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June 14, 2012

Research Notes

Hookah smoking quantified

Nearly one in three college students in the United States has smoked tobacco from a hookah, according to a study led by Pitt researchers and published in the June issue of the journal Nicotine and Tobacco Research.

The researchers surveyed more than 100,000 students from 152 U.S. universities participating in the National College Health Assessment in 2008 and 2009. Of the sample, 30.5 percent reported ever using a hookah to smoke tobacco, compared with 34.6 percent for cigarettes, 28.6 percent for cigars and 10.6 percent for smokeless tobacco.

Lead author Brian Primack, a faculty member in medicine and pediatrics and director of the medical school’s program for research on media and health, said, “Certain sociodemographic characteristics, such as male gender and fraternity membership, were associated with hookah tobacco smoking. However, the most striking finding was how consistent rates of hookah tobacco smoking were across factors such as geographic region, university size and university setting.”

He said, “Another interesting finding was that, of those who had smoked tobacco from a hookah in the past 30 days, 51 percent of them had not smoked cigarettes in those 30 days. This suggests that hookah smoking may be attracting many people who would otherwise not have been tobacco users.”

Pitt collaborators on the study were Kevin H. Kim of the Department of Psychology in Education and Mary Carroll, Michael J. Fine and Ariel Shensa of the Department of Medicine.

Human environmental legacies documented

Early human activity has left a greater footprint on today’s ecosystem than previously thought, say researchers working at Pitt and in the multidisciplinary Long Term Ecological Research (LTER) Network. The National Science Foundation created the LTER Network in 1980 to conduct long-time scale research on ecological issues that span huge geographical areas.

Highlighted in the June issue of BioScience, the Pitt/LTER collaboration shows how historic human actions caused changes in nature that continue to reverberate throughout present-day ecosystems.

In the article, researchers took a retrospective look at the impact of human activity on LTER Network sites spanning states from Georgia to New Hampshire and proposed methods for measuring the effects of such activity.

The study of legacy effects is important because it provides insights into how today’s actions can affect tomorrow’s ecological systems, said Daniel Bain, co-principal investigator at the Baltimore Ecosystem Study LTER Network site and a faculty member in the Department of Geology and Planetary Science. Bain noted that decision makers at all levels, including those creating policy, need historical information about ecosystems to make more effective environmental policies.

“Increasingly, we propose to manage our ecosystems with sophisticated and complicated strategies,” Bain said. “For example, we are attempting to manage agricultural runoff by changing how streams and floodplains are arranged. However, while designing these strategies we tend to address the most recent impacts rather than the entire history of impacts. This can lead to wasted effort and misuse of relatively limited resources.”

Legacy effects from human activities are all around us, said Bain. For example, urban systems accumulate human-made materials, some of which have large ecological footprints and ultimately will leave a legacy. Lead, for instance, has been banned from gasoline and paint in the United States for several decades but can remain in soil for much longer periods of time.

In agriculture, areas that were plowed hundreds of years ago react differently to contemporary acid deposition from air pollutants when compared with adjacent unplowed areas.

Extensive use of cement can add substantial amounts of calcium to urban soils, although the ecological impact of this practice is not yet understood fully, Bain added.

Many landscapes that provide baseline ecological data for evaluating environmental change were structured in part by previous human interactions such as settlements and agricultural practices. To make sense of the observed ecological patterns on such landscapes, Bain said, we must know something of the history of the processes acting to shape those patterns. A recent example of the need for historical data is the debate over global warming and its associated climate change.

Another major benefit of the LTER approach, according to Bain, is the network of scientists that can design a study jointly, analyze the data and produce such synthetic work efficiently. This type of historical analysis would take a small scientific team much longer to produce and perhaps be restricted to a smaller geographical and time scale, Bain said.

Longer life for melanoma brain metastasis patients

University of Pittsburgh Cancer Institute (UPCI) scientists have presented work from an international trial that showed an oral molecular inhibitor therapy more than doubled survival in people who had melanoma that had progressed to the brain.

The results were presented recently at the American Society of Clinical Oncology annual meeting. Principal investigator John M. Kirkwood, a faculty member in medicine, dermatology and translational science at the School of Medicine and UPCI, said, “This new molecular inhibitor should be considered as a first-line treatment in patients with metastatic melanoma to the brain. It has more than doubled progression-free survival and is an oral, well-tolerated pill that is likely to revolutionize treatment of patients with this feared complication of melanoma.”

The molecular inhibitor drug, called dabrafenib, selectively binds to and inhibits the activity of the mutated BRAF protein, hindering the spread of tumor cells containing the mutated BRAF gene. The BRAF protein is involved in sending signals to grow and spread in melanoma cells.

In a study of 172 patients, the treatment helped patients live for more than seven months, compared to treatments tested in other trials that resulted in survivals of only three months, Kirkwood said. “That’s never been seen before in melanoma.”

The overall survival with this treatment was 31-33 weeks for the two groups of previously untreated or previously treated brain metastasis, more than double the average survival of nine-14 weeks using the current chemotherapy drug temozolomide.

Study patients averaged 52 years old; 70 percent were men. The majority of patients had two or more brain metastases. In addition to the much longer survival, the melanoma brain metastases in most of the patients also stopped growing and, in one-third, shrank. Further study to determine how the treatment works in the brain will be addressed in a new trial that is planned for the summer.

Tests positive for protection from fibrosis

Researchers at the School of Medicine have identified an agent that in lab tests protected skin and lungs from fibrosis. Their findings were published recently in Science Translational Medicine.

Senior author Carol A. Feghali-Bostwick, a faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine and co-director of the Scleroderma Center, said there are no effective therapies for life-threatening illnesses such as idiopathic pulmonary fibrosis and systemic sclerosis, which cause progressive organ scarring and failure.

“It’s estimated that tissue fibrosis contributes to 45 percent of all deaths in developed countries because organ failure is the final common pathway for numerous diseases. Identifying a way to stop this process from happening could have enormous impact on mortality and quality of life,” she said.

The research team evaluated E4, a piece of protein or peptide derived from endostatin, a component of collagen known for its inhibition of new blood vessel growth. In lab tests, healthy human skin cells that were treated to become fibrotic remained normal when E4 was present.

The skin and lungs of mice were protected from cell death and tissue scarring by a single injection of E4 administered five or eight days after they were given the cancer drug bleomycin, which is known to induce fibrosis. The peptide also could reverse scarring that had already occurred, the researchers found.

In a unique approach, the investigators also tested E4 in human skin maintained in the laboratory to confirm it would be effective in treating fibrosis in a human tissue. E4 blocked new and ongoing fibrosis in human skin.

The agent might work by stalling the cross-linking of collagen needed to form thick scars, Feghali-Bostwick said. While the body naturally produces endostatin, it appears that it cannot make sufficient amounts to counteract fibrosis development in some diseases.

Mark T. Gladwin, chief of the Division of Pulmonary, Allergy and Critical Care Medicine, said, “This endostatin peptide passes two important hurdles that suggest it is a promising candidate drug for development for patients with idiopathic pulmonary fibrosis and systemic sclerosis. It reverses established disease in animal models and it reverses fibrosis in the human skin fibrosis model.”

In a case of serendipity, the researchers discovered E4 while exploring the process of fibrosis. Post-doctoral fellow and study co-author Yukie Yamaguchi was conducting some experiments with proteins thought to facilitate the scarring process.

“Dr. Yamaguchi showed me the tests that showed endostatin wasn’t working to increase fibrosis, but in fact shut it down,” Feghali-Bostwick said. “It was the opposite of what we expected and I was very excited about our finding. As Louis Pasteur once said, ‘Chance favors the prepared mind.’”

Other co-authors included Takahisa Takihara, Roger A. Chambers and Kristen L. Veraldi of the Division of Pulmonary, Allergy and Critical Care Medicine, the Department of Pathology and the Scleroderma Center, and Adriana T. Larregina of the dermatology and immunology departments and the McGowan Institute for Regenerative Medicine.

The project was funded by the National Institutes of Health.

Assessing kids’ concussion recovery

In findings published online in the inaugural issue of Applied Neuropsychology: Child, researchers from Pitt and UPMC say that sports medicine practitioners shouldn’t rely solely on young athletes’ reporting on recovery from concussions. Adolescents tend to neglect the more subtle symptoms — neuropsychiatric and sleep issues — and base their perceptions of their recovery primarily on physical (somatic) symptoms such as headache and nausea.

Results indicate that when athletes gauge their own readiness to return to play, their physical symptoms account for 56 percent of their self-assessment, whereas their performance on objective neurocognitive testing only accounts for 28 percent. While the statistical analyses revealed that they judged their recovery on somatic and cognitive symptoms almost twice as strongly as neurocognitive testing, the sleep and neuropsychiatric symptoms ranked ahead of their performance on the objective test data by only a few percentage points.

Anthony Kontos, a faculty member in orthopaedic surgery and assistant research director in the UPMC Center for Sports Medicine concussion program, said: “Our findings suggest that young athletes may not perceive their cognitive deficits as well as they perceive their somatic symptoms. Therefore, it is important to assess their cognitive deficits using neurocognitive concussion tests and a comprehensive clinical evaluation.”

Michael “Micky” Collins, a faculty member in orthopaedic surgery and the concussion program’s executive and clinical director, said: “These research results affirm what we see daily in our clinical experience. Athletes have a hard time understanding the cryptic nature of this injury, and relying only on self-assessment of symptoms is dangerous and naïve when it comes to allowing athletes back to play after a brain injury. Objective assessment through the use of computerized neurocognitive testing and a thorough evaluation are critical components of concussion management and return-to-play considerations.”

The research team studied 101 concussed athletes (62 males, 39 females) ages 12-18 who were evaluated by clinicians at the UPMC Center for Sports Medicine concussion program. They asked athletes to rate their “percent back to normal” and compared those numbers against the ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) battery and somatic, cognitive, sleep and neuropsychiatric symptom clusters to find significant correlations. In short, the athletes’ judgment was based on a small subset of the factors evaluated in concussion care.

Males in the study tended to feel more “recovered” from their concussions than females, suggesting females may experience more severe post-concussion symptoms than males, or that males under-report their symptoms. Such gender differences merit more study, researchers concluded.

In addition to Kontos and Collins, the research team consisted of lead author Natalie Sandel of the Department of Neuroscience; Mark Lovell, formerly of the Department of Orthopaedic Surgery, and Nathan Kegel of the concussion program.

Template used for DNA repair

In a challenge to the current scientific view, School of Medicine researchers have shown how breaks in the gene-encoding DNA of non-dividing cells are repaired.

The broken ends of the DNA strands are not merely stuck back together as had been thought, they said in a report published online in Early Edition of the Proceedings of the National Academy of Sciences.

Many studies suggest that when the double-stranded DNA in human cells is broken, it simply is rejoined at the broken ends, which is an efficient but error-prone strategy, said pathology faculty member Yuri Nikiforov, director of the Division of Anatomic Pathology. If that were the case, mistakes such as deletion of some of the building blocks of DNA would be made at the repair site that, in turn, could lead to production of abnormal proteins and other harmful consequences.

“Our new study dramatically changes our understanding of how these breaks are fixed,” Nikiforov said. “This kind of damage is actually repaired by using the complementary parental gene as a blueprint for rebuilding.”

Each human cell contains 22 paired chromosomes, plus the sex-specific X chromosomes for females and Y for males. These 46 chromosomes contain tens of thousands of genes, and there may be small variations between the versions inherited from each parent. Breaks continuously occur in DNA strands due to routine metabolic processes and exposures to ionizing radiation and other toxins.

The researchers found that when one of the chromosomes was broken in the area of a gene, the matching version of the chromosome from the other parent would get close to it to make contact at the site of the break. The uninjured chromosome’s genetic code was copied to repair the damaged one with great accuracy.

“It’s expected that malfunctioning of this DNA repair mechanism in human cells would lead to greater accumulation of errors in coding genes,” Nikiforov noted. “It is likely that this observation will help us better understand normal human cellular processes such as aging, as well as harmful conditions such as cancer and other diseases.”

Previous studies of DNA repair looked at the whole genome, but more than 95 percent of it isn’t used to make protein or regulate growth and cellular processes, he said. When damage occurs in those non-coding areas, the simple repair technique of sticking the ends back together doesn’t do any damage. Previous studies reviewed genome-wide repair and may have overlooked the sophisticated strategy that is used to fix problems in the small fraction of gene-encoding DNA, the researchers said.

Co-authors included Manoj Gandhi, Viktoria N. Evdokimova, Lindsey Kelly and Marina N. Nikiforova of pathology; Christopher J. Bakkenist of radiation oncology and Karen T. Cuenco of dental medicine.

The project was funded by the National Institutes of Health and a University of Pittsburgh Cancer Institute support grant.


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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