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Anti-Rejection Drug Can Prevent Pancreatic Inflammation Triggered by Common Procedure to Remove Gallstones

PrintPITTSBURGH, July 2, 2015 – Exposure to an X-ray dye during a common procedure to treat gallstones causes some patients to develop inflammation of the pancreas, according to researchers at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC. In a study published online in Gastroenterology, the team noted that a single dose of FK506, an anti-rejection drug typically used after organ transplantation, might be able to prevent the complication.

During the endoscopic retrograde cholangiopancreatography (ERCP) procedure, doctors insert a fiber-optic endoscope through the mouth, esophagus, stomach and duodenum to access the bile ducts, where a gallstone might be lodged. The X-ray dye, also known as radiocontrast, is infused through a catheter so doctors can visualize the bile ducts and anything obstructing them, explained senior author and principal investigator Sohail Z. Husain, M.D., associate professor of pediatrics at the Pitt School of Medicine and Children’s Hospital.

“Thousands of ERCP procedures are performed every year, particularly for the removal of gallstones,” Dr. Husain said. “But after the procedure, a fair number of patients develop acute pancreatitis, which is an exquisitely painful, life-threatening inflammation of the pancreas. Our findings provide the first explanation for why this complication occurs, namely through the signals that FK506 can block.”

The research team examined what happened to pancreatic cells in mice after they received infusions of two common radiocontrast agents. They found the agents elevated cellular calcium levels, in turn activating proteins, particularly calcineurin, involved in inflammatory pathways that cause tissue injury. Similar results were observed in experiments with human pancreatic cells. Also, mice that were genetically modified to lack calcineurin failed to develop pancreatitis after radiocontrast exposure.

Mice that were given the anti-rejection drug FK506, which is an inhibitor of calcineurin, before and after infusion of the X-ray dye also were protected from pancreatitis.

“In the future, we will test other radiocontrast agents to see if they, too, affect the same inflammatory pathways,” Dr. Husain said. “This study already sets the stage for a clinical trial to test whether calcineurin inhibitors alone or in combination with other drugs can prevent post-ERCP pancreatitis.”

The team included Shunqian Jin, Ph.D., Abrahim I. Orabi, B.S., Tianming Le, M.D., Tanveer A. Javed, B.S., Swati Sah, B.A., and John F. Eisses, M.D., Ph.D., all of the University of Pittsburgh; Rita Bottino, Ph.D., of Allegheny General Hospital; and Jeffery D. Molkentin, Ph.D., of the University of Cincinnati. The project was funded by National Institutes of Health grants DK083327, DK093491 and DK03002.

Mosquito-Borne Viruses Subject of $4M in Federal Grants to Scientists in Pitt’s Center for Vaccine Research

PITTSBURGH, July 2, 2015 – Scientists at the University of Pittsburgh Center for Vaccine Research (CVR) recently received nearly $4 million through five federal grants to study a group of related mosquito-borne viruses. The ultimate goal is to develop vaccines and therapies against the deadly diseases.

The research will be conducted in the Regional Biocontainment Laboratory (RBL) at Pitt, a unique, high-security facility that allows scientists to safely contain and examine potentially dangerous pathogens.

“This recent funding highlights the globally significant research being done right here in Pittsburgh to help develop ways to protect people against emerging diseases of growing concern,” said Ronald Montelaro, Ph.D., professor and co-director of Pitt’s CVR.

William Klimstra, Ph.D., associate professor at Pitt’s CVR, is principal investigator on three of the grants and about half the funding. Kate D. Ryman, Ph.D., also associate professor at Pitt’s CVR, is principal investigator on the other two grants.

“While the number of people who get these diseases is relatively small, the severity of disease and their potential emergence in larger populations or for use as bioweapons drive the necessity for development of countermeasures,” said Dr. Klimstra.

Two of Dr. Klimstra’s grants, both from the National Institutes of Health and totaling $847,000, focus on eastern equine encephalitis virus (EEEV), a rare disease that is found primarily in the Atlantic and Gulf states and kills about half of the people it infects. One of the grants will be used to examine a specific part of the genetic code of the virus that is largely responsible for the severity of human disease, while the other will go toward developing a novel, live-attenuated vaccine against the virus.Dr. Kilmstra

His other grant, which is a collaboration with colleagues at Washington University in St. Louis and Oregon Health and Sciences University, will provide $1.2 million to Dr. Klimstra and CVR colleagues from the U.S. Department of Defense (DOD). This will be used to develop a novel, inactivated vaccine against three strains of alphavirus, a group which comprises about 30 different viruses mainly transmitted by mosquitoes – including EEEV and Venezuelan (VEEV) and western (WEEV) equine encephalitis viruses, which cause periodic outbreaks in the Americas.

Dr. Ryman received $1 million from the DOD to study how these three encephalitic alphaviruses and another mosquito-borne virus, Rift Valley Fever virus (RVFV), enter the brain. The RVFV component is led by Amy Hartman, Ph.D., assistant professor at Pitt’s CVR. The goal is to develop ways to limit brain entry by the virus and identify biological markers of disease severity to use as a measure of the effects of the vaccines and therapeutics. This grant also involves studies with collaborators at the University of Wisconsin.

Dr. RymanFinally, Dr. Ryman received $725,000 from the DOD in collaboration with investigators at the Naval Medical Research Center to raise anti-VEEV antibodies by immunizing cows that have been genetically altered to produce human antibodies. These antibodies will then be assessed for their potential use in protection against alphavirus diseases, similar to convalescent sera, which is derived from the blood of people whose immune systems successfully fought off an infection.

Several of the grants have option periods that, given successful results in initial studies, will add an additional $3 million in funding.

“The technologies used in these studies and the systematic manner in which vaccines and therapeutics for the alphaviruses are being developed are novel and, given positive results, these approaches can be readily applied to other emerging infectious diseases,” said Dr. Ryman.

Some of the studies also involve Simon Watkins, Ph.D., of Pitt’s Center for Biological Imaging, and Douglas Reed, Ph.D., aerosol director for Pitt’s RBL.

Pitt Leads Trial to Reduce Antibiotic Overuse at Post-Acute and Long-Term Care Facilities

PITTSBURGH, June 30, 2015 – The University of Pittsburgh School of Medicine will be leading a $1.5 million national trial to examine methods to reduce unnecessary use of antibiotics in post-acute and long-term care (PA/LTC)facilities.

The three-year study, funded by the U.S. Department of Health and Human Services Agency for Healthcare Research and Quality (AHRQ), will investigate guidelines and tools to help PA/LTC facilities better manage urinary tract infections (UTIs), which are commonly misdiagnosed and incorrectly treated.

“Antimicrobial resistance is a hot button issue in health care nationally and internationally – and improper overutilization of antibiotics is the single largest culprit,” said David A. Nace, M.D., M.P.H., director of long-term care and flu programs in Pitt’s Division of Geriatric Medicine, and primary investigator on the AHRQ grant. “It is critically important that we find ways to cut unnecessary use of antibiotics.”

The World Health Organization and the White House, among others, recently made announcements declaring efforts to address antimicrobial resistance top priorities. JAMA Internal Medicine published an article today finding that antibiotic use is highly variable across nursing homes, exposing residents to an increased risk of antibiotic-related harms and indicating a need to improve antibiotic stewardship in PA/LTC facilities.

The leading reason for antibiotic use at PA/LTC facilities is to treat a suspected UTI. Antibiotics often are started before a correct diagnosis is made. However, as many as two-thirds of those suspected cases turn out not to be UTIs, and the patients don’t benefit from – and could be harmed by – the antibiotics.

When used incorrectly, antibiotics can kill good bacteria and allow harmful, drug-resistant bacteria to flourish. Antibiotics also can cause allergic reactions or side-effects and are the leading cause of adverse drug reactions in long-term care facilities.

Dr. Nace, also chief medical officer for UPMC Senior Communities, and his co-investigators at AMDA – The Society for Post-Acute and Long-Term Care Medicine and the University of Wisconsin are looking at existing guidance and research on UTIs to develop comprehensive guidelines and tools geared toward easy implementation at PA/LTC facilities. University of Wisconsin co-investigator Christopher Crnich, M.D., Ph.D., associate professor of medicine, is an expert in antimicrobial stewardship in long-term care facilities. AMDA has long been respected for improving care in nursing homes, and their reputation will be critical to disseminating the results of this project and improving care across the U.S.

Next year, the team will enroll 40 PA/LTC facilities from Pennsylvania, Texas, North Carolina and Wisconsin in their trial. Half will receive the guidelines, as well as on-going mentoring and education, while the other half will operate as normal.

For a year, the team will collect data on the number of UTIs before and after the trial, the rate of appropriate and inappropriate treatment, and adverse outcomes. Once the trial concludes, all the facilities will be given the guidelines, tools, mentoring and education.

“There’s a lot of pressure across both agriculture and medicine to rein in use of antibiotics,” said Dr. Nace. “We are very quickly running out of antibiotics to do the job for us, and the problem is only going to grow worse. New antibiotics are not being created and licensed fast enough to keep pace with bacterium’s ability to develop drug-resistance. Efforts like ours to become better stewards of existing antibiotics are among the few solutions left at our disposal.”

New Pitt Research Team Finds Different Immune Response in Severe Asthma; To Continue Such Studies

PITTSBURGH, June 29, 2015 – The immune response that occurs in patients with severe asthma is markedly different than what occurs in milder forms of the lung condition, according to researchers from the University of Pittsburgh School of Medicine. Those unique features could point the way to new treatments, they said in an article published online today in the Journal of Clinical Investigation (JCI).

People with severe asthma, in which the airways become inflamed and constrict to impair breathing, do not get better even with high doses of corticosteroids, the mainstay of treatment for typical asthma, explained Anuradha Ray, Ph.D., professor of medicine, Pitt School of Medicine.

“About 10 percent of asthma patients have a severe form of the disease, but they account for up to half of asthma costs in the U.S. and Europe,” Dr. Ray said. “That’s because these patients frequently need to go to the emergency room or be hospitalized when they have an acute asthma episode.”

For the study, conducted as part of the doctoral thesis of Mahesh Raundhal, a graduate student in the laboratory of Prabir Ray, Ph.D., Pitt professor of medicine and co-senior author, the research team examined lung cell samples obtained from patients also participating in the Severe Asthma Research Program (SARP), a National Heart, Lung, and Blood Institute of the National Institutes of Health-sponsored program to improve the understanding of severe asthma. Sally Wenzel, M.D., director of the University of Pittsburgh Asthma Institute of UPMC, serves as the Pitt SARP principal investigator.

Researchers observed that the immune cells, called CD4 T-cells, in the airways of severe asthmatics secreted different inflammatory proteins than those in mild disease, particularly interferon gamma. The analysis of human samples helped them to develop a mouse model of the disease by introducing an allergen and a bacterial product to induce an immune profile and airway hyper-reactivity that were poorly controlled by corticosteroids, comparable to human severe asthma patients.

When they subjected mice that lacked the interferon gamma gene to the severe asthma model, they found that the mice could not be induced to develop severe asthma. Using computer modeling to identify links between interferon gamma and asthma-associated genes, they learned that as interferon gamma levels rose, the levels of a protein called secretory leukocyte protease inhibitor (SLPI) dropped.

In follow-up experiments, the team found that boosting SLPI levels reduced airway hyper-reactivity in the animal model.

“We’d like to better understand why severe asthma occurs in most people right from the start,” Dr. Anuradha Ray said. “We also want to find agents that can raise SLPI levels for clinical use.”

In a new project that began this month, Drs. Anuradha Ray and Wenzel were recently awarded a five-year, $8 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), also part of the National Institutes of Health (NIH), to continue studying the immune response and genetic roots of severe asthma in 120 patients and in animal models.

The research effort signifies a union of Pitt and UPMC scientists, immunologists and clinicians working under the NIAID grant to bring bench to bedside and bedside to bench, Dr. Wenzel said.

“It’s the unmet need of asthma,” Dr. Wenzel said. “This is one of the first true opportunities to integrate top-tier immunologists with translational clinical science. To find the many different mechanisms involved, you need a team effort such as this one.”

In addition to Drs. Wenzel and Anuradha Ray, the project leaders of this grant are core leaders Timothy B. Oriss, Ph.D., of the University of Pittsburgh, and Jay Kolls, M.D., of Children’s Hospital of Pittsburgh of UPMC, who also co-authored the JCI paper. Other members of the research team are Prabir Ray, Ph.D., and Fernando Holguin, M.D., Douglas Landsittel, Ph.D., and Donald DeFranco, Ph.D., all of Pitt.

The published project was funded by NIH grants HL113956, Al106684, AI048927, AI100012, HL69174, HL079142, and DK072506; as well as the Cystic Fibrosis Foundation Research Development Program.

Children’s Hospital of Pittsburgh of UPMC Named a Center of Excellence by Food Allergy Research & Education

PrintPITTSBURGH, June 29, 2015Children’s Hospital of Pittsburgh of UPMC has been named a center of excellence by Food Allergy Research & Education, which has established the FARE Clinical Network, an initiative that aims to accelerate the development of drugs for patients with food allergies as well as improve the quality of care for this serious illness. Children’s Hospital is one of 21 centers named as inaugural members.

FARE Clinical Network members will serve as sites for clinical trials for the development of new therapeutics and will develop best practices for the care of patients with food allergies. The Network will serve as a powerful driver of collaboration to advance the field of food allergy, with member centers contributing to the development of a national food allergy patient registry and biorepositories.

“We were honored to be invited to apply for membership with the FARE Clinical Network and to receive designation as a FARE Clinical Network Center of Excellence,” said Todd D. Green, M.D., Division of Pulmonary Medicine, Allergy and Immunology, Children’s Hospital. “This will be a great opportunity for food-allergic patients and their families in our region and will allow us to collaborate with other top food allergy centers on maximizing the quality of care these patients receive, as well as to participate in more multicenter research studies.”

Participation in the FARE Clinical Network will ensure that Children’s remains on the forefront of efforts to improve the quality of life for food-allergic individuals as they work toward development of potential new treatments.

“We need to push for the development of drugs and other therapies to prevent life-threatening food allergy reactions, while ensuring that children and adults with food allergy receive the best care possible,” said James R. Baker, Jr., M.D., C.E.O. and chief medical officer of FARE. “To that end, FARE will direct the Clinical Network centers of excellence across the country to a common goal of ensuring that patients with food allergies have access to state-of-the-art diagnosis, treatments and research. We will continue to expand the number of centers to provide access to more patients. This effort is fundamental to our mission — to improve the quality of life and the health of individuals with food allergies while providing them hope through the promise of new treatments.”

In addition to Children’s, the inaugural members of the FARE Clinical Network are:

  • Ann & Robert H. Lurie Children’s Hospital of Chicago
  • Arkansas Children’s Hospital Research Institute
  • Boston Children’s Hospital
  • Children’s Hospital Colorado
  • Children’s Mercy Kansas City
  • Children’s National Health System
  • Cincinnati Children’s Hospital Medical Center
  • Joe DiMaggio Children’s Hospital – a facility of Memorial Healthcare System
  • MassGeneral Hospital for Children
  • National Jewish Health (Denver)
  • Rady Children’s Hospital/University of California, San Diego
  • Riley Hospital for Children at IU Health
  • Sean N. Parker Center for Allergy Research at Stanford University
  • Texas Children’s Hospital Food Allergy Program, Baylor College of Medicine
  • The Children’s Hospital of Philadelphia
  • The Northwest Asthma and Allergy Center (Seattle)
  • The University of Chicago Medicine
  • UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill
  • University of Arizona College of Medicine – Tucson
  • UT Southwestern Medical Center and Children’s Medical Center Dallas

The centers of excellence selected as part of the FARE Clinical Network provide high-quality clinical and subspecialty food allergy expertise and services and are focused on applying new evidence-based knowledge to this important field. Additionally, these centers meet high standards for clinical care, teaching and clinical research.

Computer Simulation Predicts Development, Progress of Pressure Sores

PITTSBURGH, June 25, 2015 – Researchers at the University of Pittsburgh School of Medicine have devised a computational model that could enhance understanding, diagnosis and treatment of pressure ulcers related to spinal cord injury. In a report published online in PLOS Computational Biology, the team also described results of virtual clinical trials that showed that for effective treatment of the lesions, anti-inflammatory measures had to be applied well before the earliest clinical signs of ulcer formation.

Pressure ulcers affect more than 2.5 million Americans annually and patients who have spinal cord injuries that impair movement are more vulnerable to developing them, said senior investigator Yoram Vodovotz, Ph.D., professor of surgery and director of the Center for Inflammation and Regenerative Modeling at the Pitt School of Medicine.

“These lesions are thought to develop because immobility disrupts adequate oxygenation of tissues where the patient is lying down, followed by sudden resumption of blood flow when the patient is turned in bed to change positions,” Dr. Vodovotz said. “This is accompanied by an inflammatory response that sometimes leads to further tissue damage and breakdown of the skin.”

“Pressure ulcers are an unfortunately common complication after spinal cord injury and cause discomfort and functional limitations,” said co-author Gwendolyn A. Sowa, M.D., Ph.D., associate professor of physical medicine and rehabilitation, Pitt School of Medicine. “Improving the individual diagnosis and treatment of pressure ulcers has the potential to reduce the cost of care and improve quality of life for persons living with spinal cord injury.”

To address the complexity of the biologic pathways that create and respond to pressure sore development, the researchers designed a computational, or “in silico,” model of the process based on serial photographs of developing ulcers from spinal cord-injured patients enrolled in studies at Pitt’s Rehabilitation Engineering Research Center on Spinal Cord Injury. Photos were taken when the ulcer was initially diagnosed, three times per week in the acute stage and once a week as it resolved.

Then they validated the model, finding that if they started with a single small round area over a virtual bony protuberance and altered factors such as inflammatory mediators and tissue oxygenation, they could recreate a variety of irregularly shaped ulcers that mimic what is seen in reality.

They also conducted two virtual trials of potential interventions, finding that anti-inflammatory interventions could not prevent ulcers unless applied very early in their development.

In the future, perhaps a nurse or caregiver could simply send in a photo of a patient’s reddened skin to a doctor using the model to find out whether it was likely to develop into a pressure sore for quick and aggressive treatment to keep it from getting far worse, Dr. Vodovotz speculated.

“Computational models like this one might one day be able to predict the clinical course of a disease or injury, as well as make it possible to do less expensive testing of experimental drugs and interventions to see whether they are worth pursuing with human trials,” he said. “They hold great potential as a diagnostic and research tool.”

The team included co-senior author Gary An, M.D., of the University of Chicago; Cordelia Ziraldo, Ph.D., Alexey Solovyev, Ph.D., Ana Allegretti, Ph.D., Shilpa Krishnan, M.S., David Brienza, Ph.D., Qi Mi, Ph.D., all of Pitt; and M. Kristi Henzel, M.D., Ph.D., of the Louis Stokes Cleveland Veterans Affairs Medical Center.

The project was funded by the U.S. Department of Education; National Institutes of Health National Institute on Disability and Rehabilitation Research grant H133E070024; and an IBM Shared University Research Award.

USA Hockey Honors UPMC Surgeon Charles “Chip” Burke III with Excellence in Safety Award

PITTSBURGH, June 25, 2015Charles “Chip” Burke III, M.D. of Fox Chapel, was honored with the Excellence in Safety Award at the 2015 USA Hockey’s Annual Congress’ Night of Tribute Awards Dinner. Dr. Burke was recognized for his outstanding contributions in improving safety and reducing injury in youth sports through his 20-year association with USA Hockey.

Dr. Burke, a UPMC orthopaedic surgeon and clinical associate professor at the University of Pittsburgh School of Medicine, has been combining his profession as an orthopaedic surgeon with his passion for the sport of ice hockey at all levels for more than 30 years. His decades of volunteering with USA Hockey have led him to a number of positions, including being a 15-year member of the Safety and Protective Equipment Committee and team physician for the 2002 Winter Olympics. He also has served as part of the Coaching Education Program, teaching coaches about safety in youth sports.

During Dr. Burke’s 25 years as team physician with the Pittsburgh Penguins of the National Hockey League (NHL), he made his most notable contribution to NHL safety by developing the NHL Concussion Program, the largest study of head injuries in sports. The 7-year initiative analyzed head injuries, making large strides in the understanding of concussions. He is past president of the NHL Team Physician’s Society (NHLTPS) and chaired the NHLTPS Injury Committee for many years.

Dr. Burke also was actively involved in establishing the UPMC Sports Medicine Concussion Program in 2000, the first and largest program of its kind, widely considered as the national leader in concussion care and treatment. The center sees patients of all ages and athletic ability, testing for and treating head injuries from a multidisciplinary approach.

“I’ve dedicated my life to making hockey safer so we have fewer injuries,” said Dr. Burke of his decades of work in the game. “Accomplishing this would allow kids to participate more often without injuries that could affect their futures outside of sports. Between USA Hockey and all the work I’ve done with the NHL and UPMC, that’s always been my goal—to give back to the sport.”

USA Hockey relies on volunteers to continue promoting youth sports as a means of providing life lessons hard to find elsewhere. Dr. Burke believes the goal of USA Hockey is not simply to create elite athletes, but to educate and develop the young participants through competition and hard work.

Dr. Burke grew up in Boston playing hockey in a backyard rink with his five brothers. He attended Harvard College, earning a varsity letter in ice hockey. Three of his brothers also lettered in collegiate hockey, two at Harvard and one at Notre Dame.

Dr. Burke practices at Burke and Bradley Orthopedics at UPMC St. Margaret.

Pitt’s Dr. Yuan Chang Appointed to National Cancer Advisory Board

PITTSBURGH, June 23, 2015 – President Barack Obama recently appointed a pathologist in the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, to a national board charged with identifying the most promising cancer research projects nationwide.

Yuan Chang, M.D., Distinguished Professor of Pathology in Pitt’s School of Medicine, has been Dr. Yuan Changappointed with four other scientists to serve as members of the National Cancer Advisory Board.

“I am honored that these talented individuals have decided to serve our country. They bring their years of experience and expertise to this administration, and I look forward to working with them,” President Obama said in announcing the appointments.

The National Cancer Advisory Board consists of 12 members appointed by the president to advise the National Institutes of Health’s (NIH) National Cancer Institute. The members review applications for grants and cooperative agreements for cancer research and training, and recommend approval of the projects that show the most promise of making valuable contributions to human knowledge.

“This is a great opportunity for me to professionally contribute to the directive of the National Institutes of Health,” said Dr. Chang, also UPMC Professor of Cancer Virology Research. “My goal is to bring my basic research expertise on infectious diseases and cancer to inform the administrative goals of the NIH.”

Dr. Chang joined the Pitt School of Medicine in 2002, after she and Patrick S. Moore, M.D., M.P.H., discovered Kaposi’s sarcoma-associated herpesvirus, which causes Kaposi’s sarcoma, the most common malignancy occurring in AIDS patients. The team then went on to discover Merkel cell polyomavirus, which causes a rare but deadly skin cancer.

Dr. Chang earned her Bachelor of Science degree from Stanford University and a medical doctorate from the University of Utah College of Medicine.

Prior to coming to Pitt, Dr. Chang served in several clinical and academic positions from 1993 to 2002 at the Columbia University College of Physicians and Surgery and Columbia Presbyterian Hospital. Before that she was a clinical instructor at Stanford University Medical Center.

Image credit: Joshua Franzos

Gene Therapy Prevents Parkinson’s Disease in Animal Model, Says Pitt Study

PITTSBURGH, June 15, 2015 – Gene therapy to reduce production of a brain protein successfully prevented development of Parkinson’s disease in an animal study, according to researchers at the University of Pittsburgh School of Medicine. The findings, published online today in the Journal of Clinical Investigation, could lead to new understanding of how genetic and environmental factors converge to cause the disease, and the development of effective treatments to prevent disease progression.

Scientists have observed dysfunction of mitochondria, which make energy for cells, in Parkinson’s disease, as well as Lewy parkinsons
bodies, which are characteristic clumps of the cellular protein α-synuclein within neurons, said principal investigator Edward A. Burton, M.D., D.Phil., associate professor of neurology, Pitt School of Medicine.

“Until now, these have been pursued largely as separate lines of research in Parkinson’s disease,” Dr. Burton said. “Our data show that mitochondria and α-synuclein can interact in a damaging way in vulnerable cells, and that targeting α-synuclein might be an effective strategy for treatment.”

The team wanted to see what would happen if they knocked out the production of α-synuclein in the brain’s substantia nigra, home to the dopamine-producing cells that are lost as Parkinson’s disease progresses. To do so, they used a harmless virus called AAV2 engineered to transport into the neuron a small piece of genetic code that blocks production of α-synuclein. They delivered the gene therapy to the brains of rats and then exposed the animals to the pesticide rotenone, which inhibits mitochondrial function.

“Our previous work established that rotenone exposure in rats reproduces many features of Parkinson’s disease that we see in humans, including movement problems, Lewy bodies, loss of dopamine neurons and mitochondrial dysfunction,” explained co-investigator J. Timothy Greenamyre, M.D., Ph.D., Love Family Professor of Neurology, and director of the Pittsburgh Institute for Neurodegenerative Diseases at Pitt. “We found that our gene therapy prevented those symptoms from appearing, which is very exciting.”

Each side of the brain controls the opposite side of the body.  The left sides of rats that received gene therapy to the right side of the brain did not become stiff and slow, while their right sides did. The researchers determined that dopamine neurons on the treated side of the brain were protected from rotenone, accounting for the substantial improvement in movement symptoms. In contrast, untreated animals and animals that received a control virus that does not reduce α-synuclein production, developed progressive Parkinsonism and loss of dopamine neurons.

In next steps, the researchers plan to unravel the molecular pathways that enable α-synuclein levels to influence mitochondrial function and develop drugs that can target the underlying mechanisms.

“The viral vector AAV2 has been used safely in Parkinson’s disease patients in clinical trials, so the gene therapy approach might be feasible,” Dr. Burton said. “We think targeting α-synuclein has great potential to protect the brain from neurodegeneration in Parkinson’s disease.”

“We hope to be able to translate this general approach of reducing α-synuclein into human clinical trials soon,” Dr. Greenamyre added.

The team included Alevtina Zharikov, Ph.D., Jason R. Cannon, Ph.D., Victor Tapias, Ph.D., Qing Bai, Ph.D., Max Horowitz, M.D., Ph.D., Vipul Shah, M.D., Amina El Ayadi, Ph.D., and Teresa G. Hastings, Ph.D., all of the University of Pittsburgh.

The project was funded by the U. S. Department of Veterans Affairs grant 1I01BX000548;  National Institutes of Health grants ES022644, NS059806, ES018058, ES020718, ES019879 and ES020327; the Blechman Foundation; the Parkinson’s Chapter of Greater Pittsburgh; the JPB Foundation; the American Parkinson Disease Association; the Parkinson’s Unity Walk; and a gift from Mr. and Mrs. Henry Fisher.

Pitt Researchers Find Genetic Testing in Thyroid Cancer May Aid in Surgical Decision Making

PITTSBURGH, June 10, 2015 – A team of researchers led by Linwah Yip, MD, associate professor in the Department of Surgery, recently found that routine genetic testing to detect mutations implicated in thyroid carcinogenesis can help guide perioperative decision making.  Their research recently was presented by Dr. Yip at the annual meeting of the American Surgical Association in San Diego.

Dr. Yip and her colleagues at the University of Pittsburgh conducted a retrospective review of a consecutive series of 1,510 patients from the electronic medical record of a single institution. The patients had initial surgery for histologically confirmed thyroid cancer. All cancers in the study were tested for mutations in seven genes associated with thyroid carcinogenesis. Although risks associated with mutations are not always clear-cut, the researchers found that distant metastases were more common in thyroid cancer patients who were positive for the RET/PTC mutation, while thyroid cancer expressing BRAF V600E or RET/PTC was associated with higher-grade cancer on presentation and early recurrence.

Additional researchers on the study were Marina N. Nikiforova, MD, Jenny Yoo, MD, Kelly L. McCoy, MD, Michael T. Stang, MD, Kristina J. Nicholson, MD, Michaele J. Armstrong, PhD, Steven P. Hodak, MD, Robert L. Ferris, MD, PhD, Yuri E. Nikiforov, MD, PhD, Sally E. Carty, MD, all currently or formerly of the University of Pittsburgh.

For more information, please visit the American College of Surgeons webpage.

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