News Article | February 23, 2017
Researchers determine that a protein required for sperm-egg fusion is identical to a protein viruses use to invade host cells; discovery could help fight parasitic diseases like malaria Sexual reproduction and viral infections actually have a lot in common. According to new research, both processes rely on a single protein that enables the seamless fusion of two cells, such as a sperm cell and egg cell, or the fusion of a virus with a cell membrane. The protein is widespread among viruses, single-celled protozoans, and many plants and arthropods, suggesting that the protein evolved very early in the history of life on Earth. The discovery, published on February 23, 2017 in the journal Cell, reveals new details about the evolution of sex. The protein acts as a nearly universal, biochemical "key" that enables two cell membranes to become one, resulting in the combination of genetic material--a necessary step for sexual reproduction. New details about the protein's function could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests. "Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," said William Snell, a senior author of the study and a research professor in the University of Maryland Department of Cell Biology and Molecular Genetics. Snell joined UMD in June 2016, but performed the majority of the work at his previous institution, the University of Texas Southwestern Medical Center. "A protein that first made sex possible -- and is still used for sexual reproduction in many of Earth's organisms -- is identical to the protein used by dengue and Zika viruses to enter human cells," Snell said. "This protein must have really put the spice in the primordial soup." Snell and his colleagues studied the protein, called HAP2, in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods -- although it is not found in fungi or vertebrates such as humans. Prior results from Snell and his collaborators, as well as other research groups, indicated that HAP2 is necessary for sex cell fusion in the organisms that possess the protein. But the precise mechanism remained unclear. For the current study, Snell and his colleagues at UT Southwestern used sophisticated computer analysis tools to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins. The results suggested a striking degree of similarity, especially in a region called the "fusion loop" that enables the viral proteins to successfully invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting HAP2's fusion loop should block its ability to fuse sex cells. Sure enough, when Snell's team changed just a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost its function. The sex cells were able to stick together -- a process that depends on other proteins--but they were not able to complete the final fusion of their cell membranes. Similarly, the cells could not fuse when the researchers introduced an antibody that covered up the HAP2 fusion loop. "We were thrilled with these results, because they supported our new model of HAP2 function," Snell said. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins. "The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable." HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other control methods. Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum. "Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." In addition to Snell and Rey, co-authors of the study include: Juliette Fedry, Gerard Péhau-Arnaudet, M. Alejandra Tortorici, Francois Traincard and Annalisa Meola (Pasteur Institute); Yanjie Liu, Jimin Pei, Wenhao Li and Nick Grishin (UT Southwestern); Gerard Bricogne (Global Phasing, Ltd.); and Thomas Krey (Pasteur Institute, Hannover Medical School and German Center for Infection Research). The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell. This work was supported by the United States National Institutes of Health (Award Nos. GM56778 and GM094575), the Welch Foundation (Award No. I-1505), the European Research Council, the Pasteur Institute and the French National Center for Scientific Research. The content of this article does not necessarily reflect the views of these organizations. University of Maryland College of Computer, Mathematical, and Natural Sciences 2300 Symons Hall College Park, MD 20742 http://www. @UMDscience About the College of Computer, Mathematical, and Natural Sciences The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.
News Article | February 16, 2017
Scientists at Winship Cancer Institute of Emory University have mapped a vast spider web of interactions between proteins in lung cancer cells, as part of an effort to reach what was considered "undruggable." This approach revealed new ways to target cells carrying mutations in cancer-causing genes. As an example, researchers showed sensitivity to an FDA-approved drug, palbociclib, for a gene that is commonly mutated in lung cancer cells, which is now being tested in a clinical study. The results are published online in Nature Communications. Many genes that drive the growth of cancer cells don't have any drugs available against them. For "tumor suppressor" genes, researchers are often not sure how to go after them. When the tumor suppressors are gone, cells often become more deranged, but there's no bullseye left to target. Exploiting the cancer cells' derangement remains a daunting challenge, says senior author Haian Fu, PhD. "Our approach is to place tumor suppressors in the context of a network of cancer-associated proteins and link tumor suppressors to drugs through a known drug target protein," Fu says. "In this way, changes in a tumor suppressor may be linked with the response of the target to the connected drug." The study is part of a push by the National Cancer Institute's Cancer Target Discovery and Development (CTD2) network to translate genomics data into therapeutic strategies, he says. Emory is a member of the NCI CTD2 network. Fu holds the Winship Partner in Research endowed chair and is leader of Winship's Discovery and Developmental Therapeutics Program, director of the Emory Chemical Biology Discovery Center and professor of pharmacology and hematology and medical oncology. Co-corresponding author Fadlo Khuri, MD, maintains his professor appointment at Winship Cancer Institute and is now president of the American University of Beirut in Lebanon. Cancer researchers have been searching for ways to target mutations in the gene STK11/LKB1, found in 15 to 25 percent of non-small cell lung cancers. The tumor suppressor STK11/LKB11 encodes an enzyme that is thought to regulate cell migration and metabolism. One of the Winship team's newly identified interactions -- a "thread" in the spider web -- suggested that palbociclib, recently approved against metastatic breast cancer, may work against cells carrying mutations in LKB1, through LKB1's connection to CDK4, the target of palbociclib. That prediction was supported by genomic data analysis and cell culture experiments: lung cancer cells with LKB1 defects showed a tendency of increased sensitivity to palbociclib. Now a study led by Taofeek Owonikoko, MD, at Winship is using LKB1 status as a biomarker for interpreting the effect of palbociclib. If cells are complex machines, then a number of ways exist for figuring out how the machines' parts, dominated by proteins, fit together. Some of them involve multiple washing steps to remove nonspecific partners after breaking cells apart, but FRET (Förster resonance energy transfer) does not. If two fluorescent molecules with colors that are near on the spectrum are close enough (less than 10 nanometers), that proximity can be detected by FRET. Fu and his colleagues established a large-scale platform for tagging proteins with two different fluorescent molecules, introducing them into cancer cells, and then detecting interactions between the proteins. They call this network of cancer-associated proteins "OncoPPI." Starting with a set of 83 lung cancer-related proteins, the team detected more than 260 interactions that were not known previously. They tested the interactions several times, in different orientations, and in other lung cancer cell lines with selected interactions to establish reliability. More than 80 percent of the interactions the researchers detected could be confirmed by another method (GST pulldown). As an additional example to illustrate the utility of a protein interaction web, the team focused on the prominent oncoprotein Myc, which was also considered "undruggable." But the researchers could connect Myc indirectly through NSD3 to another protein called Brd4, against which inhibitors have been developed. Brd4 inhibitors are being currently tested in clinical trials. This finding revealed a new pathway Brd4-NSD3-Myc as potential targets for therapeutic intervention, Fu says. The OncoPPI research was supported by the National Cancer Institute Cancer Target Discovery and Development (CTD2) network (U01CA168449), lung cancer program project (P01CA116676) and Winship Cancer Institute (P30CA138292) and the Georgia Research Alliance, and the Emory University Research Committee. The clinical study of palbociclib is sponsored by Pfizer. Co-first authors are research associate Zenggang Li, PhD, now at Michigan State University, instructor Andrei Ivanov, PhD and Xiangya Hospital medical student Rina Su, now at Chao-yang Hospital, Capital Medical University in Beijing, China. Emory/Winship co-authors include Qi Qi, PhD, Philip Webber, PhD, Yuhong Du, PhD, Wei Zhou, PhD, Adam Marcus, PhD, Carlos Moreno, PhD, Lee Cooper, PhD and Margaret Johns, PhD, graduate students Valentina Gonzalez-Pecchi and Lauren Rusnak, and visiting medical student Songlin Liu. Collaborators from UT Southwestern contributed to the paper.
News Article | February 16, 2017
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 22, 2017
Heart Screening For Teens May Cause More Problems Than It Solves Dozens of not-for-profit organizations have formed in the past decade to promote free or low-cost heart screenings for teens. The groups often claim such tests save lives by finding abnormalities that might pose a risk of sudden cardiac death. But the efforts are raising concerns. There's no evidence that screening adolescents with electrocardiograms prevents deaths. Sudden cardiac death is rare in young people, and some physicians worry screening kids with no symptoms or family history of disease could do more harm than good. The tests can set off false alarms that can lead to follow-up tests and risky interventions or force some kids to quit sports unnecessarily. "There are harms that I don't think a lot of people realize," said Dr. Kristin Burns, who oversees a two-year-old registry at the National Institutes of Health of sudden deaths in people under 20. It's one of several efforts aimed at gathering better data about cardiac abnormalities in kids. Studies using limited data have found that between 1 and 4 sudden cardiac deaths occur annually per 100,000 kids between ages 1 and 18. By comparison, 22 in 100,000 U.S. teens are killed each year in accidents, including those involving motor vehicles; 9 in 100,000 commit suicide, according to the Centers for Disease Control and Prevention. Some screening advocates believe sudden cardiac deaths are underreported and that not enough is being done to spare families from the fate of losing a child. "We have to acknowledge that every kid who drops dead, they've been failed by the current system," said Darren Sudman, who founded Simon's Fund, a screening effort in greater Philadelphia in memory of his infant son, who died of an arrhythmia. Screening programs say they're educating parents about the risks. "What we want to emphasize is, make sure your kid is heart-safe," said Dr. Jonathan Drezner, a sports and family medicine specialist at UW Medicine and medical director of the Seattle-area Nick of Time Foundation. Enthusiasm for EKGs, which measure the electrical activity in the heart to detect abnormalities, grew after a 2006 study showed they lowered death rates among athletes in Italy. But research in other countries hasn't yielded similar results, and the Italian researchers recently were accused of refusing to share their data so they could be evaluated independently. Some 60,000 to 70,000 U.S. teens were screened with EKGs in 2016, most by foundations created by families who lost a child to sudden cardiac death, said Sudman, who runs the online directory Screen Across America. It's unclear whether high school athletes face higher risk than nonathletes, so screening programs usually invite everybody. Screenings typically are held in high schools and overseen by volunteer cardiologists, with funding from individuals and businesses including hospitals. A handful of hospitals and for-profit companies also run screenings. It may be presumptuous to claim EKGs save lives, but parents often believe they do, said Sudman. "If I find a heart condition, I promise you there are parents who are thanking me for savings their kid's life," he said. That perception is stoked by tragic stories in the media of children who died suddenly after never reporting a symptom. Meanwhile, the drawbacks of EKGs are seldom depicted. As many as 1 in 10 EKGs detects a potential abnormality, and the emotional and financial toll of such a finding can be significant — especially when it turns out to be wrong. Following a screening EKG and echocardiogram last fall, Daniel Garza, 16, a talented sophomore basketball player in San Antonio, was told he had hypertrophic cardiomyopathy, a thickening of the heart muscle and the most common cause of sudden cardiac death in young people. He was advised to quit all exercise, at least temporarily. "We were shocked, just shocked," said his mother, Denise. She said her son became depressed when he couldn't play the sport he enjoyed and excelled at. "He came home and cried himself to sleep. He said, 'Mom, why did God give me this gift to take it away?' " The Garzas traveled to the Mayo Clinic in Rochester, Minn., where further tests indicated his enlarged heart was a benign condition known as athletic heart, a result of intense training. His mother estimates that correcting the misdiagnosis cost more than $20,000, including medical costs, travel and lost work. Daniel has returned to the basketball court. Still, Denise Garza said the emotional toll was rough: "It was one of the hardest things my family has ever endured." Several cardiologists said they often see cases like this — or worse. Even after follow-up testing, it can be unclear which cases are life-threatening, so kids with low risk could be restricted from exercise or given life-altering interventions such as implantable defibrillators, surgery or anti-arrhythmic medications. Medical groups have wrestled with the issue. The American Heart Association and the American College of Cardiology recommended in 2014 against mass EKG screening, noting that sudden cardiac death is rare in teens and false positives generate "excessive and costly second-tier testing." EKGs also miss at least 1 in 10 cases of hypertrophic cardiomyopathy and more than 9 in 10 cases of congenital anomalies, the second-most-common cause. But the medical panel accepted voluntary screening "in relatively small cohorts," if there's physician involvement, quality control and a recognition of unreliable results and ancillary costs. Efforts are underway to improve the accuracy of the screening programs. Some are adding echocardiograms, which use ultrasound to produce images of the heart, to assess potential abnormalities. Advocates say false positives have dropped as a result of better interpretation guidelines, known as the Seattle Criteria, which are expected to soon be endorsed by cardiology societies in revised form. But the criteria aren't perfect, and there's a "giant gap" in training cardiologists to use them, said Drezner, one of the developers. He's also a medical adviser for Parent Heart Watch, a consortium of foundations. "If I was a parent, I'd want to know about the experience of the [cardiologists] and what they're going to do to help my kid if they have a positive screen." One problem with EKGs is a lack of good data. "There's no evidence we have that [EKG] screening saves lives," said Dr. Jonathan Kaltman of the National Heart, Lung, and Blood Institute. "There's never been a controlled clinical trial, which is the only way to answer that question." At the urging of screening advocates, the NIH partnered with the CDC to rigorously track cardiac deaths as part of a Sudden Death in the Young Case Registry. So far a handful of states and counties have joined the effort, which helps local health departments collect better data. The goal is to standardize death investigations and get a firm handle on how often kids die from heart abnormalities as well as the role of factors such as genetics. Initial findings are expected to be available in about two years. The NIH is also funding three university-based research groups to answer key questions about sudden cardiac death in the young. Some screening organizations are getting behind a nascent initiative with the Cardiac Safety Research Consortium to harness their own screening data for research. It would require standardizing their practices and tracking outcomes, which organizations aren't now equipped to do. "Screening is happening. We can't avoid that," said Dr. Salim Idriss, director of pediatric electrophysiology at Duke University and co-chair of the initiative. "We have a really good opportunity to get the data we need to make it better." Separately, the UT Southwestern Medical Center in Dallas recently began a four-year pilot study involving athletes and band members at eight high schools to determine the feasibility of a full-scale randomized controlled trial. A valid finding on the overarching question of whether EKG screening saves lives could require at least 800,000 participants and a cost of $15 million, said Dr. Benjamin Levine, a cardiologist and the lead researcher. The pilot is partly a response to legislation that would mandate EKGs for student athletes in Texas. A similar bill was also introduced in South Carolina. Both bills failed, but it's expected there will be more attempts to mandate EKGs, leaving state legislators looking for better guidance. "We're not going to solve this by having more debates, but by having more data," Levine said. Kaiser Health News is an editorially independent news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. Mary Chris Jaklevic is a freelance health and environment writer based in Chicago. She's on Twitter: @mcjaklevic
News Article | February 17, 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 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.
News Article | March 2, 2017
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.
Mayo M.J.,UT Southwestern
Clinics in Liver Disease | Year: 2013
Primary biliary cirrhosis and primary sclerosing cholangitis share some clinical features with autoimmune hepatitis, but when features of autoimmune hepatitis are present, prognosis can be affected and immunosuppressive treatment warranted. The presence of severe interface hepatitis in primary biliary cirrhosis portends a worse prognosis and should prompt evaluation for possible autoimmune hepatitis overlap and treatment with immunosuppression. Specific models to identify which subjects benefit most from the addition of immunosuppression need to be developed. Drug-induced liver injury and IgG4 disease may masquerade as autoimmune hepatitis or primary sclerosing cholangitis and are important to consider in the differential diagnosis of the overlap or variant syndromes. © 2013 Elsevier Inc.
News Article | February 15, 2017
Inventory Optimization Solutions (IOS) and Texas Health Resources have expanded their partnership by offering health care consulting services wrapped around tenured, proven technology. Texas Health’s goal is to help health care organizations repair the breaks in the supply chain by leveraging the IOS procurement and inventory platform (ENVI) and proven processes that create hard-dollar savings. Texas Health has automated more than 300 facilities with IOS’ technology throughout 16 counties in the Dallas/Fort Worth area. Their experience is vast, and the partnership provides a valuable service to the non-acute market and helps create visibility across the entire health care continuum. Since 2013, Texas Health has implemented ENVI™, IOS’ next-generation complete supply chain solution, to standardize products in multiple categories and ensure consistent purchasing, receiving and accounts payable processes. Texas Health has saved $6 million through the non-acute program and its reliable, transparent supply chain. It uses ENVI to create an approval process to prevent unnecessary orders, and leverage supply chain data to make more informed, cross-enterprise buying decisions. Texas Health has also lowered risk by proactively managing product recalls and backorders. “We liked IOS’ technology so much that we wrapped consulting and outsourced supply chain services around it,” said Nate Mickish, Texas Health Resources. “Our partnership has created true value, as well as a new model for the health care market.” “Our partnership with Texas Health offers the non-acute healthcare community guaranteed success,” said Steve Britt, Managing Partner, IOS. “Through our 13 years of market experience and proven technology, and Texas Health’s expertise as one of the nation’s largest IDNs, we have a proven solution to help our customers drive cost out of the supply chain.” Both companies agree that “best practice” means leveraging both technology and process; and with acute-care programs expanding into the non-acute space, now is the time to share this information with the industry. The companies are hosting a free webinar on Wednesday, Feb. 22, 2017, at 3:00 p.m. EDT, focused on driving savings and efficiencies. Texas Health will share the winning strategies that turned its supply chain into a strategic asset. Reach out via http://www.ioscorp.com for an invite or more information. About IOS With the nation’s largest footprint in the non-acute healthcare supply chain, IOS works with more than 4,500 critical access hospitals, ambulatory surgery centers, long-term care facilities and physician clinics. Treating the supply chain like a science, IOS has carved out a leadership position in the industry with stellar customer service and years of innovative technology development. About Texas Health Resources Texas Health Resources is one of the largest faith-based, nonprofit health systems in the United States. The health system, which along with UT Southwestern founded Southwestern Health Resources in 2016 to make it easier for North Texans to access the highest quality care consistently in a responsive and coordinated manner, includes 29 hospital locations that are owned, operated, joint-ventured or affiliated with Texas Health Resources. It includes Texas Health Presbyterian Dallas, Texas Health Arlington Memorial, Texas Health Harris Methodist and Texas Health Huguley Hospitals, Texas Health Physicians Group, outpatient facilities, behavioral health and home health, preventive and fitness services, and an organization for medical research and education. For more information about Texas Health Resources, call 1-877-THR-WELL, or visit http://www.TexasHealth.org.
News Article | March 3, 2017
A new potential drug that could treat polycystic kidney disease was found. The disease is incurable, and it often happens to lead to end-stage kidney failure. The study, published in Nature Communications, on Feb. 16, was conducted by researchers at the UT Southwestern Medical Center, who collaborated with a California-based biotech company. The new medicine that could potentially cure polycystic kidney disease is called RGLS4326, and it is currently in preclinical animal testing. According to assistant professor Vishal Patel, senior author of the study, an investigational drug associated with this finding should be available later in 2017. The disease manifests through an abnormal growth of the kidney due to cysts filled with fluid, which keep growing in size until they eventually prevent the organ for serving its functions. Due to this, the kidney loses its capacity to remove bodily waste and filter blood. According to the researchers, the patients can have this disease for decades until the first symptoms show up, such as blood in the urine. At the moment, there is no available drug on the market to treat this disease, and the only two available options once the kidney reaches failure are dialysis or a transplant. Back in 2009, Dr. Patel started to look for microRNAs (MiRs) that could provide a better understanding on the disease. These MiRs are very small pieces of RNA that can interfere with normal gene expression. Researchers discovered the role of MiRs back in the 1990's, and the scientific interest in finding a viable drug to treat diseases caused by these small RNA fragments increased rapidly. The reason for this scientific interest is that, once the fragment is found, the rest of the scientific process can evolve rapidly. Because of the fragments' small dimensions, researchers can easily create drugs to annihilate their actions. Once the researchers identify the RNA fragment, the only thing left to do is preparing an anti-MiR with the very opposite sequence. As part of a 2013 research, the scientists focused their efforts on finding MiR clusters in the attempt to identify potential viable targets. As a result to that research they published a paper with a potential RNA sequence that they found promoted kidney cyst growth, called the 17~92 sequence. In the current study, the researchers employed mouse models, in which they inhibited the microRNA sequence, finding that the genetic deletion of the 17~92 sequence slowed cyst growth. Additionally, the lifespan of the tested mice increased more than twice its initial value. "In support of this conclusion, we show that genetic deletion of miR-17∼92 attenuates disease progression in ADPKD mouse models irrespective of the mutated gene, the type of mutation (null or hypomorphic) or the dynamics of cyst growth (rapidly fatal, aggressive but long-lived or slowly progressing)," noted the study. Polycystic kidney disease is a genetic disorder that affects approximately 600,000 people in the United States, about half of those affected with the disease experience kidney failure by the age of 60. The cysts cause high blood pressure, as well as problems with blood vessels in the heart and brain, according to the National Institute of Diabetes and Digestive and Kidney Diseases. For the patients who are currently suffering from this disease, it is highly recommended to regulate a healthy diet, in order to have control on blood pressure. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
News Article | February 21, 2017
The findings, to be published on February 21, 2017, in the journal Nucleic Acids Research by scientists in a research collaboration between NIST and Stanford University, demonstrate that there are at least 47 possible start codons, each of which can instruct a cell to begin protein synthesis. It was previously thought that only seven of the 64 possible triplet codons trigger protein synthesis. "It could be that many potential start codons had remained undiscovered because no one could see them," said lead author Ariel Hecht, a team member at the Joint Initiative for Metrology in Biology, a research collaboration that includes NIST and Stanford. Scientists made many of their initial discoveries about DNA and RNA, including start codons, in the 1950s and 1960s. Those ideas have since become enshrined in textbooks around the globe as the modern understanding of the rules of molecular biology. Genetic code is typically represented via sequences of four letters—A, C, G, and T or U—which correspond to the molecular units known as adenine, cytosine, guanine and thymine (for DNA code) or uracil (for RNA code). Fifty years ago, the best available research tools indicated that there were only a few start codons (with sequences of AUG, GUG and UUG) in most living things. Start codons are important to understand because they mark the beginning of a recipe for translating RNA into specific strings of amino acids (i.e., proteins). The JIMB team's realization that there might be something amiss in the general understanding of how codons perform began unexpectedly over a round of bagels and coffee. Hecht and his colleagues Jeff Glasgow, Lukmaan Bawazer and Matt Munson were discussing colleague Paul Jaschke's unsuccessful attempt to refactor a virus, phiX174. Refactoring is a kind of re-coding or rearranging used to study genomes and to identify essential genes. phiX174 can be used to infect E. coli cells as a part of such studies. Jaschke had replaced the start codons of several genes with codons that should not have started translation (AUA and ACG). However, to Jaschke's surprise, he was still detecting the expression of those genes that should have been silenced due to removal. Hecht pondered what seemed like a rather naïve question: Was Jaschke's experimental result actually wrong? What if the results indicated that codons didn't fit a traditional description of start or not, but instead had varying likelihoods to initiate start translation? To the best of their knowledge, no one had ever systematically explored whether translation could be initiated from all 64 codons. No one had ever proved that you cannot start translation from any codon. "We kind of all collectively asked ourselves: had anyone ever looked?" said Hecht. A further review of available literature on the topic indicated that the answer was no. Unlike geneticists working a half-century ago, the JIMB team and others who peer into the inner workings of cells now have far more powerful tools at their disposal, including green fluorescent protein (GFP), a protein adapted from jellyfish, and nanoluciferase, another protein adapted from a deep sea shrimp. Both GFP and nanoluciferase emit light when expressed inside cells and have been optimized within the past decade to produce very strong signals that can be used to probe the cells in depth. "Ten years ago the tools to make this kind of measurement didn't exist," Hecht said. NIST specializes in the process of precision measurement, and the start codon challenge proved irresistible to the JIMB team. The collaboration was formed in 2016 with the goal of advancing biomeasurement science and facilitating the process of discovery by bringing together experts from academia, government labs and industry for collective scientific investigations. With the use of GFP and nanoluciferase, the team measured translation initiation in the bacteria E. coli from all 64 codons. They were able to detect initiation of protein synthesis from 47 codons. The implications of the work could be quite profound for our understanding of biology. "We want to know everything going on inside cells so that we can fully understand life at a molecular scale and have a better chance of partnering with biology to flourish together," said Stanford professor and JIMB colleague and advisor, Drew Endy. "We thought we knew the rules, but it turns out there's a whole other level we need to learn about. The grammar of DNA might be even more sophisticated than we imagined." Still, the JIMB team cautions, this paper is really just the first step, and it is unclear what studies of other organisms will reveal. "We need to be very careful about extrapolating from these findings or applying them to other organisms without further, deeper research," said Hecht. He hopes that this paper will encourage or inspire other researchers to explore the topic to find even more answers. "It could be that all codons could be start codons," Hecht said. "I think it is just a matter of being able to measure them at the right level." Explore further: A hidden genetic code for better designer genes