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Tag: Grant Funded News

  • Comparative Study of Two Heart Failure Drugs Finds No Difference in Outcomes

    Comparative Study of Two Heart Failure Drugs Finds No Difference in Outcomes

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    Newswise — DURHAM, N.C. – In a head-to-head comparison of two so-called ‘water pills’ that keep fluid from building up in patients with heart failure, the therapies proved nearly identical in reducing deaths, according to a large study led by Duke Health researchers.

    The study compared the diuretics torsemide and furosemide that were prescribed to patients with heart failure starting in the hospital setting. While prior data suggested a potential reduction in deaths among patients taking torsemide, the current study found no such benefit, providing clarity for both doctors and patients.

    “Given that the two different therapies provide the same effect on outcomes, we shouldn’t spend time switching patients from one to the other, and instead concentrate on giving the right dose and adjusting other therapies that have been proven to have long-term benefits,” said cardiologist Robert J. Mentz, M.D., chief of the heart failure section in the Division of Cardiology at Duke University School of Medicine and member of the Duke Clinical Research Institute.

    Mentz was lead author of the study, called TRANSFORM-HF and funded by the National Heart, Lung and Blood Institute. He presented the findings as a late-breaking clinical trial on Nov. 5 at the American Heart Association’s 2022 Scientific Sessions in Chicago.

    The study was designed as a direct comparison of loop diuretics, which are commonly prescribed to reduce the fluid buildup that causes swelling and breathing difficulties in patients with heart failure.

    Mentz and colleagues enrolled more than 2,800 patients hospitalized with heart failure. Participants were randomly assigned to receive either torsemide or furosemide, and doctors determined the dosing. The study group was diverse, with women comprising 37% of participants and Black patients comprising 34%.

    The main question was whether torsemide reduced patient deaths due to any cause over long-term follow-up (average of more than 17 months). The researchers found that death occurred in 373 of 1,431 study participants (26.1%) in the torsemide group and 374 of 1,428 patients (26.2%) in the furosemide group.

    A secondary outcomes analysis looked at deaths or hospitalizations within 12 months, and again found little difference, with death or hospitalization occurring in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group.

    “This study has immediate clinical applications,” Mentz said. “Doctors spend a lot of time considering whether they will change from one diuretic to another, but there is no difference between the two for outcomes. This provides much-needed clarity. The insights from TRANSFORM-HF add to the evidence base that should help us improve patient care.”

    In addition to Mentz, study authors include Kevin J. Anstrom, Eric L. Eisenstein, Shelly Sapp, Stephen J. Greene, Shelby Morgan, Jeffrey M. Testani, Amanda H. Harrington, Vandana Sachdev, Fassil Ketema, Dong-Yun Kim, Patrice Desvigne-Nickens, Bertram Pitt, and Eric J. Velazquez.

    The study received support from the NHLBI (U01-HL125478, U01-HL125511, R01HL148354-04, R01HL154768-02).

     

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    Duke Health

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  • $50M Perot Family Gift Expands UT Southwestern’s Medical Scientist Training Program

    $50M Perot Family Gift Expands UT Southwestern’s Medical Scientist Training Program

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    Newswise — DALLAS – Nov. 04, 2022 – The Perot family, The Perot Foundation, and The Sarah and Ross Perot, Jr. Foundation have provided a transformative $50 million endowment for UT Southwestern’s Medical Scientist Training Program (MSTP), among the nation’s elite programs that provide graduates a dual M.D./Ph.D. degree to strengthen the advancement of laboratory discoveries into the clinical arena.

    Funding will provide a permanent endowment for the Perot Family Scholars Medical Scientist Training Program – one of just 54 M.D./Ph.D. training programs in the country supported by the National Institutes of Health (NIH). The program is celebrating its 40th anniversary of graduating top-level physician-scientists from UT Southwestern Medical School and UT Southwestern Graduate School of Biomedical Sciences, both among the top-ranked schools nationally.

    “This extraordinary gift provides a permanent foundation at UT Southwestern for this distinctive dual-degree program that will not only benefit top UT Southwestern students, but also help address a disturbing national trend in the diminishing number of fully trained physician-scientists,” said Daniel K. Podolsky, M.D., President of UT Southwestern Medical Center. “The Perot family’s beneficent support further cements their historical commitment to the continuous advancement of academic medicine and its benefits.”

    UT Southwestern’s faculty includes a number of distinguished physician-scientists with the dual degree, including the late Nobel Laureate Alfred G. Gilman, M.D., Ph.D., former Dean of UT Southwestern Medical School; three of UT Southwestern’s 18 members of the National Academy of Medicine; and two of UT Southwestern’s 14 Howard Hughes Medical Institute (HHMI) Investigators.

    “Ross was an enthusiastic supporter of the Medical Scientist Training Program because he considered it to be one of our best investments in people and intellect,” Margot Perot said. “Our family is delighted to sustain our support and association with the MSTP program. We know that it will yield enormous rewards in the years to come. We are certain our funds will go far to train young scientists destined to make significant medical breakthroughs in the future.” 

    The Perot Family Scholars program builds on a legacy that Ross and Margot Perot invested in for the past four decades, starting in 1987 with a $20 million gift supporting Nobel Laureates Michael Brown, M.D., and Joseph Goldstein, M.D., and the Medical Scientist Training Program, followed by more than $23 million in additional support in 1996 for training and biomedical research. In addition, the Perot family has generously supported the Perot Foundation Neuroscience Translational Research Center, mental health programs, and veterans research, including groundbreaking research by Robert Haley, M.D., on Gulf War Syndrome. 

    “I think the Perot family’s contribution is, as it was back in the 1980s, enormously forward-looking,” Dr. Brown said. “This latest gift will make it possible for us to produce a whole new generation of physician-scientists who will then go on to develop new cures and ultimately the means to prevent many diseases.”

    Since its launch in 1978, UT Southwestern’s M.D./Ph.D. program has graduated nearly 300 physician-scientists with approximately 75% going on to faculty positions at academic medical centers, including many prestigious institutions such as Harvard, Yale, Columbia, and Stanford, in addition to UT Southwestern. Twenty-four of the graduates serve on the faculty at UT Southwestern, where they train the next generation of physician-scientists. UT Southwestern Medical School is ranked among the top 25 in the U.S. for research and in the top 20 for primary care nationwide by U.S. News & World Report. Only six institutions in the country rated above UTSW in both categories, and UTSW has nationally rated programs in the UT Southwestern Graduate School of Biomedical Sciences, including ranking 25th nationally in Biology.

    The Perot family’s support will expand the number of students admitted to the dual-degree program as well as research disciplines in which they study, to include biomedical engineering, computational biology, bioinformatics, and data science. The investment also will enhance the curriculum and experiences of MSTP students and increase efforts to recruit students from elite U.S. colleges, including top international students who wish to stay in the U.S. for their careers. 

    MSTP Research Success 

    The National Institute of General Medical Sciences (NIGMS) bridges the gap between basic science and clinical research by providing both graduate training in the biomedical sciences and clinical training offered through medical schools. A 2014 report by the NIH Physician-Scientist Workforce (PSW) Working Group, which included Helen H. Hobbs, M.D., Professor of Internal Medicine at UTSW and an HHMI Investigator, identified a need to strengthen the biomedical workforce. In the past three decades, the proportion of physicians engaged in research has declined to approximately 1.5% of the overall physician workforce, according to the Physician-Scientist Support Foundation.

    Studies from the NIGMS show that NIH MSTP graduates are more likely to have performed both research and clinical postdoctoral training, to hold academic appointments, to publish more, and to receive research support. Three-quarters of MSTP graduates who applied were successful in obtaining NIH support, for example. 

    UT Southwestern is ranked No. 1 among global health care institutions in the 2022 Nature Index for its published research and among the top 20 for global academic life sciences institutions. UTSW faculty includes four active Nobel Laureates, 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 HHMI Investigators.

    Dr. Brown holds The W. A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research, and the Paul J. Thomas Chair in Medicine. Dr. Goldstein holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research, and the Paul J. Thomas Chair in Medicine. Dr. Haley holds the U.S. Armed Forces Veterans Distinguished Chair for Medical Research, Honoring Robert Haley, M.D., and America’s Gulf War Veterans. Dr. Hobbs holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development, the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Chair in Developmental Biology, and the 1995 Dallas Heart Ball Chair in Cardiology Research. Dr. Podolsky holds the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration, and the Doris and Bryan Wildenthal Distinguished Chair in Medical Science.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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    UT Southwestern Medical Center

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  • Defect in Gene Caused Massive Obesity in Mice Despite Normal Food Intake

    Defect in Gene Caused Massive Obesity in Mice Despite Normal Food Intake

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    Newswise — DALLAS – Oct. 28, 2022 – A faulty gene, rather than a faulty diet, may explain why some people gain excessive weight even when they don’t eat more than others, UT Southwestern researchers at the Center for the Genetics of Host Defense have discovered.

    The findings, published in Cell Metabolism, describe how a defect in a gene called Ovol2 caused mice with normal activity levels and food intake to become obese as they reached adulthood due to problems generating body heat. If the same holds true in humans, who share a nearly identical gene and its protein product, the findings could eventually help identify potential treatments for obesity.

    “Most cases of obesity are caused by overeating or by lack of physical activity, but our research has shown that a mutation of a little-studied gene called Ovol2 causes massive obesity – due solely to a defect in thermogenesis, or heat production,” said study leader Zhao Zhang, Ph.D., Assistant Professor of Internal Medicine who co-led this study with Nobel Laureate Bruce Beutler, M.D., Professor of Immunology and Director of the Center for the Genetics of Host Defense.

    About 42% of people in the U.S. are obese, a condition that drives up the risk of many other health problems including heart disease, stroke, Type 2 diabetes, and certain types of cancer. Although researchers agree obesity appears to stem from an interplay between a person’s genes and his or her environment, the genes that play important roles in the most common forms of obesity aren’t well understood, and the most famous obesity mutations in mice and humans cause a voracious appetite.

    To learn more about basic mechanisms of obesity, Drs. Zhang and Beutler and their colleagues used a chemical to generate random mutations in the DNA of mice. In a particular family of mice, obesity began at about 10 weeks of age – young adulthood for the rodents – and continued until the animals were massively overweight. The researchers identified the responsible mutation in a gene called Ovol2.

    “No one had associated this gene with obesity before,” Dr. Beutler said, “because it’s essential for life. The mutation we created was mild enough to allow survival but damaging enough to reveal a striking metabolic defect.”

    The obese mice experienced a 556% increase in fat weight, accompanied by a 20% reduction in lean weight, compared to littermates who had not undergone mutagenesis. Experiments showed the obese animals weren’t able to maintain their core body temperature when exposed to cold, which appeared to result from an inability to effectively use a type of tissue called brown fat, the primary function of which is to generate heat. Further tests suggested that the healthy Ovol2 gene suppressed development of white fat, the main tissue responsible for energy storage.

    When the researchers overexpressed the normal Ovol2 protein, they found that animals gained far less weight than wild-type controls in mice fed a high-fat diet. The authors said these findings suggest Ovol2 is a key player in energy metabolism – which probably holds true for humans since the human Ovol2 protein is very similar to the mouse version. Eventually, said Dr. Zhang, doctors may be able to treat obesity by giving patients drugs that drive up Ovol2 function.

    Drs. Beutler and Zhang are inventors on a patent related to these findings.

    UT Southwestern is a Nutrition Obesity Research Center, one of 12 in the nation funded by the National Institutes of Health and the only one in Texas. The Center supports work by more than 150 UT Southwestern scientists to investigate the causes, prevention, and treatment options for obesity.

    Dr. Beutler is a Regental Professor who holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. He received the 2011 Nobel Prize in Physiology or Medicine for his discovery of how the innate immune system is activated.

    Other UTSW researchers who contributed to this study include Yiao Jiang, Lijing Su, Sara Ludwig, Xuechun Zhang, Miao Tang, Xiaohong Li, Priscilla Anderton, Xiaoming Zhan, Mihwa Choi, Jamie Russell, Chun-Hui Bu, Stephen Lyon, Darui Xu, Sara Hildebrand, Lindsay Scott, Jiexia Quan, Rochelle Simpson, Qihua Sun, Baifang Qin, Tiffany Collie, Meron Tadesse, and Eva Marie Y. Moresco.

    This work was supported by the National Institutes of Health (K99 DK115766, R00 DK115766, R01 AI125581, and U19 AI100627) and the Lyda Hill Foundation.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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    UT Southwestern Medical Center

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  • UA Little Rock Receives $150,000 NSA Grant to Host Cybersecurity Educational Program Across Arkansas

    UA Little Rock Receives $150,000 NSA Grant to Host Cybersecurity Educational Program Across Arkansas

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    Newswise — The University of Arkansas at Little Rock has received a nearly $150,000 grant from the National Security Agency to hold a year’s worth of free cybersecurity educational events for junior high and high school students in Arkansas.

    UA Little Rock will partner with Philander Smith College to host the 2nd Arkansas GenCyber Strength Training camp in Arkansas, which will support the state’s long-term investment in secondary school cybersecurity education.

    The grant will fund a free two-week cybersecurity summer camp at UA Little Rock in July 2023. In addition to the summer camp, UA Little Rock will host a series of quarterly education events designed as escape rooms with cybersecurity challenges to get Arkansas students excited about cybersecurity education.

    Those working on the grant include Dr. Philip Huff, assistant professor of cybersecurity at UA Little Rock, Sandra Leiterman, managing director of the UA Little Rock Cyber Arena, and Dr. Suzan Anwar, a UA Little Rock graduate, assistant professor, and department chair of computer science at Philander Smith College.

    The Arkansas GenCyber Strength Training program will be offered at no cost to up to 100 rising 7th-12th grade students in Arkansas. There will be both a virtual and in-person camp option so that students from across the state can participate even if they are unable to travel to Little Rock.

    Students will also participate in hands-on activities in cyber attacks and defense provided through UA Little Rock’s Cyber Arena, which already provides cloud-based cybersecurity labs to more than 500 virtual students in Arkansas.

    “Students will learn how to think like a hacker and stop cyber criminals in their tracks,” Leiterman said. “Each day will feature a world-renowned expert speaker in cybersecurity and the top hands-on cybersecurity training in the region. We will bring partners from industry, academia, and professional development organizations to provide multiple pathways to a cybersecurity career.”

    This two-week camp focuses on the GenCyber Cybersecurity Concepts. Participants will hear from industry experts about career opportunities and will learn about cybersecurity with state-of-the art hands-on activities that allows the students to experience cyberattacks from both the victim and adversary side.

    “I will teach portions of the camp, provide assistance to the teachers teaching the camp, assist in content and curriculum development to ensure it is relevant and unbiased to the target audience,” Anwar said. “Philander Smith College undergraduate student researchers will assist with camp preparation and develop cybersecurity labs and the GenCyber escape room used for outreach activities.”

    Those interested in the GenCyber programming should fill out this online form for more information.

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    University of Arkansas at Little Rock

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  • Building a 3D Brain Atlas

    Building a 3D Brain Atlas

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    Newswise — SAN ANTONIO (October 26, 2022) – Texas Biomed will help map the developing brain with unprecedented detail for the National Institutes of Health’s BRAIN Initiative Cell Atlas Network (BICAN). NIH recently awarded a total of $500 million to 11 teams that will work together to build a 3D brain atlas at single cell resolution over the next five years.

    Texas Biomed and its Southwest National Primate Research Center are part of a team led by the University of California, San Francisco (UCSF), and also includes Yale University, University of Pennsylvania, University of Wisconsin—Madison, and University of California, Los Angeles.

    “This is an example of what you could call ‘Big science’ with a capital B,” says UCSF Professor Arnold Kriegstein, MD, PhD, who is overseeing the team’s $36.4 million portion of the initiative. “It’s much larger than any individual lab, or even a single institute, could hope to accomplish. It can only be done with a large collaborative group of investigators working together.”

    The team’s contribution to the overall effort is mapping the developing brain – identifying cell types, activities and locations as they differentiate during development and change throughout childhood and into adolescence. They will also be the only team to draw direct comparisons between humans and nonhuman primate relatives.

    “We are truly excited to be a part of this collaboration and see this 3D single cell brain map come to life,” says Texas Biomed Associate Professor Marcel Daadi, PhD, one of the co-principal investigators of the NIH grant. “This project will help us better understand what makes our brains different and uniquely vulnerable to certain neurodegenerative diseases compared to our closest relatives.”

    By mapping female and male developing brains at key phases before birth, after birth, during childhood and teen years, the group aims to learn more about normal, healthy brain development. This will also provide a baseline to better understand how diseases like autism, schizophrenia and Parkinson’s emerge.

    “Usually, by the time we see symptoms of Parkinson’s, about 80% of dopamine nerve terminals are already gone,” Dr. Daadi says. “Changes in the brain that happen early in life might contribute to faulty brain connections and neurodegeneration in later years. This project could help us learn what those critical changes are and find new treatment targets.”

    This builds on the BRAIN Initiative’s first phase, called the Cell Census Network, which catalogued brain cell types, with an emphasis on mice. Now, in this phase, the teams will complete a comprehensive list of human brain cell types, and clarify how all those cells work together, showing what cell types are present in different structures of the brain.

    “There are 80 billion cells in the brain and we don’t really understand the composition, how those cells are distributed, or how that changes during development,” Dr. Kriegstein says. “But we have technology now that allows us to look at these questions at extremely high resolution.”

    To create the atlas, researchers will not just identify individual cells, but also where they are located in the brain, which can shift, especially during development. They will use a combination of advanced single cell sequencing techniques as well as advanced imaging techniques to ultimately merge the data into an interactive map. A key feature of the BRAIN Initiative is making sure all teams are using standardized methods and technologies so all the data can be compiled together into a final product.

    “When complete, the single-cell brain atlas will provide a resource that will inform future research into a wide range of health conditions for decades to come,” says Joanne Turner, PhD, Texas Biomed’s Executive Vice President of Research. “We are proud to contribute our expertise in animal models and can’t wait to see what new mechanisms are revealed.”

    The collaboration will also greatly benefit up-and-coming researchers, and is poised to inspire the next generation of scientists and leaders, much like the Human Genome Project did in the 1990s and early 2000s.

    “I really think we’ve put together some of the best experts in the field, anywhere in the world, for this initiative,” Dr. Kriegstein says. “I’m really excited for our early-career scientists to work alongside them and with each other on such a significant collaboration.”

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    About Texas Biomed

    Texas Biomed is one of the world’s leading independent biomedical research institutions dedicated to eradicating infection and advancing health worldwide through innovative biomedical research. Texas Biomed partners with researchers and institutions around the world to develop vaccines and therapeutics against viral pathogens causing AIDS, hepatitis, hemorrhagic fever, tuberculosis and parasitic diseases responsible for malaria and schistosomiasis disease. The Institute has programs in host-pathogen interaction, disease intervention and prevention and population health to understand the links between infectious diseases and other diseases such as aging, cardiovascular disease, diabetes and obesity. For more information on Texas Biomed, go to www.TxBiomed.org.

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    Texas Biomedical Research Institute

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  • Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness

    Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness

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    Newswise — PHILADELPHIA—Adults with a genetic form of childhood-onset blindness experienced striking recoveries of night vision within days of receiving an experimental gene therapy, according to researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

    The patients had Leber Congenital Amaurosis (LCA), a congenital blindness caused by mutations in the gene GUCY2D. The researchers, whose findings are reported in the journal iScience, delivered AAV gene therapy, which carries the DNA of the healthy version of the gene, into the retina of one eye for each of the patients in accordance with the clinical trial protocol. Within days of being treated, each patient showed large increases, in the treated eye, of visual functions mediated by rod-type photoreceptor cells. Rod cells are extremely sensitive to light and account for most of the human capacity for low-light vision.

    “These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness,” said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology at Penn.

    LCA is one of the most common congenital blindness conditions, affecting roughly one in 40,000 newborns. The degree of vision loss can vary from one LCA patient to another but all such patients have severe visual disability from the earliest months of life. There are more than two dozen genes whose dysfunction can cause LCA.

    Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the “phototransduction cascade”—the process that converts light to neuronal signals. Prior imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, especially in rod-rich areas, hinting that rod-based phototransduction could work again if functional GUCY2D were present. Early results with low doses of the gene therapy, reported last year, were consistent with this idea.

    The researchers used higher doses of the gene therapy in two patients, a 19- year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits. In daylight, the patients had some, albeit greatly impaired, visual function, but at night they were effectively blind, with light sensitivity on the order of 10,000 to 100,000 times less than normal.

    The researchers administered the therapy to just one eye in each patient, so the treated eye could be compared to the untreated eye to gauge treatment effects. The retinal surgery was performed by Allen C. Ho, MD, a professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests revealed that, in both patients, the treated eyes became thousands of times more light-sensitive in low-light conditions, substantially correcting the original visual deficits. The researchers used, in all, nine complementary methods to measure the patients’ light sensitivity and functional vision. These included a test of room navigation skills in low-light conditions and a test of involuntary pupil responses to light. The tests consistently showed major improvements in rod-based, low-light vision, and the patients also noted functional improvements in their everyday lives, such as “can [now] make out objects and people in the dark.”

    “Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy,” said study co-author Artur V. Cideciyan, PhD, a research professor of Ophthalmology at Penn.

    To the researchers, the results confirm that GUCY2D gene therapy to restores rod-based photoreceptor functions—and suggest that GUCY2D–LCA patients with more severe rod-based dysfunction are likely to benefit most dramatically from the therapy. The practical message is that there should be an emphasis on rod vision measurements at screening of LCA candidates and in monitoring them throughout a treatment trial.

    The findings, the researchers said, also underscore the remarkable fact that in some patients with severe congenital vision loss, the retinal cell networks that mediate vision remain largely alive and intact, and need only the resupply of a missing protein to start working again, more or less immediately.

    The ongoing clinical trial is registered at clinicaltrials.gov as trial NCT03920007.

    Support for the research was provided by Atsena Therapeutics, Inc., the developer of the GUCY2D gene therapy; the National Institutes of Health (R01 EY11522); and by a CURE Formula grant from the Pennsylvania Department of Health.

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    Perelman School of Medicine at the University of Pennsylvania

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  • 3D map reveals DNA organization within human retina cells

    3D map reveals DNA organization within human retina cells

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    Newswise — National Eye Institute researchers mapped the organization of human retinal cell chromatin, the fibers that package 3 billion nucleotide-long DNA molecules into compact structures that fit into chromosomes within each cell’s nucleus. The resulting comprehensive gene regulatory network provides insights into regulation of gene expression in general, and in retinal function, in both rare and common eye diseases. The study published in Nature Communications.

     “This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,” said the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health.

    Adult human retinal cells are highly specialized sensory neurons that do not divide, and are therefore relatively stable for exploring how the chromatin’s three-dimensional structure contributes to the expression of genetic information.

    Chromatin fibers package long strands of DNA, which are spooled around histone proteins and then repeatedly looped to form highly compact structures. All those loops create multiple contact points where genetic sequences that code for proteins interact with gene regulatory sequences, such as super enhancers, promoters, and transcription factors. 

    Such non-coding sequences were long considered “junk DNA.” But more advanced studies demonstrate ways these sequences control which genes get transcribed and when, shedding light on the specific mechanisms by which non-coding regulatory elements exert control even when their location on a DNA strand is remote from the genes they regulate.

    Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Maps were constructed using post-mortem retinal samples from four human donors.

    The researchers then integrated that chromatin topology map with datasets on retinal genes and regulatory elements. What emerged was a dynamic picture of interactions within chromatin over time, including gene activity hot spots and areas with varying degrees of insulation from other regions of DNA.

    They found distinct patterns of interaction at retinal genes suggesting how chromatin’s 3D organization plays an important role in tissue-specific gene regulation.

    “Having such a high-resolution picture of genomic architecture will continue to provide insights into the genetic control of tissue-specific functions,” Swaroop said. 

    Furthermore, similarities between mice and human chromatin organization suggest conservation across species, underscoring the relevance of chromatin organizational patterns for retinal gene regulation. More than a third (35.7%) of gene pairs interacting through a chromatin loop in mice also did so in human retina.

    The researchers integrated the chromatin topology map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, two leading causes of vision loss and blindness. The findings point to specific candidate causal genes involved in those diseases.

    The integrated genome regulatory map will also assist in evaluating genes associated with other common retina-associated diseases such as diabetic retinopathy, determining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases. 

    The study was supported by the NEI Intramural Research Program, grants ZIAEY000450 and ZIAEY000546. 

    Reference: Marchal C, Singh N, Batz Z, Advani J, Jaeger C, Corso-Diaz X, and Swaroop A. “High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci.” Published October 7, 2022, Nature Communications. DOI:10.1038/s41467-022-33427-1

     

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    This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process— each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit https://www.nih.gov/news-events/basic-research-digital-media-kit.

    NEI leads the federal government’s efforts to eliminate vision loss and improve quality of life through vision research…driving innovation, fostering collaboration, expanding the vision workforce, and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to broaden opportunities for people with vision impairment. For more information, visit https://www.nei.nih.gov.

    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 https://www.nih.gov/.

    NIH…Turning Discovery Into Health®

     

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    NIH, National Eye Institute (NEI)

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  • Taking aim at triple-negative breast cancer and multiple myeloma to improve prognoses

    Taking aim at triple-negative breast cancer and multiple myeloma to improve prognoses

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    Newswise — Two Houston Methodist cancer researchers have been awarded a half million dollars in funding from the Cancer Prevention and Research Institute of Texas (CPRIT) to further research two of the most lethal, difficult-to-treat cancers that all-too-often have poor prognoses.

    Jenny C. Chang, M.D., director of Houston Methodist Dr. Mary and Ron Neal Cancer Center and Emily Hermann Chair in Cancer Research, received a $250,000 grant to study the interaction between obesity and nitric oxide synthase (NOS) in triple-negative breast cancer (TNBC).

    Chang says TNBC, already the worst prognosis among the subtypes of breast cancer, has even worse outcomes in obese patients. These patients have a higher chance of resisting chemo and an increased risk of relapse and poorer survival. She says the reason is unclear, but evidence indicates it’s associated with chronic inflammation and that two essential players of chronic inflammation – tumor neutrophil infiltration and nitric oxide (NO) levels – have been identified to play pivotal roles in obesity-associated TNBC.

    Studies have shown that obesity reprograms the tumor microenvironment and that this reprograming is accompanied by increased nitric oxide levels that, along with infiltrating neutrophils, compromise vascular integrity and cause increased breast cancer metastasis. Chang and her team propose that NOS inhibition will reverse the immunosuppressive tumor microenvironment to enhance the efficacy of the current standard of care. Successful completion of their proposed work will provide an improved understanding of the role of the NOS inhibitors in TNBC and may define prognostic markers in obese TNBC patients at a higher risk of mortality, as well as help the design of successful clinical trials to enhance the appropriate selection of TNBC patients who would benefit from chemotherapy and/or immune checkpoint therapy.

    Jing Yang, Ph.D., an associate professor of oncology with the Houston Methodist Research Institute and member of the Houston Methodist Neal Cancer Center, received a $250,000 grant to study multiple myeloma, which is the second most common blood cancer, to improve the therapeutic efficacy and survival in these patients. Specifically, Yang and her team are looking at a novel FDA-approved monoclonal antibody treatment, daratumumab (DARA), that has shown to improve therapeutic efficacy when combined with other drugs, but falls short in patients with high-risk multiple myeloma who too often relapse or don’t respond to the treatment at all.

    Yang’s team believe they found a clue to better understand how multiple myeloma cells resist DARA and keep it from being effective. Using the largest public database for multiple myeloma patients, they examined tumor gene expression and patients’ best clinical response, which led them to identifying a protein called NHE6 that may be involved in multiple myeloma’s resistance to treatment with DARA. They found that the NHE6 protein is highly expressed in multiple myeloma cells, and its high expression is correlated with patients’ poorer prognoses, high-risk genetic features and multiple myeloma stage progression. Ultimately, these multiple myeloma cells with the high NHE6 level were less responsive to DARA.

    Yang and team’s plan is to investigate the role and mechanism by which NHE6 induces DARA resistance and develop NHE6 as a new target to improve DARA efficacy in murine models and patients. The knowledge gained from their study should uncover innovative insight into how multiple myeloma cells escape from DARA treatment. Given that DARA is an emerging compound used as standard care for multiple myeloma patients, they believe their new strategy of targeting NHE6 and developing an inhibitor to do so could significantly improve DARA-based multiple myeloma therapy outcomes.

     

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    For more information:

    Targeting Nitric Oxide Synthase (NOS) pathway to remodel obesity induced tumor inflammation in patients with TNBC; Cancer Prevention and Research Institute of Texas; awarded Sept. 14, 2022; $250,000 grant (RP220650); PI: Jenny C. Chang, M.D.; https://www.cprit.state.tx.us/grants-funded/grants/rp220650

     

    Targeting NHE6 to improve clinical efficacy of daratumumab in myeloma; Cancer Prevention and Research Institute of Texas; awarded Sept. 14, 2022; $250,000 grant (RP220639); PI: Jing Yang, Ph.D.; https://www.cprit.state.tx.us/grants-funded/grants/rp220639

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