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May 30, 2013

Research Notes

Jet engine plant not associated with brain cancer increase

Researchers at the Graduate School of Public Health have concluded a 12-year, multi-part study into a perceived increase in brain cancer at the Pratt & Whitney jet engine manufacturing plant in North Haven, Conn., and have found no statistically significant elevations in the overall cancer rates among the workforce.

In May 2000, the Connecticut Department of Public Health began an investigation of a reported increase in brain cancer at the North Haven facility and identified several cases of glioblastoma (GB), the most common form of brain cancer. A preliminary comparative cancer incidence analysis was inconclusive, and the public health department recommended Pratt & Whitney hire an independent research group to conduct a comprehensive study.

In 2002, Gary Marsh, director of the public health school’s Center for Occupational Biostatistics and Epidemiology, and a colleague from University of Illinois-Chicago began an investigation to determine whether mortality from or the incidence of central nervous system (CNS) neoplasms, or tumors, including GB, were elevated among workers at the North Haven plant or seven other Pratt & Whitney facilities serving as comparison sites, and whether those rates were associated with specific workplace exposures.

Researchers analyzed the records of almost a quarter million subjects over a 53-year period, making it one of the largest and most comprehensive cohort studies in an occupational setting. Marsh said it was the first large-scale study of workers in the jet engine manufacturing industry.

Pitt epidemiologists and biostaticians studied the employment records and death certificates of more than 223,000 Pratt & Whitney workers employed during 1952-2001. Researchers identified 723 workers diagnosed with CNS neoplasms from 1976 to 2004. Those tumors were malignant, benign or unspecified, and included 277 GB cases. Researchers interviewed workers or family members to gain more information on behavioral and lifestyle factors. Low participation rates precluded analysis of this data, but the Pittsburgh case-control study provided the basis for a more refined assessment of workplace exposures.

The exposure assessment considered 11 chemical or physical agents on the basis of known or suspected carcinogenic potential that could affect the central nervous system or other organs. Researchers generated quantitative exposure estimates for soluble and mineral oil metalworking fluids, nickel, cobalt, chromium, solvents and a combustion aerosol generated during high-speed and high-temperature grinding that was unique to the North Haven plant. They assigned qualitative exposures for ionizing radiation, electromagnetic fields, polychlorinated biphenyls and lead-cadmium. Exposure to one or more of 20 jet engine-part families and 16 process categories created for the study also was assigned.

The quantitative estimates showed workers had decreasing exposures to these chemicals over the course of the study period; in addition, the quantitative exposure levels were similar to or lower than those in published data from other industries.

At the conclusion of the study, researchers found no statistically significant increase in overall CNS neoplasm rates among the Pratt & Whitney workforce as compared with the corresponding rates in the general populations of the United States and Connecticut. Comparisons among the Pratt & Whitney plant groups revealed a slightly higher incidence of CNS neoplasms and GB among workers at the North Haven plant; however, further evaluation found no association with estimated workplace exposures.

“If not due to chance alone, the slightly elevated GB rates at the North Haven plant may reflect external occupational factors that we did not measure, or other factors unique to North Haven or the baseline plant used in the internal comparisons,” said Marsh.

During an overall evaluation of mortality rates from all causes of death, researchers noted elevated chronic obstructive pulmonary disease (COPD)-related mortality rates in two of five plant groups studied, but found no association with the occupational factors examined in the study. Researchers could not rule out exposures workers received outside of the workplace, or other risk factors, such as smoking, as reasons for the observed COPD excesses.

Pitt co-authors were Ada O. Youk, Jeanine Buchanich and Sarah Downing of the Department of Biostatistics. Other co-authors include those from the University of Illinois-Chicago, Indiana School of Medicine and ChemRisk.

Pratt & Whitney contributed funding for the study. The research results will be published in the June edition of the Journal of Occupational and Environmental Medicine.

Drug reverses Alzheimer’s deficits in mice

An anti-cancer drug reverses memory deficits in an Alzheimer’s disease mouse model, Graduate School of Public Health researchers have confirmed.

The research reviewed previously published findings on the drug bexarotene, approved by the U.S. Food and Drug Administration for use in cutaneous T cell lymphoma. The Pitt researchers were able to verify that the drug significantly improves cognitive deficits in mice expressing gene mutations linked to human Alzheimer’s disease, but could not confirm the effect on amyloid plaques.

Said senior author Rada Koldamova, faculty member in the Department of Environmental and Occupational Health: “We believe these findings make a solid case for continued exploration of bexarotene as a therapeutic treatment for Alzheimer’s disease.”

Koldamova and her colleagues were studying mice expressing human apolipoprotein E4 (APOE4), the only established genetic risk factor for late-onset Alzheimer’s disease, or APOE3, which is known not to increase the risk for Alzheimer’s disease, when a Case Western Reserve University study was published last year stating that bexarotene improved memory and rapidly cleared amyloid plaques from the brains of Alzheimer’s model mice expressing mouse apolipoprotein E (APOE). Amyloid plaques consist of toxic protein fragments called amyloid beta that seem to damage neurons in the brain and are believed to cause the associated memory deficits of Alzheimer’s disease and, eventually, death.

Bexarotene is a compound chemically related to vitamin A that activates retinoic X receptors (RXR) found everywhere in the body, including neurons and other brain cells. Once activated, the receptors bind to DNA and regulate the expression of genes that control a variety of biological processes. Increased levels of APOE are one consequence of RXR activation by bexarotene. The researchers began studying similar compounds a decade ago. Said co-author Iliya Lefterov, also an environmental and occupational health faculty member: “We were already set up to repeat the Case Western Reserve University study to see if we could independently arrive at the same findings. While we were able to verify that the mice quickly regained their lost cognitive skills and confirmed the decrease in amyloid beta peptides in the interstitial fluid that surrounds brain cells, we did not find any evidence that the drug cleared the plaques from their brains.”

The researchers postulate that the drug works through a different biological process, perhaps by reducing soluble oligomers which, like the plaques, are composed of the toxic amyloid beta protein fragments. However, the oligomers are composed of smaller amounts of amyloid beta and, unlike the plaques, are still able to “move.”

“We did find a significant decrease in soluble oligomers,” said Koldamova. “It is possible that the oligomers are more dangerous than the plaques in people with Alzheimer’s disease. It also is possible that the improvement of cognitive skills in mice treated with bexarotene is unrelated to amyloid beta and the drug works through a completely different, unknown mechanism.”

In the researchers’ experiments, mice with the Alzheimer’s gene mutations expressing human APOE3 or APOE4 were able to perform as well in cognitive tests as their non-Alzheimer’s counterparts 10 days after beginning treatment with bexarotene. These tests included a spatial test using cues to find a hidden platform in a water maze and a long-term memory test of the mouse’s ability to discriminate two familiar objects following introduction of a third, novel object.

Bexarotene treatment did not affect the weight or general behavior of the mice. The drug was equally effective in male and female mice.

First author Nicholas F. Fitz and co-author Andrea A. Cronican both are public health faculty members.

The work, funded by the National Institute on Aging of the National Institutes of Health (NIH) and the Alzheimer’s Association, was published in the journal Science.

Skipping medication requires treatment

Doctors should assess their patients to determine if they are consistently taking prescribed medications for long-term ailments and treat patients’ non-adherence behaviors as they would other medical problems, according to School of Medicine researchers.

Noted Zachary A. Marcum, geriatric medicine faculty member and corresponding author of the paper: 30-50 percent of U.S. adults do not adhere to long-term medication regimens, leading to an estimated $100 billion in preventable costs annually. Despite the widespread prevalence and cost of medication non-adherence, the problem goes undetected and undertreated in a significant proportion of adults, he said.

While there are reliable screening tests to “diagnose” medication non-adherence, the authors noted most clinicians are not trained to do this or on how best to treat the problem.

They also observed that diagnostic accuracy can be improved by focusing on some of the most common underlying patient factors that often lead to non-adherence:

• a lack of understanding that medication adherence fosters improved health;

• a belief that the cost of a medication is not balanced by its benefit;

• complex or confusing regimens that are hard to follow;

• lack of vigilance in taking medications regularly;

• inaccurate, irrational or conflicted beliefs about medications;

• perceptions that medication isn’t working.

“Each medication non-adherence behavior requires different diagnostic tools and treatments, in the same way that specific medical conditions require specific treatments,” said Marcum. “An incorrect diagnosis can waste resources and cause harm to the patient.”

Educational interventions with behavioral support and regular patient outreach can improve medication adherence for diseases such as hypertension and myocardial infarction, the authors noted. They also suggested that medication non-adherence be included in electronic health records to allow for sharing of information among health care professionals and monitoring of trends over time.

Co-authors of the article included Mary Ann Sevick and Steven M. Handler, both in the School of Medicine.

The article was published in the Journal of the American Medical Association.

Grant funds development of social personalized learning architecture

Peter Brusilovsky, faculty member in the graduate information science and technology program of the School of Information Sciences, has been awarded a contract by the U.S. Army Contracting Command to participate in the Advanced Distributed Learning (ADL) Initiative. Brusilovsky’s contract, for $623,005 over three years, will support his work on the architecture, algorithms and interfaces for a Personal Assistant for Learning (PAL), one of the major endeavors undertaken by the ADL Initiative.

Through a PAL, the ADL Initiative will provide state-of-the-art education and training — using technology and innovative learning methodologies — for workforce members in the Department of Defense (DoD) and the federal government. Specifically, Brusilovsky will explore the benefits of open social learner modeling and adaptive navigation support to PAL users; he then will develop the infrastructure and algorithms necessary to implement social personalized learning over multiple domains as part of the ADL.

Introduced in 1999, the ADL Initiative is part of the DoD Office of the Deputy Assistant Secretary of Defense for Readiness. Its mission is to employ learning and information technologies to standardize and enhance learning and training in the government. The ADL’s goals are to identify and recommend training software and educational services standards, foster development of technical training standards and develop guidelines for the development, implementation and assessment of learning systems.

Experimental treatment for asthma made in lab

An experimental, lab-made molecule was able to stick to certain inflammatory proteins and reduce acute breathing problems among people with a type of moderate-to-severe asthma, according to School of Medicine researchers.

According to senior author Sally Wenzel, faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine and director of the Asthma Institute, recent estimates suggest that 24.6 million Americans have asthma and 10-20 percent of them don’t have optimal control of their symptoms despite modern medications. Effective treatment of persistent, moderate-to-severe asthma has been challenging.

“We suspect that there are different underlying causes that lead to the clinical syndrome of asthma, so different treatment approaches are likely needed depending on what type of asthma a patient has,” said Wenzel. “A one-size-fits-all strategy might not, in fact, work for everyone.”

For the Phase IIa trial, the researchers assessed asthma patients who were taking moderate to high doses of inhaled steroids and airway-opening drugs called long-acting beta agonists and had high counts of eosinophils, a kind of white cell usually associated with allergy. For 12 weeks, 52 participants received weekly injections of a placebo and 52 others received weekly injections of dupilumab, a monoclonal antibody that inhibits the activity of signaling molecules involved in inflammation. After four weeks, both groups stopped using their long-acting beta agonist. Between the sixth and ninth weeks, they gradually stopped taking the inhaled steroid.

Three patients in the dupilumab group (5.8 percent) had asthma attacks compared to 23 (44.2 percent) in the placebo group, a reduction of 87 percent. The experimental agent was associated with lower levels of biomarkers of inflammation. Minor irritation at the injection site and of the nose and throat, headache and nausea occurred more frequently in the dupilumab group.

“Our findings suggest that dupilumab holds promise for the treatment of moderate-to-severe asthma,” Wenzel said. “However, further studies are needed to better define the patients who will do the best with this new approach, as well as longer-term efficacy and safety.”

The study team included other researchers from Pitt; Colorado Allergy and Asthma Centers; California Allergy & Asthma Medical Group; Peninsula Research Associates; Sanofi, and Regeneron Pharmaceuticals.

The research was funded by Sanofi and Regeneron and published this month by the New England Journal of Medicine and presented concurrently at the national convention of the American Thoracic Society.

State water quality data missing for shale region

What to do with Marcellus shale wastewater is one of the biggest concerns in Pennsylvania, and few published studies have evaluated wastewater effects on regional groundwater, according to a review undertaken by lead author Radisav Vidic, William Kepler Whiteford Professor and Chair in the Swanson School of Engineering’s Department of Civil and Environmental Engineering, and a colleague at Penn State.

The review stresses the need for scientific data on water pollution caused by hydraulic fracturing and cites a lack of monitoring stations and confidentiality requirements for documentation as potential causes.

Said Vidic: “Since the advent of hydraulic fracturing, more than one million treatments have been conducted with perhaps only one documented case of direct groundwater pollution resulting from the injection of chemicals. There is no evidence of groundwater contamination — even if it does exist.”

Vidic cites state regulations as a possible cause.

“This gaping hole is likely there because Pennsylvania is one of only two states in the entire United States that doesn’t require monitoring for water quality in individual well supplies,” he said.

Intensive gas extraction from the Marcellus Shale began in the eastern United States in 2005; it quickly has become one of the top five unconventional gas reservoirs in the country. Previous studies have estimated this area could yield 489 trillion cubic feet of natural gas, an amount requiring high volumes of water use for what is often referred to as “slickwater fracturing.” In this method, no viscosity modifiers (thickening agents) are added to the water before being injected into wells.

“It is likely that the water needs will change from these initial projections as the industry continues to improve and implement water reuse,” said Vidic. “However, it is still necessary to develop specific policies regarding when and where water can be taken from streams to be used for fracturing.”

Vidic noted that it is well known that a large portion — nearly 90 percent — of slickwater is not recovered during the flowback period, indicating the importance of documenting potential transport pathways and the ultimate disposition of the water. In addition, “stray gas” or gas leakage is a concern for the region.

“As these well fields mature and the opportunities for wastewater reuse diminish,” said Vidic, “the need to find alternative management strategies for this wastewater will likely intensify. Now is the time to work on these issues in order to avoid an adverse environmental legacy similar to that from abandoned coal mine discharges in Pennsylvania.”

Co-authors were Jorge Abad and Julie Vandenbossche, both of engineering.

The study was published this month in Science.

Postdoc wins research award

Dio Kavalieratos, a postdoctoral student at the RAND-University of Pittsburgh Health Institute, has received the Young Investigator Award from the American Academy of Hospice and Palliative Medicine (AAHPM).

He presented his abstract titled “What Do Providers Perceive as Patient-level Palliative Care Uptake Barriers in Heart Failure? A Qualitative Analysis” to the 2013 AAHPM scientific subcommittee.

His research examined why patients with advanced heart failure use palliative care less often than do patients with advanced cancer, despite similarities in symptoms and prognosis.

Heart failure affects 5.7 million Americans, according to the CDC. Through his research, Kavalieratos found that many physicians are hesitant to discuss palliative care with patients, fearing they will interpret this as the doctor’s “giving up” on them. Palliative care often is misinterpreted narrowly as end-of-life care, but it also is focused on relieving pain, symptoms and stress related to a serious illness, relief that can improve overall care.

Kavalieratos interviewed cardiologists, primary care physicians and other health-care providers and found that “the term ‘palliative care’ was at best ambiguous and at worst misleading.” He said physicians waited for patients to have severe symptoms to refer them to palliative care, or until patients faced the end of life, whereas palliative care may be useful from the day of diagnosis, since the proper trigger for offering palliative care is a decrease in function.

Added Kavalieratos: “If they are using the wrong triggers to refer patients out, patients may not receive the best care when they need it most.”

Biological pathway to organ rejection found

Transplant researchers in the School of Medicine have challenged a long-held assumption about how biologic pathways trigger immune system rejection of donor organs. Their study suggests a different paradigm is needed to develop better anti-rejection therapies.

Explained senior author Fadi Lakkis, Frank & Athena Sarris Chair in Transplantation Biology, surgery faculty member and scientific director of the Thomas E. Starzl Transplantation Institute: Immune system T-cells migrate to transplanted organs, fighting the foreign tissue. Until now, scientists had thought these T-cells were drawn to the site by chemokines, proteins secreted by cells in the lining of the blood vessels, or endothelium, of the organ when it becomes inflamed.

“The prevailing view was that when the endothelium gets inflamed, it gets a little sticky, so T-cells that are zipping by in the bloodstream begin to slow down and bind to chemokines that trigger their arrest and migration into the affected tissue,” Lakkis said. “We decided to test that hypothesis and found out to everyone’s surprise that’s not the way it works.”

If the chemokine receptors on T-cells were blocked, the researchers reasoned, the cascade of immune events would not happen, stalling rejection. So two days after mice received a heart or kidney transplant, they received T-cells treated with pertussis toxin, which irreversibly binds to a key molecule in the receptor to inhibit its activity, and presumably prevent the migration of memory and effector T-cells already sensitized to recognize the foreign proteins of the donor tissue.

Using a technique called two-photon microscopy, which allows real-time visualization of living tissue, they found that pertussis-treated T-cells invaded the donor organs just as they did if they were untreated, leading to organ rejection.

“This showed us that chemokines are not necessary to start the rejection response,” Lakkis said. “So then we wondered which cells were sounding the alarm to the immune system.”

The sophisticated microscopy technique revealed that the donor kidney’s dendritic cells, which identify antigens or foreign proteins and present them on their cell surfaces to be recognized by other immune cells, “stick their feet,” as Lakkis put it, in the bloodstream, thereby exposing donor surface antigens to the recipient’s immune system.

“So, anti-rejection therapies that target chemokine responses have very little effect,” he said. “But novel drugs that interfere with antigen presentation by the endothelium or the dendritic cells could be very helpful.”

Lead author was MD/PhD student Jeff Walch; co-authors were from the Starzl Transplantation Institute and the departments of surgery, immunology and medicine in the School of Medicine, as well as from Yale.

The project was funded by NIH and published online in the Journal of Clinical Investigation.

Bright nanoscale alloys may have medical applications

Alloys like bronze and steel have been transformational for centuries, yielding top-of-the-line machines necessary for industry. As scientists move toward nanotechnology, however, the focus has shifted toward creating alloys at the nanometer scale  — producing materials with properties unlike their predecessors.

Research led by principal investigator Jill Millstone, chemistry faculty member in the Dietrich School of Arts and Sciences, demonstrated that nanometer-scale alloys possess the ability to emit light so bright they could have potential applications in medicine.

Said Millstone: “We demonstrate alloys that are some of the brightest, near-infrared-light-emitting species known to date. They are 100 times brighter than what’s being used now. Think about a particle that will not only help researchers detect cancer sooner but be used to treat the tumor, too.”

Millstone presented alloys with drastically different properties than before — including near-infrared (NIR) light emission — depending on their size, shape and surface chemistry. NIR is an important region of the light spectrum and is integral to technology found in science and medical settings, said Millstone. She used a laser pointer as an example.

“If you put your finger over a red laser [which is close to the NIR light region of the spectrum], you’ll see the red light shine through. However, if you do the same with a green laser [light in the visible region of the spectrum], your finger will completely block it,” said Millstone. “This example shows how the body can absorb visible light well but doesn’t absorb red light as well. That means that using NIR emitters to visualize cells and, ultimately, parts of the body, is promising for minimally invasive diagnostics.”

Millstone’s demonstration showed, for the first time, a continuously tunable composition for nanoparticle alloys; this means the ratio of materials can be altered based on need.

In traditional metallurgical studies, materials such as steels can be highly tailored toward the application, say, for an airplane wing versus a cooking pot. Alloys at the nanoscale follow different rules, said Millstone. Because the nanoparticles are so small, the components often quickly separate, like oil and vinegar.

In her paper, Millstone described using small organic molecules to “glue” an alloy in place, so that the two components stay mixed. This strategy led to the discovery of NIR luminescence and also paves the way for other types of nanoparticle alloys that are useful not only in imaging, but in applications like catalysis for the industrial-scale conversion of fossil fuels into fine chemicals.

Millstone said that taken together these observations provide a new platform to investigate the structural origins of small metal nanoparticles’ photoluminescence and of alloy formation in general. She believes these studies should lead directly to applications in such areas as health and energy.

The paper was published in the Journal of the American Chemical Society. Funding was provided by the University’s Central Research Development Fund.

Two receive pulmonology honors

Two of the four honorees receiving “Recognition for Scientific Accomplishments” awards from the American Thoracic Society are leaders from Pitt’s Division of Pulmonary, Allergy and Critical Care Medicine (PACCM).

Mark Gladwin, PACCM chief and director of the Vascular Medicine Institute, and Naftali Kaminski, PACCM faculty member and director of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases at UPMC, received the scientific awards.

Said John J. Reilly, Jack D. Myers Professor and Chair, Department of Medicine: “The fact that two of the four honorees this year come from the same program is emblematic of the overall strength of the PACCM program.”


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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