, but of other organs as well," said Dr. Sadek, who holds the J. Fred Schoellkopf, Jr. Chair in Cardiology. "Although exposure to this level of hypoxia can result in complications, it is tolerated in humans when performed in a controlled setting." The latest findings build upon previous research by UT Southwestern scientists that includes: This work was supported by the National Institutes of Health, in addition to support from the Hamon Center for Regenerative Science and Medicine, whose goal is to understand the basic mechanisms for tissue and organ formation, and then to use that knowledge to regenerate, repair and replace tissues damaged by aging and injury. UT Southwestern established the Hamon Center for Regenerative Science and Medicine in 2014 with a $10 million endowment gift from the Hamon Charitable Foundation to further research into the relatively new field of regenerative medicine. Other UT Southwestern researchers who contributed to the study are Dr. Yuji Nakada, Assistant Instructor of Internal Medicine; Dr. Diana Canseco, Instructor of Internal Medicine; SuWanee Thet, Research Associate; Dr. Salim Abdisalaam, postdoctoral researcher; and Dr. Wataru Kimura, Visiting Assistant Professor of Internal Medicine. 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 | December 2, 2016
Site: www.eurekalert.org

DALLAS - Dec. 1, 2016 -Hospitals in which the administration of epinephrine to patients whose hearts have stopped is delayed beyond five minutes have significantly lower survival rates of those patients, a new study led by a cardiologist at UT Southwestern Medical Center finds. Using data from a large registry, the national team of cardiologists found that nearly 13 percent of patients survived cardiac arrest when epinephrine shots were given within the first five minutes of the heart stopping, compared to about 11 percent when the epinephrine was given after five minutes, independent of all other aspects of care. "That is a 20 percent better survival rate for patients at hospitals where epinephrine is given quickly, which is a big difference," said Dr. Rohan Khera, a Cardiology Division fellow at UT Southwestern and the first author on the study published online in the journal Circulation. Delays in giving the epinephrine shots also had a negative effect on functional recovery, the researchers noted. "These data are important for hospitals and patients. Improving epinephrine administration time, a likely correlate with overall CPR performance, may improve outcomes in cardiac arrest," said Dr. Mark Link, Professor of Internal Medicine at UT Southwestern and a specialist in heart-rhythm disorders, who was not involved in the study. Researchers reviewed more than 100,000 records of patients whose heart stopped while at the hospital, using data from a large national registry run by the American Heart Association. The review involved nearly 550 hospitals across the country. Researchers found considerable variability in how quickly epinephrine, commonly called adrenaline, was administered among the hospitals reviewed. Although individual hospitals were not identified in the study, the data showed that hospitals treating a high volume of cardiac arrest cases tended to administer the adrenaline shots more quickly than those with a lower volume of cases. While TV shows commonly portray doctors dramatically shocking the heart with paddles, this is not the reality for most cardiac arrest patients in hospitals. About 80 percent of in-hospital cardiac arrests are due to causes that cannot be addressed using a defibrillator. These non-shockable heart stoppages are treated with CPR (cardio-pulmonary resuscitation) chest compressions and epinephrine, and these non-shockable cardiac arrests have much lower survival rates. "Treatment options for non-shockable cardiac arrest are so limited that there has been an emphasis on improving current processes," said Dr. Khera. "Administering epinephrine promptly and improving the quality of CPR - these are the easily improved practices, which may be life-saving." Researchers plan to examine processes at hospitals with few delays and compare processes at hospitals with more frequent delays to see if they can identify patterns that could help speed more timely administration of adrenaline shots and whether doing so would improve survival. The multi-center study involved researchers Dr. Saket Girotra of University of Iowa Carver College of Medicine, Dr. Paul Chan of Mid-America Heart Institute and the University of Missouri-Kansas City, and Dr. Michael Donnino of Beth Israel Deaconess Medical Center. Support for the research came from the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, and the National Center for Advancing Translational Sciences of the National Institutes of Health. 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 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 21, 2017
Site: www.eurekalert.org

DALLAS - Feb. 20, 2017 - How we think and fall in love are controlled by lightning-fast electrochemical signals across synapses, the dynamic spaces between nerve cells. Until now, nobody knew that cancer cells can repurpose tools of neuronal communication to fuel aggressive tumor growth and spread. UT Southwestern Medical Center researchers report those findings in two recent studies, one in the Proceedings of the National Academy of Sciences (PNAS) and the second in Developmental Cell "Many properties of aggressive cancer growth are driven by altered cell signaling," said Dr. Sandra Schmid, senior author of both papers and Chair of Cell Biology at UT Southwestern. "We found that cancer cells are taking a page from the neuron's signaling playbook to maintain certain beneficial signals and to squelch signals that would harm the cancer cells." The two studies find that dynamin1 (Dyn1) - a protein once thought to be present only in nerve cells of the brain and spinal cord - is also found in aggressive cancer cells. In nerve cells, or neurons, Dyn1 helps sustain neural transmission by causing rapid endocytosis - the uptake of signaling molecules and receptors into the cell - and their recycling back to the cell surface. These processes ensure that the neurons keep healthy supplies at the ready to refire in rapid succession and also help to amplify or suppress important nerve signals as necessary, Dr. Schmid explained. "This role is what the cancer cells have figured out. Aggressive cancer cells have usurped the mechanisms that neurons use for the rapid uptake and recycling of neural transmitters. Instead of neural transmitters, the cancer cells use Dyn1 for rapid uptake and recycling of EGF (epidermal growth factor) receptors. Mutations in EGF receptors are drivers of breast and lung cancers," she said of the Developmental Cell study. In order to thrive, cancer cells must multiply faster than nearby noncancerous cells. EGF receptors help them do that, she explained. Cancer cell survival is another factor in disease progression. In the PNAS study, the Schmid lab found that aggressive cancer cells appear to have adapted neuronal mechanisms to thwart a key cancer-killing pathway triggered by activating "death receptors" (DRs) on cancer cells. Specifically, aggressive cancer cells appear to have adapted ways to selectively activate Dyn1 to suppress DR signaling that usually leads to cancer cell death. "It is amazing that the aggressive cancers use a signaling pathway to increase the activity of EGF and also turn on Dyn1 pathways to suppress cancer death - so you have this vicious circle," said Dr. Schmid, who holds the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology. She stressed that less aggressive cancers respond to forms of chemotherapy that repress EGF signaling and/or die in response to the TRAIL-DR pathway. However, aggressive lung and breast cancer cells have adapted ways to commandeer the neuronal mechanisms identified in these studies. The hope is that this research will someday lead to improved strategies to fight the most aggressive cancers, she said. Currently, her laboratory is conducting research to identify Dyn1 inhibitors as potential anticancer drugs using a 280,000-compound library in a shared facility at UT Southwestern. "Cancer is a disease of cell biology. To grow, spread, and survive, cancer cells modify normal cellular behavior to their advantage. They can't reinvent the underlying mechanisms, but can adapt them. In these studies, we find that some cancer cells repurpose tools that neurons use in order to get a competitive advantage over nearby normal cells," she said. Lead author of the PNAS study is Dr. Carlos Reis, a former postdoctoral researcher. Other UT Southwestern co-authors in Cell Biology are Dr. Nawal Bendris, a former postdoctoral researcher, and Dr. Ping-Hung Chen, a postdoctoral fellow. This research was supported by grants from the National Institutes of Health (NIH) and the Cancer Prevention and Research Institute of Texas (CPRIT). Dr. Chen is lead author of the Developmental Cell study. Other UT Southwestern co-authors include: Dr. Bendris, Dr. Reis, and Dr. Marcel Mettlen, Assistant Professor of Cell Biology. Researchers from Taiwan also participated. This study received support from the NIH and a National Science Council of Taiwan grant. Other assistance came from the National Cancer Institute-supported Harold C. Simmons Comprehensive Cancer Center and the Texas Institute for Brain Injury and Repair-supported Whole Brain Microscopy Facility, both of which are located at UT Southwestern. The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated comprehensive cancer center in North Texas and one of just 47 NCI-designated comprehensive cancer centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. 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 Southwestern via email, subscribe at http://www.


News Article | October 26, 2016
Site: www.eurekalert.org

DALLAS - Oct.24, 2016 - Carol White can't help but worry when she misplaces keys or can't recall a name ever since relatives have been diagnosed with early onset Alzheimer's. "I live with the possibility Alzheimer's might also touch my life," she said. "You just take a deep breath and wonder." But the 69-year-old doesn't plan to sit around waiting to find out. She's joined a study at the UT Southwestern Peter O'Donnell Jr. Brain Institute to determine whether regular aerobic exercise and taking specific medications to reduce high blood pressure and cholesterol levels can help preserve brain function. "There is plenty of evidence to suggest that what is bad for your cardiovascular system is bad for your brain, but the body is one machine and you cannot separate the heart from the brain," said Dr. Rong Zhang, Associate Professor of Neurology and Neurotherapeutics at UT Southwestern Medical Center. Dr. Zhang is Principal Investigator for the 5-year study being carried out at six medical centers around the nation. They plan to enroll more than 600 older adults at high risk to develop Alzheimer's disease and measure whether certain interventions can be linked to slower brain decline. Participants will take part in regular aerobic exercise and take specific medications to reduce high blood pressure and cholesterol levels. Information on this study is available on the rrAD trail website or contact Tammy Lewis at 214-345-4665 or ieembrain@texashealth.org">ieembrain@texashealth.org. Other trial sites include Texas Health Resources in Dallas, the University of Kansas Medical Center, Washington University School of Medicine, Pennington Biomedical Research Center at Louisiana State University, and Michigan State University. There is compelling evidence that hypertension is linked to development of dementia later in life, according to a statement from the American Heart Association issued earlier this month. But more data are needed to determine whether treating high blood pressure can preserve the brain's function. Doctors also need to know what kind of exercise or which medications or blood pressure levels will benefit at-risk patients the most. "That's the point of this study. People are looking for a silver bullet to stop the disease. But Alzheimer's is a multi-factorial disease. You have to do A, B, C, and D together, which will hopefully make the difference," said Dr. Zhang, Director of the Cerebrovascular Laboratory in the Institute for Exercise and Environmental Medicine (IEEM) at Texas Health Presbyterian Hospital Dallas, where the Dallas arm of the study will be carried out. The IEEM, a joint program between Texas Health Presbyterian Hospital Dallas and UT Southwestern, is among the most sophisticated human physiology laboratories in the world. Researchers there are working to find treatments and contribute to the development of cures for many of society's most debilitating and chronic diseases, including hypertension, diabetes, congestive heart failure, Alzheimer's disease, Obstructive Sleep Apnea (OSA), and obesity. This new study builds upon prior research linking healthy lifestyles to better brain function. That includes a 2013 study from Dr. Zhang's team that found neuronal messages are more efficiently relayed in brains of older adults who exercise, and a recent UCLA study that found a healthy diet and regular exercise can reduce the incidence of toxic protein buildup associated with Alzheimer's. Other teams at the O'Donnell Brain Institute are designing tests for the early detection of patients who will develop dementia, and seeking methods to slow or stop the spread of toxic proteins associated with the disease such as beta-amyloid and tau, which are blamed for destroying certain groups of neurons in the brain. In the current study, supported by funding from the National Institutes on Aging, researchers will measure the effectiveness of various combinations of intervention in four groups of participants, including those who receive both aerobic training and medication that aggressively targets cardiovascular risks, and others that only receive some or none of these interventions. Researchers will watch for changes in the participants' memory and other functions using cognitive testing and MRIs that will monitor brain cell communication and blood flow, which is important for prevention of any buildup of toxic proteins. They will also measure brain volume and other factors to help them assess which combinations of interventions are most effective in slowing the decline in brain function. Ms. White was the first to sign up. "I'm just interested in doing anything that I can that might help in some small way to find a cure," said Ms. White, who does government and public affairs contract work in the Dallas area. "It's not a pleasant thing to see your relatives go through." Join the Friends of the Alzheimer's Disease Center for "From Astronauts to Alzheimer's Disease: How Understanding the Heart-Brain Connection May Prevent Cognitive Impairment," presented by Benjamin Levine, M.D., and Rong Zhang, Ph.D. Seating is limited for this free public event. RSVP today at rsvp@utsouthwestern.edu or call 214-648-2344.


DALLAS - March 1, 2017 - A large national study suggests that treating pregnant women for mildly low thyroid function does not improve the IQs of their babies or reduce preterm births or other negative outcomes. The 10-year study, conducted at UT Southwestern Medical Center and 14 other universities and medical centers in the National Institutes of Health's (NIH) Maternal Fetal Medicine Units Network, found no benefit in treating the women during their pregnancies. The results are published today in The New England Journal of Medicine (NEJM). Full-blown hypothyroidism during pregnancy, especially when untreated, has long been associated with lower mental functioning in offspring, as well as low birth weight, stillbirth, and preterm labor. It is commonly treated by giving expectant mothers a synthetic substitute to boost their low thyroid hormone, thyroxine. In 1999, another NEJM study raised concerns that the same problems might occur in women with even mild, or subclinical, hormone abnormalities. As a result, several physician groups called for routine testing of all pregnant women in the U.S. -- about 4 million women a year -- and treatment for these marginal hormone problems. The American College of Obstetricians and Gynecologists has recommended against universal screening for thyroid disease in pregnant women. "Our study found that treatment did not benefit children born to these women," said Dr. Brian Casey, Professor of Obstetrics and Gynecology at UT Southwestern Medical Center and first author of the new study. "There's no evidence that treatment improves either pregnancy outcomes or the children's neurodevelopmental or behavioral outcomes through 5 years of age." Dr. Casey is Division Director of Maternal-Fetal Medicine at UT Southwestern and holds the Gillette Professorship of Obstetrics and Gynecology. He is also Chief of Obstetrics at Parkland Health & Hospital System. The NIH study grew out of research begun in 2000 at UT Southwestern, when Dr. Casey and his colleagues performed a study on thyroid disease during pregnancy in over 25,000 women at Parkland Memorial Hospital. That study culminated in his proposal of a multicenter treatment study to the NIH in 2005. Dr. Casey now is principal investigator of the NIH study and chair of the protocol subcommittee. Starting in October 2006, researchers screened more than 97,000 pregnant women for the study and enrolled 1,203 who had either subclinical hypothyroidism or isolated hypothyroxinemia. Subclinical hypothyroidism is characterized by high levels of a pituitary gland hormone, TSH, which stimulates the thyroid to produce thyroxine. In isolated hypothyroxinemia, the pituitary hormone level is normal, but thyroxine, or free T4, is abnormally low. Half the study participants were given levothyroxine, a synthetic substitute for their thyroid hormone; the other half received a placebo. Researchers then analyzed pregnancy outcomes of both groups and followed the neurocognitive development of the women's babies for five years. IQ levels and other test scores were not significantly different between the children of women given levothyroxine and children whose mothers received a placebo, Dr. Casey said. Children of the women treated for subclinical hypothyroidism scored an average of 97 on the IQ test, compared with 94 for those born to women in the placebo group. In the hypothyroxinemia part of the study, the children of those treated averaged 94, while offspring of those given placebos averaged 91. These scores are considered normal and the three-point differences are not viewed as significant, Dr. Casey said. The results suggest there is no benefit to widespread testing and treatment for subclinical thyroid problems during pregnancy, he said. "If treatment doesn't improve outcomes, then it calls into question whether we should be screening every pregnant woman for this mild degree of thyroid deficiency." A 2012 study published in The Journal of Clinical Endocrinology & Metabolism estimated a cost of $25 (in 2009 dollars) for the TSH test and $13 to test the free T4 thyroid hormone level, in addition to the cost of the physician visits and consultation. Pregnant women diagnosed with a thyroid problem would then need continued testing, as well as potential treatment with levothyroxine at an estimated cost of $170 (again, in 2009 dollars) for a year's supply. The current study's findings followed those of a large British study, published in NEJM in 2012, which screened more than 20,000 pregnant women. That study concluded treatment for reduced thyroid function in pregnant women did not improve cognitive function in their children at age 3. The newly published study was funded by the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, along with the National Institute of Neurological Disorders and Stroke. 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 Southwestern via email, subscribe at http://www.


News Article | February 27, 2017
Site: www.eurekalert.org

DALLAS - February 27, 2017 - Lack of exercise and excessive weight are strongly associated with a type of heart failure that has a particularly poor prognosis, UT Southwestern Medical Center researchers determined in an analysis of data from three large studies. Heart failure is a chronic condition in which the heart is unable to supply enough oxygenated blood to meet the demands of the body. Heart failure is approximately equally divided between two subtypes: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Ejection fraction refers to the percentage of the blood that exits the heart with each contraction. "Previous studies have consistently found an association between low levels of physical activity, high BMI, and overall risk of heart failure, but this study shows that the association is more pronounced for heart failure with preserved ejection fraction, the type of heart failure that is the most challenging to treat," said preventive cardiologist Dr. Jarett Berry, Associate Professor of Internal Medicine at UT Southwestern, and the study's senior author. The study appears in the Journal of the American College of Cardiology. In heart failure with preserved ejection fraction, the heart stiffens. Instead of being soft, it's rigid and it resists expansion. Cardiologists often explain the difference between the two types of heart failure by saying that in heart failure with preserved ejection fraction, the heart doesn't relax enough, while in heart failure with reduced ejection fraction the heart doesn't squeeze enough. Many treatments have been developed for treating the latter but there are no evidence-based treatments for the former. "The five-year survival rate among heart failure with preserved ejection fraction patients is around 30 to 40 percent. While heart failure with reduced ejection fraction survival has improved significantly over the years, heart failure with preserved ejection fraction prognosis is little changed," said Dr. Ambarish Pandey, a cardiology fellow in Internal Medicine at UT Southwestern Medical Center and first author of the study. The pooled analysis looked at data from 51,000 participants in three cohort studies, the Women's Health Initiative, the Multiethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study. Among the 51,000 participants, there were 3,180 individuals who developed heart failure. Of these, 39 percent were heart failure with preserved ejection fraction, 29 percent were heart failure with reduced ejection fraction, and 32 percent had not been classified when the data was gathered. The incidence of heart failure with preserved ejection fraction was 19 percent lower for individuals who exercised at recommended levels. Similarly, body mass index (BMI) had an inverse relationship with heart failure with preserved ejection fraction. Higher BMI levels were more strongly associated with heart failure with preserved ejection fraction than with heart failure with reduced ejection fraction. Heart failure with preserved ejection fraction is a growing problem as the population ages, and is particularly a problem among elderly women. Medications such as ACE inhibitors, beta blockers, and aldosterone antagonists have been shown in large-scale randomized trials to reduce mortality in patients with heart failure with reduced ejection fraction. Clinical trials have not identified medications that reduce mortality in patients with heart failure with preserved ejection fraction. Heart transplant is the ultimate option for some patients with heart failure with reduced ejection fraction but is not an option for patients with heart failure with preserved ejection fraction, all of which means that prevention is crucial for heart failure with preserved ejection fraction. "These findings highlight the importance of lifestyle interventions such as increasing physical activity levels and reducing weight to combat the growing burden of this disease," said Dr. Berry, Dedman Family Scholar in Clinical Care. Other UT Southwestern researchers who contributed to this study are Colby Ayers, faculty associate, and Dr. James de Lemos, Professor of Internal Medicine and holder of the Sweetheart Ball?Kern Wildenthal, M.D., Ph.D. Distinguished Chair in Cardiology. Funding for this study was provided by the American Heart Association. 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 Southwestern via email, subscribe at http://www.

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