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Children’s Pulmonologist Honored By Association of American Physicians and American Thoracic Society

PITTSBURGH, May 6, 2015 – Juan Celedón, MD, DrPH, Chief of Service in the Division of Pediatric Pulmonology, Allergy, and Immunology at Children’s Hospital of Pittsburgh of UPMC recently was elected to the Association of American Physicians. Dr. Celedón also was chosen for the Innovations in Health Equality — Lifetime Achievement Award from the American Thoracic Society’s Clinicians Advisory Committee and its Health Equality Subcommittee.

Dr. Celedón’s research is focused on the genetics and epidemiology of asthma in Puerto Rican and black children. He also is leading a study of chronic obstructive pulmonary disease (COPD) genetics in Costa Rica.

For more information on Dr. Celedón’s work, please visit the Division of Pulmonary, Allergy, and Critical Care Medicine page.

Pitt Team Follows the Zinc to Uncover Brain Pathway that Fine-Tunes Neural Signaling

PITTSBURGH, May 4, 2015 – A study team led by researchers at the University of Pittsburgh School of Medicine who used specially developed technologies to “follow the zinc” have uncovered a previously unknown pathway the brain uses to fine-tune neural signaling—and that may play a role in Alzheimer’s and other diseases. Their findings appear online this week in the Proceedings of the National Academy of Sciences.Zinc signals in the brain

Scientists have long observed the presence of bubble-like vesicles that contain the neurotransmitter glutamate and zinc at the synapses, specialized contacts among neurons where neurotransmitters are released to propagate electrical signals through the brain. Glutamate is the major excitatory neurotransmitter in the brain, but the need for synaptic zinc, an essential element that acts as a co-factor for many enzyme and regulatory proteins, has not been understood, said Thanos Tzounopoulos, Ph.D., associate professor in the Auditory Research Group, Department of Otolaryngology, Pitt School of Medicine.

“Until now, we haven’t had the ability to quantify or follow zinc when it is released into the synaptic cleft,” he said. “In this study, we employed new tools to do that and found a pathway that could be important for conditions such as Huntington’s disease and Alzheimer’s.”

Co-investigator Stephen Lippard, Ph.D., and his team at the Massachusetts Institute of Technology (MIT) developed an agent that fluoresces when it binds zinc, making it possible for the first time to measure zinc levels accurately and track the element’s movements. They also created an agent that blocks zinc activity, thus allowing them to disrupt the metal’s actions to determine its function.

The researchers learned that, indeed, zinc was released from vesicles and diffused from the release site. Surprisingly, it could bind to so-called extrasynaptic glutamate NMDA-type receptors, just like the neurotransmitter glutamate. Whereas glutamate activates these receptors, zinc inhibits them.

“Glutamate acts like an accelerator of neuronal activity, while zinc behaves like a brake that fine tunes that signal,” Dr. Tzounopoulos said. “The receptors that zinc influences are thought to play a role in neurodegenerative diseases, so these findings could open new research avenues in the field.”

The team included Charles T. Anderson, Ph.D., of the University of Pittsburgh; as well as Robert J. Radford, Ph.D., Melissa L. Zastrow, Ph.D., Daniel Y. Zhang and Ulf-Peter Apfel, Ph.D., of MIT. The project was funded by National Institutes of Health grants DC011499, DC013734-01A, GM065519 and DC007905.

National Thyroid Cancer Experts Meet at UPMC to Advance Patient Care

PITTSBURGH, April 30, 2015 – Nearly 200 physicians and researchers from across the country will gather in the Herberman Conference Center at UPMC Shadyside Saturday to discuss adapting the new American Thyroid Association (ATA) guidelines into clinical practice and to find new ways of working together to improve patient care.

The Seventh Annual Multidisciplinary Thyroid Cancer Symposium, which is sponsored by UPMC, the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter and the University of Pittsburgh School of Medicine, will bring together leading experts in the field to cover a wide variety of topics, including best practices in managing patients with advanced thyroid cancer, the value in predictive molecular testing,  and the latest surgical approaches in the field.

“Our understanding of thyroid cancer has advanced significantly in recent years, and new treatment guidelines were necessary to incorporate the latest research,” said Robert Ferris, M.D., Ph.D., chief of the Division of Head and Neck Surgery at Pitt and one of the conferences co-chairs. “The predictive molecular testing, which was researched and developed at UPMC, will be part of the recommendations for evaluation of a thyroid nodule and will arise in a new consensus statement recently developed by the ATA.  We are looking forward to the discussion this meeting will generate.”

Approximately 63,000 cases of thyroid cancer will be diagnosed in 2015. Thyroid cancer commonly is diagnosed at a younger age than most other adult cancers, and the chance of being diagnosed has risen in recent years as a result of the increased use of thyroid ultrasound.

The event includes a continuing medical education credit component for physicians.

Two-Week International Diet Swap Shows Potential Effects of Diet on Colon Cancer Risk

PITTSBURGH, April 28, 2015 – African-Americans and Africans who swapped their typical diets for just two weeks similarly exchanged their respective risks of colon cancer as reflected by alterations of their gut bacteria, according to an international study led by researchers at the University of Pittsburgh School of Medicine published online today in Nature Communications.

Principal investigator Stephen O’Keefe, M.D., professor of medicine, Division of Gastroenterology, Hepatology and Nutrition, Pitt School of Medicine, observed while practicing in South Africa that his rural patients rarely had colon cancer or intestinal polyps, which can be a cancer precursor. In the Western world, colon cancer is the second-leading cause of cancer death and African-Americans carry the greatest disease burden in the United States.

“The African-American diet, which contains more animal protein and fat, and less soluble fiber than the African diet, is thought to increase colon cancer risk,” Dr. O’Keefe explained. “Other studies with Japanese migrants to Hawaii have shown that it takes only one generation of Westernization to change their low incidence of colon cancer to the high rates observed in native Hawaiians. In this project, we examined the impact of a brief diet change on the colon in a controlled setting where we didn’t have to worry about the influence of smoking and other environmental factors on cancer risk.”

After assessment of their in-home diets, 20 African-American and 20 rural South African volunteers ages 50 to 65 were housed at a University of Pittsburgh site and at an African lodging facility respectively. There they ate meals prepared by the researchers using ingredients and cooking techniques typical of the other group. The team examined fecal and colon content samples, obtained during colonoscopy, of each volunteer at baseline and after the two-week study period.

Although the diet change was brief, each group took on the other’s rates of turnover of cells of the intestinal lining, levels of fiber fermentation, and markers of bacterial metabolic activity and inflammation associated with cancer risk. In particular, African-Americans experienced an increase in butyrate production, which is thought to play a key role in anti-cancer pathways. The researchers also noted they removed intestinal polyps from nine of the African-American volunteers, but none were present in the Africans.

“We can’t definitively tell from these measurements that the change in their diet would have led to more cancer in the African group or less in the American group, but there is good evidence from other studies that the changes we observed are signs of cancer risk,” said co-author Jeremy Nicholson, Ph.D., of Imperial College London.

According to Dr. O’Keefe, increasing the amount of fiber in the diet – from approximately 10 grams to more than 50 for African-Americans in the diet swap – likely led to biomarker changes reflecting reduced cancer risk, but eating less animal fat and proteins also could be helpful.

“These findings are really very good news,” he said. “In just two weeks, a change in diet from a Westernized composition to a traditional African high-fiber, low-fat diet reduced these biomarkers of cancer risk, indicating that it is likely never too late to modify the risk of colon cancer.”

The team included other researchers from the University of Pittsburgh and Imperial College London, as well as Wageningen University in the Netherlands; University of Helsinki, Finland; University of Illinois; and the University of KwaZulu-Natal in South Africa.

Funding for the study was provided National Institutes of Health grants CA135379, RR024153 and TR000005; the National Institute for Health Research Imperial Biomedical Research Centre, UK; the Academy of Medical Sciences; the Spinoza Award of the Netherlands Organization for Scientific Research, the European Research Council and the Academy of Finland.

Geriatric Incontinence Expert to Present at AUA 2015

PITTSBURGH, April 27, 2015 – Neil Resnick, MD, Thomas Detre Professor and Chief of the Division of Geriatric Medicine, is schedule to present on brain activity in overactive bladder at the upcoming American Urological Association (AUA) Annual Meeting.

Dr. Resnick’s research has helped to pioneer the field of geriatric voiding dysfunction and incontinence, improving the understanding of these conditions and leading to the development of novel diagnosis and treatment strategies. His work has been recognized nationally by the National Institutes of Health (NIH), the International Continence Society, the Society for General Internal Medicine, and the AUA.

Dr. Resnick’s presentation, entitled “Aging and Urologic Manifestations: Brain Activity in Overactive Bladder,” is scheduled to be presented during a basic science symposium on Friday, May 15.

For more information about the AUA Annual Meeting, please visit the conference page.

Geriatric Medicine Faculty to Present at AGS 2015

PITTSBURGH, April 27, 2015 – The Division of Geriatric Medicine and UPMC will be well-represented at the American Geriatrics Society 2015 Annual Scientific Meeting in National Harbor, MD. Faculty research will be presented in oral and poster presentations throughout the conference, including topics such as:

  • Cultural Differences and Approaches to Care: Cardiology
    Daniel Forman, MD
  • 2012 JCDA, Effect of Aging and Aortic Wall Behavior as Predictors of Aortic Aneurysm Growth
    Rabih Chaer, MD

Additionally, Daniel Forman, MD, will serve as a mentor in the One-on-One AGS Mentoring Program for students, residents, fellows, junior faculty, and other healthcare professional trainees.

For more information about the AGS Annual Scientific Meeting, please visit the conference page.

Inflammation-Cancer Feedback Loop Discovery is a Step Toward Better Cancer Drugs

PHILADELPHIA, April 20, 2015 – New findings hidden within the complex machinery behind the vicious cycle of chronic inflammation and cancer are presented today by researchers from the University of Pittsburgh Cancer Institute, partner with UPMC Cancer Center, at the American Association for Cancer Research (AACR) Annual Meeting in Philadelphia.

The research is funded by the National Institutes of Health (NIH) and Fondazione RiMED, of Palermo, Italy.

Inflammation is an important immune system tool that helps the body rid itself of foreign invaders, such as bacteria. However, chronic inflammation can fuel tumor growth by facilitating formation of cancer blood vessels, supplying nutrients and setting cancerous cells free to colonize other parts of the body.

The basic research into the specific mechanisms promoting cancer inflammation is a critical step in the development of drugs that could interrupt this process.

“In the last 20 years we’ve recognized that chronic inflammation and cancer are connected – long-term inflammation leads to the development of dysplasia and tumor progression,” said lead author Sandra Cascio, Ph.D., a research associate in Pitt’s Department of Immunology. “Recently, scientists have provided detailed insights into molecules and cellular pathways linking inflammation and cancer. In our study, we found a new mechanism that had previously escaped us.”

The mechanism is driven by a complex of MUC1, a molecule long studied in the laboratory of senior author and Pitt immunologist Olivera Finn, Ph.D., and p65, a molecule belonging to a protein complex family known to be activated in inflammation.

Dr. Cascio, in collaboration with Dr. Finn, looked for MUC1/p65-mediated epigenetic modifications affecting inflammatory genes. Epigenetics refers to outside factors that modify the activity of a gene, but do not cause a more obvious genetic mutation. Sure enough, the researchers discovered that this complex, which they found specifically in cancer cells, was causing DNA to be transcribed differently than expected.

“Normally MUC1 is covered in sugar molecules, like leaves cover a tree in spring,” said Dr. Cascio. “When it is made by a tumor, it lacks sugar and is more like a tree in fall. Our research shows that this form of MUC1 associates with p65 and regulates transcription of pro-inflammatory cytokine genes in tumor cells. This leads to the recruitment of inflammatory cells into the tumor site. Inflammatory cells, including macrophages, produce additional cytokines that enhance the activity of MUC1 and p65, establishing a continuous positive feedback loop, or a vicious circle, resulting in tumor progression.”

In order to pinpoint this altered pro-inflammatory mechanism in cancer cells, Dr. Cascio and her team combed through more than 20 types of epigenetic modifications and 300 factors that allow for the remodeling of chromatin, which are macromolecules in cells that control gene expression and DNA replication.

Specifically, the researchers found that MUC1 and p65 involve an enzyme called the Enhancer of Zeste homolog 2, or EzH2, known to induce epigenetic modifications, in order to prompt chromatin remodeling on cytokine gene promoters.

“Developing drugs that could keep these genes from being improperly turned on and off could interrupt this cancer-inflammation process and stop the tumor growth and spread,” said Dr. Cascio. “It’s a promising avenue for future exploration.”

Joshua Sciurba, B.S., of Pitt at the time of this research, also participated in this work.

This research was funded by Fondazione RiMED and NIH National Cancer Institute grant CA56103.

New Study Will Test if Anti-Amyloid Antibody Can Prevent Development of Alzheimer’s Disease

PITTSBURGH, April 20, 2014 – Researchers at the University of Pittsburgh School of Medicine will be part of a multicenter trial that will test for the first time whether a drug that treats brain plaques can prevent later development of memory loss in Alzheimer’s Disease.

Studies have shown that brain changes in Alzheimer’s begin many years before disease onset, and that all patients have deposits of beta amyloid in their brains, said Oscar Lopez, M.D., professor of neurology, Pitt School of Medicine, and co-director of the Alzheimer’s Disease Research Center (ADRC). He is the principal investigator of the Pittsburgh arm of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.

“This is the first study to assess whether an experimental antibody that counteracts amyloid will have long-term impact that can prevent Alzheimer’s,” said Dr. Lopez, who noted that many people have beta amyloid deposits in the brain but never develop dementia. “We suspect that these plaques have a role in disease development, but it’s not been proven that they affect memory and cognition. The A4 study could shed light on that.”

For A4, the researchers will perform a baseline PET scan on otherwise healthy volunteers, ages 65 to 85, to determine if brain plaques are present. If so, participants will be randomly assigned to receive monthly intravenous infusions of the experimental anti-amyloid antibody or a placebo. All participants will have regular assessments and blood tests for three years.

“Because of the nature of the disease, a friend or family member also must be willing to answer questions annually about how the participant is doing at home,” Dr. Lopez explained. “This study could help us find ways of predicting who might be at greater risk for progressing to Alzheimer’s.”

People who are interested in participating should call study coordinator Katy Orchowski Zorich at 412-624-2730 or email her at orchowskik3@upmc.edu.

Pitt, Children’s Research Papers Receive Top 10 Awards from Clinical Research Forum

PrintPITTSBURGH, April 20, 2015 – Three scientific papers published in 2014 by research teams from the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC have each been selected to receive a Clinical Research Forum Annual Top 10 Clinical Research Achievement Award. The awards were announced last night at the Forum’s annual meeting in Washington, D.C. The winning papers from Pitt and UPMC were chosen based on their degree of innovation from a pool of more than 50 nominations from 30 research and academic health centers nationwide. The Forum and its supporters believe these and other top ten papers represent the best and brightest work in the field, and will lead to advancements in medicine that will change lives and patient outcomes worldwide. “It is extraordinary to have three University of Pittsburgh projects in a variety of disciplines recognized by the Forum for their clinical impact and rigorous science,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and the John and Gertrude Petersen Dean of Medicine. “This impressive showing reflects the commitment and caliber of the researchers on our campus, and is a tribute to the University’s Clinical and Translational Science Institute, which facilitates and supports these endeavors.” The three winners are:

  • “Upper-Airway Stimulation for Obstructive Sleep Apnea,” published Jan. 9, 2014, in the New England Journal of Medicine, showed implanting a device called Inspire® Upper Airway Stimulation led to a 70 percent reduction of severe obstructive sleep apnea symptoms. Project investigators included lead author Patrick Strollo, M.D., professor of medicine and clinical and translational science, Pitt School of Medicine, and medical director of the UPMC Sleep Medicine Center, and Ryan Soose, MD.
  • A Randomized Trial of Protocol-Based Care for Early Septic Shock,” published May 1, 2014, in the New England Journal of Medicine, showed that a structured, standardized approach to diagnose and treat sepsis in its early stages did not change patient survival rates. Project investigators included Derek Angus, M.D., M.P.H., distinguished professor and Mitchell P. Fink Chair, Department of Critical Care Medicine, Pitt School of Medicine, and Donald M. Yealy, M.D., professor and chair of Pitt’s Department of Emergency Medicine.
  • Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux,” published June 19, 2014, in the New England Journal of Medicine, showed that children with abnormal flow of urine from the bladder to the upper urinary tract, called vesicoureteral reflux (VUR), can avoid recurrent urinary tract infections by taking daily low-dose antibiotics. Project investigators included senior author Alejandro Hoberman, M.D., chief, Division of General Academic Pediatrics at Children’s Hospital, and professor of pediatrics, Pitt School of Medicine.

“I applaud the researchers recognized for their groundbreaking clinical research that will advance new treatments to reduce suffering and bring hope to millions of people,” said National Institutes of Health director, Francis S. Collins, M.D., Ph.D. “And I’m especially proud that NIH funding makes these advances possible.” Other awardees include scientists from Harvard Medical School, Yale University, the University of Pennsylvania, UCLA and other leading institutions. The Clinical Research Forum was formed in 1996 to discuss the unique and complex challenges to clinical research in academic health centers. The mission of the Forum is to provide leadership to the national clinical and translational research enterprise and promote understanding and support for clinical research and its impact on health and health care.

Magee, UPCI Researchers Seek New Targets for Ovarian Cancer Treatment

PHILADEPHIA, April 19, 2015 – Identifying molecular changes that occur in tissue after chemotherapy could be crucial in advancing treatments for ovarian cancer, according to research from Magee-Womens Research Institute and Foundation (MWRIF) and the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, presented today at the American Association for Cancer Research (AACR) Annual Meeting 2015.

For years now, intraperitoneal chemotherapy, a treatment which involves filling the abdominal cavity with chemotherapy drugs after surgery, has been considered the standard of care for ovarian cancer. According to Shannon Grabosch, M.D., a gynecologic oncology fellow at Magee-Womens Hospital of UPMC and the study’s lead investigator, treatment advances for this disease haven’t moved forward as quickly as they have for other cancers.

“The addition of intraperitoneal chemotherapy for women with ovarian cancer was one of the biggest achievements in improving survival outcomes, but unfortunately, we still don’t understand the biological mechanisms by which this works,” said Dr. Grabosch. “We wanted to understand what changes occurred to the local tumor environment after chemotherapy was administered, with the idea that these changes could eventually be targets for new, personalized ovarian cancer treatments.”

Dr. Grabosch and her team examined peritoneal cavity fluid and peripheral blood samples of 13 patients. The samples were obtained prior to intraperitoneal treatment and after the first and second rounds of chemotherapy. Using multiple sequencing techniques, Dr. Grabosch and her team identified chemotherapy-induced molecular changes.

“We were able to identify changes in both miRNA and genes which appear to be related to chemotherapy. Furthermore, we identified different, significant changes between the peritoneal cavity and blood samples, proving that the local tumor environment is an underutilized wealth of information,” said Dr. Grabosch. “Now we need larger studies to determine whether the changes that occur in the tumor microenvironment after chemotherapy could be potential targets for new, more personalized drugs and to further understand the mechanisms of intraperitoneal chemotherapy.”

Additional authors on this research, which was funded by the Magee-Womens Research Institute and Foundation and the Gynecologic Oncology Group, are Anda M. Vlad, M.D., Ph.D., Tianzhou Ma, M.S., Jyothi Mony, Ph.D., Mary Strange, M.S., Joan Brozick, M.H.A., Julia Thaller, M.B.A., George Tseng, Ph.D., Xin Huan, Ph.D., Katie Moore, M.D., Kunle Odunsi, M.D., Ph.D., and Robert P. Edwards, M.D., all with MWRIF and UPCI.

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