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July 12, 2007

RESEARCH NOTES

Colonial film archive funded

Distinguished Professor of English Colin MacCabe has been awarded nearly $1 million by the Arts and Humanities Research Council for his research project, “Colonial Film: Moving Images of the British Empire.”

The project will digitize colonial film archives in order to make the films available to scholars, researchers and the public via a web site.

The award also will fund the production of a new catalog of colonial films for the National Film and Television Archive at the British Film Institute and a new film catalog at the British Empire and Commonwealth Museum. It also will enhance the existing catalog of colonial films at the Imperial War Museum.

The two new catalogs will be valuable to historians seeking to understand the interplay of political control and cultural representation in the late colonial period and to film studies scholars seeking to understand the ways cinema has been used as part of projects of governance.

The online accessibility of this material will create the potential for a global exchange among researchers of the Empire and post-colonialism, and will “return” some of the material to the countries of origin.

The material will be used as the basis for major international conferences in London and Pittsburgh and for two essay collections.

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Pitt No. 1 in AHA funding

For the first time, Pitt ranked first among U.S. academic medical centers and hospitals for heart disease and stroke research funding from the American Heart Association. The total amount of AHA funding for 2006 was more than $8.9 million.

Barry London, chief of cardiology and director of the UPMC Cardiovascular Institute, and his team of cardiologists and scientists are principal investigators on more than 20 grants from both the AHA and the National Institutes of Health, in addition to dozens of other clinical and translational trials funded by other foundations and industry.

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Prof co-authors public health report

Joseph J. Schwerha, professor in the Graduate School of Public Health’s Department of Environmental and Occupational Health, is the co-author of “Training Physicians for Public Health Careers,” a recent report issued by the Institute of Medicine. Schwerha also is director of the occupational and environmental medicine residency and the public health preparedness and disaster response certificate program at Pitt.

Out of concern about a lack of well-trained physicians, the U.S. Congress mandated the study to determine what knowledge and skills are needed by public health physicians, how many programs are needed to maintain an adequate supply of physicians trained for public health careers and how these programs can be funded.

New public health challenges including the increasing burden of chronic diseases, persistent and emerging infectious diseases, and disaster response, require the medical and public health communities to work together, the report found. In addition, increasing understanding of the multiple factors that affect health shows that physicians need to be aware of biological risk factors as well as the behavioral and environmental factors that can affect health in order to tailor interventions for individual treatment.

Training physicians in population-based medicine as well as clinical medicine holds promise for improving the quality and effectiveness of clinical practice. But, the committee found, integrating these content areas into an already crowded medical school curriculum will require the development of creative approaches to curriculum development and teaching in addition to a cadre of faculty with the requisite knowledge.

The report is available online at http://books.nap.edu/catalog.php?record_id=11915.

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Tissue engineering research presented

School of Medicine researchers presented findings from a number of research studies at the recent Tissue Engineering and Regenerative Medicine International Society North American chapter meeting.

Highlights included:

*Grow your own vascular grafts?

Researchers led by David A. Vorp, associate professor of surgery and bioengineering and a faculty member of the McGowan Institute for Regenerative Medicine, have developed a vascular graft by “bulk seeding,” or spraying, muscle-derived stem cells (MDSCs) inside a biodegradable porous, tubular polyester urethane scaffold.

After culturing their vascular constructs, the investigators implanted them in the abdominal aortas of rats eight weeks before performing tests to determine how well the grafts had performed. The cell-seeded constructs showed a significantly higher blockage-free rate than unseeded controls. In addition, at eight weeks, there was an extensive remodeling of the MDSC-seeded polymer by surrounding tissue, exhibiting tissue formation that is consistent with a mature artery.

According to Vorp, these findings demonstrate the feasibility of developing MDSC-seeded tissue-engineered vascular grafts for eventual human application. “The next step is to demonstrate the use of the tissue-engineered blood vessel in a larger animal model, such as a pig, which has a coagulation system more similar to that in humans,” he said.

The saphenous vein taken from a patient’s leg continues to be the most commonly used graft for coronary artery bypass grafting even though a significant percentage of vein grafts eventually fail. Arterial grafts are the preferred conduits because they are less prone to becoming obstructed. However, they are in very limited supply, as many patients require multiple grafts. Thus, there is an ongoing search for the ideal small-caliber arterial substitute for revascularization procedures.

“The advantage of our approach is that the graft could utilize the patient’s own stem cells and be ready for implantation almost immediately or, at most, after a relatively short culture period. This suggests that we could make these available ‘off-the-shelf,’ which is an essential element for clinical translation,” Vorp said.

Other members of the Pitt team were Alejandro Nieponice, Lorenzo Soletti, Timothy M. Maul, Burhan Gharaibeh, Bridget M. Deasy, Jianjun Guan, Johnny Huard and William R. Wagner, all of the surgery, bioengineering and orthopaedic surgery departments.

*Cancer stem cells resist treatment

Current cancer therapies often initially succeed at eliminating the bulk of the disease but eventually are thwarted because they cannot eliminate a small reservoir of multiple-drug-resistant tumor cells, called cancer stem cells, which ultimately become the source of disease recurrence and eventual metastasis. Now, School of Medicine researchers suggest that for chemotherapy to be effective in treating lung cancers, for example, it must be able to target a small subset of cancer stem cells, which they have shown share the same protective mechanisms as normal lung stem cells.

The researchers, led by Vera Donnenberg, assistant professor of surgery and pharmaceutical sciences in the medical and pharmacy schools, identified a very small, rare set of resting cancer stem cells in lung cancer samples that looked and behaved much like normal adult lung tissue stem cells. Both the cancer and normal stem cells were protected equally by multiple drug resistance transporters, even if the bulk of the tumor responded to chemotherapy.

“Because of the similarities between the way that normal stem cells and cancer stem cells protect themselves, cancer therapies have to be designed specifically to target cancer stem cells while sparing normal stem cells,” she said.

Other Pitt researchers involved in this study were Rodney J. Landreneau of the Department of Surgery and Albert D. Donnenberg of the Department of Medicine.

*Fat cells may restore bone marrow

Pitt researchers have isolated and cultured human hematopoietic stem cells from adipose tissue (fat), suggesting that they have found another important source of cells for reconstituting the bone marrow of patients undergoing intensive radiation therapy for blood cancers.

Adipose tissue has the ability to expand or contract in accordance with nutritional constraints. To do so, it requires rapid adjustment in its blood supply and supporting connective tissue, or stroma.

Based on previous reports that the “stromal vascular” fraction of adipose tissue contains stem cells that give rise to pericytes — cells surrounding small blood vessels — the researchers, led by Albert D. Donnenberg, professor and director of the Hematopoietic Stem Cell Laboratory, University of Pittsburgh Cancer Institute, isolated and grew the stromal vascular fraction from human adipose tissue.

In examining the cells, they detected a broad spectrum of blood-forming, or hematopoietic, cells among the cultured cells at varying stages of differentiation.

“We took cells from the stromal vascular fraction of normal adipose tissue and basically gave them bone marrow food to see what would happen. We were able to culture a variety of hematopoietic cells, including blood progenitor cells,” Donnenberg said.

He noted that the use of a patient’s own bone marrow or blood-derived stem cells for bone marrow reconstitution carries some risk that these cells are contaminated with the patient’s own tumor cells. “Since it has been shown in some cases that tumor cells contaminating bone marrow grafts are the source of recurrent malignancies after autologous transplantation, this might be a way of giving patients who need bone marrow reconstitution their own hematopoietic cells derived from a source other than their defective bone marrow,” he explained.

Other Pitt people involved in the study were J. Peter Rubin, Vera Donnenberg, Kacey Marra and Bret Schipper.

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Site-specific drug delivery studied

Song Li, associate professor of pharmaceutical sciences, received $445,500 from the National Institutes of Health for “Nanosized Delivery System for Site-Specific Drug Release,” which could lead to the development of novel liposomal drugs that will advance cancer treatments.

Liposomal drugs improve the outcome of treatment mainly through increasing the amount of drugs accumulated at tumor sites and through decreasing the systemic toxicity that is associated with free drugs.

Li’s studies propose to further improve current liposomal vectors to facilitate the drug release selectively at the tumor site, improving the bio-availability of chemotherapeutic drugs and further enhancing anti-tumor activity.

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Evolution of 1998 Rome Treaty to be studied

Assistant professor Charli Carpenter of the Graduate School of Public and International Affairs has been awarded $67,463 by the National Science Foundation to study developments in the definition of crimes against humanity.

Her project, “Defining ‘Crimes Against Humanity’ in International Law” will focus on the 1998 Rome Treaty establishing the International Criminal Court (ICC) and investigate how language on gender-based crimes made it into the document. New legal concepts like “sexual slavery” and “forced pregnancy” were codified for the first time in 1998, but only after heated negotiations between competing transnational advocacy groups.

Carpenter plans to interview activists from both progressive and conservative delegations who participated in the Rome conference and those now involved with the ICC in order to better understand that process and the legal outcome. She will speak with officials at the International Criminal Court and activists in The Netherlands at the Hague-based Women’s Initiative for Gender Justice and will conduct additional interviews at the Holy See in Rome.

According to Carpenter, much can be learned about global civil society by reconstructing significant political debates over complex and controversial issues such as these, to understand the politics of international humanitarian law treaty making.

“The idea of the project is to track down and interview activists who were involved in getting language on sexual slavery, forced pregnancy and other gender crimes into this treaty,” Carpenter said. “I want to analyze the political dynamics of the negotiating process itself.”

The NSF’s Law and Social Sciences Division funded the research.

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Diabetes research presented

Researchers from the University of Pittsburgh Diabetes Institute (UPDI) and the Graduate School of Public Health (GSPH) were among the presenters discussing their research at the annual meeting of the American Diabetes Association June 22-26.

Highlights included:

*Healthy lifestyle offers sustainable results

UPDI researchers have found that long-term positive results can be sustained through a healthy lifestyle intervention focused on healthy eating and physical activity in urban residents at risk for diabetes and heart disease.

Study co-author Mim Seidel, a diabetes program manager for UPDI, said, “Previous research has demonstrated that people in underserved urban communities have a higher risk of developing type 2 diabetes, but lifestyle interventions could help prevent diabetes and heart disease. However, there is very little research on the sustainability of improvements following lifestyle interventions designed to prevent diabetes and heart disease in these community settings. Therefore, we implemented a modified diabetes prevention program in an urban, underserved suburb of Pittsburgh to determine not only if the program was successful initially, but whether or not the improvements could be sustained in the long term.”

The Diabetes Prevention Program (DPP) demonstrated a 58 percent reduction in the incidence of type 2 diabetes through intensive lifestyle intervention in people at risk for diabetes.

The program focuses on losing weight, healthy eating and reducing the patient’s risk of diabetes and heart disease. For this particular report, researchers focused on 83 participants enrolled in a modified version of the DPP at UPMC Braddock. Most participants were female and a quarter were African American. Participants were invited to be reassessed every three months following completion of the 12-week intervention.

After the end of the DPP, 45.9 percent of the participants lost at least 5 percent of their initial body weight. The weight loss was sustained in nearly one-half of the participants at their six-month reassessment and in one-third at their one-year reassessment.

“These results are impressive because this study is one of the few in the United States that demonstrated that improvements observed following a lifestyle intervention in a community-based setting can be sustained in the long-term,” said co-author Gretchen Piatt of UPDI.

Robert Powell of UPMC Braddock also was among the study authors.

*Is fat a plus for type 1 diabetics’ arteries?

Researchers in Pitt’s Schools of the Health Sciences have found that more fat may have some advantages for people who have type 1 diabetes. Cardiovascular complications, including heart disease, are a leading cause of death for people with diabetes, who tend to suffer cardiovascular disease decades earlier than non-diabetics.

“Gaining weight may reflect good or better treatment with insulin therapy, which may partly explain why participants who gained weight over time had lower mortality rates,” said Trevor Orchard, a professor of epidemiology at GSPH.

Orchard and his colleagues were studying links between an early sign of heart disease called coronary artery calcification and body fat. They focused on 315 patients with type 1 diabetes participating in the Pittsburgh Epidemiology of Diabetes Complications Study, an 18-year prospective study of childhood-onset type 1 diabetes, which began in 1986. As part of the study, the patients recently received a computed tomography scan (CT) to assess coronary artery calcification. They also were evaluated for fat underneath the skin and in the abdominal region, body mass index (BMI) and waist circumference.

Although investigators noted a positive association for all measures of fatness and having any coronary artery calcification, in the two-thirds of patients who had calcification the relationship reversed so that people with more fat had less severe calcification.

This association also varied by gender. Women with less fat under the skin had more evidence of coronary artery calcification than those with more fat. Thinner men also had more evidence of coronary artery calcification than men with a higher BMI.

Baqiyyah Conway, lead author of the abstract, said these associations of less severe artery calcification with greater fat persisted even when controlling for standard cardiovascular disease risk factors such as increased levels of LDL, or bad cholesterol, triglycerides, high blood pressure and lower levels of HDL, or good cholesterol. Controlling for kidney disease, another common complication of diabetes, weakened the association in men but not in women.

Orchard, who also is professor of medicine and pediatrics in the School of Medicine, noted, “This does raise the possibility that weight recommendations in type 1 diabetes may be somewhat different than those for the general population, and emphasizes the complex relationship between body fat and cardiovascular risk in diabetes.”

Other Pitt authors were Rachel G. Miller and Tina Costacou of GSPH and Daniel Edmundowicz of the Division of Cardiology in the School of Medicine.

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Arthritis drug may prevent diabetes

According to a Pitt-led study, far fewer rheumatoid arthritis patients treated with the drug hydroxychloroquine (HCQ) went on to develop diabetes compared to those who never took the drug. In addition, those using HCQ who did develop diabetes were less likely to take medications to manage their disease after diagnosis.

The findings, from a study led by School of Medicine researchers, were reported July 10 in the Journal of the American Medical Association.

The multi-center study of 4,905 adults with rheumatoid arthritis over more than 20 years found that relative risk progressively declined by as much as 77 percent after four years of treatment with HCQ, a common anti-malarial medication that also is used for rheumatoid arthritis and other auto-immune disorders.

Additional participating centers in the study were Stanford University, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the University of Cincinnati.

Mary Chester Wasko, associate professor in the School of Medicine, said, “This reduction in risk persisted even after adjusting for other diabetes risk factors among these patients, such as body mass index, degree of disability and use of corticosteroids.”

An important limitation of the study, however, is that investigators used self-reported information from patients collected in followups twice yearly that did not include confirmation by laboratory tests.

Because people with rheumatoid arthritis tend to be less active and take corticosteroids that can cause weight gain, they often are considered to be at higher risk for developing diabetes. Other studies of the blood sugar-lowering effects of HCQ have shown minimal use for the drug as a treatment for people with established diabetes, Wasko said, stressing the treatment’s real promise may be in prevention.

Results show that HCQ’s association with reduction in diabetes risk is comparable or superior to that of a number of other drugs studied in clinical trials for diabetes prevention and treatment, including rosiglitazone, hormones, metformin, acarbose and ramipril.

Jennifer R. Elliott of the School of Medicine was among other co-authors of the study.

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