University Times

Artificial heart valve paper voted in top 5 at conference

Research authored by Pitt bioengineering professor Michael Sacks on a new way of making artificial heart valves with properties similar to natural heart tissue was voted one of the “Top 5 Hot Talks” at the fall meeting of the Materials Research Society.

The paper, “Analysis and Design of Novel Electrospun PEUU Scaffolds for Soft Tissue Engineering,” discussed how variations in mandrel speed affected the fiber orientation in electrospun poly (ester urethane) urea (PEUU) scaffolds.

Sacks’ research found PEUU scaffolds showed increasingly higher orientation with increasing mandrel speeds. High RPM specimens were found to have properties that resemble natural heart valves, making them potentially valuable in soft tissue engineering applications.

More than 5,000 scientists from around the world presented papers on innovations in materials research at the meeting, held Nov. 28-Dec. 2 in Boston. The top five talks were selected by a committee of technical and non-technical judges, based on their relevance to changing the world.

Other authors are Todd Courtney, John Stankus, Jinjuan Guan and William R. Wagner.

************************

Data show medication good for heart, wallet

A follow-up to the African-American Heart Failure Trial (A-HeFT) has found the use of medication containing isosorbide dinitrate and hydralazine (ISDN/HYD) is good for the wallet as well as the heart.

Researchers led by School of Medicine professor of critical care medicine Derek Angus examined A-HeFT data to determine the trial participants’ ongoing health care costs. A-HeFT, the results of which were published November 2004 in the New England Journal of Medicine, compared outcomes in heart patients who, along with their regular therapy, took a medication with ISDN/HYD to patients receiving a placebo regimen in addition to their regular therapy. The trial demonstrated the effectiveness of ISDN/HYD for treating heart failure in African-American patients.

The new analysis found total health care costs for the A-HeFT participants who were treated with ISDN/HYD were 22 percent lower. Their total health care costs — those resulting from hospitalizations, doctor visits for any conditions or illnesses, but not including the cost of the drug itself — averaged $15,384 over the course of the 12-month trial. Those who did not receive the drug averaged $19,728. Health care costs specifically related to heart failure were almost 34 percent lower on average, $5,997 versus $9,144. When the cost of the drug was factored in, there was still an average savings of 6 percent, or $533, on heart failure-related costs for ISDN/HYD patients compared to those who didn’t receive the drug, and a 9 percent, or $1,730, average savings on total health care costs.

“This medication clearly decreased health care costs for A-HeFT participants during the course of the clinical trial, even when the cost of the drug itself was taken into account,” Angus said. “Based on the savings we’ve seen for one year and our modeling that projects future health care cost expenditures, it’s likely that the cost-effectiveness of this drug will bear out in the long term as well.”

Angus and his colleagues developed a model to predict costs over the course of the patient’s lifespan beyond the 12-month trial period. Even under the most pessimistic assumption — that, over time, the drug would no longer provide therapeutic benefits — the model predicted that for 95 percent of patients, health care costs would still amount to less than what is considered to be a reasonable threshold for cost-effectiveness.

“The key will be appropriate patient selection and careful attention to compliance with treatment. Our findings apply to the types of individuals, African Americans with moderate to severe heart failure, who were enrolled in A-HeFT. We do not know whether similar benefits would be found in other groups of patients.”

The cost analysis incorporated actual data, such as frequency and length of hospitalization, office and emergency room visits and physician services during the 12-month clinical trial, and projections for the long-term model. Medicare guidelines were used to estimate and calculate costs. “Because we relied on the actual data regarding health care resource use, our primary findings are likely to be very robust, as robust as the overall clinical trial results from A-HeFT,” said Angus.

A-HeFT involved 1,050 African-American patients at 11 sites with New York Heart Association Class III or Class IV failure, which is defined as moderate to severe heart failure resulting in significant limitations to physical activity. The patients were followed for an average of 12.8 months, and the study ended prematurely when a preliminary analysis showed that patients treated with ISDN/HYD had a significantly lower mortality — 6.2 percent compared to 10.2 percent. Last June, the drug won approval by the U.S. Food and Drug Administration for the treatment of heart failure in African-American patients and is now being marketed as BiDil by NitroMed, Inc.

The study was funded by NitroMed, which also sponsored the African-American Heart Failure Clinical Trial.

************************

Prof receives grant for groundwater & earth structure imaging

William Harbert was awarded $227,404 from the National Energy Technology Laboratory of the U.S. Department of Energy for research in environmental geophysics. This one-year award is focused in the application of geophysics on towards groundwater and earth structure imaging.

Associate professor Harbert, his colleagues at DOE and two Ph.D. students, Brian Lipinski and Vladislav Kaminaki, are researching groundwater imaging using electromagnetic and reflection seismic geophysics.

Harbert also was awarded $36,500 from the DOE’s National Energy Technology Laboratory to support a graduate student. Emmett Rafferty will work as a GIS technologist in support of environmental geophysical research.

************************

Aspirin a cancer-killer?

Low doses of aspirin have been found to ward off Alzheimer’s disease, heart attacks and stroke. Could cancer be added to the list? A study published in the Dec. 9 issue of the Journal of Biological Chemistry indicates that may be the case.

In the study, Pitt researchers found that aspirin, combined with a promising new cancer therapy known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), can induce cancer cells previously resistant to TRAIL therapy to self-destruct. If these findings hold up in larger studies, investigators say, aspirin could become a routine therapy for helping to prevent the recurrence of many aggressive cancers, such as prostate and colon cancers.

“When cancers recur after initial therapy, they tend to be extremely aggressive and patient prognosis is poor,” said Yong J. Lee, professor in the departments of surgery and pharmacology at the School of Medicine and lead author of the study.

“If we could find ways to prevent these secondary cancers from occurring, we could save many lives. Aspirin is a low-cost medicine that, in our studies, appears to have great potential for helping to prevent such cancer recurrences,” Lee said.

TRAIL is a protein that is expressed by cells of the immune system. Numerous studies have shown that TRAIL induces programmed cell death, or apoptosis, in cancer cells while having little or no effect in normal healthy cells.

Unfortunately, studies have found that not all cancers are sensitive to TRAIL. In fact, many tumor cells are completely resistant to TRAIL’s effects, creating an intensive search for compounds that can overcome this resistance.

Based on other studies showing that aspirin can prevent the formation of tumors caused by ultraviolet radiation and carcinogens, Lee and his co-workers decided to test its ability to increase the sensitivity of TRAIL-resistant cancer cells to apoptosis.

To do this, they treated human prostate cancer cells with aspirin and then treated the cells with a combination of TRAIL and/or aspirin. Cancer cells treated with either aspirin or TRAIL alone showed little or no cell death. However, pretreatment of the TRAIL-resistant cancer cells with aspirin promoted cell death when TRAIL was added.

To determine whether TRAIL was indeed inducing apoptosis in the aspirin-sensitized cells or killing the cells through some other mechanism, Lee’s team looked for molecular signs of apoptosis. In the cancer cells pretreated with aspirin followed by TRAIL, there was significant cleavage, or cutting up, of a compound known as poly (ADP-ribose) polymerase, or PARP. PARP cleavage, a hallmark feature of apoptosis, did not occur in normal cells nor in cancer cells treated with aspirin alone.

Interestingly, the investigators discovered that, for PARP cleavage to occur, it was necessary to pretreat cancer cells with aspirin at least 12 hours before the administration of TRAIL.

Lee and his colleagues also found that aspirin treatment causes cancer cells to decrease their production of a cellular protein known as Bcl-2, which has been shown in numerous studies to protect healthy cells from premature apoptosis.

Lee and his colleagues believe these findings could soon be applied in the clinical setting and result in the increased effectiveness of TRAIL for treating a number of aggressive cancers, particularly those that overexpress the human epidermal growth factor receptor 2 (HER-2/neu) gene. This gene is amplified up to 30 percent in some human cancers, which leads to an increase in the expression of the HER-2/neu protein on the cell surface. Numerous studies suggest that a high concentration of the HER-2/neu protein on the surface of cancer cells makes them more aggressive and difficult to treat. In this study, Lee and co-workers demonstrated that the combination of aspirin and TRAIL undercuts the effects of HER-2/neu overexpression.

“HER-2/neu overexpression in cancer cells, such as prostate and colon, is associated with a higher cell proliferation rate, faster metastases and greater tumor burden,” Lee said. “It is our hope that aspirin and other agents we are currently testing can negate this effect and dramatically improve the prognosis of patients with these types of cancer.”

Contributors to this study include Kim M. Kim and Jae J. Song of the School of Medicine, and Jee Young An and Yong Tae Kwon of the Center for Pharmacogenetics in the School of Pharmacy.

The study was supported by grants from the National Cancer Institute, National Institutes of Health, the Elsa U. Pardee Foundation, The Pittsburgh Foundation, the Department of Defense Prostate Program Fund and Department of Defense Prostate Traineeship.

************************

Immune Modeling Center funded

The National Institutes of Health (NIH) has awarded the Pitt School of Medicine a five-year, $9.1 million contract to develop sophisticated mathematical models for investigating how the immune system responds to the pathogens that cause flu, tuberculosis (TB) and tularemia, an infection that some authorities believe could be used as a biological weapon. Such models should help expedite the development of vaccines and therapies against these and other infectious agents and help researchers and public health officials predict or prevent disease outbreaks as well as determine the best courses of treatment.

The contract establishes Pitt as one of four immune modeling centers supported by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID.) The others are Duke University, the University of Rochester and Mount Sinai School of Medicine.

The contract also takes advantage of Pitt’s existing collaborations with Carnegie Mellon University and the University of Michigan.

“This center’s work will draw upon our expertise in mathematical modeling of the immune system as well as our knowledge about immunity to infectious diseases. Working as a team of immunologists, computational biologists, computer scientists and mathematicians, our goal is to capture the complexity of the immune system through mathematics,” said Penelope A. Morel, associate professor of immunology and medicine at the School of Medicine and principal investigator of the Pitt-based Immune Modeling Center. Schlomo Ta’asan of Carnegie Mellon is co-principal investigator of the center.

The Immune Modeling Center will focus on understanding the natural and adaptive immune responses to influenza A virus, Mycobacterium tuberculosis, which causes TB, and Francisella tularensis, the bacterium responsible for tularemia. Since each of these organisms enters the body via the lung, the investigators will study the specific immune cells recruited to the lung and identify the particular genes expressed and the molecules produced in response to infection. A combination of mathematical and animal models will be employed to test different vaccine and therapeutic strategies, including a novel approach that aims to enhance immune response through certain proteins called cytokines.

“Mathematical modeling has tremendous potential to help improve the safety and efficacy of vaccines as well as to facilitate prediction of outcomes and prevention and treatment of emerging and re-emerging infectious diseases. One of the advantages of generating a computerized mathematical system that mimics how our immune system responds to specific pathogens is its use for conducting meaningful studies with minimal use of the infectious agents themselves,” Morel said.

Studies focused on developing models of the immune response to TB will be headed by JoAnne L. Flynn, Department of Molecular Genetics and Biochemistry in the School of Medicine and Denise Kirschner, a mathematician in the Department of Microbiology and Immunology at the University of Michigan. Gerard J. Nau, also of the School of Medicine’s Department of Molecular Genetics and Biochemistry, will lead the project modeling the immune response to tularemia. Modeling of flu virus infection and immunity will be undertaken by Ted M. Ross of the Division of Infectious Diseases in the School of Medicine’s Department of Medicine and Ta’asan of CMU.

Morel is leading a project focused on modeling the innate immunity of the lung, which also includes from the School of Medicine: Nau; Russell Salter, Department of Immunology; and Takis Benos, Department of Computational Biology.

The Immune Modeling Center contract includes a bioinformatics component for managing the data generated by each project and developing a web-based collaboration platform that will allow investigators from other institutions to access data and use the models developed over the next five years. Leading this effort are Panos K. Chrysanthis and Alexandros Labrinidis, both of the Department of Computer Science.

Ta’asan, Kirschner and Morel will develop an educational program that will focus on the value of using mathematical approaches to the understanding of immunological processes.

************************

Dental informatics on-line group planned

The National Library of Medicine’s (NLM) extramural research funding program will fund the development and implementation of a dental informatics on-line community by the Center for Dental Informatics at Pitt’s School of Dental Medicine. The NLM has been authorized to pay 80 percent of the requested $350,000 in project funds.

Dental informatics, the application of computer and information sciences to improve dental practice, research, education and management, is a new discipline that has complex and multidisciplinary research questions but not enough qualified researchers to address them. The goal is to facilitate the development of research projects and the collaborations that support them.

Principal investigator of the project will be Heiko Spallek, assistant professor in the School of Dental Medicine, who has joint appointments in the Center for Biomedical Informatics and the School of Information Sciences.

His collaborators are from the Katz Graduate School of Business and the Department of Library and Information Science; the University of Michigan; Uppsala University, Sweden, and Harvard Medical School.

“The dental informatics on-line community supports the formation of collaborations by making information about researchers, projects, information resources and opportunities explicit, and by providing mechanisms to inform community members about developments in dental informatics,” said Spallek.

“The philosophy and characteristics of the community make it somewhat different from traditional research communities. It is open and free. Members are not restricted to a specific discipline, association membership, nationality or qualification,” said Titus Schleyer, co-investigator of the project and director of the Center for Dental Informatics.