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January 9, 2014

Research Notes

NIH awards $1.5 million for study of pancreatic cancer

The National Institutes of Health (NIH) has awarded a five-year grant of more than $1.5 million to Herbert J. Zeh III, surgery faculty member and chief of the Division of Gastrointestinal Surgical Oncology at the University of Pittsburgh Cancer Institute (UPCI) and UPMC CancerCenter, and Michael T. Lotze, faculty in surgery, immunology and bioengineering and assistant vice chancellor, Schools of the Health Sciences, at UPCI. They are partnering with the CancerCenter to study a novel treatment for pancreatic ductal adenocarcinoma (PDA), the most common form of pancreatic cancer.

PDA is the fourth-leading cause of cancer deaths in the United States. The five-year survival of patients suffering from PDA is less than 5 percent.

The pair hypothesize that the cancer progresses and is difficult to treat because of a biological pathway called autophagy, a form of programmed cell survival that tumor cells use to avoid apoptosis, or cell death.

Said Lotze: “It is our hope that blocking autophagy, a new approach to treating cancer, will improve the efficacy of chemotherapy for pancreatic cancer patients.”

HIV/AIDS researchers get almost $80 million

The federal government has awarded nearly $80 million to Pitt HIV/AIDS researchers.

The Microbicide Trials Network (MTN) has received $70 million in new funding from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), as well as the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health (NIMH). Now, MTN will continue through 2021 to develop and test products that aim to reduce the spread of HIV, the virus that causes AIDS. The program, begun in 2006, is based at Pitt and Magee-Womens Research Institute (MWRI). It has completed 13 trials since 2006; 11 more are in progress or will begin within the year, and several new studies will be designed and implemented during the new funding period.

The MTN brings together international investigators and community and industry partners whose work is focused on the development and rigorous evaluation of promising microbicides, which are products applied inside the vagina or rectum that are intended to prevent the sexual transmission of HIV.

Said co-principal investigator Sharon Hillier, vice chair for faculty affairs in obstetrics, gynecology and reproductive sciences in the School of Medicine and an MWRI member: “Although progress in the field of HIV prevention and treatment has been nothing short of breathtaking over the last decade, there are two groups who continue to have high rates of new HIV infections — young women and men who have sex with men. The MTN is focused on developing products to address their unmet needs. To address the HIV epidemic in young women, we currently are conducting a large phase III trial of a vaginal ring that women use for a month at a time. Moving forward, we are committed to developing products that could prevent both HIV and unwanted pregnancy, which would empower young women to take charge of their own reproductive health.”

Another high-priority research area is to address the unmet need for new HIV prevention products for use by men who have sex with men, transgender women and heterosexual women who have anal sex.

Said co-principal investigator Ian McGowan, medicine faculty in the Division of Gastroenterology, Hepatology and Nutrition in the School of Medicine and an MWRI member: “Our entire scientific agenda is focused on conducting the kind of studies that can get safe and effective HIV prevention products approved for widespread use, whether these be vaginal or rectal microbicides. Clearly, we can’t end the HIV epidemic with condoms alone.”

The MTN is composed of three major components: a leadership and operations center, which is led by Hillier and McGowan; a laboratory center, based at MWRI and led by Charlene Dezzutti, faculty in obstetrics, gynecology and reproductive sciences in the School of Medicine, and a statistical data and management center based at the Fred Hutchinson Cancer Research Center in Seattle. The $70 million from NIAID supports the work of the leadership and operations center and the laboratory center.

The network is affiliated with more than 25 clinical research sites in Africa, North America, South America and Asia, which are part of NIAID-funded clinical trials units (CTUs).

An additional $8.7 million was awarded to Pitt by NIAID over seven years to remain one of 37 CTUs for HIV/AIDS research. The CTUs are responsible for implementing the scientific agendas of NIAID’s networks. John Mellors, medicine faculty and chief of the Division of Infectious Diseases in the School of Medicine, is the principal investigator for the unit, which will oversee MTN studies conducted at Pitt and studies of the AIDS Clinical Trial Group (ACTG), another NIH-funded clinical trials network, at research sites at Pitt and Ohio State University. Mellors also leads the virology cores of the MTN’s and ACTG’s laboratory centers and the ACTG’s efforts to cure HIV infection.

Anxiety may increase long-term stroke risk

People with high levels of anxiety may be at an increased risk for stroke, according to a new study published in the journal Stroke. Pitt researchers evaluated more than 6,000 participants and found those with the highest levels of anxiety are 33 percent more likely to suffer a stroke, as compared to their less anxious counterparts.

Previous studies have found that higher levels of anxiety are associated with increased risk for coronary heart disease; few studies have investigated the connection between anxiety and stroke. This study is the first to report an association between higher anxiety symptoms and an increased risk for stroke, despite other risk factors such as depression.

Said Maya Lambiase, post-doctoral scholar in psychiatry at the School of Medicine and lead author: “Anxiety is a very common condition in the general population, but it’s also a modifiable behavior. Assessment and treatment of anxiety has the potential to not only improve overall quality of life, but also reduce the risk of cardiovascular diseases, such as stroke, later in life.”

Anxiety disorders affect nearly 20 percent of American adults in any given year, and are characterized by feelings of fear, unease and worry, often lasting at least six months.  Feelings of stress and anxiety also are common in people who feel depressed or have other mental health problems, including alcohol or substance abuse.  Stroke, which occurs when blood flow to a part of the brain stops, is the No. 4 killer and a leading cause of disability in the U.S.

Said Rebecca Thurston, psychiatry faculty member and co-author of the study: “Most of the focus up until this point has been on depression. These findings underscore the importance of also considering anxiety when considering cardiovascular diseases [and] encourage practitioners to assess and treat anxiety, as well as to reconsider popular notions such as ‘worried well’ — this worrying may not make us so well.”

Researchers studied people aged 25-74 who had not experienced a stroke and were representative of the general U.S. population. All participants were enrolled in the National Health and Nutrition Examination Survey (NHANES), which collected data from 1971-75. Participants filled out a questionnaire that measured anxiety and depression levels, and then were followed for a period of up to 22 years.  Researchers tracked stroke occurrences in these people through death certificates as well as hospital and nursing home reports.

“Even a modest increase in anxiety was associated with an increase in stroke risk, so greater education and awareness of anxiety management is important,” added Lambiase. The researchers also noted that people with high anxiety levels are more likely to smoke and be physically inactive which may help explain part of the anxiety-stroke link.

A researcher from Harvard contributed to this study, which was funded by the National Heart, Lung and Blood Institute and NIMH.

Race a factor in weight loss

African-American women may need to eat fewer calories or burn more than their Caucasian counterparts to lose a comparable amount of weight, according to School of Medicine researchers in a study published in the International Journal of Obesity.

Several studies have suggested that African-American women don’t lose as much weight as Caucasian women in response to the same behavioral interventions of calorie restriction or increased physical activity, noted lead investigator James P. DeLany, medicine faculty member in the Division of Endocrinology and Metabolism in the School of Medicine.

Said DeLany: “At first, it was thought that perhaps the African-American women didn’t adhere as closely to their calorie prescriptions or that the interventions were not culturally sensitive. But even in research projects that were designed to address those possibilities, the difference in weight loss remained.”

DeLany’s team decided to see if there were metabolic reasons behind the discrepancy by examining body weight changes, energy expenditure, physical activity and energy intake among 39 severely obese African-American and 66 Caucasian women who were participating in a six-month weight loss program of calorie restriction and increased physical activity. They measured body composition and daily energy expenditure at the beginning and end of the intervention period and assessed physical activity levels using multisensor activity monitors. By combining these measures, they obtained objective assessment of intake during the intervention.

The researchers found that the African-American women lost about seven pounds fewer than the Caucasian women, even though their starting body mass index, or BMI, measures were comparable and they followed as closely to the calorie restriction and activity prescriptions. But the African-American women had lower resting metabolic rates and expended less energy daily than the other group.

Calorie prescriptions typically are calculated by determining how many calories are needed to fuel the body’s basic physiological processes and adding the calories needed for other activities. To maintain weight, calorie intake and output should be equal. If more calories are burned than are taken in by eating, weight loss should occur.

“We prescribe how many calories are allowed and how much activity is needed during weight-loss interventions based on the premise that people of the same weight have similar metabolic rates,” DeLany said. “But to account for their lower metabolic rate, African-American women must further reduce the number of calories they eat or use up more of them with exercise in order to lose the same number of pounds in the same time span as a Caucasian woman of the same weight.”

Other members of the research team were John M. Jakicic, health and physical activity faculty member in the School of Education and the Physical Activity and Weight Management Research Center in the Division of Endocrinology in the School of Medicine; Jolene B. Lowery, now of Morehouse College; Kazanna C. Hames, now of Mayo Clinic; David E. Kelley, now of Merck Sharp & Dohme Corp., and Bret H. Goodpaster, now of Florida Hospital, Orlando.

The study was funded by the Commonwealth of Pennsylvania Department of Health.

Possible pharmacologic solution to cocaine addiction

Imagine kicking a cocaine addiction simply by popping a pill that alters the way your brain processes chemical addiction. New research led by neuroscience professor Yan Dong in the Dietrich School of Arts and Sciences suggests that a method of biologically manipulating certain neurocircuits could lead to a pharmacological approach that would weaken post-withdrawal cocaine cravings. The findings were published in Nature Neuroscience.

Dong’s team used rat models to examine the effects of cocaine addiction and withdrawal on nerve cells in the nucleus accumbens, a small region in the brain that is associated with reward, emotion, motivation and addiction. Specifically, they investigated the roles of synapses, the structures at the ends of nerve cells that relay signals.

When an individual uses cocaine, some immature synapses are generated, which are called silent synapses because they send few signals under normal physiological conditions. After that individual quits using cocaine, these silent synapses go through a maturation phase and acquire the ability to send signals. Once they can send signals, the synapses will send craving signals for cocaine if the individual is exposed to cues that previously led him or her to use the drug.

The researchers hypothesized that if they could reverse the maturation of the synapses, the synapses would remain silent, thus rendering them unable to send craving signals. They examined a chemical receptor known as CP-AMPAR that is essential for the maturation of the synapses. In their experiments, the synapses reverted to their silent states when the receptor was removed.

Said Dong, the study’s corresponding author: “Reversing the maturation process prevents the intensification process of cocaine craving. We are now developing strategies to maintain the ‘reversal’ effects. Our goal is to develop biological and pharmacological strategies to produce long-lasting de-maturation of cocaine-generated silent synapses.”

Dong collaborated with neuroscience colleague Susan Sesack and researchers from the European Neuroscience Institute, National Institute on Drug Abuse (NIDA); Icahn School of Medicine at Mount Sinai, and the Chicago Medical School of the Rosalind Franklin University of Medicine and Science.

The research was supported by NIDA and the German Research Foundation.

Immune avoidance mechanism discovered

A mosquito-borne virus that kills about half of the people it infects uses a never-before-documented mechanism to “hijack” one of the cellular regulatory systems of its hosts to suppress immunity, researchers from the Center for Vaccine Research (CVR) found.

The discovery, which will be published in Nature and was funded by NIH, could aid in the development of vaccines and treatments for eastern equine encephalitis virus (EEEV), a rare but deadly disease that is found primarily in the Atlantic and Gulf states. It also may be useful in efforts to inhibit other diseases, such as West Nile virus, dengue, rhinovirus and SARS.

Said senior author William Klimstra, microbiology and molecular genetics faculty member and part of the CVR: “Anytime you understand how a virus causes a disease, you can find ways to interrupt that process. And this discovery is particularly exciting because it is the first time that anyone has shown a virus using this particular strategy to evade its host’s immune system and exacerbate disease progression.”

EEEV carries ribonucleic acid (RNA) as its genetic material. Klimstra and his colleagues discovered that EEEV evolved to have a binding site in its RNA that fits perfectly with a small piece of RNA, called microRNA, in the cells of the organism that the virus is invading. Typically, microRNAs are produced by the host to control its own cellular processes.

When the virus binds with the microRNA in certain cells involved in triggering an immune response in a human, it restricts its own replication. This allows the virus to evade an immune response because the viral replication in these cells is what would normally tip off the host’s immune system and induce it to mount an attack to rid the body of the virus.

Meanwhile, the virus is able to replicate and spread undetected in the cells of the host’s neurological system and cause overwhelming disease.

EEEV causes inflammation of the brain that begins with the sudden onset of headache, high fever, chills and vomiting and can quickly progress to disorientation, seizures and coma.

There is no treatment for the disease, but it is rare, with about five-30 cases reported in the U.S. annually, according to the U.S. Centers for Disease Control and Prevention. It has a 30-70 percent fatality rate, the highest of any North American mosquito-borne virus, with significant brain damage in most survivors.

It does not transmit easily to humans, and the mosquito species that typically carries it usually is found in swampy areas that aren’t highly populated, though it has been found in more common mosquitoes, spurring pesticide spraying, curfews and outdoor event cancellations in recent years in states such as Massachusetts, where EEEV is found more frequently.

In the laboratory, Klimstra and his colleagues created a mutant version of EEEV without the microRNA binding site, which allowed them to discover that the binding site is key to the virus evading detection. When this manufactured mutant version was tested in the laboratory, the researchers found that the host’s immune system was able to mount an effective response to the mutant virus. Klimstra added that the studies mostly were done in the Regional Biocontainment Laboratory at Pitt, a unique, high-security facility constructed with Pitt and NIH funds.

“Viruses are constantly evolving and changing,” said Klimstra. “However, the genetic sequence that allows EEEV to bind to our microRNA has persisted. We find it in samples from the 1950s, which indicates tremendous evolutionary selection pressure to maintain this mechanism. Ultimately, these results suggest that the mutant virus could be used as an EEEV vaccine and that microRNA blockers could have potential for use as a therapeutic treatment for EEEV-infected patients who currently can be treated only with supportive care.”

Co-authors on this research were Derek W. Trobaugh, Cristina L. Gardner, Chengqun Sun and Kate D. Ryman of the CVR and microbiology and molecular genetics, along with researchers from the University of Texas and the Weizmann Institute of Science.

Lung lesion variants give hope for TB treatment

The lung lesions in an individual infected with tuberculosis (TB) are surprisingly variable and independent of each other, whether the patient has clinically active or latent disease, according to a new animal study led by School of Medicine researchers. The findings, published in Nature Medicine, could point the way to new vaccines to prevent the hard-to-treat infection.

More than 30 percent of the world’s population is infected with mycobacterium tuberculosis, the bacterium that causes TB, yet only 5-10 percent of those infected develop active, contagious disease with symptoms of coughing, chest pain, night sweats and weight loss. Most have asymptomatic, or “latent,” infections that are not contagious, but could become active years later.

When the lungs become infected with M. tuberculosis, the body’s immune system walls off the bacteria into lesions called granulomas, explained co-senior investigator JoAnne Flynn, microbiology and molecular genetics faculty member in the School of Medicine. “It’s long been thought that the patient with a weakened immune system or some other immune vulnerability was more likely to develop active disease. But to our surprise, our study showed that every infected individual has a collection of granulomas, some containing live bacteria and some that are sterile because the immune system has killed all the bacteria. So in this sense, there’s no such thing as a latent or active granuloma.”

The research team infected monkeys with TB and then tracked the granulomas that developed in the lungs. They determined that each granuloma starts with only one bacterium, and that bacterial replication continues for about four weeks before the body counters with an adaptive immune response to kill off the invaders.

“This response was sufficient to kill all the bacteria and sterilize some granulomas, but bacteria persisted in others and spread to create new granulomas,” Flynn said. “You need only one granuloma to ‘go bad’ in order to get active TB.”

Even when an animal had a severe active infection, some of their granulomas were sterile, indicating the immune system was capable of killing bacteria, the researchers found.

“We don’t know yet why the immune response produced different results in different lesions,” Flynn said. “When we develop a deeper understanding of why the immune response produced different results in different lesions, we will be closer to harnessing the right mechanisms to develop effective vaccines to prevent TB.”

The research team included team medicine faculty Philana Ling Lin, M. Teresa Coleman and Amy J. Myers. Other researchers were from Harvard and Texas A&M.

The project was funded by the Bill & Melinda Gates Foundation, the Otis Childs Trust of the Children’s Hospital of Pittsburgh Foundation, NIH and its National Institute of Allergy and Infectious Diseases, Howard Hughes Medical Institute, the Physician Scientist Early Career Award, the Harvard Merit Fellowship, the Burroughs Wellcome Foundation Investigator in the Pathogenesis of Infectious Diseases Fellowship, the Robert A. Welch Foundation and the Melvin J. and Geraldine L. Glimcher Associate Professorship.

Pharm prof gets grant

The Vasculitis Foundation has awarded a two-year grant to Carolyn Thorpe, faculty member in pharmacy and therapeutics at the School of Pharmacy, for her study “Impact of Healthcare Utilization and Informal Caregiver for Primary Systemic Vasculitis: A National Perspective.”

Thorpe and her team will use national administrative data from Medicare as well as the Healthcare Cost and Utilization Project to characterize variations in healthcare utilization, medication use, costs and mortality by individuals who have a form of primary systemic vasculitis. They also will survey patients and their family and friends to describe the nature and impact of informal caregiving for systemic vasculitis and identify predictors of greater burden.

Co-investigators included pharmacy faculty member Joshua Thorpe and researchers from the University of North Carolina.

NCI supports pharm prof

Pharmaceutical sciences faculty member Song Li has received a grant from the National Cancer Institute for his study “Targeted Combination Therapy for Breast Cancer.”

The goal of this five-year study is to develop a dual functional drug carrier to achieve synergistic antitumor activity with codelivered anticancer agents to improve the treatment of breast cancer.

Results of reproductive coercion studied

Birth control sabotage and pressure to become pregnant by male partners, also called “reproductive coercion,” in the previous three months is associated with recent unintended pregnancy among adolescent and young adult females utilizing reproductive health services, according to a study appearing in Contraception.

The study, led by Elizabeth Miller, pediatrics faculty member in the School of Medicine, adds to the growing body of research on how abusive relationships increase young women’s risk for unwanted and unplanned pregnancies.

Said Miller: “More than half of the pregnancies in the United States are unintended and can result in poor health for mothers and their infants. We need to pay attention to ways in which male partners may influence women’s reproductive decisions.

“Clinicians providing reproductive health care should discuss reproductive coercion in addition to physical and sexual violence in relationships to help women reduce their risk for pregnancies that are mistimed, unwanted or unplanned.”

More than 3,600 English and Spanish-speaking women ages 16-29 at 24 family planning clinics in western Pennsylvania from October 2011 to November 2012 agreed to respond to a computerized survey about their experiences with relationships and pregnancy. They were asked questions about birth control sabotage, pregnancy coercion and intimate partner violence, including the questions: “Has someone you were dating or going out with ever taken off the condom while you were having sex so that you would get pregnant?” and “Has someone you were dating or going out with ever told you not to use any birth control?”

Five percent of respondents reported reproductive coercion in the past three months and 12 percent reported an unintended pregnancy in the past year. Among those who reported recent reproductive coercion, 21 percent reported an unintended pregnancy in the past year. The association occurred independently of any history of reported physical or sexual violence in the relationship.

The findings also highlight the importance of clinics that provide reproductive health services as sites for identification, assessment and interventions for young women to reduce harm related to intimate partner violence and reproductive coercion. These settings can serve as a connection to support services and prevention education to increase women’s safety and reduce pregnancy risk.

The study was funded by the National Institute of Child Health and Human Development.

Collaborators included researchers from Children’s Hospital, the University of California-Davis, Johns Hopkins and UC-San Diego.

Surgery may help certain advanced breast cancers

Patients newly diagnosed with advanced breast cancer and a solitary bone metastasis could benefit from surgery prior to other treatment, according to early results from a clinical trial presented in December at the 2013 San Antonio breast cancer symposium.

Said the study’s lead investigator, surgery faculty member Atilla Soran: “In the U.S., approximately 5 percent of breast cancer patients are diagnosed with advanced disease when they first see their physician. Around the world, that percentage can go as high as 10 percent. Current standard of care recommends avoiding surgery in these patients and prescribing systemic therapy and radiation therapy instead. Previous research, however, has shown that surgery can actually prolong survival in other advanced cancers and we wanted to see if the same held true for breast cancer.”

As a Turkish native, Soran approached the Turkish Federation of Societies for Breast Diseases about conducting a clinical trial to test the survival benefit of such a treatment approach.

In 2007, under scientific advisement with UPMC, the trial launched.

The study enrolled 278 patients with advanced breast cancer from across Turkey, 140 of whom underwent breast cancer surgery. The primary goal of the study was to assess whether early surgical treatment in women with advanced disease could affect overall survival.

“Our initial results don’t show any difference in survival rates, but we are early in the follow-up phase,” said Soran. “However, we did notice that one patient subgroup — patients with a singular metastasis to the bone — is trending toward prolonged survival.”

Patients with aggressive forms of the disease and patients with multiple metastases on the liver and lungs derived less benefit from the treatment approach.

“Breast cancer isn’t just a U.S. concern, it’s a global disease,” Soran said.

Swanson research may yield ultrathin electronics, synthetic cells

Synthetic, man-made cells and ultrathin electronics built from a new form of “zero-dimensional” carbon nanotube may be possible through research at the Swanson School of Engineering published in Angewandte Chemie.

Principal investigators are Steven R. Little, CNG Faculty Fellow and chair of the Department of Chemical and Petroleum Engineering, and Anna C. Balazs, Distinguished Robert v. d. Luft Professor of Chemical and Petroleum Engineering.

Said Little: “Since its discovery, carbon nanotubes have held the promise to revolutionize the field of electronics, materials science and even medicine. Zero-dimensional carbon nanotubes present the possibility to build ultrathin, superfast electronic devices, far superior to the best existing ones, and it could be possible to build strong and ultralight cars, bridges and airplanes.”

One of the most difficult hurdles is processing the carbon nanotubes into smaller forms. However, previous research at Pitt has managed to cut the carbon nanotubes into the smallest dimensions ever to overcome this problem.

The organization of the atoms within nanotubes makes them particularly interesting materials to work with. However, they are barely soluble, making industrial processing difficult. One aspect of the team’s research will focus on creating more soluble and therefore more usable carbon nanotubes. These shorter nanotubes have the same dimensions as many proteins that compose the basic machinery of living cells, presenting the potential for cell- or protein-level biomedical imaging, protein or nucleic acid vaccination carriers, drug delivery vehicles or even components of synthetic cells.

Overall, the project is aimed at developing and working with these more dispersible carbon nanotubes with the aim of making them easier to process. The creation of the smaller nanotubes is the first step toward reaching this goal.

Co-investigators include Riccardo Gottardi, Ri.MED Foundation Fellow; Alexander Star, faculty member in chemistry; Bhaskar Godugu, director of Pitt’s mass spectrometry facility; Swanson faculty member Susheng Tan, postdoctoral researchers Yanan Chen and Kaladhar Kamalasanan, and a researcher from Qron.


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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