UPMC Physician Resources

Archives for Gastroenterology

Surgical, Other Advances Made at UPMC Improve Graft Survival of Intestinal, Multi-Visceral Transplant Patients

SAN FRANCISCO, July 30, 2014 – Innovations in surgical techniques, drugs and immunosuppression have improved survival after intestinal and multi-visceral transplants, according to a retrospective analysis of more than 500 surgeries done at UPMC over nearly 25 years.

The study was led by Goutham Kumar, M.D., a transplant surgery fellow at UPMC’s Thomas E. Starzl Transplantation Institute. Dr. Kumar was recognized for his work with the Young Investigator Award by the 2014 World Transplant Congress and presented his findings at the group’s July 26 to 31 meeting in San Francisco.

“UPMC has led the way in the development of new surgical techniques and important research involving transplantation, and our analysis shows that our innovations have made a real difference to patients,” Dr. Kumar said.

The researchers examined 541 intestinal and multi-visceral transplants done at UPMC from 1990 to 2013. The total consisted of 228 pediatric transplants and 313 adult transplants; 252 were intestine-only transplants, 157 were liver-intestine, 89 were full multi-visceral, and 43 were modified multi-visceral. A majority of the pediatric patients suffered from gastroschisis, followed by volvulus and necrotizing entercolitis. The adult patients needed transplants because of thrombosis, Crohn’s disease or some kind of obstruction.

Researchers analyzed several outcomes and found that pre-conditioning with certain immunosuppressants, the time the graft is outside of the body, certain blood types and a disparity in the gender of donor and recipient were among the factors predicting graft survival.

Co-authors on the study are George Mazariegos, M.D., Guillerme Costa, M.D., Gaurav Gupta, M.D., Dolly Martin, Geoff Bond, M.D., Kyle Soltys, M.D., Rakesh Sindhi, M.D., Abhinav Humar, M.D., and Hiroshi Sogawa, M.D., all of either the Thomas E. Starzl Transplantation Institute, Children’s Hospital of Pittsburgh of UPMC or UPMC.

In addition to Dr. Kumar, six other UPMC and University of Pittsburgh Schools of the Health Sciences researchers were recognized this year with Young Investigator Awards by the World Transplant Congress. They and their presentations are:

Aravind Cherukuri, M.D., Ph.D.
“Transitional B Cell (TrB) T1/T2 Ratio is a Marker for Graft Dysfunction in Human Kidney Transplant Recipients (KTRs)”

Vinayak Rohan, M.D.
“Outcomes of Liver Transplantation for Unresectable Liver Malignancy in Children”

Qing Ding, Ph.D.
“TIM-1 Signaling is Required for Maintenance and Induction of Regulatory B Cells Through Apoptotic Cell Binding or TIM-1 Ligation”

Kanishka Mohib, Ph.D.
“TIM-4 Expression by C Cells Identifies an Inflammatory B Effector 1 Subset that Promotes Allograft Rejection and Inhibits Tumor Metastases”

Dalia Raich-Regue, Ph.D.
“Myeloid Dendritic Cell-Specific mTORC2 Deficiency Enhances Alloreactive Th1 and Th17 Cell Responses and Skin Graft Rejection”

Tripti Singh, M.D.
“B Cell Depletion of Naïve Recipients Enhances Graft Reactive T Cell Responses”

Pitt-led Study Suggests Cystic Fibrosis is Two Diseases, One Doesn’t Affect Lungs

PITTSBURGH, July 17, 2014 – Cystic fibrosis (CF) could be considered two diseases, one that affects multiple organs including the lungs, and one that doesn’t affect the lungs at all, according to a multicenter team led by researchers at the University of Pittsburgh School of Medicine. The research, published online today in PLOS Genetics, showed that nine variants in the gene associated with cystic fibrosis can lead to pancreatitis, sinusitis and male infertility, but leave the lungs unharmed.

People with CF inherit from each parent a severely mutated copy of a gene called CFTR, which makes a protein that forms a channel for the movement of chloride molecules in and out of cells that produce sweat, mucus, tears, semen and digestive enzymes, said co-senior investigator David Whitcomb, M.D., Ph.D., chief of gastroenterology, hepatology and nutrition, Pitt School of Medicine. Without functional CFTR channels, secretions become thick and sticky, causing problems such as the chronic lung congestion associated with CF.

“There are other kinds of mutations of CFTR, but these were deemed to be harmless because they didn’t cause lung problems,” Dr. Whitcomb said. “We examined whether these variants could be related to disorders of the pancreas and other organs that use CFTR channels.”

Co-senior author Min Goo Lee, M.D., Ph.D., of Yonsei University College of Medicine in Seoul, Korea, conducted careful tests of CFTR in pancreatic cell models and determined that a molecular switch inside the cell called WINK1 made CFTR channels secrete bicarbonate rather than chloride molecules.

“Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids,” Dr. Whitcomb said. “When that doesn’t happen, the acids cause the inflammation, cyst formation and scarring of severe pancreatitis.”

The research team found nine CFTR gene variants associated with pancreatitis after testing nearly 1,000 patients with the disease and a comparable number of healthy volunteers. They also learned that each variant could impair the WINK1 switch to prevent CFTR from becoming a bicarbonate-secreting channel.

Co-senior author Ivet Bahar, Ph.D., Distinguished Professor and John K. Vries Chair of Computational Biology, Pitt School of Medicine, built a computer model of the CFTR protein’s structure and determined that all the nine variants alter the area that forms the bicarbonate transport channel, thus impairing secretion of the molecule.

“It turns out that CFTR-mediated bicarbonate transport is critical to thin mucus in the sinuses and for proper sperm function,” Dr. Whitcomb said. “When we surveyed pancreatitis patients, there was a subset who said they had problems with chronic sinusitis. Of men over 30 who said they had tried to have children and were infertile, nearly all had one of these nine CFTR mutations.”

He added that identification of the mechanisms that cause the conditions make it possible to develop treatments, as well as to launch trials to determine if medications that are used by CF patients might have some benefit for those who do not have lung disease, but who carry the other mutations.

The team includes researchers from the University of Pittsburgh, the Mayo Clinic, Brigham and Women’s Hospital, and many other institutions that are part of the North American Pancreatitis Study Group.

The study was supported by National Institutes of Health grants DK061451, DK062420, GM086238, DK063922, CA047904 and RR024153; the Ministry for Health & Welfare, Republic of Korea; and Brain Korea 21 Project for Medical Sciences, Seoul.

Jeffrey I. Gordon, M.D., Will Receive Pitt’s Dickson Prize at Science 2014—Sustain It!

PITTSBURGH, July 17, 2014 – A scientist who has explored how the tens of trillions of microbes that live in the gastrointestinal tract and their genes influence human physiology, metabolism and nutritional status will receive the University of Pittsburgh’s 2014 Dickson Prize in Medicine.

Jeffrey I. Gordon, M.D., will accept the University of Pittsburgh School of Medicine’s most prestigious honor during Science 2014—Sustain It!, a showcase of the region’s latest research in science, engineering, medicine and computation that will be held from Oct. 1 to 3 at Alumni Hall in Oakland. Dr. Gordon is the Dr. Robert J. Glaser Distinguished University Professor and director of the Center for Genome Sciences and Systems Biology at Washington University School of Medicine in St. Louis.

“Dr. Gordon’s work describes our species as a rich and meaningful ecosystem of interactions between human and microbial components,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine. “His fascinating work has broadened our understanding of obesity in the western world and malnutrition in developing countries and has the potential to stimulate new therapies directed at the microbiome.”

In the body, microbes, primarily bacteria, but also fungi and archaeons, and the viruses that infect them, outnumber an individual’s human cells by a factor of 10. The number of genes in the body’s indigenous microbial communities far exceeds the number of genes in the human genome. Most of these microorganisms reside in the gut. Through innovative experimental and computational methods, including studies of twins of different ages, geographic locales and cultural traditions, and the use of germ-free animal models colonized with gut microbial communities (microbiota) harvested from healthy and unhealthy humans, Dr. Gordon and his students have provided new insights about how the gut microbiota contribute to obesity and metabolic abnormalities, as well as to childhood undernutrition.

Their interdisciplinary studies have helped create a new field of research, altering ways to define the health benefits of foods being produced or that could be produced in response to the global challenges of population growth and sustainable agriculture. Also, Dr. Gordon’s lab is providing a microbial view of human development, including how functional maturation of the gut microbiota is related to healthy growth of infants and children, and helping to usher in a new era of microbiota-directed therapeutics.

At 11 a.m., Thursday, Oct. 2, Dr. Gordon will deliver the Dickson Prize in Medicine Lecture. His talk is titled “A Microbial View of Human Development: The Gut Microbiota and Childhood Undernutrition.”

Dr. Gordon earned his bachelor’s degree in biology at Oberlin College in 1969 and his medical degree at the University of Chicago Pritzker School of Medicine in 1973. He completed a residency in medicine at Barnes Hospital in St. Louis, a postdoctoral fellowship in biochemistry and molecular biology at the National Institutes of Health, and a fellowship in gastroenterology at Washington University in St. Louis. He is the recipient of the Danone International Prize for Nutrition, the Selman A. Waksman Award in Microbiology from the National Academy of Sciences, the Robert Koch Award, and many other honors. He is a member of the National Academy of Sciences, the Institute of Medicine of the National Academies, the American Academy of Arts and Sciences and the American Philosophical Society.

In addition to Dr. Gordon, other renowned researchers also will deliver plenary lectures at Science 2014. The Mellon Lecture will be given by Stuart Orkin, M.D., of Harvard Medical School; the Hofmann Lecture will be given by Jeannie T. Lee, M.D., Ph.D., also of Harvard Medical School; and the Provost Lecture will be given by Jonathan Rothberg, Ph.D., founder of Ion Torrent Systems, Inc., and a pioneer in the field of next-generation DNA sequencing.

Nominations for the 2015 Dickson Prize in Medicine are now being accepted.

UPMC Named to U.S. News & World Report Honor Roll of ‘Best Hospitals’ for 15th Time

UPMC Ranks #1 in Pennsylvania, #1 in Pittsburgh for Clinical Excellence

PITTSBURGH, July 15, 2014 UPMC has once again received national recognition for its clinical expertise, earning 12th position on the annual U.S. News & World Report Honor Roll of America’s “Best Hospitals.” UPMC is the highest-ranked medical center in both Pennsylvania and in Pittsburgh.

“While we’re very proud that UPMC was recognized for the 15th year, it is our patients who are the ultimate winners. Our exceptionally skilled and devoted health care professionals do what they do best every day — provide the finest health care in the state and in the region,” said Leslie C. Davis, president, UPMC Hospital and Community Services Division.

“We are honored to receive this national distinction, which recognizes UPMC’s unique combination of high-quality medical care, a top health insurance plan, and close affiliation with the University of Pittsburgh, one of the best medical schools in the country,” added Steven Shapiro, M.D., executive vice president and chief medical and scientific officer at UPMC. “Furthermore, it emphasizes UPMC’s commitment to our patients and showcases how we are leading the way in the development of new technologies and methods of care.”

Nationally, UPMC is ranked for excellence in 15 of 16 specialty areas, and is among the top 10 hospitals in six specialties: ear, nose and throat; gastroenterology; gynecology; psychiatry; pulmonology; and rheumatology.

U.S. News analyzed 4,743 medical centers in the nation, but only those that achieved high scores in six or more specialties were included in the distinguished Honor Roll group. Scores were based on a variety of factors including hospital volume, patient safety, outcomes and reputation for delivering high-quality care.

Last month, U.S. News named its 2014 Honor Roll of America’s Best Children’s Hospitals, recognizing Children’s Hospital of Pittsburgh of UPMC as 9th in the country.

UPMC Expands Reach in Italy with Outpatient Diagnostic Center

PITTSBURGH, June 6, 2014 – Adding to its successful transplant and cancer treatment facilities in Italy, UPMC announced today that it is expanding its Italian operations to include outpatient diagnostic services for liver and digestive disorders in the Region of Tuscany.

UPMC is managing and operating the new center, the UPMC Institute for Health, at the Terme di Chianciano Spa in Chianciano Terme. Located near Siena, between Florence and Rome, the facility will build on the traditional attraction of the spa’s thermal water therapies and is expected to attract patients from throughout Italy and beyond when it opens on June 9, 2014.

The new center will offer diagnostic screenings, imaging and procedures for liver and digestive disorders, cardiovascular diseases, diabetes and other illnesses. Patients also will be educated about personal risk factors, healthy lifestyle and diet. Those who need more advanced care may be referred to local hospitals or to other UPMC facilities in Italy, namely the ISMETT transplant hospital in Palermo and the UPMC San Pietro Cancer Center in Rome.

“Building on our long reputation for clinical excellence in Italy, we are proud to expand our high-quality services into a new region of the country,” said Charles Bogosta, president of UPMC’s International and Commercial Services Division. “This popular destination for patients will now have the only facility in the area that can offer a complete digestive check-up in a place that already draws thousands of people every year to its healing waters.”

UPMC is partnering with Terme di Chianciano, a company that operates and manages historical thermal premises in the region, as well as with the municipality and the local health care authority. UPMC is leasing and renovating the spa’s existing medical center.

“With UPMC’s clinical, scientific and management know-how and the well-established treatments of Chianciano Spa, this partnership will deliver a higher level of services to patients in one convenient location,” said Bruno Gridelli, M.D., medical and scientific director of UPMC’s International and Commercial Services Division and chief executive officer of ISMETT.

UPMC’s international footprint already includes operations or services in Italy, Ireland, India, Canada, China, Singapore, Japan and Kazakhstan. Through its international growth and commercialization efforts with industry partners, UPMC is diversifying its revenue base, fueling economic development in its communities, and strengthening its ability to recruit and retain the best and brightest clinicians who are working together to improve health care outcomes globally.

Gastroenterology Experts Present at 2014 Digestive Disease Week

The Division of Gastroenterology, Hepatology, and Nutrition was well represented in Chicago at the recent Digestive Disease Week annual meeting, DDW 2014. Division research was featured in both oral and poster presentation throughout the week.

There were more than 50 faculty presentations highlighting topics such as pediatric IBD; nausea and vomiting; pancreatic genetics, physiology, and cell biology; and colon cancer screening. Presenters from the division included:

For more information on the presentations at DDW 2014, please visit the conference page.

  • Nijole Pollock

Laboratory Detective Work Points to Potential Therapy for Rare, Drug-Resistant Cancer

PITTSBURGH, Feb. 13, 2014 University of Pittsburgh Cancer Institute (UPCI) scientists have shown that old drugs might be able to do new tricks.

By screening a library of FDA-approved anticancer drugs that previously wouldn’t have been considered as a treatment for a rare type of cancer, UPCI scientists were surprised when they found several potential possibilities to try if the cancer becomes resistant to standard drug treatment.

The discovery, which will be published in the February 15th issue of Cancer Research, demonstrates that high-throughput screening of already FDA-approved drugs can identify new therapies that could be rapidly moved to the clinic.

“This is known as ‘drug repurposing,’ and it is an increasingly promising way to speed up the development of treatments for cancers that do not respond well to standard therapies,” said senior author Anette Duensing, M.D., assistant professor of pathology at UPCI. “Drug repurposing builds upon previous research and development efforts, and detailed information about the drug formulation and safety is usually available, meaning that it can be ready for clinical trials much faster than a brand-new drug.”

Dr. Duensing and her team ran the screening on 89 drugs previously approved by the FDA in an attempt to find more treatment options for patients with gastrointestinal stromal tumors (GISTs), which are uncommon tumors that begin in the walls of the gastrointestinal tract. According to the American Cancer Society, about 5,000 cases of GISTs occur each year in the United States with an estimated five-year survival rate of 45 percent in patients with advanced disease.

GISTs are caused by a single gene mutation and can be successfully treated with the targeted therapy drug imatinib, known by the trade name Gleevec. However, about half of the patients treated with Gleevec become resistant to the drug within the first two years of treatment.

After studying how samples of GIST responded to various concentrations of the 89 drugs in the laboratory, Dr. Duensing and her colleagues identified 37 compounds that showed some anticancer activity in at least one of the concentrations tested. Importantly, they noted that the most promising candidates all belonged to only two major drug classes: inhibitors of gene transcription and so-called topoisomerase II inhibitors. Based on these findings, the research team selected the two most promising compounds for further testing – gene transcription inhibitor mithramycin A, which is in clinical trials to treat Ewing sarcoma, and topoisomerase II inhibitor mitoxantrone, which is used in metastatic breast cancer and leukemia.

Both drugs were highly effective in fighting GIST in laboratory tests. Moreover, the mechanism of action of each drug was linked to the specific underlying biology of these tumors.

“These are very encouraging results,” said Dr. Duensing. “The next step will be moving our findings to clinical exploration to see if the results we found in the lab hold up in patients.”

Additional co-authors of this study include Sergei Boichuk, M.D., Ph.D., Derek J. Lee, B.S., Keith R. Mehalek, M.S., Kathleen R. Makielski, M.S., Danushka S. Seneviratne, B.S., Rolando Cuevas, M.S., Joshua A. Parry, B.S., Matthew F. Brown, Ph.D., James P. Zewe, B.S., and Shih-Fan Kuan, M.D., Ph.D., all of Pitt; Agnieszka Wozniak, Ph.D., Patrick Schöffski, M.D., M.P.H., and Maria Debiec-Rychter, M.D., Ph.D., all of the Catholic University in Leuven, Belgium; Nina Korzeniewski, Ph.D., of the University of Heidelberg in Germany; and Takahiro Taguchi, M.D., of Kochi Medical School in Japan.

This research was supported by American Cancer Society grant no. RSG-08-092-01-CCG, The Life Raft Group, GIST Cancer Research Fund and the Howard Hughes Medical Institute.

Developer of Innovative Surgical Technique Leads New Center for Colorectal Issues at Children’s Hospital of Pittsburgh of UPMC

PITTSBURGH, Feb. 12, 2014Children’s Hospital of Pittsburgh of UPMC has recruited an internationally renowned surgeon, Luis De la Torre, M.D., to establish the new Colorectal Center for Children that will serve as a resource for children from around the world with complex colorectal issues.

Children’s Colorectal Center for Children will provide multidisciplinary medical and surgical care for children who are born with or acquire issues of the bowel or rectum. Dr. De la Torre, who pioneered a unique, less invasive surgical approach to the treatment of Hirschsprung’s disease, specializes in the diagnosis, treatment and rehabilitation of children with complex colorectal conditions, including anorectal malformations; cloaca; fecal incontinence; idiopathic constipation; bowel management; colostomy care; appendicostomy; colon polyps; anal fistula; anal abscesses; and colorectal problems in children with myelomeningocele.

“Dr. De la Torre is recognized as a leader in his field and his recruitment to Children’s enables us to establish a multidisciplinary center that focuses not only on the diagnosis and treatment of these conditions, but on the quality of life of these patients,” said George K. Gittes, M.D., surgeon-in-chief at Children’s and the Benjamin R. Fisher Chair of Pediatric Surgery at the University of Pittsburgh School of Medicine. “Dr. De la Torre is an innovative surgeon, but his focus is on providing comprehensive and ongoing care that allows children with these complex colorectal issues to return to lives that are as normal as possible.”

The Colorectal Center for Children will provide comprehensive diagnosis, appropriate treatment and intestinal rehabilitation for children with these complex disorders. The Center will include specialists within gastroenterology, pediatric surgery, and urology with additional training in colorectal diseases, and pediatric nurses specializing in the treatment of wounds, colostomies and bowel management. Pediatric radiologists and pathologists specializing in diseases of the colon also are a part of the center.

“One of the goals of the Colorectal Center is to help recover children’s quality of life and integration into society, including the possible challenges of puberty, sexual function and childbearing as they relate to colorectal issues,” said Dr. De la Torre, a surgeon in the Division of Pediatric General and Thoracic Surgery.

Dr. De la Torre, also associate professor of surgery at the Pitt School of Medicine, comes to Children’s from Hospital Ángeles Puebla in Mexico, where he was founding director of the Colorectal Center for Children and chief of Pediatric Surgery.

Dr. De la Torre completed his residency training in Pediatrics and Pediatric Surgery at the Instituto Nacional de Pediatría at Universidad Nacional Autónoma de México, a hospital internationally known for contributions in the field of pediatric colorectal surgery. He also completed a fellowship in pediatric colorectal surgery at Schneider Children’s Hospital Medical Center, where he trained under internationally known Alberto Pena, M.D.

Dr. De La Torre is author of more than 35 peer reviewed articles and numerous book chapters, with many focusing on Hirschsprung’s disease, rehabilitation of children with congenital, acquired and complicated colorectal diseases. He also belongs to the editorial committees of four pediatric surgery journals.

For more information about Dr. De la Torre and the Colorectal Center for Children, please visit www.chp.edu/CHP/colorectal+center+for+children.

Analysis of Telephone Calls to IBD Clinic Predicts Emergency Visits and Hospitalizations, Pitt Finds

PITTSBURGH, Feb. 7, 2014 – A comprehensive analysis of patient telephone records at an inflammatory bowel disease (IBD) clinic revealed that 15 percent of patients account for half of all calls to the clinic. Forty-two percent of frequent-caller patients also were seen in the emergency department or hospitalized within the following year.

The results, which can help doctors identify patients with the most severe disease and those at risk of potentially avoidable high-cost medical interventions, were reported in a study published online this week in the journal Clinical Gastroenterology and Hepatology.

Inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) are chronic lifelong conditions which affect the gastrointestinal tract of up to 2 million Americans, the majority of whom are diagnosed as young adults. Telephone communication in IBD care is common, and involves reporting clinical status, treatment, reassurance, and completion of health care forms and insurance authorization. Yet, until now, there has been limited information on telephone activity volume or the reasons for calls in the care of chronic illness, including IBD.

“Telephone surveillance and the use of big data allowed us to find red flags identifying patients at risk of high-cost medical interventions, such as emergency department use and/or hospitalization. These findings can help to identify disease severity and teach us how to take better care of our patients,” noted senior author David Binion, M.D., visiting professor of medicine, clinical and translational science and co-director of the IBD Center at the University of Pittsburgh School of Medicine.

Researchers tracked more than 50,000 phone calls over a period of two years, from over 3,000 patients. The researchers assessed associations between clinical factors and logged telephone encounters, and between patterns of telephone calls and future visits to the emergency room or hospitalization.

Calls were categorized into five groups:

  • Problem/follow-up (incoming calls from patients), representing 52 percent of all calls
  • Resolution/plan (outgoing calls to patients), representing 25 percent of all calls
  • Refill requests/pharmacy contacts, representing 12 percent of all calls
  • Insurance authorization, representing 10 percent of all calls
  • Completion of forms or record requests, representing 1 percent of all calls

Researchers also measured telephone encounters logged into electronic medical records in consented subjects from a prospective IBD research registry. Patients calling more than 10 times per year were considered high telephone encounters.

Results showed that:

  • Telephone calls are predictors of how likely patients are to enter the emergency room: clusters of phone calls over time were highly predictive of who ended up in the hospital over the course of the next year.
  • Frequent telephone calls correlated with:
    • Poorly controlled inflammation of IBD
    • Patients with a high degree of pain and difficulty coping

“We believe we will ultimately be able to use this information to prevent hospitalization, since we now have better insight into the heterogeneous factors which are getting our patients into trouble,” added Dr. Binion. “Our next step is to set up an intervention trial, where patterns of telephone activity will be used as an early warning strategy to identify at-risk patients. Perhaps the most important aspect of the study was its simplicity and generalizability, as records of telephone communication in health care are an important part of electronic health records available throughout the U.S.”

Mood-stabilizing Drug Could be New Treatment for Inherited Liver Disease, Says Pitt/Children’s Team

PITTSBURGH, Feb. 3, 2014 – Opening up a can of worms is a good way to start hunting for new drugs, recommend researchers from Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine. In a study published today in the Public Library of Science One, they used a primitive worm model to show that a drug typically used to treat agitation in schizophrenia and dementia has potential as a treatment for α-1 antitrypsin (AT) deficiency, an inherited disease that causes severe liver scarring.

In the classic form of AT deficiency, which affects 1 in 3,000 live births, a gene mutation leads to production of an abnormal protein, dubbed ATZ, that unlike its normal counterpart is prone to clumping, explained David H. Perlmutter, M.D., physician-in-chief and scientific director, Children’s Hospital, and Distinguished Professor and Vira I. Heinz Endowed Chair, Department of Pediatrics, Pitt School of Medicine.

“These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation,” Dr. Perlmutter said. “If we could find a drug that slows or stops this process, we might be able to prevent the need for liver transplantation in these patients.”

To find that drug, Dr. Perlmutter’s team worked with Pitt’s Stephen Pak, Ph.D., assistant professor of pediatrics, and Gary Silverman, M.D., Ph.D., Twenty-five Club Professor of Pediatrics, Cell Biology and Physiology, who developed a model of AT deficiency in Caenorhabditis elegans, or C. elegans, a harmless microscopic worm or nematode typically found in soil. Previous experiments conducted by Drs. Pak and Silverman, in which more than 2,000 compounds were screened, showed that fluphenazine, a drug approved for human use as a mood stabilizer, could reduce ATZ accumulation in the worm, so the team studied it further.

Worms that produce ATZ die sooner than normal ones, which typically have a life span of fewer than 20 days.  Those that were exposed to fluphenazine, however, had lower burdens of ATZ and lived more than a day longer that untreated animals. The lifespan of normal worms was unchanged by fluphenazine exposure. The researchers also labeled with fluorescent markers intracellular structures called autophagosomes, which help clear abnormal proteins out of the cell in a process called autophagy. Fluphenazine exposure was associated with a greater presence of autophagosomes, suggesting that increased autophagy led to reduced ATZ accumulation.

Follow-up experiments showed that fluphenazine reduced ATZ accumulation in several mammalian-cell line models of AT deficiency, D. Silverman said.

“We found when we gave this drug for three weeks to mice with the disease, autophagy is activated, the abnormal protein load is diminished, and liver scarring is reversed. It’s truly amazing,” he said. “And because fluphenazine is already being safely prescribed for other conditions, it should be easier to bring it to clinical trials for AT deficiency.”

The project also reveals the power of the worm model to rapidly screen drug candidates, Dr. Perlmutter noted.

“This is the first extensive investigation of a drug that was discovered through the C. elegans screening method,” he said. “It’s remarkable that you can take a completely unbiased, high-content screen using a primitive organism and end up identifying a drug that reduces the accumulation of an abnormal protein in mammalian cell lines and a living mouse. It’s proof-of-principle of this research pipeline. Furthermore, this drug is very similar pharmacologically to carbamazepine, another mood stabilizer that we found to enhance autophagy and reverse liver fibrosis in the mouse model of α1-antitrypsin deficiency.”

Other co-authors of the paper include Jie Li, M.D., Ph.D., Linda P. O’Reilly, Ph.D., Joshua A. Benson, Yan Wang, Ph.D., Tunda Hidvegi, Ph.D., Pamela Hale, Christine Dippold, and Michael Ewing, all of the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC.

The project was funded by U.S. Public Health Service grants DK079806, DK081422, DK076918, and DK096990, and a grant from the Hartwell Foundation.

Page 1 of 6:1 2 3 4 »Last »