UPMC Physician Resources

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.

Broccoli Sprout Extract Promising for Head and Neck Cancer Prevention

PHILADELPHIA, April 19, 2015 – Broccoli sprout extract protects against oral cancer in mice and proved tolerable in a small group of healthy human volunteers, the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, announced today at the American Association for Cancer Research (AACR) Annual Meeting in Philadelphia.

The promising results will be further explored in a human clinical trial, which will recruit participants at high risk for head and neck cancer recurrence later this year. This research is funded through Pitt’s Specialized Program of Research Excellence grant in head and neck cancer from the National Cancer Institute.

“People who are cured of head and neck cancer are still at very high risk for a second cancer in their mouth or throat, and, unfortunately, these second cancers are commonly fatal,” said lead author Julie Bauman, M.D., M.P.H., co-director of the UPMC Head and Neck Cancer Center of Excellence. “So we’re developing a safe, natural molecule found in cruciferous vegetables to protect the oral lining where these cancers form.”

Previous studies, including large-scale trials in China, have shown that cruciferous vegetables that have a high concentration of sulforaphane – such as broccoli, cabbage and garden cress – help mitigate the effects of environmental carcinogens.

Dr. Bauman collaborated with Daniel E. Johnson, Ph.D., professor of medicine at Pitt and a senior scientist in the UPCI Head and Neck Cancer Program, to test sulforaphane in the laboratory. For several months, Dr. Johnson and his team gave sulforaphane to mice predisposed to oral cancer and found that it significantly reduced the incidence and number of tumors.

“The clear benefit of sulforaphane in preventing oral cancer in mice raises hope that this well-tolerated compound also may act to prevent oral cancer in humans who face chronic exposure to environmental pollutants and carcinogens,” said Dr. Johnson.

Dr. Bauman treated 10 healthy volunteers with fruit juice mixed with sulforaphane-rich broccoli sprout extract. The volunteers had no ill-effects from the extract and protective changes were detectable in the lining of their mouths, meaning it was absorbed and directed to at-risk tissue.

These findings were enough to prompt a clinical trial that will recruit 40 volunteers who have been curatively treated for head and neck cancer. The participants will regularly take capsules containing broccoli seed powder to determine if they can tolerate the regimen and whether it has enough of an impact on their oral lining to prevent cancer. From there, larger clinical trials could be warranted.

“We call this ‘green chemoprevention,’ where simple seed preparations or plant extracts are used to prevent disease,” said Dr. Bauman, also an associate professor in Pitt’s School of Medicine. “Green chemoprevention requires less money and fewer resources than a traditional pharmaceutical study, and could be more easily disseminated in developing countries where head and neck cancer is a significant problem.”

Additional authors on this research are Yan Zhang, Ph.D., Malabika Sen, Ph.D., Daniel P. Normolle, Ph.D., Thomas W. Kensler, Ph.D., Sumita Trivedi, M.B.B.S., and Siddharth H. Sheth, D.O., M.P.H., all of Pitt; Jennifer R. Grandis, M.D., F.A.C.S., of Pitt at the time the research was conducted; and Patricia A. Egner, M.S., of Johns Hopkins University.

Trial Co-Led by Pitt Researcher Shows Greater Function after Stroke When Blood Clots Removed from Brain Blood Vessels

PITTSBURGH, April 17, 2015 – A technique that removes blood clots from large brain blood vessels reduced disability after stroke in a trial conducted in Catalonia, Spain, and co-led by an expert from the University of Pittsburgh School of Medicine. The findings will be announced today at the annual meeting of the European Stroke Organisation in Glasgow, Scotland, and published online in the New England Journal of Medicine.

The results of the trial, known as REVASCAT, echo findings from other recent large studies that were stopped early when  the technique, called endovascular therapy or stent retriever thrombectomy, appeared to be highly effective, said co-principal investigator Tudor Jovin, M.D., associate professor of neurology and neurological surgery, and director of the UPMC Stroke Institute. Originally, the REVASCAT trial expected to enroll nearly 700 participants.

“This is a giant step forward that will change the way we approach triage and treatment of stroke patients,” Dr. Jovin said. “After an interim analysis once 25 percent of the original participant sample size were enrolled, the data safety monitoring board of the study recommended stopping the trial as it became clear that it was no longer ethically justified to randomly assign patients to receive only conventional therapy. “And, as other studies found, removing blood clots from the brain did indeed lead to better outcomes for patients.”

Endovascular therapy is performed by inserting a thin tube into a groin artery to thread it through the aorta and into the brain vessels using X-ray-guided imaging. A retrievable stent opens the blocked vessel to restore blood flow and then is withdrawn, pulling the clot out with it. Dr. Jovin discusses and demonstrates the treatment in this video: http://youtu.be/s7wY9RgAFTk.

For the study, conducted at four large designated stroke centers in Catalonia, Spain, between November 2012 and December 2014, the researchers treated and monitored 206 patients whose stroke symptoms began not more than eight hours earlier and who had evidence of vessel blockage in imaging studies. For the 70 percent of patients who received an intravenous dose of the clot-busting drug tPA, or alteplase, imaging studies conducted 30 minutes after tPA administration had to confirm the vessel was still blocked. Half the patients were randomly assigned to receive medical therapy alone and the other half to medical therapy plus stent retriever thrombectomy.

The researchers found a 1.7 fold reduction in disability and a 15.5 percent increase in the rate of return to functional independence in the endovascular therapy group compared to the medical intervention-alone group.

Because the Catalan Department of Health keeps a registry of all  stroke patients treated with clot busting therapies (intravenous or intra-arterial) , the researchers were able to determine that nearly all eligible patients who were treated at participating centers and in Catalonia over the duration of the trial were actually enrolled in REVASCAT. This unique feature distinguished the trial from other similar recently published randomized studies, removing any lingering concerns that endovascular therapy for stroke is only beneficial for a minority of eligible patients, Dr. Jovin noted.

“We now have five global studies that provide an overwhelming body of clinical evidence in support of stent retriever thrombectomy. Based on these findings, it is time for the stroke community to come together to re-evaluate stroke treatment guidelines and to look for systems to facilitate the access of treatable patients to specialized centers,” said co-principal investigator Antoni Dávalos, M.D., Ph.D., of Hospital Universitari Germans Trias i Pujol, and professor of neurology at the Universitat Autònoma de Barcelona in Spain.

The researchers say that more work needs to be done to determine whether the technique is effective when performed more than eight hours after stroke onset, in vessels that are smaller and in different locations in the brain than those treated in REVASCAT, and in the very elderly.

The study team included researchers from Barcelona, Spain; the University of Calgary in Canada; and the Dresden University of Technology in Germany. The project was funded by the Fundació Ictus Malaltia Vascular through an unrestricted grant from device manufacturer Covidien, and by a grant from the Spanish Ministry of Health co-financed by FEDER (Instituto de Salud Carlos III).

Published the same day in the NEJM and presented at the European Stroke Organisation Meeting, researchers announced further results of another large stroke trial of nearly 200 patients called SWIFT PRIME. That study showed endovascular treatment within six hours of stroke onset led to increased functional recovery and decreased 90-day disability. The Pitt arm of SWIFT PRIME, led by Dr. Jovin, was the second-leading enroller in the trial.

Pitt Experts Evaluate Efficacy and Safety of Osteoporosis in Frail Elderly Women

PITTSBURGH, April 14, 2015 – Experts from the Division of Geriatric Medicine at the University of Pittsburgh conducted a randomized clinical trial to test the efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women in long-term care facilities. The results recently were published online in JAMA Internal Medicine.

Led by Susan Greenspan, MD, Professor of Medicine in the Department of Endocrinology and the Division of Geriatric Medicine, the authors conducted a randomized, placebo-controlled, double-blinded study from December 2007 through March 2012 of 181 women 65 or older with osteoporosis — including those with cognitive impairment, immobility, and multimorbidity — who were living in nursing homes and assisted-living facilities.

According to the authors, eighty-five percent of institutionalized elderly people have osteoporosis and bone fracture rates are eight to nine times higher in this population than in community-dwelling elderly people. However, most of these people are left untreated and are excluded from osteoporosis trials.

“This study is important because trials of younger and healthier elderly suggest that the risk of a devastating hip fracture can be cut in half with such therapy so it’s important to know if that’s also true for seniors in nursing homes,” says Neil Resnick, MD, chief of the Division of Geriatric Medicine and a co-author of the study.

The authors found that, “in this group of frail elderly women with osteoporosis, 1 dose of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant increases in fracture and mortality rates in the treatment group needs further study. Since it is not known whether such therapy reduces the risk of fracture in this cohort, any change in nursing home practice must await results of larger trials powered to assess fracture rates.”

“We expected to see a positive trend of fewer fractures, but we did not; if anything, there were more fractures in the treatment group,” says Dr. Greenspan. “We had postulated such a possible dissociation between bone metabolism and fracture reduction in a paper we published in JAMA in 1989, but this may be the first evidence for it. It will be important to prove whether or not that’s the case in follow-up studies.”

Additional authors included Subashan Perera, PhD, Mary Ann Ferchak, BSN, David Nace, MD, MPH, and Dr. Resnick, all of the Division of Geriatric Medicine.

 

To view the full abstract, please visit PubMed.gov.

Pitt Cancer Virology Team Reveals New Pathway that Controls How Cells Make Proteins

PITTSBURGH, April, 13, 2015 – A serendipitous combination of technology and scientific discovery, coupled with a hunch, allowed University of Pittsburgh Cancer Institute (UPCI) researchers to reveal a previously invisible biological process that may be implicated in the rapid growth of some cancers.

The project, funded by the National Institutes of Health (NIH), is described in today’s issue of the Proceedings of the National Academy of Sciences (PNAS).

“I was so amazed by what I was seeing,” said lead author Masahiro Shuda, Ph.D., research assistant professor in Pitt’s Department of Microbiology & Molecular Genetics. “We repeated and repeated our work to prove that the standard scientific dogma wasn’t the complete story.”

Dr. Shuda and his colleagues showed that a well-known cancer protein called mTOR, previously thought to be solely responsible for controlling a form of protein production important in cancer cells, called cap-dependent translation, can actually hand its work off to a different protein, CDK1, when cells are dividing. They observed the process while examining a viral oncoprotein that allows a common and usually harmless virus to transform healthy cells into cancer cells.

Merkel cell polyomavirus (MCV) was discovered in 2008 by co-authors Yuan Chang, M.D., and Patrick S. Moore, M.D., M.P.H., in the Cancer Virology Program at UPCI, partner with UPMC CancerCenter. It causes a rare but deadly skin cancer called Merkel cell carcinoma. They later found a viral protein called “small tumor protein,” or sT. It may start a chain reaction that enables tumor growth resistant to cancer drugs that inhibit the protein mTOR.

In studies dating back to the 1960s, scientists had assumed that cap-dependent protein synthesis was turned off during cell division. The new study reveals that this is not necessarily so and that CDK1 can substitute for mTOR. Both mTOR and CDK1 work by inhibiting a gatekeeper protein, called 4E-BP1, that shuts off cap-dependent protein synthesis.

Less than 1 percent of cells are in the active division cycle called mitosis, even in very aggressive cancers, which makes studying cells in mitosis difficult. In addition, a drug traditionally used to arrest the cells during division inhibits protein production by CDK1. This is likely why previous research did not identify the important role that CDK1 appears to play.

Dr. Shuda used a technology called flow cytometry to identify cells undergoing division. With special fluorescent tags, he was able to see mitotic cells produce fully inactivated 4E-BP1 by CDK1. He also directly measured proteins being made during mitosis.

Sure enough, even when mTOR was knocked out, CDK1 was still present and able to allow protein synthesis needed for cell division to progress.

“Now, we still can’t say that this process involving CDK1 contributes to cancer – that’s something we’ll tackle with future research,” said Dr. Moore, senior author and professor of molecular genetics and biochemistry at Pitt. “But it does point toward a fundamental control mechanism in cell biology and leads to the interesting possibility that creating or combining cancer drugs, so that they inhibit both mTOR- and CDK1-related protein synthesis, could be a very useful therapy to pursue.”

Additional researchers on this work are Celestino Velásquez, B.S., Erdong Cheng, Ph.D., Daniel G. Cordek, Ph.D., and Hyun Jin Kwun, Ph.D., all of Pitt. Drs. Moore and Chang jointly run their laboratory at UPCI.

This research was supported by NIH National Cancer Institute grants R01CA136806, CA136363 and CA170354. The flow cytometry was performed using a facility supported in part by NIH grant P30CA47904.

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