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October 15, 2015

Research Notes

Adolescent brain development, substance abuse studied

A research team in the School of Medicine’s Department of Psychiatry has been awarded a $5 million National Institutes of Health (NIH) grant to participate in a multisite study focusing on the impact of adolescent marijuana, alcohol and other drug use on the developing brain.

The adolescent brain cognitive development (ABCD) study will follow nearly 10,000 children ages 9 and 10 over the next several years, beginning prior to drug use and continuing through the period of highest risk for substance abuse and other mental health disorders. Nearly 500 local children are expected to participate in the study.

Duncan B. Clark, psychiatry faculty member, will lead the local research site. In total, the ABCD grants will fund 11 research sites, a coordinating center and a data analysis and informatics center.

Said Clark: “There is much to learn about the effects of marijuana, alcohol and other substances on the development of the adolescent brain. At this time, there are inconsistent findings in small studies. For that reason, the NIH has decided to fund this very large prospective study to follow children before they have engaged in any substance use or abuse, through their teen years and into young adulthood.”

Armed with the NIH funding, the Pitt team, which includes David Lewis, Beatriz Luna, Rolf Loeber and Claudiu Schirda, will address issues such as the impact of occasional versus regular substance use on brain development, the link between substance use and mental illness, physical health and development, academic achievement and which factors influence substance use and its consequences. Study results will be used to prioritize prevention and treatment research as well as influence public health strategies and policy decisions.

Said Luna: “This will be the first research project to study such a large group of individuals from early in development, when most would not have used drugs, to possibly peak use in adolescence, and to explore different pathways that contribute to decreases in substance use with maturation. This will enable us to understand predictors of use and the nature of effects of substance use during brain development through childhood and adolescence.”

The ABCD study was initiated by the Collaborative Research on Addiction at NIH, including the National Institute on Drug Abuse, the National Institute on Alcoholism and Alcohol Abuse and the National Cancer Institute, with additional support from other NIH organizations, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, the National Institute on Minority Health and Health Disparities, the National Institute of Neurological Disorders and Stroke and the Office of Behavioral and Social Sciences Research.


Working to mass-produce stem cells

Human stem cells hold great promise for medicine. They can be used therapeutically, they can help model disease and they can be used to help discover new drugs. But it is very difficult to culture enough cells to meet the demand.

Ipsita Banerjee, faculty member in chemical and petroleum engineering and in bioengineering in the Swanson School of Engineering, received a $300,000 grant from the National Science Foundation to explore an idea that would allow the manufacture of human pluripotent stem cells, which can become virtually any tissue, on an industrial scale.

At present, Banerjee says, culturing stem cells is a delicate proposition, with only a 30 percent chance of survival. Current methods are limited by the low viability of initial cell-seeding populations and a tendency for the cells to be heterogeneous, a problem when uniformity is required.
Banerjee and co-investigator Prashant Kumta, bioengineering faculty member in the Swanson school, think that by creating a biomimetic hydrogel encapsulation system to mimic the cell-to-cell interaction without which stem cells die, they’ll be able to overcome these obstacles.

Said Banerjee: “It’s kind of a simple idea, but it hasn’t been done. I thought someone must have done it, at least with other kinds of cells, but no one has.”

The capsules she and Kumta plan to create will use an as-yet-unidentified peptide to convince individual cells they’re in the company of others, enhancing survival. “[A cell] will think that it is in contact with another cell and will not activate the cell-death pathway,” Banerjee said.

If they find the right peptide and their theories about stem cell behavior and viability are confirmed, Banerjee and Kumta are hopeful that their method of stem-cell cultivation will allow labs around the world to generate enough stem cells to meet demand.

“Our method is cheap and simple,” Banerjee concluded. “If we’re right, just about anyone in any lab will be able to reproduce it.”


Therapies for breast cancer examined

Physicians at the University of Pittsburgh Cancer Institute (UPCI) and Magee-Womens Hospital have started a clinical trial to learn more about how three commonly prescribed anti-estrogen therapies affect the tumor tissue of patients diagnosed with invasive lobular breast cancer (ILC), a less common type of breast cancer. This is the first study of its kind to employ a prospective clinical trial approach to understanding ILC, the researchers say.

Patients with ILC represent 5-15 percent of breast cancer patients, and it is unclear how their cancers differ from those with invasive ductal carcinoma, which is more common. Previous laboratory models studied by researchers at the Women’s Cancer Research Center (WCRC) at UPCI and Magee-Womens Research Institute (MWRI) and Foundation suggest that patients with ILC may respond differently to anti-estrogen therapies commonly given to those with either cancer type.

Said Rachel Jankowitz, medicine faculty member in the School of Medicine’s Division of Hematology/Oncology, medical director of Magee’s breast and ovarian cancer risk assessment and prevention program and the trial’s principal investigator: “Currently, there is a one-size-fits-all approach in how we treat patients with invasive lobular breast cancer and invasive ductal carcinoma. Our goal is to increase understanding of how to tailor treatment for women with ILC in order to ultimately improve their long-term outcomes.”

During the 21-day period before surgery is performed, study participants will be randomized into three groups that will receive one of three different drugs that are commonly used in breast cancer treatment.

Said Steffi Oesterreich, faculty member in the Department of Pharmacology and Chemical Biology and the WCRC’s director of education: “Our trial will examine how ILC tumor tissue responds to the current standards of care — treatment with either tamoxifen or anastrazole, as compared to fulvestrant, a drug currently approved only to treat advanced breast cancer.” Oesterreich will direct the analyses of the breast tumor tissues to identify molecular markers of response or resistance to therapies.

Jankowitz’s team plans to open the study at several other large cancer centers that have expressed interest in enrolling their patients through the Translational Breast Cancer Research Consortium, a collaborative group of 17 clinical sites that aims to conduct innovative and high-impact clinical trials for breast cancer.

The trial is supported by the Susan G. Komen Foundation and by AstraZeneca.


Massive pulmonary clinical trials set

Graduate School of Public Health and School of Medicine investigators will lead a $15 million, five-year federal initiative to manage national clinical trials aimed at developing new treatments for breathing disorders.

The effort is funded by the National Heart, Lung and Blood Institute (NHLBI), part of the NIH.

The Network Management Core — or NEMO — will coordinate and support trials related to the Pulmonary Trials Cooperative (PTC), which will carry out multiple clinical studies on a variety of chronic lung conditions, including interstitial lung disease, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, sarcoidosis and obstructive sleep apnea.

Chronic lung diseases are some of the most common medical conditions in the world, with more than 15 million people in the U.S. alone suffering from COPD, a condition that is the third-leading cause of death nationwide, according to the American Lung Association.

NEMO will be led by Stephen Wisniewski, epidemiology faculty member, and Frank Sciurba, director of the Emphysema COPD Research Center in the Division of Pulmonary, Allergy and Critical Care Medicine.

Said Wisniewski, who also is associate vice provost for planning: “Across the country, multiple clinical trials will be in operation to address the urgent need for new treatments and to test existing treatments for people with chronic lung conditions, all managed under one program. This will create a massive amount of data and requires diligent coordination and collaboration among trial sites.”

Sciurba, who is a faculty member in medicine, said: “Investigators in our pulmonary division have offered leadership in many clinical trials over the years and have successfully translated the latest scientific findings into improved patient care. This expertise will be a great asset as we recruit and organize several dozen medical centers to work together to test new treatments for pulmonary patients.”

The PTC has letters of support from over 100 clinical research programs nationwide with registries totaling 72,000 people.

Through the NEMO, Pitt will recruit and manage the clinical centers that will carry out specific trials awarded separately by NHLBI. To improve efficiency and expedite the trials, the NEMO will develop and distribute study-specific manuals, train staff at the clinical centers, manage a bank of biospecimens, provide a secure web portal for communication among researchers and coordinate meetings, among many other responsibilities.

Additional Pitt NEMO investigators include Maria Mori Brooks, Scott O’Neal, Heather Eng, Christina Ledezma, Kevin Gibson, Kathleen Lindell, Patrick Strollo, Daniel Buysse, Mark Gladwin, Michael Mathier, Alison Morris, Joseph Pilewski, Yingze Zhang, Joseph Leader and Michael Becich. Other researchers come from the University of Nebraska Medical Center, the Medical University of South Carolina, Yale School of Medicine and Penn State Milton S. Hershey Medical Center.


Dengue spread linked to strong El Niño

An international research team led by the Graduate School of Public Health has shown that epidemics of dengue, which is caused by a mosquito-borne virus, across southeast Asia appear to be linked to the abnormally high temperatures brought by the El Niño weather phenomenon.

Now, as the most intense El Niño in nearly two decades is emerging in the Pacific, the finding — reported in the Proceedings of the National Academy of Sciences — may be a harbinger of a spike in cases of the dangerous hemorrhagic fever throughout southeast Asian countries early next year.

Said lead author Willem G. van Panhuis, epidemiology faculty member: “Large dengue epidemics occur unexpectedly, which can overburden the health care systems. Our analysis shows that elevated temperatures can create the ideal circumstance for large-scale dengue epidemics to spread across a wide region. The ability to predict and prepare for these epidemics should lead to more effective disease surveillance and control efforts.”

Dengue virus is transmitted by mosquitoes in the tropics and subtropics. It causes an estimated 390 million infections each year. Though there is no specific pharmaceutical treatment, supportive therapy can greatly improve outcomes.

In many countries, reported cases of dengue wax and wane during the rainy season following a repeating annual cycle. So far, it has been difficult to predict when these epidemics will become unusually large, spreading beyond country borders.

The research team collected and analyzed 18 years of monthly dengue surveillance reports on a total of 3.5 million reported cases in 273 provinces in eight countries in southeast Asia. By bringing the data together from several countries, the scientists were able to see patterns — or synchronicity — in dengue transmission across the entire region.

“This is another example of extracting valuable information from routinely collected public health data that was just sitting around in basements and computer archives across these countries,” said van Panhuis.

In 1997 and 1998, dengue transmission was very high, matching up perfectly with high temperatures that allowed mosquitoes to reproduce faster and spread dengue virus more efficiently.

These high temperatures were caused by an exceptionally strong El Niño season, which occurs when rising seawater temperatures in the eastern Pacific move westward. This phenomenon occurs about every five years, with one of the largest episodes expected in the coming months.

This study also found that urban areas act as dengue epidemic “pacemakers” because of their constant supply of new people who are susceptible to dengue.

In addition, traveling waves of large epidemics were found to emerge from west Thailand, central Laos and the southern Philippines.

“Given the increased cross-border mobility of people, strong evidence of global warming and the potential for rapid global proliferation of infectious diseases, a better understanding of how contagious diseases spread over long distances is essential for global health security,” said van Panhuis.

The international team involved scientists from 18 institutions around the world, including the Ministries of Health in each study country. Donald S. Burke, dean of public health and UPMC Jonas Salk Professor of Global Health, was the principal investigator of the study, which included authors from the University of Florida, the Johns Hopkins Bloomberg School of Public Health and the University of Malaya in Malaysia.

This research was funded by the Bill & Melinda Gates Foundation and the NIH National Institute of General Medical Sciences.


Conflict seen in board service

Nearly 1 in 10 U.S. for-profit health care company board positions is held by individuals with an academic affiliation, a potential conflict of interest not explicitly addressed by national guidelines, a review led by the School of Medicine reveals.

The analysis, published in The BMJ, found that academically affiliated board members were compensated an average of $193,000 in 2013 for their board memberships and often also held significant company stock.

Said senior author Walid Gellad, faculty member in medicine and co-director of the Center for Pharmaceutical Policy and Prescribing: “Academia should encourage collaboration with industry and these partnerships have the potential to advance science and improve health, but board membership is a step beyond consulting or collaborating. Board members are part of the company’s leadership, have substantial equity in the company and have a duty to shareholders, which can potentially lead to conflicts of interest with their academic duties.”

Gellad, with Timothy Anderson, chief medical resident in the Department of Internal Medicine, and Chester B. Good, faculty member in medicine and pharmacy, analyzed the public disclosures of all publicly traded U.S. health care companies listed on the NASDAQ exchange and New York Stock Exchange in January 2014 that specialized in pharmaceuticals, biotechnology, medical equipment and providing health care services.

Of the 442 companies with publicly accessible disclosures on boards of directors, 180 (41 percent) had one or more academically affiliated directors in 2013. These individuals included faculty members, trustees, chief executive officers, vice presidents, presidents, provosts, chancellors and deans from 85 nonprofit academic research and health care institutions.

The 279 academically affiliated board members received annual compensation totaling over $54 million and owned over 59 million shares of company stock.

The U.S. Physician Sunshine Act, which requires nearly all payments to physicians and academic medical centers to be reported annually by pharmaceutical and medical device companies, does not require separate reporting of payments for serving as a company director.

Said Anderson, lead author of the study: “As our analysis shows, many academic leaders and professors in medicine may have significant industry relationships not captured by the Sunshine Act. Often when we talk about conflicts of interest in medicine, we are talking about physicians receiving pens and meals from sales representatives. The stakes are much higher for the board members in our study.”

The team intentionally did not disclose the names of the academically affiliated board members in their analysis in an effort to highlight the issue, not the individuals.

“Our goal was not to pass judgment but to start an open discussion,” said Anderson. “We do not expect a one-size-fits-all approach would work in managing these relationships, but we risk undermining the public’s trust if these conflicts of interest are not addressed openly.”

Gellad previously received and reported consulting fees from IMS Health and grant funding from Express Scripts for work unrelated to The BMJ publication. He was supported through a VA Health Services Research & Development award.


Concussions misunderstood by most Americans

A survey of U.S. adults found that the vast majority do not know the definition of a concussion and many do not know the injury is treatable. The national survey of 2,012 Americans age 18 and over was conducted in April by Harris Poll on behalf of UPMC. The survey further showed that, despite a lack of knowledge and understanding, there is a high level of concern and even fear across the country.

A fear of concussions may be affecting parents’ decisions to let their kids play contact sports:

• 89 percent of adults believe concussions are a moderate to severe health concern;

• 32 percent of parents live in fear that their child will get a concussion;

• 25 percent do not let their kids play some contact sports because of fear of concussion;

• 41 percent of adults feel that getting a concussion is a “living nightmare”;

• Many Americans (57 percent) have personal experience with concussions;

• 26 percent of adults did not see a health care professional when someone in their family had a concussion;

• 87 percent of Americans do not know the definition of a concussion;

• 37 percent of adults admit that they are confused about what a concussion truly is;

• Slightly fewer than 3 in 5 adults can correctly identify immediate symptoms of a concussion: headache (58 percent), dizziness/motion sensitivity (58 percent) and cognitive difficulty (55 percent);

• Far fewer — roughly 1 in 3 or fewer — understand that the following also are symptoms: fatigue (34 percent) and changes in mood (13 percent);

• 29 percent of Americans believe that all concussions can be treated;

• 79 percent of adults incorrectly believe or are unsure that there is no real way to cure a concussion, that the symptoms can only be lessened;

• 81 percent of Americans aren’t comfortable that they would know the steps to manage or treat a concussion if they sustained one;

• 83 percent feel that major progress has been made in the past 10 years in assessing and treating concussions;

• 49 percent of adults know that a person does not need to stay awake for 24 hours after sustaining a concussion;

• 83 percent of adults believe people generally do not take concussions seriously enough;

• 25 percent of Americans understand that safety equipment — such as helmets or mouth guards — cannot prevent the majority of all concussions, as scientific research shows; and

• 16 percent of adults believe there are no best practices to treat concussions.

Said Micky Collins, faculty member in orthopaedic surgery and executive and clinical director of the UPMC Sports Medicine concussion program: “This survey highlights the myths about concussion and the need for education. The reality is that we have made tremendous progress in the diagnosis, management and rehabilitation of this injury. The study results are cause for concern because, given these advances, parents should not be living in fear. Sports can be an integral part in a child’s physical and social development. As clinicians and scientists, we need to disseminate more accurate information.”

Erin Reynolds, orthopaedic surgery faculty member and fellowship director of UPMC Sports Medicine concussion program, said: “We see this injury all day long and we also see that with proper management, kids recover and return to play. With careful evaluation and treatment by a well-trained specialist, even the most complex injuries are manageable.”


Regeneration of diseased aortas studied

Abdominal aortic aneurysm (AAA), caused by the loss of elastin, a critical protein for blood vessel function, is responsible for approximately 10,000 American deaths every year. Through a grant from NIH, vascular bioengineering researchers at the Swanson school are proposing a new strategy for delivering therapeutic cells to the diseased cells to restore elastin levels and regenerate the aorta.

The research is being led by David A. Vorp, associate dean for research at the Swanson school and the William Kepler Whiteford Professor of Bioengineering. The proposal, “Outside-In Regenerative Therapy for Abdominal Aortic Aneurysm (AAA),” will receive $439,220 in funding through April 2017, and is a collaborative effort with a researcher at Vanderbilt.

Said Vorp: “Elastin is a highly elastic protein that allows soft tissues in our body — including blood vessels — to stretch and contract, but it is susceptible to the effects of aging, high blood pressure, high cholesterol and smoking. Therefore, abdominal aortic aneurysms greatly impact the elderly, especially men, and, if left untreated, can ultimately result in structural failure or rupture of the aortic wall and, many times, death.”

According to Vorp, the research will focus on development and delivery of mesenchymal stem cells to the outside of the aneurysm and will be tested in an established rodent model of the disease. Following treatment, the researchers will study whether the stem cells slow, halt or even reverse the structural degeneration of the AAA. The results eventually could lead to an effective treatment for humans using a patient’s own stem cells.

“Few diseases present greater potential for regenerative cellular therapy than AAA, and the possibility of reconstitution and strengthening of the aorta is very exciting,” Vorp said. “By delivering stem cells to restore elastin, we can effectively treat a life-threatening disease without complex invasive surgery.”


“Acoustic tweezers” will track placenta health

A transdisciplinary team led by researchers at the School of Medicine and MWRI will be developing “acoustic tweezers” and other ways of tracking placental health in real time during pregnancy. The five-year program was one of 19 selected for the Human Placenta Project, led by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of NIH, which has committed approximately $46 million to the effort for this fiscal year.

Throughout human pregnancy, the placenta is indispensable for embryonic development, fetal growth and maintaining the health of baby and mother, noted Yoel Sadovsky, MWRI director, Elsie Hilliard Hillman Professor of Women’s and Infants’ Health Research in Medicine and principal investigator. Said Sadovsky: “Placental dysfunction can be the cause of common pregnancy complications, such as preeclampsia and fetal growth restriction. A fundamental challenge in perinatal medicine arises from our limited ability to diagnose placental disorders in real time and throughout pregnancy.”

The team, which includes investigators from Carnegie Mellon University, MIT and Penn State, will focus on the outermost layer of the placenta called the trophoblast, which regulates maternal-fetal gas exchange, nutrient delivery, waste removal and hormone production.

Scientists discovered recently that throughout pregnancy, the trophoblast secretes into the mother’s bloodstream tiny, bubble-like vesicles that contain small bits of genetic material called RNA.

By testing the trophoblast-specific RNA obtained from maternal blood samples, the researchers hope to monitor placental health. In one technique, they will employ “acoustic tweezers” in which sound waves will be used to separate vesicles for study based on their size and other physical properties.

—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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