McGowan Institute?
June 2010 | VOL. 9, NO. 6 | www.McGowan.pitt.edu
Discovery Allows Researchers to Further Study and Characterize Cancer Stem Cells
McGowan Institute for Regenerative Medicine affiliated faculty member Jean Latimer, PhD, assistant professor at the University of Pittsburgh in the Department of Obstetrics, Gynecology and Women’s Health, and also a faculty member in the Cellular and Molecular Pathology Graduate Training Program and the University of Pittsburgh Cancer Institute, along with a team of scientists from Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine have discovered an unprecedented method of permanently blocking cancer stem cells so they remain stem cells instead of differentiating into other types of tumor-forming cells. The discovery is significant because it will allow researchers to further study and characterize cancer stem cells, as well as screen drugs that could specifically target them.
The research, which involved four different lines of breast cancer stem cells, was led by Edward Prochownik, MD, PhD, director of Oncology Research at Children’s Hospital and the Paul C. Gaffney Professor of Pediatrics and of Molecular Genetics and Biochemistry at the University of Pittsburgh School of Medicine.
Cancer stem cells are heartier than other types of tumor cells because they are generally more resistant to standard chemotherapy and to conditions found inside tumors, such as low oxygen and acidity levels. Although they make up a relatively small portion of a tumor, cancer stem cells are believed to initiate and sustain tumors as they grow and metastasize.
Cancer stem cells differentiate into other cells within 3 to 5 weeks of being isolated, making them difficult to study, according to Dr. Prochownik. He and his colleagues at the John G. Rangos Sr. Research Center at Children’s Hospital were able to tag the breast cancer stem cells they isolated with green fluorescent protein and a stem cell-specific promoter know as Oct3/4.
“Using this approach, we can essentially freeze the stem cells in their current state, grow them in unlimited quantities and then study them at our leisure so we’ll be able to understand what makes cancer stem cells more efficient than other types of cancer cells,” Dr. Prochownik said. “More importantly, having this unlimited supply of cancer stem cells allows us to use existing technology to screen them for chemotherapy agents and other therapies to determine which therapies are most effective at destroying the cancer stem cells. The goal is an arsenal of therapies to target both the tumor as a whole as well as those specific to the cancer stem cells.”
The discovery of how to block these cancer stem cells was serendipitous; the team was initially trying to develop a way to track the cancer stem cells to determine what other types of cells they differentiated into and how long the process takes. Now, the team at the Rangos Research Center is studying whether their method of blocking breast cancer stem cells also blocks those from other types of tumors. They also are screening large numbers of drugs to identify new ones that may be more effective against breast cancer stem cells.
SCIENTIFIC ADVANCES
A team of Children’s Hospital of Pittsburgh of UPMC and University of Pittsburgh School of Medicine researchers including McGowan Institute for Regenerative Medicine affiliated faculty members (pictured top to bottom) David H. Perlmutter, MD, physician-in-chief and scientific director, Children’s Hospital, and Vira I. Heinz Professor and Chair of the Department of Pediatrics, Pitt School of Medicine, Simon C. Watkins, PhD, Professor, Department of Cell Biology and Physiology, University of Pittsburgh, and George Michalopoulos, MD, PhD, Professor and Chairman of the Department of Pathology, Founder and Director of the Center for Biologic Imaging, University of Pittsburgh, found the liver scarring of a1-antitrypsin (AT) deficiency, the most common genetic cause for which children undergo liver transplantation, might be reversed or prevented with a medication that has long been used to treat seizures.
Because the anti-seizure drug is familiar to doctors and has a well-understood safety profile, clinical trials could begin immediately to see whether it can help patients with AT deficiency, said senior author Dr. Perlmutter.
In the classic form of the disease, which affects 1 in 3,000 live births, a gene mutation leads to an abnormal protein, dubbed ATZ, that, unlike its normal counterpart, is prone to aggregation.
“These aggregates of ATZ accumulate in the liver cells and eventually lead to scarring, or fibrosis, of the organ and set the stage for tumor development,” Dr. Perlmutter said. “The disease sometimes doesn’t show itself until adulthood, when the liver starts to fail due to cirrhosis or cancer.”
For the study, he and his colleagues treated an ATZ cell line with carbamazepine, or Tegretol. Although this drug has been used primarily to treat seizure disorders, some recent work has suggested that it could enhance a natural cellular pathway called autophagy, or self-digestion, and so the Pitt researchers reasoned that it might be able to rid the cells of the toxic aggregated ATZ.
They found that carbamazepine did, indeed, cause a marked decrease in ATZ because the abnormal proteins were degraded more quickly via autophagy, and so they did another experiment in a mouse model of AT deficiency.
“The amount of ATZ decreased in the livers of the mice treated with carbamazepine,” Dr. Perlmutter said. “The most amazing finding was that the drug reversed the fibrosis in the livers of the mice and, after 2 weeks of treatment, the liver tissue resembled that of a healthy mouse.”
The ability of carbamazepine and drugs like it to “soup up” the cell’s autophagy machinery might have value in other disorders ? such as Alzheimer’s disease, Huntington’s disease, and Parkinsonism ? that are thought to be caused by toxic effects of protein clumping in the brain. Dr. Perlmutter and his colleagues are now exploring these possibilities in preclinical studies.
As the largest rehab network in western Pennsylvania, UPMC Institute for Rehabilitation and Research (IRR) works with patients to make every day independence day. Rehabilitation for individuals who have suffered strokes, traumatic brain injuries, or neurological disorders resulting in hand and arm impairment can be tough work, however efforts at the IRR look to having fun with video games as a means to achieving best possible patient outcomes. Per McGowan Institute for Regenerative Medicine affiliated faculty member Michael Boninger, MD, chair of the Department of Physical Medicine and Rehabilitation at University of Pittsburgh Medical School and director of the IRR, “It is great to see patients enjoying playing a game, when you know what they are actually doing is the hard work of rehabilitation.”
One sustainable and powerful comprehensive therapy concept based on research development activities at the University of Twente and Roessingh Research and Development in Enschede, Netherlands, and created by Hocoma, a Swiss manufacturer of robotic rehabilitative equipment, is the Armeo Therapy Concept. The RRI is the only U.S. facility using its products—the Armeo Boom (pictured top) and the Armeo Spring (pictured bottom)—in a clinical setting. Hocoma’s computer software interface offers several reach-and-retrieval computer games, such as solitaire and catching raindrops with a teacup, along with simulated everyday tasks, like virtually frying an egg or cleaning a picture. To use the Armeo Boom, patients strap their arms into a neoprene sling attached to an overhead boom. The Armeo Spring is an ergonomically designed, lightweight metal exoskeleton that embraces the whole arm and has a handgrip.
Despite a patient’s disorder, research suggests that the neural plasticity of the brain is retained and new connections can be made through intensive, repetitive, and task-oriented movements. Using clinical evidence as a basis and through the combination of three key features—arm weight support, augmented feedback, and assessment tools—the Armeo Therapy Concept addresses different patient and therapeutic needs across the whole continuum of rehabilitation. The Armeo Therapy Concept improves the efficiency of therapy treatments because the exercises are self-initiated, self-directed, functional, and intense. Even severely impaired patients can practice independently, without the constant presence of a therapist, allowing patients to exploit their full potential for recovery.
“We are excited to see the progress our patients make while they have fun using this equipment,” says Dr. Boninger.
McGowan Institute for Regenerative Medicine affiliated faculty member Raphael Hirsch, MD, the Aldo V. Londino Jr., MD, Professor of Pediatrics and chief of the Division of Pediatric Rheumatology at Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, directs Children's pediatric rheumatology program, which has grown from a one-physician division to one of the largest and most comprehensive programs in the United States, with six full-time faculty, an experienced clinical staff, and a National Institutes of Health (NIH)-funded research laboratory. The program treats hundreds of young patients from as far away as Altoona, western New York, eastern Ohio, and West Virginia.
The NIH-funded research program focuses on answering fundamental questions about arthritis. Dr. Hirsch’s areas of expertise include gene transfer, gene expression in arthritis, modulation of T-cell immune responses, and therapy of autoimmune diseases. Currently, the rheumatology division has in progress two NIH-funded studies on new proteins it discovered, which in turn could lead to new therapies. Assistant professor Margalit Rosenkranz, MD, is credited with one discovery and Dr. Hirsch with the other.
Another study in progress at Children's is on a new diagnostic tool called an arthritis imager developed in conjunction with Carnegie Mellon University software engineers and the University of Pittsburgh. "It takes two kinds of pictures; there are two cameras in it," Dr. Hirsch said. "One takes a thermal image showing heat in the joint. The other takes a three-dimensional picture of the hand to show the contours for a search for swelling."
It quantifies the diagnoses rheumatologists now have to make by observation. "It's hard to get agreement among doctors," Dr. Hirsch said.
Dr. Hirsch said 100 children and 100 adults are being recruited for the imaging trial. "We think we can conclude the study in about a year."
Also, Dr. Hirsch and his division are actively training fellows to treat young patients under a NIH grant. Taking 2 new fellows a year for 3-year fellowships, Children's has produced 10 U.S. fellows and 2 international fellows since the program began in 2003. Dr. Hirsch said that's between 10 percent and 15 percent of all fellows being trained nationally.
In addition, Children's is working on a telemedicine program that would allow its farflung patients to go to local hospitals for checkups by their Children's rheumatologists. The goal is to start the system later this year or in 2011.
Juvenile rheumatoid arthritis (JRA) is a type of arthritis that happens in children age 16 or younger. It causes joint swelling, stiffness, and sometimes reduced motion. It can affect any joint, and in some cases it can affect internal organs as well. One early sign of JRA may be limping in the morning. Symptoms can come and go. Some children have just one or two flare-ups. Others have symptoms that never go away. JRA causes growth problems in some children. No one knows exactly what causes JRA. Scientists do know it is an autoimmune disorder, which means your immune system, which normally helps your body fight infection, attacks your body's own tissues.
McGowan McGowan Institute for Regenerative Medicine affiliated faculty member Steven Belle, PhD, MScHyg, professor of epidemiology, University of Pittsburgh Graduate School of Public Health, and the world’s foremost hepatitis experts gathered in Pittsburgh to launch the University of Pittsburgh-coordinated Hepatitis B Clinical Research Network – a consortium of 15 clinical and research centers across the U.S. and Canada. The meeting coincided with the third-annual World Hepatitis Day, which raises awareness about the 1 in 12 people living with hepatitis B and C worldwide.
The network, whose data coordinating center was funded in 2009 by a 7-year, $11 million grant to Pitt from the National Institute of Diabetes and Digestive and Kidney Diseases, is facilitating clinical and basic research on hepatitis B and developing a multi-site treatment trial and major database of study results. During the meeting, experts discussed initiating clinical trials to address current challenges of when to start and stop treatment.
“Current treatments for hepatitis B are effective in addressing symptoms and containing the infection, but they do not cure it,” said Dr. Belle, principal investigator of the data coordinating center for the grant. “Many patients need to stay on therapy for a long time, which often allows the virus to become resistant and makes further treatment ineffective.”
“Despite the availability of safe and effective vaccines for almost 30 years, the number of adults with chronic hepatitis B in the United States has remained relatively unchanged,” said Anna Lok, MD, chair, Hepatitis B Clinical Research Network Steering Committee and professor, University of Michigan School of Medicine. “These people are at risk of cirrhosis, liver failure, and liver cancer.”
The Hepatitis B Research Network brings together clinical centers with expertise in caring for patients with chronic hepatitis B virus (HBV) infection. An estimated 2 billion people worldwide (more than 1 million Americans) have been infected with HBV and about 400 million persons are living with chronic HBV infection. Of those with childhood-acquired chronic HBV infection, it is estimated that 25% will later die from the liver-related complications of cancer and cirrhosis if left untreated. The prevalence of HBV infection is uneven throughout the world, with significant burdens in Asia and the Pacific Islands, sub-Saharan Africa, the Amazon Basin, and Eastern Europe. National surveys indicate that 0.3% to 0.5% of U.S. residents have chronic HBV infection, and 47% to 70% of these persons were born outside the United States. The goal of the Network is to conduct research on chronic hepatitis B, in order to better understand the physiological effects of the disease and develop effective treatment strategies with the currently available therapies.
AWARDS AND RECOGNITIONS
The International Symposium on Ligaments and Tendons (ISL&T) has honored McGowan affiliated faculty member Savio L-Y Woo, PhD, DSc, University Professor of Bioengineering and the Founder and Director of the Musculoskeletal Research Center, by establishing the Professor Savio Woo Young Researcher Awards. These awards are for researchers who have conducted the best research studies in three major areas: biomechanics, biological research, and clinical research.
The intention of the awards are to provide partial support (up to $1,000) towards either the winners’ research or for travel expenses to attend the ISL&T-X meeting. The awards are open to all graduate students and postdoctoral fellows, provided they are the first author of the abstract and are present at the ISL&T-X meeting to accept the award.
The objective of the ISL&T is “to promote awareness of the field, the exchange of information and collaboration nationally and
internationally.”
McGowan Institute for Regenerative Medicine affiliated faculty member Rory Cooper, PhD, FISA/PVA Endowed Chair and a Distinguished Professor of the Department of Rehabilitation Science and Technology, School of Health and Rehabilitation Sciences, University of Pittsburgh, is a contributing editor of the Borden Institute’s 2009 book entitled Care of the Combat Amputee, the latest volume in the Textbooks of Military Medicine series. The Washington Book Publishers (WBP) recently announced its winners of its Design & Effectiveness Awards competition and Care of the Combat Amputee received the First Place Award in the Technical Text category for small to medium nonprofit organizations. This First Place Award also means that the book is in the running for the highest accolade of the competition--Best in Show. The latter award will be announced at the gala Reception and Award Ceremony held on June 10, in Washington, D.C.
Care of the Combat Amputee addresses all aspects of combat amputee care ranging from surgical techniques to long-term care, polytrauma, and comorbidities such as traumatic brain injury and burns, pain management, psychological issues, physical and occupational therapy, VA benefits, prosthetics and adaptive technologies, sports and recreational opportunities, and return to duty and vocational rehabilitation. Written by experts in the military, Veterans Administration, and private sector, the book provides a significant update to the field of rehabilitation, with comprehensive coverage of emerging approaches, techniques, and technologies for amputee care.
The Borden Institute, an agency of the U.S. Army Medical Department Center & School, publishes the Textbooks of Military Medicine. The volumes in the series, now numbering 20, constitute a comprehensive treatise on the art and science of military medicine, covering such diverse topics as military preventive medicine, military medical ethics, harsh environments, and care of combat injuries.
WBP, begun in 1976, is an informal, all-volunteer group of professionals in book publishing. Six or seven meetings each year provide opportunities for members to get acquainted with their colleagues throughout the area, to trade ideas and information, and to listen to expert speakers. Program topics are suggested by members and have included writing, editing, design, production, marketing, rights, new media, the world of book and electronic publishing. Generous cooperation from members allows for various meeting locations.
The WBP annual Book Design & Effectiveness Competition, held in the spring, is a highlight for the Washington-area book publishing community. These awards recognize, celebrate, and encourage excellence in bookmaking across the greater Washington, D.C. book publishing community. The competition's judges evaluate the excellence of each book's design and effectiveness in achieving the publisher's goals, meeting the readers' needs, and reaching its market. Prizes are awarded in 15 categories -- 5 designs for each of 3 publisher categories -- plus Best of Show.
Dr. Cooper is also the Center Director at the Center of Excellence for Wheelchair and Related Technology, VA Rehabilitation Research & Development Center, and a Senior Research Career Scientist at the VA Rehabilitation Research and Development Service, U.S. Department of Veterans Affairs. In addition, Dr. Cooper holds a secondary appointment as Professor in both the Departments of Orthopaedic Surgery and Mechanical Engineering and Bioengineering.
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| Authors: | Antaki JF, Ricci MR, Verkaik JE, Snyder ST, Maul TM, Kim J, Paden DB, Kameneva MV, Paden BE, Wearden PD, Borovetz HS |
| Title: | PediaFlow Maglev Ventricular Assist Device: A Prescriptive Design Approach |
| Summary: | This report describes a multi-disciplinary program to develop a pediatric blood pump, motivated by the critical need to treat infants and young children with congenital and acquired heart diseases. The unique challenges of this patient population require a device with exceptional biocompatibility, miniaturized for implantation up to 6 months. This program implemented a collaborative, prescriptive design process, whereby mathematical models of the governing physics were coupled with numerical optimization to achieve a favorable compromise among several competing design objectives. Computational simulations of fluid dynamics, electromagnetics, and rotordynamics were performed in two stages: first using reduced-order formulations to permit rapid optimization of the key design parameters; followed by rigorous CFD and FEA simulations for calibration, validation, and detailed optimization. Over 20 design configurations were initially considered, leading to three pump topologies, judged on the basis of a multi-component analysis including criteria for anatomic fit, performance, biocompatibility, reliability, and manufacturability. This led to fabrication of a mixed-flow magnetically levitated pump, the PF3, having a displaced volume of 16.6 cc, approximating the size of a AA battery and producing a flow capacity of 0.3-1.5 L/min. Initial in vivo evaluation demonstrated excellent hemocompatibility after 72 days of implantation in an ovine. In summary, combination of prescriptive and heuristic design principles have proven effective in developing a miniature magnetically levitated blood pump with excellent performance and biocompatibility, suitable for integration into chronic circulatory support system for infants and young children; aiming for a clinical trial within 3 years. |
| Source: | Cardiovascular Engineering. 2010 Mar 1;1(1):104-121 |
| PI | Eric Lagasse |
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| Title | Cancer Stem Cells from HBV-Associated Hepatocellular Carcinoma |
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| Co-Investigators | Stephen Strom, David Geller | |
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| Source | Vertex Pharmaceuticals, Inc. |
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| Term | 05/01/10 – 04/30/12 |
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| Amount: | $655,629 |
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