Skip to Navigation
University of Pittsburgh
Print This Page Print this pages

April 14, 2011

Research Notes

Pharmacy publications, grants announced

The School of Pharmacy recently announced the following publications and research grants:

• Wen Xie, a faculty member in pharmaceutical sciences and pharmacology, was awarded a $416,625 grant from the National Institutes of Health to study the regulation of human hydroxysteroid sulfotransferase, a Phase II drug-metabolizing enzyme, by the retinoid-related orphan receptors.

• Song Li, a faculty member in pharmaceutical sciences, was awarded $362,464 from the National Institutes of Health for a two-year study to develop a novel therapy for the management of advanced prostate cancer.

• Kim Coley, a faculty member in pharmacy and therapeutics, was awarded an $85,625 grant from Takeda Pharmaceuticals America for a study that aims to help health care providers decide the appropriate care and treatment for western Pennsylvanians with gout.

• Graduate student Mark Donnelly received the Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellows for his grant “Role of 20-HETE and EETs in Cerebrovascular Complications After Aneurysmal Subarachnoid Hemorrhage.” The research was funded by a $29,192 grant from the National Institutes of Health.

• Fourth-year pharmacy student Eric Gardner co-authored the first guideline put forth by the Clinical Pharmacogenetics Implementation Consortium of the NIH’s Pharmacogenomics Research Network.

His article, “Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing,” was published in the March issue of Clinical Pharmacology and Therapeutics.

UPB faculty study PA wine industry

Pitt-Bradford faculty members James Dombrosky of hospitality management and Shailendra Gajanan of economics have received a $47,400 grant from the Center for Rural Pennsylvania to study the Pennsylvania wine industry. For Dombrosky, the proposal is an extension of the doctoral thesis he is writing: “Distribution of Pennsylvania Wine Through Restaurants: Barriers and Opportunities,”  but to determine the industry’s current capacity and growth potential, Dombrosky turned to Gajanan.

The project will analyze Pennsylvania’s wine industry, identify growth strategies and make policy recommendations to the state government.

Dombrosky’s research will involve conducting one-on-one and focus-group interviews with industry experts, winery operators, grape growers and other stakeholders.

“Winemaking is a big industry in Pennsylvania,” said Gajanan, noting that the state ranks seventh nationally in wine production. “The question is, can it get bigger and can the government do something to help it get bigger?”

As part of the study, the faculty members will compare practices and results in Pennsylvania with those in New York, Ohio, Maryland, New Jersey, Virginia, Texas, Arizona and Colorado.

Gajanan will look at existing data that can inform policy on production and expansion. “Are Pennsylvania wineries efficient right now?” he asked. “Is it possible for them to increase production without incurring too much additional cost? Right now nobody knows if there are advantages to greater production.”

Team studies how toxoplasma infects

Researchers from Pitt and Stanford have discovered that a supposedly inactive protein actually plays a crucial role in the ability of one of the world’s most prolific pathogens to cause disease. These findings suggest the possible role of similarly errant proteins in other diseases.

The team reports in the Proceedings of the National Academy of Sciences (PNAS) that Toxoplasma gondii, the parasitic protozoa behind toxoplasmosis, attacks healthy cells by injecting them first with pseudokinases, which are enzymes that have abandoned their original function of transferring phosphates.

When the researchers engineered strains of T. gondii without a particular pseudokinase gene cluster called ROP5, the pathogen subsequently was unable to cause disease in mice — a notable loss of potency in an organism that can infect nearly any warm-blooded animal.

These results are among the first to implicate pseudokinases as indispensable actors in pathogen-based disease, said senior author Jon Boyle, a faculty member in the Department of Biological Sciences.

Boyle co-authored the paper with John Boothroyd of Stanford School of Medicine, and researchers from Boothroyd’s lab.

The Pitt-Stanford project suggests that the significance of these aimless enzymes to T. gondii could apply to pseudokinases in other pathogens, Boyle said, including the parasite’s close relative plasmodium, which causes malaria.

“Our work shows that just because these proteins have lost their original function does not mean they don’t do anything,” Boyle said. “T. gondii cannot cause disease without them, and if one is trying to understand how pathogens work, the role of these proteins should obviously be considered.”

Once T. gondii injects ROP5 into the host cell, the parasite enters the cell and forms a protective membrane pocket, or vacuole, around itself to which ROP5 and other proteins attach. While the other secreted kinases are known to help disable or disrupt activity in the host cell, the ROP5 cluster, a kind of infectious ringleader, appeared to have a more dominant role in causing severe disease in mice than other virulence factors, Boyle said.

In the PNAS paper, the researchers suggested that ROP5 has undergone multiple rounds of gene duplication followed by mutation of the individual copies. Thus, the authors proposed, the ROP5 cluster may act like a genetic Swiss army knife, a multipurpose tool that allows T. gondii to adapt to and infect its famously wide variety of hosts.

Cancer research presented

University of Pittsburgh Cancer Institute (UPCI) and Pitt School of Medicine researchers presented more than 80 posters, talks and tutorials, led educational sessions and chaired panel discussions during the annual meeting of the American Association for Cancer Research last week.

Their presentations included:

Mechanisms of complications of multiple myeloma treatments

Suzanne Lentzsch, a faculty member in medicine and clinical director of the multiple myeloma program at UPCI, discussed her research that shows how immunomodulatory derivatives of thalidomide, such as lenalidomide and pomalidomide, used in multiple myeloma treatment, also affect blood cell production pathways by decreasing production of a key protein needed for blood cell specialization.

“That leads to treatment complications including a reduction in the numbers of neutrophils, a kind of white blood cell, and an increase in a protein that promotes platelet clumping that in turn increases the risk for blood clots,” Lentzsch explained.

Inflammatory mediator drives suppressor cells that cause immune system dysfunction in cancer

Postdoctoral fellow Natasa Obermajer presented a project conducted in the lab of senior investigator Pawel Kalinski, a faculty member in surgery and UPCI researcher, that shows a single cancer-associated inflammatory mediator called prostaglandin E2 (PGE2) drives the differentiation and stability of myeloid-derived suppressor cells that play a key role in causing immune system dysfunction and a microenvironment that allows cancer cells to thrive.

Kalinski said, “Our findings suggest that a positive feedback loop exists between PGE2 and COX-2, which regulates PGE2 production. When we disrupted this feedback loop in suppressor cells taken from cancer patients by blocking COX-2 or PGE2 signaling receptors, we stopped the cells’ ability to suppress cancer-killing immune cells. This might be a new avenue to explore for future cancer treatments.”

Cancer vaccines targeting pre-malignant lesions

Olivera Finn, chair of the Department of Immunology, presented her work in developing vaccines that target abnormal peptides, or small pieces of protein, that are produced during the development of certain cancers. Tumor formation might be prevented with a vaccine that generates an immune response against the cells that carry these peptides.

“Vaccines that are administered as a possible treatment after cancer has already developed have not been very effective,” she noted. “But if we can help the immune system find these dangerous cells in people who are at high risk for cancer but are still healthy, we might have an intervention that could prevent many cases of disease.”

Donor care saves organs for transplant

More than twice as many lungs and nearly 50 percent more kidneys could be recovered for transplant operations if intensive care physicians were to work with organ procurement organization (OPO) coordinators to monitor and manage donor bodies after brain death has occurred, according to an analysis by UPMC and School of Medicine physicians in the online version of the American Journal of Transplantation.

After a patient who has consented to be an organ donor is declared brain-dead, an OPO coordinator takes over medical management and intensive care unit (ICU) physicians typically are no longer involved, explained lead author Kai Singbartl, a faculty member in critical care medicine and a UPMC intensivist. The OPO coordinators follow established protocols to maintain tissues and organs for eventual transplant.

In 2008, UPMC Presbyterian implemented an intensivist-led organ donor support team (ODST) approach in which, after a potential organ donor was declared brain-dead, one of six dedicated intensivists, who did not provide care for the donor prior to death, joined the OPO coordinator at the bedside. Standard protocols were supported by physician interventions, such as adjustments to optimize oxygenation and balance blood pressure and flow, fluids and other bodily functions to optimize the likelihood of sustaining as many organs as possible for transplant.

Singbartl said, “The number of donors in our study is not large enough to determine whether a particular medical intervention played a key role, but it’s very clear from our experience that this team approach did make a difference.”

Data from adult brain-dead donors between July 1, 2008, and June 30, 2009, were compared to prior-year data. In the time period prior to the use of the ODST approach, 31 percent or 66 out of 210 potentially available organs were transplanted. In the ODST period, 44 percent or 113 out of 258 potentially available organs were transplanted.

Most of the increase after implementation of the ODST approach was due to a more than 200 percent increase in transplanted lungs and a nearly 50 percent increase in transplanted kidneys. Heart and liver transplant rates did not change significantly.

“Conversion of medically unsuitable donors into actual donors, better resuscitation of unstable donors, optimization of organ function and improved communication between OPO staff, ICU team and transplant surgeons” or the combination of these factors likely contributed to success and should be further evaluated, the researchers said.

Co-authors included Raghavan Murugan, A. Murat Kaynar, David W. Crippen, Richard L. Simmons and Joseph M. Darby, all of the departments of critical care medicine and surgery, and nurses Kurt Shutterly and Susan A. Stuart of the Center for Organ Recovery and Education.

Depression, suicidality higher among gay teens

A School of Medicine study reported online in the Journal of Adolescent Health found that gay and lesbian teens reported higher rates of suicidality and depression than did heterosexual youth.

Lead author Michael P. Marshal, a faculty member in psychiatry and pediatrics, said, “We combined the results of 18 studies involving more than 100 different comparisons and over 100,000 teenage participants.

“Overall, gay teens were almost three times more likely to report a history of suicidality.”

According to the Centers for Disease Control and Prevention, suicide is the third-leading cause of death among adolescents and young adults in the United States, with the rate of suicide attempts during the lifetime of this population ranging from 1 to 10 percent. Teen suicide results in approximately 4,500 lives lost each year. The overwhelming majority of teens who make suicide attempts demonstrate mood psychopathology, with depression being the most prevalent disorder.

This study found that, on average, 28 percent of gay teens reported a history of suicidality compared to 12 percent of heterosexual teens. The studies also showed that even after controlling for variables such as depression, low self-esteem, substance use and conflict with family, gay and lesbian youth remained more than twice as likely to report a history of suicidality as heterosexual youth.

“These results suggest that it is extremely important that health professionals create a clinical environment that makes it easy for gay and lesbian youth to discuss their sexual orientation with their doctors,” said Marshal.

“Doctors and clinics need to emphasize their privacy policies and assure teens that they will not discuss their sexual orientation with parents or caregivers. It also is critical that primary care physicians are trained to screen youth for suicidal thoughts and behaviors and be prepared to help them seek the appropriate treatment services.”

Marshal and his colleagues now are trying to understand why being  a member of a sexual minority puts a teen at increased risk for suicidal thoughts and behavior so that the proper interventions can be provided.

Co-authors included Laura J. Dietz, David A. Brent and Helen A. Smith of the School of Medicine and Mark S. Friedman and Ron Stall of the Graduate School of Public Health.

Cocaine affects cognition

Cocaine use directly contributes to the development of cognitive deficits such as impairments of visual working memory and difficulty adapting to rule changes in reward tasks, according to a report by School of Medicine researchers published in the March 30 issue of The Journal of Neuroscience.

A wide range of cognitive difficulties are seen among cocaine users, but it hasn’t been clear whether that reflects pre-existing traits that made them more susceptible to drug abuse or to the drug itself, said senior investigator Charles W. Bradberry, a faculty member in psychiatry and neuroscience.

“It’s well known that the level of cognitive deficit can predict how successful treatment is likely to be,” he said. “If we understand what the problems are and whether the drug itself was the cause, then we might be able to design treatments that have a better chance of working.”

Researchers assessed cognitive skills in 14 rhesus monkeys that learned to touch an abstract shape on a touch screen to receive either a sip of water or a cocaine infusion via a special access port into a blood vessel. Within a week, the cocaine group was regularly self-administering the maximum of six doses daily from Tuesdays to Fridays.

On Mondays, after three days without receiving drugs, the monkeys’ associative learning skills were assessed. Each animal was presented with two consistent stimuli on the touch screen with a correct answer recorded for touching the one associated with a higher volume of water reward. But once a threshold number of correct answers was achieved, the rules were reversed.

The researchers found that the cocaine group learned the initial rules as quickly and at first responded as accurately as the water-only group, but only five of the eight achieved the threshold of correct responses. The researchers then increased the difference between high and low rewards, which allowed the remaining three monkeys in the cocaine group to get to the threshold.

“That tells us the cocaine users have a hard time maintaining focus and attention,” Bradberry said. “But if we increase the reward value of these things they’re trying to learn, we can overcome that cognitive deficit.”

He added that once the stimuli were reversed, the cocaine group had much greater difficulty learning and adapting to the change in rules, indicating a deficit in cognitive control processes or executive brain functions that require focus and guide volitional, goal-directed behavior.

In another task, the animals saw a single image that when touched resulted in a supplemental water reward. Then they were shown the same image along with a random one, and if they chose the correct one after a delay of up to 40 seconds they got the reward. The cocaine group’s performance was less accurate as the delay increased.

“This experiment reveals that cocaine use causes impairments of visual working memory,” Bradberry said. “This could reflect problems with attention in addition to the impairment in cognitive control.”

Co-authors included psychiatry faculty member Hank P. Jedema, doctoral candidate Jessica N. Porter and Bradberry lab members Kate Gurnsey and Brian P. Dugan.

The study was funded by the National Institute on Drug Abuse and the Veterans Affairs Medical Research Service.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

We welcome submissions from all areas of the University. Submit information via email to:, by fax to 412/624-4579 or by campus mail to 308 Bellefield Hall.

For submission guidelines, visit

Leave a Reply