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July 7, 2016

Research notes

NIH funds study of artificial stem cells in vascular grafts

The National Institutes of Health (NIH) have awarded David Vorp, the William Kepler Whiteford Professor of Bioengineering and associate dean for research of the Swanson School of Engineering, and his colleagues more than $1.54 million for a study investigating artificial stem cells in the development of engineered vascular grafts.

Some current regenerative medicine approaches use mesenchymal stem cells (MSCs) harvested from the patient to help rebuild or repair damaged or diseased tissues.

Vorp and his team have pioneered the use of MSCs in the development of tissue-engineered vascular grafts (TEVGs), which may be effective in small diameter arterial bypass procedures or arteriovenous access for dialysis. However, MSCs taken from patients at high risk for cardiovascular disease, such as the elderly and diabetics, may be dysfunctional. Furthermore, the use of harvested cells that require extended culture expansion also runs the risk of cellular contamination or transformation, as well as high costs and substantial waiting time before a graft can be made and implanted.

Said Vorp: “Fully functional human MSCs secrete a host of biochemicals, including those that prevent blood clotting and those that ‘call’ into the TEVGs important cells from the host, such as inflammatory cells, smooth muscle cells and endothelial cells. We have found that MSCs from diabetics, for example, are relatively ineffective in yielding a successful TEVG compared to MSCs from non-diabetics. Considering that diabetics make up a large proportion of patients who need bypass grafts, we needed to find an alternative means to achieve our goal for this significant population.”

To answer this challenge, the research team has developed artificial stem cells that are created by encapsulating the veritable cocktail of biochemicals secreted by normally functioning MSCs in culture into biodegradable microspheres that are similar in size to actual MSCs.

“By ‘tuning’ or adjusting the degradation rate of the microspheres, we can replicate the release of these biochemicals by real, fully functional MSCs,” said Vorp. He and his colleagues then will seed the artificial stem cells into porous, tubular scaffolds and implant them in a rat model as they have done with MSCs in fabricating TEVGs.
The study aims to accelerate the clinical translation of the team’s TEVG technology. This will be achieved, according to Vorp, “both by making the technology applicable to all patients — even those with dysfunctional MSCs — and by reducing the regulatory barriers associated with the need for culture-expanding cells to the numbers necessary to fabricate a TEVG.”

Vorp is joined on this study by Pitt colleagues Steven Little, William Wagner, Morgan Fedorchak and Justin Weinbaum.


Broccoli sprouts may prevent oral cancer

Potent doses of broccoli sprout extract activate a “detoxification” gene and may help prevent cancer recurrence in survivors of head and neck cancer, according to a trial by the University of Pittsburgh Cancer Institute, partner with UPMC CancerCenter, confirming preliminary results presented last year at the American Association for Cancer Research annual meeting.

It is the first study demonstrating that the extract protects against oral cancer, with the results of human, animal and laboratory tests reported in Cancer Prevention Research.

Said lead author Julie Bauman, co-director of the UPMC Head and Neck Cancer Center of Excellence: “With head and neck cancer, we often clear patients of cancer only to see it come back with deadly consequences a few years later. Unfortunately, previous efforts to develop a preventative drug to reduce this risk have been inefficient, intolerable in patients and expensive. That led us to ‘green chemoprevention’ — the cost-effective development of treatments based upon whole plants or their extracts.”

Cruciferous vegetables, such as broccoli, cabbage and garden cress, have a high concentration of the naturally occurring molecular compound sulforaphane, which previously has been shown to protect people against environmental carcinogens.

Bauman and her colleagues treated human head and neck cancer cells in the laboratory with varying doses of sulforaphane and a control, and compared them to normal, healthy cells that line the throat and mouth. The sulforaphane induced both types of cells to increase their levels of a protein that turns on genes that promote detoxification of carcinogens, like those found in cigarettes, and protect cells from cancer.

In a small preclinical trial, 10 healthy volunteers drank or swished fruit juice mixed with broccoli sprout extract for several days. The volunteers had no significant problems tolerating the extract and the lining of their mouths showed that the same protective genetic pathway that was activated in the laboratory cell tests was activated in their mouths, meaning that the sulforaphane was absorbed and directed to at-risk tissue.

Bauman also collaborated with senior author Daniel E. Johnson, faculty member in medicine and a senior scientist in the UPCI head and neck cancer program, to see how the extract performed in mice predisposed to head and neck cancer. The mice that received the sulforaphane developed far fewer tumors than their counterparts who did not receive the extract.

The results of the mouse, human and lab studies have been so successful that Bauman has started a larger clinical trial in volunteers previously cured of head and neck cancer. These participants are taking capsules containing broccoli seed powder, which is more convenient to take regularly than the extract mixed with juice.

“Head and neck cancers account for approximately 3 percent of all cancers in the U.S., but that burden is far greater in many developing countries,” said Bauman. “A preventative drug created from whole plants or their extracts may ease the costs of production and distribution, and ultimately have a huge positive impact on mortality and quality of life in people around the world.”

Additional Pitt authors on this research were Yan Zang, Malabika Sen, Changyou Li, Lin Wang, Daniel P. Normolle and Thomas W. Kensler, with colleagues from Johns Hopkins University and the University of California-San Francisco.

It was funded through Pitt’s specialized program of research excellence grant in head and neck cancer, via the National Cancer Institute and the Lewis B. and Dorothy Cullman Foundation.


Blacks with AFib at greater risk

Blacks with atrial fibrillation (AFib) have nearly double the risk of their white counterparts for stroke, heart failure, coronary heart disease (CHD) and mortality from all causes, according to a study published in JAMA Cardiology.

The study, funded by a grant from the Doris Duke Foundation and led by Jared Magnani, medicine faculty member in the School of Medicine’s Division of Cardiology and cardiologist at the UPMC Heart and Vascular Institute, analyzed data from the atherosclerosis risk in communities (ARIC) study to examine racial differences in adverse outcomes associated with AFib.

AFib is the most common heart rhythm problem in the U.S. It affects approximately 1 percent of the adult population and more than 5 percent of those 65 years old and older. It also is known to be strongly associated with increased risks of stroke, heart failure and mortality.

Said Magnani: “We knew blacks were likely to have an increased risk of stroke, but the findings for heart failure, CHD and mortality are novel and important. This should put the focus on improving prevention efforts for adverse outcomes in blacks with atrial fibrillation, and drive further studies into the reasons behind why this is happening.”

The ARIC study, sponsored by the National Heart, Lung and Blood Institute, recruited 15,792 men and women, 45-64 years old, from four communities in the U.S. — Forsyth County, North Carolina; Jackson, Mississippi; the northwest suburbs of Minneapolis, Minnesota; and Washington County, Maryland. The community-based cohort was designed to investigate causes of atherosclerosis and cardiovascular disease, and included baseline examinations in 1986 and more than 20 years’ follow-up.

“ARIC provided an opportunity to examine racial differences in outcomes related to atrial fibrillation. In general, most large studies of individuals with atrial fibrillation are predominantly of white participants,” Magnani said. “We know that atrial fibrillation is associated with adverse outcomes, but these data provided important insights into differences by race.”

After exclusions, 15,080 participants (8,290 women and 3,831 blacks) were included in the new analysis. Noteworthy racial differences at baseline examination included a body mass index of 27 percent for whites and 29.6 percent for blacks. Black participants also had a higher prevalence of hypertension and diabetes.

During analysis of the 20-year follow-up, 2,348 cases of AFib were identified — 1,914 in whites with an incidence rate of 8.1 per 1,000 person-years, and 434 in blacks, with an incidence rate of 5.8 per 1,000 person-years. Researchers found that adverse outcomes in black participants were almost double that for whites.

The incidence rate of strokes in black participants was 21.4 compared to 10.2 in their white counterparts. For heart failure and CHD, the rate difference was almost two-fold higher in blacks than whites. Blacks also had a rate difference of 106 for mortality compared to 55.9 in whites.

Researchers also believe the results are enough to warrant an addition to the current guidelines for the management of patients with AFib developed by the American College of Cardiology, American Heart Association task force on practice guidelines and the Heart Rhythm Society to include the significant difference in adverse outcomes between blacks and whites with AFib.

Limitations of the study noted by researchers included that ARIC participants were from only four geographic regions and that the study is biracial. The researchers were careful to note that generalizability to other geographic regions or to other races and ethnicities may be limited.

“There needs to be further investigation,” said Magnani, who completed his research while at Boston University School of Medicine. “It’s going to be important to dissect the mechanisms behind why blacks with atrial fibrillation are highly more likely to have adverse outcomes than whites.”


Places, situations can trigger addiction relapse

Drug addiction researchers have long been puzzled by how the brain’s “reward” center encodes conditioned reward — how a specific environment repeatedly paired with a drug of abuse can alone trigger an affective state, which often leads to relapse. A recent study led by neuroscientists may have solved that puzzle.

Nicholas Graziane, a postdoctoral associate in the translational neuroscience program, along with his colleagues at Pitt, the Icahn School of Medicine at Mount Sinai and the Centre for Brain Health at the University of British Columbia, found that withdrawal from cocaine or morphine increased the excitatory drive on one type of neurons (D1R MSNs) relative to another type of neurons (D2R MSNs) in the nucleus accumbens.

Said Graziane: “The nucleus accumbens is a key hub for encoding reward and reward-related associations in the brain. The activation of the specific types of neurons in this brain region can dictate responses to reward; activation of D1R MSNs enhances reward, while activation of D2R MSNs inhibits reward.”

The authors discovered that preventing this shift in excitatory drive on D1R MSNs relative to D2R MSNs blocked the conditioned reward of morphine. Specifically, these studies in rodents found that the situation or location previously associated with morphine no longer was preferred compared to the neutral context.

“This shift in excitatory input is important because it may highlight a cellular mechanism whereby drugs become associated with places or situations,” said Graziane. “We found that at the cellular level in the accumbens, long-term withdrawal from either cocaine or morphine increased the excitatory input on D1R MSNs vs. D2R MSNs. In other words, a street corner or pub alone, in absence of the drug, is capable of eliciting the drug’s affective state, often leading to relapse.

“Potentially, by blocking the D1R MSNs vs. D2R MSNs shift, we could prevent the affective-state produced by the drug-paired environmental stimuli in patients suffering from context-induced forms of relapse,” Graziane added. “With the knowledge from this paper, future addiction-related research can further test the importance of the shift in excitatory input on D1R MSNs vs. D2R MSNs.”

Still needed are tests to determine whether blocking the increase in D1R MSN to D2R MSN excitatory input in cocaine-treated animals would have the same effect. If so, that would mean that the D1R MSN/D2R MSN balance is a key mediator in the long-term retention of pathologically rewarding associations.

The study was published online by Nature Neuroscience and was funded by the National Institute on Drug Abuse and the Pennsylvania Department of Health.


Swanson faculty gets petrochemical research grant

Giannis Mpourmpakis, chemical engineering faculty member at the Swanson School of Engineering, received a $110,000 Petroleum Research Fund doctoral new investigator grant from the American Chemical Society for computer modeling research to investigate the conversion of ethane, propane, butane and other alkanes used in the petrochemical industry.

The study, “Identifying Structure-Activity Relationships for the Dehydrogenation of Alkanes on Oxides,” will look to gain a fundamental understanding of the dehydrogenation of small hydrocarbons to olefins on metal oxides under experimental conditions.

Said Mpourmpakis: “Olefins are the building blocks for the production of chemicals and plastics. We can avoid the time and money it takes performing experiments in a traditional chemical lab through computer simulations and then design new catalysts, again, without the need to perform tedious experiments.”

Mpourmpakis and his team will attempt to identify structure-activity relationships (SARs) — the relationships between a molecule’s 3-D structure and its catalytic activity — on metal oxides. Although much research has been done on the SARs on metals, the scientific community has little understanding of these relationships on metal oxides.

At the Computer-Aided Nano and Energy Lab, Mpourmpakis and colleagues have been successful investigating the dehydration of simple alcohols on various metal oxides. Mpourmpakis’ previous research outlined a simple but powerful model to allow researchers to easily test different alcohols and metal-oxide catalysts according to their dehydration activity. It was the cover article in Catalysis Science & Technology, which is published by the Royal Society of Chemistry.

“We are building on our previous knowledge of alcohol dehydration on metal oxides and applying the understanding we have of in-silico experimentation to a different scientific problem: the alkane dehydrogenation,” said Mpourmpakis.


UCSUR names Manners awardees

Each year, the University Center for Social and Urban Research (UCSUR) awards the Steven D. Manners Faculty Development Awards to promising research projects in the social, behavioral and policy sciences on campus. These awards honor the memory of Manners, a sociologist who began working at the center in 1974 and served as its assistant director from 1989 until his death in 2000. His research and service to the center and the University community were dedicated to improving social conditions in the urban environment.

UCSUR made the first Manners awards in 2001 and this year is awarding two research development grants to support pilot research with scientific merit and a strong likelihood that the projects will lead to subsequent external peer reviewed funding:

Victoria Shineman, faculty member in political science, received an award for “A Field Experiment Mobilizing Convicted Felons During the 2016 General Election.”

Alicia Sufrinko, a neuropsychology faculty member, and Anthony Kontos, orthopaedic surgery faculty member, received an award for “An Integrative Mobile Platform for Assessment of Sleep Dysfunction and Physical Activity Level Following Sport/Recreation-related Concussion.”

Shineman will conduct a field experiment during the 2016 general election with two primary goals: identify the most effective methods of mobilizing convicted felons to vote; and identify the downstream effects that occur after felons are politically mobilized.

This experiment will integrate an intensive mobilization treatment within a panel survey completed by a population of convicted felons before and after the November 2016 election. A paid survey opportunity will be used to recruit an attentive population of convicted felons, and this attentiveness will be used to personally deliver information and assistance regarding registration and voter turnout.

Subjects will be randomly assigned to receive a placebo control treatment, or one of three mobilization treatments.

One mobilization treatment will offer a generic “get out the vote” appeal, along with assistance with registration and voting. The other mobilization treatments will add details clarifying common misinformation about the eligibility of convicted felons, and information intended to shift perceptions regarding expectations of felon participation.

Treatment effects will be assessed using data from official voter history records, as well as data from pre-treatment and post-election surveys.

Shineman predicts that felons can be mobilized, and that mobilization will cause felons to become more politically informed and more trusting of government, and will aid them in developing a stronger sense of political efficacy.

Sufrinko and Kontos’ pilot study will use a mobile ecological momentary assessment (EMA) application to monitor post-concussion symptoms and wrist actigraphy to monitor sleep and physical activity in patients with sport/recreation-related concussion (SRC).

One aim of the study is to test the feasibility of concurrently using an EMA approach to assess post-concussion symptoms and actigraphy for measuring sleep and physical activity level in a sample of patients diagnosed with SRC.

The other study goal is to evaluate the predictive utility of sleep and physical activity data on EMA post-concussion symptoms and clinical outcomes, such as neurocognitive test performance, total symptom scores and vestibular/oculomotor function.

The proposed study represents the first effort to evaluate objective sleep and physical activity data concurrently with clinical outcomes following concussion. The study will involve 20 adolescent SRC patients who will be followed for approximately one month post-injury.

The researchers intend to use the preliminary data to support a grant application to study a larger sample. Understanding the complex relationships between sleep, physical activity and concussion outcomes is vital to developing clinical guidelines for behavioral management strategies, including instructional sleep techniques and physical activity recommendations, for optimal recovery following SRC.


Program helps at-risk adults double activity levels

Adults at risk for type 2 diabetes, heart disease or both can substantially increase their physical activity through a lifestyle intervention program developed in the Graduate School of Public Health for use in community settings such as senior centers or worksites.

Previous studies have demonstrated that such programs decrease weight and reduce diabetes risk, but this NIH-funded evaluation is one of the first to document that these programs also result in significant increases in the participants’ physical activity levels. The results were reported in the Translational Journal of the American College of Sports Medicine.

The analysis also confirmed that season matters, with participants getting more physical activity in the summer than in winter months. Said lead author Yvonne L. Eaglehouse, a postdoctoral researcher at public health: “This may seem like an obvious finding, but this evidence that season influences the physical activity levels of participants in community-based lifestyle interventions will allow us to adjust these programs accordingly and offer extra encouragement and strategies to continue striving to meet physical activity goals during the winter.”

Eaglehouse and her colleagues investigated the impact of the group lifestyle balance program, modified from the lifestyle intervention program used in the U.S. diabetes prevention program (DPP).

The DPP was a national study that demonstrated that people at risk for diabetes who lost a modest amount of weight and sharply increased their physical activity levels reduced their chances of developing diabetes or metabolic syndrome, and outperformed people who took a diabetes drug instead.

Group lifestyle balance is a 22-session year-long program aimed at helping people make lifestyle changes to lower their risk for diabetes and heart disease. The goals of the program are to help participants reduce their weight by 7 percent and increase their moderate intensity physical activity (such as brisk walking) to a minimum of 150 minutes per week.

As part of the Pitt community intervention effort, 223 participants were enrolled to test the effectiveness of the program at a worksite and three community centers. The participants averaged 58 years of age and had pre-diabetes or metabolic syndrome or both.

As a result of participating in the program, participants added an average of 45-52 minutes of moderate intensity activity similar to a brisk walk to their weekly routine, which was maintained after the program ended at one year.

Said senior author Andrea Kriska, faculty member in the Department of Epidemiology and principal investigator of the study: “This is one of the few programs of its kind to report on physical activity-related outcomes in a large group and the only known diabetes prevention healthy lifestyle program to examine the effect of season and weather on changes in physical activity levels. Since increased physical activity is one of the primary targets of these programs, it is critical to know if it is working and what can be done to improve the chances that participants reach their goals.”

Additional Pitt authors on this research were Bonny J. Rockette-Wagner, Mary Kaye Kramer, Vincent C. Arena, Rachel G. Miller and Karl K. Vanderwood.
This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

—Compiled by Marty Levine


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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