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November 21, 2013

Research Notes

NIH funds study of trauma-induced hemorrhaging

Stephen Wisniewski, who is a faculty member in epidemiology, senior associate dean and co-director of the Epidemiology Data Center in the Graduate School of Public Health, will coordinate a new multicenter, multidisciplinary effort to study the deadly bleeding syndrome coagulopathy, which occurs without warning in some trauma patients.

The research is supported by a five-year, $23.8 million National Institutes of Health (NIH) grant.

Led by a University of Vermont researcher, the Trans-Agency Consortium for Trauma-Induced Coagulopathy (TACTIC) study is a cooperative effort funded by the National Heart, Lung and Blood Institute (NHLBI) that establishes a collaboration between NIH and the Department of Defense.

Said Wisniewski: “Multiple, parallel research projects will each explore a different side of coagulopathic syndromes in an effort to discover why they occur and, ultimately, to explore ways to treat and prevent them. Those projects will produce a massive amount of data, something we at Pitt Public Health are well-equipped to collect, analyze and organize into useful information.”

Trauma is the major cause of death in people younger than 34 and the third-leading cause of mortality in the United States, with uncontrollable hemorrhage representing the major cause of preventable deaths, according to NIH. Each year, nearly 50 million traumatic injuries in the U.S. result in 170,000 deaths.

Little is known about the biological phenomena that lead to coagulopathy. When a person sustains a traumatic injury, some, regardless of proper treatment, suddenly suffer from uncontrolled bleeding and die. It is believed that the shock from the trauma induces a “storm” of coagulation and inflammatory problems that prevent the blood from clotting.

Today, there are no analytical tools that allow emergency department staff to conclude that coagulopathy is occurring in trauma victims and no resources to guide an effective therapeutic approach.

A study co-leader at the Oklahoma Medical Research Foundation will look at the role played by DNA and histones that escape from cells in initiating the inflammatory and coagulation abnormalities that occur in trauma.

Other institutions involved in the research are Massachusetts Institute of Technology, Mayo Clinic, Scripps Research Institute, University of California-San Francisco, University of Illinois, University of Pennsylvania, University of Colorado and Virginia Commonwealth University.


Grant targets childhood cancer

Linda M. McAllister-Lucas, Department of Pediatrics faculty member in the School of  Medicine and chief and fellowship program director of the Division of Pediatric Hematology and Oncology, has been awarded a one-year, $50,000 grant from the St. Baldrick’s Foundation, which supports childhood cancer research.

Said McAllister: “This grant will allow our program to perform Phase I clinical trials aimed at identifying new and improved treatment options for childhood cancer.”

More than 60 percent of childhood cancer patients receive treatment as part of clinical trials.


Skin cancer research receives $12 million

A grant to the University of Pittsburgh Cancer Institute (UPCI) melanoma and skin cancer program, led by John Kirkwood, has been renewed through the National Cancer Institute’s (NCI) competitive specialized program of research excellence (SPORE). The grant is for more than $12 million.

The award is the fourth grant awarded to UPCI through SPORE; the three previous grants at UPCI were in head and neck, lung and ovarian cancers.

The latest SPORE grant will fund three new projects and the expansion of one prior project:

Biomarkers of the proinflammatory response and elements of immune suppression. The goal of this project is to find biomarkers in melanoma patients at diagnosis or early in the disease that may predict the benefit of treatment with the drugs ipilimumab or interferon-a (IFNa) for each individual, as well as to assess the risk of melanoma recurrence and death. This effort continues earlier research that revealed biomarker patterns associated with pro-inflammatory immune responses and with immunosuppression in both tumor tissue and circulating blood.

Multiple antigen-engineered dendritic cell immunization and IFNa-2b boost for vaccine immunotherapy of metastatic melanoma. This project tests an improved dendritic cell vaccine targeting tumor antigens given in combination with IFNa-2b with the aim of boosting the immune response against the cancer.

Safety and efficacy of vemurafenib and high-dose IFNa-2b for advanced melanoma. This project will test whether vemurafenib, a drug that inhibits a signaling protein called BRAF, can enhance the therapeutic efficacy of IFNa-2b in patients with metastatic melanoma. In earlier work, the team found BRAF inhibitors make melanoma cells more sensitive to the effects of IFN-a, suppressing cell proliferation and encouraging apoptosis, or programmed cell death; increase T cell-mediated immune responses to melanoma cells, and prolong the survival of mice in a model of melanoma.

A microneedle vaccine program for immunotherapy of melanoma and cutaneous T cell lymphoma.

Kirkwood’s melanoma research team first received SPORE funding five years ago and the grant’s last five projects have focused on immune approaches to treatment of melanoma and other skin cancers. The incidence of melanoma continues to rise dramatically. There has not been effective therapy to improve overall survival for the majority of patients with inoperable metastatic disease, although progress in the molecular therapy and immunotherapy of melanoma now has improved prospects for patients with melanoma considerably.

Said Kirkwood: “We want to improve our understanding of the molecular and immunologic mechanisms underlying melanoma progression and to validate prognostic and predictive biomarkers that will lead to the personalized treatment of melanoma and other skin cancers. Our research is unique because we have integrated an approach that includes experts in melanoma from medical oncology, dermatology, surgery, immunology, biostatistics, bioinformatics and biomarker discovery.”

About 76,000 cases of melanoma are diagnosed every year in the United States and about 9,400 people die annually from the disease, according to the NCI. Kirkwood said the work being done through the SPORE grants already is making a difference. There have been several new therapies for melanoma approved since 2011, compared to just three agents approved in the 30 years prior.


Public health research presented

Pitt researchers presented findings at the recent annual meeting of the American Public Health Association.

Study of HIV transmission rate challenges beliefs

The number of HIV-positive men who have sex with both men and women likely is no higher than the number of HIV-positive heterosexual men, according to a U.S.-based analysis by public health researchers. The finding challenges a popular assumption that bisexual men are responsible for significant HIV transmission to their female partners.

The research builds a case for federal investment in research on HIV prevalence among bisexually behaving men.

Said Mackey R. Friedman, faculty member in Pitt’s Department of Infectious Diseases and Microbiology, who led the research: “Some observers have exaggerated the idea of viral ‘bridging,’ where a bisexual man contracts HIV from another man and then transmits it to a female partner. But, at least in the U.S., the data supporting the extent of this is quite limited.”

Currently, the U.S. Centers for Disease Control and Prevention (CDC) does not report on HIV data specific to bisexually behaving people, though it does report data on homosexually and heterosexually behaving people, as well as injection drug users.

Friedman and his colleagues reviewed more than 3,000 scientific articles to obtain data on HIV prevalence and risks among men who have sex with men only and men who have sex with men and women.

The bisexually behaving men were only 40 percent as likely to be infected with HIV as the homosexually behaving men. The researchers propose that this is because the bisexually behaving men reported lower rates of unprotected receptive anal intercourse, the biggest risk factor for HIV transmission among men in the U.S.

The analysis also estimates that there are approximately 1.2 million bisexual men in the U.S., of whom 121,800 are HIV-positive. That estimate aligns with CDC estimates for HIV infection in male heterosexuals and intravenous drug users.

Friedman, who has conducted HIV prevention and research for more than 15 years, believes that while bisexually behaving men may have a lower risk profile than homosexually behaving men, their HIV burden still warrants the development of targeted interventions.

“The HIV infection risk that bisexual men pose to their female partners has likely been overstated,” said Friedman. “However, that doesn’t mean that HIV-prevention campaigns targeting bisexual men and their male and female partners aren’t needed. HIV does exist in the bisexual community, and national, bisexual-specific data collection, research and HIV prevention and care delivery are necessary to ameliorate this population’s HIV burden.”

Additional Pitt collaborators on this research were Chongyi Wei, Mary Lou Klem, Anthony Silvestre, Nina Markovic and Ron Stall.

Attitudes toward bisexuality vary

Men who identify themselves as heterosexual are three times more likely to categorize bisexuality as “not a legitimate sexual orientation,” an attitude that can encourage negative health outcomes in people who identify as bisexual, said Friedman, director of Project Silk, an HIV prevention initiative.

“Bisexual men and women face prejudice, stigma and discrimination from both heterosexual and homosexual people,” he said. “This can cause feelings of isolation and marginalization, which prior research has shown leads to higher substance use, depression and risky sexual behavior. It also can result in lower rates of HIV testing and treatment.”

Building on previous work assessing attitudes toward bisexual men and women, Friedman and his colleagues surveyed hundreds of adult college students for words that come to mind in relation to bisexual people, such as “confused,” “different” and “experimental.” The researchers then developed a 33-question survey and administered it to an online sample of 1,500 adults.

Overall, respondents were generally negative in terms of their attitudes toward bisexual men and women, with almost 15 percent of the sample in disagreement that bisexuality is a legitimate sexual orientation. However, women, white people and people who identified themselves as lesbian, gay or bisexual had less bias and prejudice against bisexual people. Of note, respondents who identified as gay or lesbian responded significantly less positively toward bisexuality than those identifying as bisexual, indicating that even within the sexual minority community, bisexuals face profound stigma. In addition, these findings indicate that male bisexuals likely suffer more stigma than female bisexuals.

When a bisexual person perceives that his or her sexual orientation is not recognized by peers, Friedman explained, it can cause the person to feel socially isolated and unable to talk openly with friends, family and school mates.

He added: “Having hard data to back up why a bisexual person might feel the need to be secretive about sexual orientation, something that can lead to higher depression and many other negative health outcomes, is very useful to people trying to fight stigma and marginalization. For example, this information can guide social marketing interventions and outreach to reduce that stigma, and improve rates of HIV prevention, testing and treatment within the bisexual community.”

Additional collaborators on this research were from Indiana University-Bloomington, which sponsored the research along with NIH.


Compounded Rx to prevent preterm birth not a risk

A study published online in the American Journal of Obstetrics and Gynecology by researchers from the schools of medicine and pharmacy reports that 17-hydroxyprogesterone caproate (17-OHPC), a medication that reduces the rate of preterm birth in high-risk women, did not raise any safety concerns when the medication was prepared and dispensed by independent compounding pharmacies throughout the United States.

The medication has been proven to reduce by one-third the risk of preterm births in women with a clinical history of early delivery. Until recently, this medication was available only from independent compounding pharmacies at a cost of $10-$15 per injection. A pharmaceutical company in February 2011 received Food and Drug Administration (FDA) approval to license the medication under the name Makena and established the price at $1,500 per injection. The public outcry that followed led the FDA to issue a statement that it would not enforce action against compounding pharmacies that continued to produce and provide the medication.

Since then, researchers from the company that markets Makena published a report suggesting compounded 17-OHPC poses a risk to patients because of the potential for drug impurity and inconsistent potency. The FDA conducted its own study and could not identify any safety problems with the drug, but decided it would apply its normal enforcement policy on compounding the product.

Pitt’s researchers conducted an independent study to determine the quality of 17-OHPC obtained from compounding pharmacies across the country. Specialists in treating high-risk pregnancies supplied a representative sample of the compounded 17-OHPC used in their practices. Eighteen samples of compounded 17-OHPC were obtained from 15 pharmacies and analyzed here.

Said Steve N. Caritis, obstetrics and gynecology faculty member and the study’s corresponding author: “Contrary to the report provided by the company that markets Makena, we found that 17-OHPC from compounding pharmacies raised no safety concerns about drug potency, sterility or purity.” He cautioned, however, that the sample size was small and the findings cannot be applied to all compounded products or pharmacies.

“If a compounding pharmacy is used for preparation of 17-OHPC, a discussion with the pharmacy preparing the product is prudent, to assure production of a high-quality product,” Caritis said.

The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Pitt’s research team included Justine Chang, Yang Zhao, Wen Chen Zhao and Raman Venkataramanan.


Program yields personalized care for cancer patients

In a move away from a one-size-fits-most approach to treating cancer, Pitt and UPMC are expanding capabilities to use next-generation sequencing to provide personalized care for cancer patients. The program, initiated a year ago, has completed the analysis of 250 patients with advanced cancer who failed standard therapies, leading to new therapeutic targets and a more dynamic model of care for cancer patients.

In a newly expanded University laboratory, molecular pathologists are using a machine the size of a computer printer to sequence large regions of genome for patients suffering from late-stage lung, colon, breast and other common cancers. The team, under the direction of Yuri Nikiforov, vice chair of the Department of Pathology and director of the Division of Molecular and Genomic Pathology, offers testing for UPMC patients with every cancer type and stage when there is clinical necessity.

Said Nikiforov: “The genetic alterations that lead to the dysfunction of cancer-related genes are important diagnostic, prognostic and predictive biologic markers. The newest technologies known as next-generation sequencing allow us to sequence numerous cancer genes at the same time, giving us valuable information about cancer mutations that can be targeted by new drugs, allowing for the use of personalized cancer therapies.”

The program uses the Personalized Cancer Mutation Panel (PCMP) developed at Pitt that can identify 2,800 mutations in 50 key cancer genes.


Benefits from bariatric surgery found

For millions of Americans struggling with obesity and considering surgical procedures to achieve weight loss and alleviate obesity-related health complications, a new study confirms the health benefits attributed to bariatric surgery.

Pitt researchers from medicine and public health, with several other clinical centers throughout the country, found that most severely obese patients who underwent gastric bypass or laparoscopic adjustable gastric banding surgical procedures experienced substantial weight loss three years after surgery, with most of the change occurring in the first year.

The study findings, published online in the Journal of the American Medical Association, also found variability in both weight change and improvements in obesity-related complications, including diabetes, hypertension and high cholesterol.

Gastric bypass and laparoscopic adjustable gastric banding are common bariatric surgical procedures that aid in weight loss by intestinal bypass, stomach restriction and possibly gut hormone changes.

Led by Anita Courcoulas, a surgery faculty member, researchers used detailed data from the Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, a multicenter observational cohort study encompassing 10 hospitals in six geographically diverse clinical centers and a data coordinating center, which assesses the safety and efficacy of bariatric surgical procedures performed in the United States. The researchers gathered highly standardized assessments and measures from adult study participants undergoing bariatric surgery procedures and followed them over the course of three years.

At baseline, study participants ranged in age from 18 to 78 years, 79 percent were women, and the median body mass index was 45.9; 1,738 participants chose to undergo gastric bypass surgery, and 601 underwent laparoscopic gastric banding.

In the three-year follow-up after bariatric surgery, the researchers observed substantial weight loss for both procedures, with most of the change occurring during the first year. Participants who underwent gastric bypass surgery or laparoscopic adjustable gastric banding experienced median weight loss of nearly 32 percent and 16 percent, respectively.

Additionally, of the gastric bypass surgical participants who had specific obesity-related health problems prior to surgery, 67 percent experienced partial remission from diabetes and 38 percent remission from hypertension. High cholesterol resolved in 61 percent of the participants who underwent bypass surgery. For those who underwent laparoscopic adjustable gastric banding, 28 percent and 17 percent experienced partial remission from diabetes and remission from hypertension respectively, and high cholesterol was resolved in 27 percent of participants.

Said Courcoulas: “Bariatric surgery is not a ‘one size fits all’ approach to weight loss. Our study findings are the result of data collected from a multicenter patient population, and emphasize the heterogeneity in weight change and health outcomes for both types of bariatric surgery that we report. Longer-term follow-up of this carefully studied cohort will determine the durability of these improvements over time and identify the factors associated with the variability in effect.”

The research was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), Columbia University Medical Center, University of Washington, Neuropsychiatric Research Institute, UPMC and Oregon Health and Science University.

Courcoulas’s team included Pitt faculty Steven H. Belle, Nicholas Christian, Melissa A. Kalarchian and Wendy C. King. Also contributing were researchers from Columbia University, University of Washington, University of North Dakota, NIDDK, Legacy Good Samaritan Medical Center, East Carolina University, Weill Cornell Medical College, Virginia Mason Medical Center and Oregon Health and Science University.


Sexual health better after surgery for weight loss

In another study using LABS data, researchers measuring the changes in sexual function and sex hormone levels in women following bariatric surgery have found that, on average, women reported significant improvements in overall sexual functioning and satisfaction.

The findings were published online in the Nov. 4 issue of JAMA Surgery.

Said Nicholas Christian, epidemiology faculty member in public health, who analyzed the study data: “Thirteen percent of the participants who reported sexual dysfunction before undergoing weight loss surgery saw dramatic improvement in function after surgery. Another 53 percent saw a modest improvement, on average.”

The study used a subset of the LABS data that looks at the long-term effects of bariatric surgery on the weight of study participants, as well as on their physical and mental health.

Researchers recruited 106 of the women who were part of the larger LABS-2 study at the clinical sites in Pittsburgh and Fargo, N.D., to participate in this ancillary study. In addition to the LABS forms assessing quality of life and depression, the women answered questions focusing on their body image and their sexual health, and gave blood samples.

Sexual function significantly improved from before surgery to the first year post-surgery. By the second year, women reported improvements in arousal, lubrication, desire and satisfaction. They also had significant improvements in sex hormone levels.

In addition to improved sexual function, the women reported significant improvements in quality of life, as well as body image and depression symptoms.

The study team included researchers from the University of Pennsylvania, University of North Dakota, UPMC and the New England Research Institutes.

The ancillary study was funded by the NIDDK.


Researchers explore remote environmental monitoring

Pitt and Indiana University faculty hope to improve the ability of researchers to collect greater amounts of field data through the development of large-scale wireless sensor networks (WSN). The researchers at both universities were awarded a parallel grant of $465,582 in total, with $232,474 to Pittsburgh through NSF’s Division of Computer and Network Systems. The team’s research focuses on advances in WSNs and the opportunities they enable for large-scale environment monitoring applications.

Principal investigator is Xu Liang, civil and environmental engineering faculty in the Swanson School of Engineering. Liang’s research focuses on the laws that govern water, energy and carbon cycles, and how these cycles affect the health of the environment.

The research is fundamentally important because an extension of the battery lifetime for large-scale viable WSNs would allow an extended lifetime for field monitoring, which in turn would allow for the effective and efficient collection of valuable field data at unprecedented high special densities and long-time durations.

The research is focused specifically on ecohydrology, an interdisciplinary field that studies the interaction between water and ecosystems.

Said Liang: “In the end we want to improve our understanding of how some of the ecohydrological processes behave at different spatial scales. The ultimate goal is to substantially reduce the prohibitive cost of large-scale WSN deployments for scientific, national security and military purposes by creating a new paradigm of optimal design, development, management and operations for these WSNs. This would significantly extend their lifetimes and have them help us find solutions to the challenging ecohydrological problems.”

The project investigates the energy-efficient networks through a large, outdoor WSN using a test bed at the Audubon Society of Western Pennsylvania’s Beechwood Farms Nature Reserve, about 50 minutes from Pitt. The research uses the test bed to study innovative compressed data collection in WSN under wireless link dynamics through an integrated theoretical and empirical approach. The test bed also allows the team to investigate the heterogeneity of hydrological processes within the ecosystem. The WSN allows for collection of valuable ecohydrological data at a finer resolution, which is much better than what satellite data has provided in the past. This data helps to explore certain fundamental ecohydrological laws.

By using this particular test bed, researchers at Indiana are also able to develop a novel and rigorous framework of topology tomography for real-world WSNs operated in noisy communication environments. The developed framework can be essential not only for routing improvement, topology control, hot spot elimination and anomaly detection in practice, but also for the emerging compressed sensing-based data collection.

In addition, the project creates an educational component for students. Middle and high school students will be invited to participate in two free summer camps during the summers of 2015 and 2016.

The camps will offer lectures on the basics of what researchers are doing in the fields of environmental science and engineering as well as wireless sensor networking. The Audubon Society also will give lectures on the reserve and the birds and plants that are a part of it.

“The camps will also have a hands-on component for students. We will show students how to use our instruments to measure hydrological variables and how the WSN works using our real-world WSN test bed,” said Liang. “Our goal is to educate and stimulate students’ interests in science and engineering at their early development stages.”

Undergraduate and PhD students, in addition to their direct participation in this research project, will take a lead in the hands-on section with the middle and high school students in summer camps, as well as conduct their own creative projects based on the WSN test bed in Liang’s classes.


Polymers that react, move to light may be possible

Micro-vehicles and other devices that can change shape or move with no power source other than a beam of light may be possible through research led by the Swanson school. The researchers are investigating polymers that “snap” when triggered by light, thereby converting light energy into mechanical work and potentially eliminating the need for traditional machine components such as switches and power sources.

The research was performed by M. Ravi Shankar, faculty member in industrial engineering, in collaboration with researchers from Air Force Research Laboratory at Wright-Patterson Air Force Base and Hope College in Holland, Mich. It was published in the early edition of the Proceedings of the National Academy of Sciences, the journal of the United States National Academy of Sciences, and was enabled through an Air Force Office of Scientific Research summer faculty fellowship.

Said Shankar: “I like to compare this action to that of a Venus fly trap. The underlying mechanism that allows the Venus fly trap to capture prey is slow. But because its internal structure is coupled to use elastic instability, a snapping action occurs, and this delivers the power to shut the trap quickly. A similar mechanism acts in the beak of the hummingbird to help snap up insects.”

Focusing on this elastic instability, Shankar examined polymeric materials, prepared by researchers at the Air Force Research Laboratory, which demonstrated unprecedented actuation rates and output powers. With light from a hand-held laser pointer, the polymers generate high amounts of power to convert the light into mechanical work without any onboard power source or wiring. Specific functions would be preprogrammed into the material so that the device would function once exposed to a light source and controlled by changing the character of the light.

“As we look to real-world applications, you could activate a switch simply by shining light on it,” Shankar said. “For example, you could develop soft machines such as stents or other biomedical devices that can be more adaptive and easily controlled.

“In a more complex mechanism, we could imagine a light-driven robotic or morphing structure, or micro-vehicles that would be more compact because you eliminate the need for an on-board power system. The work potential is built into the polymer itself and is triggered with light.”


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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