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December 10, 2009

Research Notes

Transplantation milestone reported

Scientists report in the December issue of the American Journal of Transplantation that they have achieved survival of islet cells and normal glucose regulation without diet restrictions or insulin injections in a diabetic primate for longer than one year.

The findings, involving genetically altered islet cells from donor pigs, are an important step toward the potential clinical application of islet cell xenotransplantation, according to senior author Massimo Trucco, director of the Division of Immunogenetics at Children’s Hospital and Hillman Professor of Pediatric Immunology at the School of Medicine.

In the study, Trucco and colleagues isolated the genetically altered pig pancreas cells and then transplanted them into several monkeys with diabetes by infusion into a large liver vein.

Sufficient numbers of the infused cells survived, resulting in correction of blood glucose levels — without the use of insulin or diet modification — for longer than three months in four out of five subjects. One monkey was followed for more than one year and maintained normal blood sugar levels.

The gene manipulation of the cells transplanted by Trucco’s team also may have influenced the antibody-driven rejection response to foreign cells, which reduced the need for immunosuppression to preserve a sufficient mass of islet cells for glucose control over the long term.

“Until now, long-term survival of transplanted pig islet cells has not been achieved, clinically or in the laboratory, without significant rejection and other issues,” Trucco said. “Now, we have been able to achieve functionality of transplanted cells, and complete reversal of diabetes, for longer than one year in a monkey.”

The islet cells were isolated from genetically altered pigs produced by Revivicor, a regenerative medicine company. The company, of which UPMC is a shareholder, is a long-time collaborator with Trucco.

Islet cells from these pigs contain a gene that produces the human version of a cell surface protein called CD46, which plays a key role in modulating an immunological pathway that leads to immediate rejection of foreign cells.

Human islet cell transplantation has been performed for approximately a decade to treat patients with type 1 diabetes, in which the body’s immune system destroys the insulin-producing beta cells (a type of islet cell) of the pancreas. Patients with type 1 diabetes must take insulin every day to live, and the vast majority of those who have received islet cell transplants have been forced to return to insulin injections because the transplanted cells lose function within months, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

The potential use of donor cells from pigs in human islet cell transplantation also alleviates the problem of lack of pancreases available for transplant, according to Trucco.

Co-authors of the paper included researchers from Erasmus University Medical Center in The Netherlands; Revivicor, and Austin Research Institute in Australia.

The study was funded by the U.S. Department of Defense.

Heat resistant nanomaterial developed

A Pitt team has overcome a major hurdle plaguing the development of nanomaterials such as those that could lead to more efficient catalysts used to produce hydrogen and render car exhaust less toxic.

The researchers reported Nov. 29 in the journal Nature Materials the first demonstration of high-temperature stability in metallic nanoparticles, materials typically hampered by a vulnerability to extreme heat.

Götz Veser, CNG Faculty Fellow of chemical and petroleum engineering in Pitt’s Swanson School of Engineering, and Anmin Cao, the paper’s lead author and a postdoctoral researcher in Veser’s lab, created metal-alloy particles in the range of 4 nanometers that can withstand temperatures of more than 850 degrees Celsius — at least 250 degrees more than typical metallic nanoparticles. Forged from the catalytic metals platinum and rhodium, the highly reactive particles work by dumping their heat-susceptible components as temperatures rise, a quality Cao likened to a gecko shedding its tail in self-defense.

“The natural instability of particles at this scale is an obstacle for many applications, from sensors to fuel production,” Veser said. “The amazing potential of nanoparticles to open up completely new fields and allow for dramatically more efficient processes has been shown in laboratory applications, but very little of it has translated to real life because of such issues as heat sensitivity. For us to reap the benefits of nanoparticles, they must withstand the harsh conditions of actual use.”

Veser and Cao present an original approach to stabilizing metallic catalysts smaller than 5 nanometers. Materials of this size have a higher surface area and permit near-total particle utilization, allowing for more efficient reactions. But they also fuse together at around 600 degrees Celsius — lower than usual reaction temperatures for many catalytic processes — and become too large.

To overcome this, Veser and Cao blended platinum with rhodium, which has a high melting point. They tested the alloy via a methane combustion reaction and found that the composite was not only a highly reactive catalyst, but that the particles maintained an average size of 4.3 nanometers, even during extended exposure to 850-degree heat. And, small amounts of 4-nanometer particles remained after the temperature topped 950 degrees Celsius, although most had become eight times that size.

Veser and Cao were surprised to find that the alloy did not simply endure the heat. Instead it sacrificed the low-tolerance platinum then reconstituted itself as a rhodium-rich catalyst to finish the reaction. At around 700 degrees Celsius, the platinum-rhodium alloy began to melt. The platinum “bled” from the particle and formed larger particles with other errant platinum, leaving the more durable alloyed particles to weather on. Veser and Cao predicted that this self-stabilization would occur for all metal catalysts alloyed with a second, more durable metal.

Their work was conducted with support from the U.S. Department of Energy’s National Energy Technology Laboratory, the DOE’s Office of Basic Energy Sciences and the National Science Foundation.

STI research center set up

Researchers at the School of Medicine have received a $12.5 million grant from the National Institutes of Health to establish the UPMC Sexually Transmitted Infections (STI) Cooperative Research Center.

The center will be led by principal investigator Toni Darville, faculty member in pediatrics and immunology and chief of the Division of Pediatric Infectious Diseases at Children’s Hospital.

Scientists in the center will focus their research on the prevention of female reproductive tract complications caused by sexually transmitted infections. Their research, based in the School of Medicine’s Department of Obstetrics, Gynecology and Reproductive Sciences, Children’s Hospital and the Magee-Womens Research Institute (MWRI), will be funded through a five-year grant from the National Institute of Allergy and Infectious Diseases.

“This center will bring together many promising research initiatives already underway at Children’s Hospital and the Magee-Womens Research Institute and is led by scientists with many years of experience leading basic science and clinical research trials related to sexually transmitted diseases,” said Darville, whose laboratory at Children’s Hospital is recognized internationally for its research related to chlamydia infections.

“Through our collaboration, we hope to speed the development of interventions that will limit or prevent genital tract disease in millions of women worldwide and ultimately limit ectopic pregnancy and protect fertility.”

The research projects will focus on bacterial infections of the female upper genital tract that produce pelvic inflammatory disease. PID is a complication of some sexually transmitted pathogens, including chlamydia and gonorrhea. It can damage the fallopian tubes and tissues in and near the uterus and ovaries, and can lead to infertility, ectopic pregnancy, abscess formation and chronic pelvic pain.

The UPMC STI Cooperative Research Center will consist of four projects:

• Harold Wiesenfeld, director of the Division of Reproductive Infectious Diseases at the School of Medicine and associate investigator at MWRI, will lead a project that seeks to determine the importance of anti-anaerobic therapy in the treatment of women with PID.

• Sharon Hillier, faculty member in obstetrics, gynecology and reproductive sciences, and in microbiology and molecular genetics at the School of Medicine, and director of reproductive infectious disease research at MWRI, will lead a project that seeks to identify novel bacteria that might play a role in the development of PID.

• Darville will lead a project to determine the role of Toll-like receptor 2 signaling in innate and adaptive responses to chlamydiae. Toll-like receptor 2 is a protein important in the innate immune system.

• Thomas Cherpes, faculty member in obstetrics, gynecology and reproductive sciences and MWRI researcher, will lead a project that seeks to identify the specific lymphocyte-mediated immune responses most strongly associated with protection against chlamydia trachomatis infection and containment of the pathogen to the lower genital tract in a cohort of women at high risk for PID.

GSPH center to analyze environmental threats

The Center for Healthy Environments and Communities (CHEC) at the Graduate School of Public Health will conduct an analysis of the major threats to the environment and health of people who live and work in southwestern Pennsylvania. The Pittsburgh Regional Environmental Threat Analysis (PRETA), funded through a $250,000 grant from the Heinz Endowments, will identify these threats throughout the region’s 10 counties.

Conrad D. Volz, faculty member in environmental and occupational health and director of CHEC, is PRETA principal investigator. Volz said:

“Environmental health encompasses all aspects of the natural and built environment that may affect human health. Given southwestern Pennsylvania’s industrial legacy and diverse topography, this kind of analysis is vitally important to the health of residents across the region.”

Study investigators plan to identify and interview key informants from southwestern Pennsylvania about their perspectives of the most important local environmental threats. The data they gather will guide the development of an online survey targeting environmental, regulatory, academic and policy-making organizations in the region. Analyses also will involve scanning and surveying related databases, publications, web sites, newspapers and the monitoring of well-documented regional environmental threats.

Data gathered and analyzed will be compared to current regulatory standards and national norms.

Other CHEC faculty and staff involved in PRETA include Ravi Sharma, faculty member in  behavioral and community health sciences; Charles Christian, director of operations; Andrew Michanowicz, research assistant, and Samantha Malone, communications specialist.

Gene therapy research continues

Dexi Liu of pharmaceutical sciences has received a two-year $485,889 grant from the National Institutes of Health to continue development of an image-guided hydrodynamic gene delivery system for site-specific gene delivery to the liver that someday could be used in humans.

Gene therapy has been studied as an alternative method for treatment of many different diseases, ranging from a single gene defect to complex conditions due to both genetic and environmental factors. However, its potential to provide highly specific, safe and effective treatments can be realized only with development of safe and effective gene delivery system.

Liu’s hydrodynamic gene delivery procedure involves the injection of a relatively large volume of saline containing plasmid DNA. Prior research has demonstrated in rodents that the hydrodynamics-based procedure is superior in gene delivery to liver cells.

More recent work, using pigs, also has demonstrated that image-guided hydrodynamic gene delivery is highly effective and safe for liver gene delivery.

The new study will evaluate the effectiveness and safety of the gene delivery system in baboons in order to establish the hydrodynamic parameters that can be used for development of a computer program to guide gene delivery in humans.

Smokers’ craving, zoning linked

Pitt researchers have found that craving a cigarette while performing a cognitive task not only increases the chances of a person’s mind wandering, but also makes that person less likely to notice when his or her mind has wandered.

The research, titled “Out for a Smoke: The Impact of Cigarette Craving on Zoning Out During Reading,” is published in the January issue of Psychological Science.

Pitt psychology faculty member Michael Sayette; Erik Reichle, chair of Pitt’s cognitive program in psychology, and Jonathan Schooler of  the University of California-Santa Barbara recruited 44 smokers who each smoked nearly a pack a day and refrained from smoking before arriving at the lab.

Participants were assigned at random to either a crave-condition or low-crave group. Those in the latter group were permitted to smoke throughout the study; members of the crave-condition group had to abstain.

Participants were asked to read portions of Tolstoy’s “War and Peace” from a computer screen and instructed to press a ZO key if they caught themselves zoning out. Periodically, a tone sounded, and they were asked via the computer, “Were you zoning out?” to which they responded by pressing a “Yes” or “No” key. After 30 minutes, a reading comprehension test was administered.

Although both groups were prompted a similar number of times, the people craving cigarettes acknowledged three times as many mind-wandering episodes as those in the low-crave group.

But as far as independently recognizing (meta-awareness) that they were zoning out, those who were craving were no more likely to do so than the other group. The cravers had at least three times as many opportunities to catch themselves zoning out, but did not. They were impaired in their ability to notice their own mind-wandering episodes.

The findings could be of interest to those who study workplace accidents, where smokers must refrain. The study also offers a new way to examine factors that interfere with learning among college students who smoke and must abstain for extended periods during classes.

Sayette said, “Similar to what we found in a previous study about the impaired concentration of people who drank, this ‘double whammy’ (i.e., more zoneouts that take longer to recognize) may explain why craving often disrupts efforts to exercise self-control — a process requiring the ability to become aware of your current state in order to regulate it.”


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

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