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University of Pittsburgh

March 2, 2017

Research Notes

green soybeans on white backgroundWhy soy cuts heart disease risk for some

A product of digesting a micronutrient found in soy may hold the key to why some people seem to derive a heart-protective benefit from eating soy foods while others do not, a Graduate School of Public Health-led study has discovered.

Japanese men who are able to produce equol — a substance made by some types of “good” gut bacteria when they metabolize isoflavones (micronutrients found in dietary soy) — have lower levels of a risk factor for heart disease than their counterparts who cannot produce it, according to the research, published in the British Journal of Nutrition.

Said senior author Akira Sekikawa, epidemiology faculty member: “Scientists have known for some time that isoflavones protect against the buildup of plaque in arteries, known as atherosclerosis, in monkeys, and are associated with lower rates of heart disease in people in Asian countries. We were surprised when a large trial of isoflavones in the U.S. didn’t show the beneficial effects among people with atherosclerosis in Western countries. Now, we think we know why.”

All monkeys can produce equol, as can 50-60 percent of people in Asian countries. However, only 20-30 percent of people in Western countries can.

Sekikawa and his colleagues, who include scientists in Japan, performed blood tests on 272 Japanese men aged 40-49 to find out if they were producing equol. After adjusting for other heart disease risk factors such as high blood pressure, cholesterol, smoking and obesity, the team found that the equol-producers had 90-percent lower odds of coronary artery calcification, a predictor of heart disease, than the equol non-producers.

The daily intake of dietary isoflavones — found in traditional soy foods such as tofu, miso and soymilk — is 25-50 milligrams in China and Japan, while it is less than 2 milligrams in Western countries. Equol is available as a supplement — bypassing the need for gut bacteria to produce it — though no clinical trials have been performed to determine a safe dosage for heart protective effects, or even if it does provide such protection.

“I do not recommend that people start taking equol to improve their heart health or for any other reason unless advised by their doctor,” said Sekikawa. “Much more study is needed.”

Sekikawa and his team are pursuing funding for a much larger observational study to expand on their findings and eventually a randomized clinical trial to examine the effect of taking equol on various medical conditions and diseases.

“Our discovery about equol may have applications far beyond heart disease,” said Sekikawa. “We know that isoflavones may be associated with protecting against many other medical conditions, including osteoporosis, dementia, menopausal hot flashes and prostate and breast cancers. Equol may have an even stronger effect on these diseases.”

Additional authors on this research included lead author Vasudha Ahuja of public health and Pitt colleagues Abhishek Vishnu and Rhobert Evans. Also contributing were researchers from Japanese institutions Shiga University of Medical Science, Shimane University and Keio University.

This research was funded by the National Institutes of Health (NIH), the Japanese Ministry of Education, Culture, Sports, Science and Technology and Pitt’s Department of Epidemiology.

New way to predict cancer drug response

Researchers at the School of Medicine have uncovered a novel genetic mechanism of thyroid cancer, as well as a marker that may predict response to a particular class of drugs, not just in patients with thyroid cancer but in those with many other types of cancer as well. The findings were published in Proceedings of the National Academy of Science.

Explained lead study author Yuri Nikiforov, pathology faculty member, vice chair for molecular pathology and director of UPMC’s Division of Molecular and Genomic Pathology: “These results … also suggest a potential treatment strategy for many different types of cancer.”

Thyroid cancer is the fastest-growing type of cancer in the U.S., and more than 55,000 people will be diagnosed this year. Like many other cancers, thyroid tumors usually result from specific genetic abnormalities. Although previously identified mutations are found in about 90 percent of thyroid cancers, in the remaining cases the culprit is a mystery.

To identify new genetic abnormalities associated with thyroid cancer, Nikiforov and his team applied a powerful technology called next-generation sequencing to analyze a series of papillary thyroid carcinomas (the most common form of thyroid cancer) that did not contain any of the known mutations.

The researchers found that a significant proportion of these tumors had a complex genetic alteration involving fusion of a gene named THADA to a previously unknown region near a gene called IGF2BP3. The result of this gene fusion was elevated levels of IGF2BP3 protein, an important component of the IGF1R protein signaling pathway that is known to play a role in tumor formation and growth.

“Up until now, we knew that alterations in the THADA gene were associated with thyroid cancer, but we didn’t know how this genetic change actually leads to tumor development,” said Nikiforov. “Our study uncovers a new mechanism of thyroid cancer, one that is actually quite common.”

The team went on to find that elevated IGF2BP3 also was present in many other types of cancer.

“When we looked at other common cancers, such as those of the lung, pancreas, colon and ovary, we found that 5-15 percent of them had elevated levels of IGF2BP3,” said Nikiforov.

The team then performed cell culture and animal model experiments that revealed the growth of these tumors could be blocked by IGF1R pathway-inhibiting drugs.

A number of IGF1R inhibitors have been developed and tested in more than 25 clinical trials in the last several years, Nikiforov explained. Unfortunately, these trials failed because only a small subpopulation of patients responded to the drugs, and researchers were not able to determine which tumors would be susceptible to the treatment.

“Our results suggest that we now have a genetic marker — IGF2BP3 — that may be able to tell us who will benefit from these drugs,” he said. “What’s really exciting is that our study could renew interest in the use of IGF1R inhibitors to treat cancer. We hope that the manufacturers of IGF1R and IGF2 inhibitors will consider initiating clinical trials for these drugs specifically in patients whose tumors show elevated levels of IGF2BP3.”

Funding for the study was provided by NIH and David and Nancy Brent.

Additional Pitt collaborators included the paper’s co-first authors Federica Panebianco and Lindsey Kelly, as well as Shan Zhong, Sanja Dacic, Xiaosong Wang, Aatur Singhi, Rajiv Dhir, Simion Chiosea, Shih-Fan Kuan, Rohit Bhargava, David Dabbs, Sumita Trivedi, Abigail Wald, Sally Carty, Robert Ferris, Adrian Lee and Marina Nikiforova. Colleagues from Zhejiang University, China and Affymetrix, Inc. also contributed.

Using genes to determine best anticoagulation

A research idea submitted by School of Pharmacy faculty member Inmaculada Hernandez was one of four selected among 200 submissions for an AHA/PCORI researcher and clinician challenge. Through this challenge, the American Heart Association and the Patient-Centered Outcomes Research Institute hopes to generate research ideas that address evidence gaps in the treatment of cardiovascular diseases. The proposed research designs had to use precision medicine approaches as well comparative effectiveness research methods.

Using her previous research on the comparative effectiveness of anticoagulant treatments as a starting point, Hernandez’s awarded idea aims to identify optimal anticoagulation treatment in atrial fibrillation patients based on their genetics.

Controlled delivery of particles via fluid flow developed

Capitalizing on previous studies in self-powered chemo-mechanical movement, researchers at the Swanson School of Engineering and Penn State have developed a novel method of transporting particles that uses chemical reactions to drive fluid flow within microfluidic devices. Their research was published in Nature Communications.

The computational modeling research was led by Anna C. Balazs, distinguished professor of chemical and petroleum engineering, with post-doctoral associates Oleg E. Shklyaev and Henry Shum. The researchers’ combined theoretical and experimental findings could enable controllable transport of particles and cells, allowing highly sensitive chemical assays to be performed more rapidly and efficiently.

Said Balazs: “One of the critical challenges in transporting microparticles within devices is delivering the particle to a specific location. Much like a conveyor belt in a factory, you want to move the particle within a closed system without any modification to its surface or damage to its structure.”

Balazs noted that in addition to successfully delivering the particles, the other challenges the researchers faced were maintaining unidirectional flow from point A to point B within a closed chamber and ensuring that a critical concentration of these particles could be delivered to sensors, which only operate above a critical threshold.

The solution was to generate a gradient of a chemical reagent by introducing the reagent at one end of the chamber, point A. Enzymes on the surface of the chamber consumed the reagent so that it was completely depleted at point B. Since the presence of the reagent increases the fluid density, a density gradient was established between points A and B, leading to convective flow that transported particles like a conveyor belt.

“Previously, to generate spontaneous propulsion of microparticles, one needed to chemically modify the surface of these particles, thus altering their inherent properties. Moreover, modifying the particle’s surface does not necessarily allow you to direct its motion within the chamber. We were able to predicate through our computational models and demonstrate in the experiments performed at Penn State that the flow generated by the catalytic chemical reaction in the chamber could effectively transport particles to a particular sensor, and could permit control over the speed and direction of the particle transport, without having to use an external pump or any modification of the cargo.”

Predicting immune response to biomedical implants

NIH has awarded Bryan Brown, bioengineering faculty member in the Swanson school, a five-year, $1.54 million grant for his investigation into the immune system response to implanted medical materials.

The study will build on Brown’s previous research demonstrating that macrophage M1 and M2 polarization at early time points after the implantation of a biomedical material can predict long-term reactions by the host’s immune system. The information gathered by the study could significantly improve the success of biomaterial implants and minimize the negative response from the patient’s immune system.

Said Brown: “Our current tests have shown that the first week of macrophage activity near the host-implant interface can predict the immune system response downstream as far as 90 days. We have developed methods for modulating macrophage activity, which we will use to understand why and how these early events after implantation serve as a precursor to the lifespan of the implant. Our research is suggesting, contrary to conventional understanding of host-biomaterial interactions, macrophages can be used to encourage positive, long-term outcomes for the implant and the patient.”

Macrophages are white blood cells charged with protecting the body from health threats, including foreign bodies like biomaterial implants. When an implant is placed inside the body, the macrophages recognize its presence and can exhibit either a pro-inflammatory or anti-inflammatory response. Brown and his team have developed methods for observing, measuring and controlling these responses. They will attempt to find optimal designs for biomaterials that not only accommodate the involvement of the immune system but promote positive interaction between the body’s natural defenses and the implanted material.

A variety of medical fields rely on biomaterial implants for patients: orthopaedics for joint repair, ophthalmology to restore vision, cardiovascular surgery for heart valve and artery replacement and dentistry for tooth and gum tissue support. Biomaterial implants also are common in the healing of wounds and bone fractures.

Brown believes his study will provide researchers with a framework for understanding how the host’s immune system responds to implanted materials and how to use that response to develop more successful procedures for any treatment involving biomaterial implantation.

Co-investigators are Pamela Moalli, faculty member in the Department of Obstetrics, Gynecology and Reproductive Sciences in the School of Medicine, and Stephen Badylak, faculty member in medicine’s Department of Surgery.

Sore Throat. Sick Woman Suffering From Pain, Painful Swallowing.NSF funds analysis of swallowing disorders

The swallowing disorder dysphagia affects nearly one in 25 adults, especially the elderly and those who have suffered a stroke or neurological disease, and results in approximately 150,000 hospitalizations annually. A patient’s risk for dysphagia is diagnosed by screening, and may require an endoscopy or fluoroscopy for further evaluation. However, some patients who aspirate do so silently, causing doctors to misdiagnose.

To develop an improved screening method for dysphagia, the National Science Foundation (NSF) awarded a researcher at the Swanson school a CAREER Award through the NSF’s Division of Chemical, Bioengineering, Environmental and Transport Systems. Ervin Sejdic, electrical and computer engineering faculty member, received a five-year, $549,139 award to further research using high-resolution vibration and sound recordings that would help doctors diagnose dysphagia and assist patients in improving how to properly swallow while eating or drinking.

Sejdic, who began this research while a postdoctoral associate at the University of Toronto and Holland Bloorview Kids Rehabilitation Hospital, Canada’s largest children’s rehabilitation hospital, explained that an improved, non-invasive method to detect dysphagia could help to reduce patient risk and hospitalization.

Said Sejdic: “By using modern data analytics we can compare and contrast the sound and vibrations of normal swallowing against patients with dysphagia. This allows us to understand how the airway normally protects itself during swallowing to avoid aspiration, and how this is affected during dysphagia, without the need for surgery or intubation.”

Patients with silent dysphagia may pass a traditional screening, which increases the potential for choking and suffocation. Analyzing the sounds and vibrations from the neck would not only reduce the incidence of silent aspiration, but also the need for conservative recommendations that limit eating and drinking for individuals with neurological disabilities such as multiple sclerosis or ALS.

In addition to helping develop the technology, the award will allow Sejdic to collaborate with speech language pathologists to develop an online learning module to further education and outreach throughout the U.S. He would also like to use the data analysis to design a mobile device that would help patients while eating, but notes that possibility is several years in the future.

“Endoscopy and fluoroscopy are still the gold standard for detecting dysphagia,” Sejdic said. “For now we’re not looking at replacing them but rather enhancing and improving the screening process.”

Poverty influences chronic medical conditions in kids

Researchers from Children’s Hospital have shown how poverty status influences the prevalence of three common chronic medical conditions: asthma, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

The study was led by Amy Houtrow, faculty member and vice chair in the Department of Physical Medicine and Rehabilitation for Pediatric Rehabilitation Medicine in the School of Medicine, and is published in Pediatrics.

Researchers analyzed data obtained by the National Survey of Children’s Health for the years 2003, 2007 and 2011-12. They identified trends of each condition and other chronic medical conditions that children with these conditions may have.

poor, sad little child girl sitting against the concrete wallSaid Houtrow: “Children living in poverty experience numerous threats to their well-being, including being at higher risk for multiple chronic conditions.”

Among study participants, the lifetime prevalence of asthma rose 18 percent; ADHD rose by 44 percent; and ASD rose nearly 400 percent. For children with asthma, the rise was most prominent among the poor, at nearly 26 percent.

The percent change by poverty status for ADHD was similar, though the rise in ASD was not associated with poverty status. It also was found that children with asthma and ADHD from impoverished households were more likely to have additional chronic medical conditions.

The research team concluded that there is a need to further research the adverse effects of poverty on children to make informed decisions about their health and well-being.

Christian Pulcini of Pitt contributed to the research, as did colleagues from UCLA and Ohio State.

Chong awarded DFG Mercator Fellowship

Lillian Chong, faculty member in the Dietrich School of Arts and Sciences’ Department of Chemistry, has been awarded a DFG Mercator Fellowship for a research collaboration with Thomas Kiefhaber at the Martin Luther University Halle-Wittenberg in Halle, Germany, titled “Conformational Dynamics of Peptides and Proteins on the Nanoseconds to Microseconds Timescale.” The award supports travel, accommodation and salary for two months each year for the next three years.

The fellowships enable intensive, long-term project-based collaboration between researchers from both domestic and foreign institutions.

Humanities, social sciences projects funded

The Office of the Provost has awarded funding for 14 humanities and social sciences research projects through two initiatives.

The Integrative Social Science Research Initiative expands Pitt social scientists’ involvement in research that uses integrative approaches from multiple disciplines. Funding is awarded for new collaborations, up to $50,000 per project.

The Special Initiative to Promote Scholarly Activities in the Humanities supports proposals for new scholarly projects or to advance existing efforts. The maximum funding amount is $20,000, with most projects funded at $5,000 or less. The initiative is open to individuals or groups of tenured and tenure-stream faculty in the humanities.

The awardees and projects for the Integrative Social Science Research Initiative are:

• “Clouded Judgment: Air Pollution and Decision Making in China,” by principal investigator Iza (Yue) Ding, political science faculty member, and co-investigators Andrea La Nauze, faculty member, and Graham Beattie, postdoc, both in economics, all in the Dietrich school;

• “We Are Strong! Leveraging Information Technology to Empower Marginalized Communities,” by principal investigator Rosta Farzan, School of Information Sciences faculty member, and co-investigators Jaime Booth and Mary L. Ohmer, School of Social Work faculty members;

• “Development of Interdisciplinary Geophysical and Geochemical Methods for the Analysis and Spatial Modeling of Prehistoric Landscapes in the Frank Church Wilderness, Idaho, and Southeastern Slovenia,” by principal investigator Bryan Hanks, faculty member and chair, Department of Anthropology, and co-investigator Rosemary Capo, faculty member in the Department of Geology and Environmental Science in the Dietrich school;

• “Chinese Nuclear Power: Growth Prospects, Challenges, Global Impact,” by principal investigator Ravi Madhavan, business administration faculty member, Alcoa Foundation International Faculty Fellow and director of the International Business Center, Katz Graduate School of Business; and co-investigators Daniel G. Cole, faculty member and director of the Stephen R. Tritch nuclear engineering program, Department of Mechanical Engineering and Materials Science in the Swanson school; Thomas G. Rawski, economics and history faculty member in the Department of Economics and UCIS Research Professor; and Kaoru (Kay) Shimizu, Department of Political Science faculty member, both in the Dietrich school; and

• “From Barely Making It to …? Effects of Raising Wages Among Low-Wage Workers” by principal investigator Jeffrey Shook, faculty member and doctoral program director in the School of Social Work; and co-investigators Waverly Duck, sociology faculty member in the Dietrich school; Rafael Engel, School of Social Work faculty member; Sara Goodkind, faculty member in the School of Social Work as well as the Department of Sociology and the gender, sexuality and women’s studies program in the Dietrich school; Rachel Fusco, faculty member in the School of Social Work, Clinical and Translational Science Institute, and direct practice concentration chair; and Sera Linardi, faculty member in the Graduate School of Public and International Affairs and the Dietrich school’s Department of Economics.

The Special Initiative to Promote Scholarly Activities in Humanities awardees are:

• “Earl Theisen, Film Historical Display and the Film Frame Collection at the Los Angeles Museum in the 1930s,” by Mark Lynn Anderson, faculty member in the Department of English, Dietrich school;

• “Digital Mitford Project Initiatives: Prosopography Research, Interface Design and Data Visualization” by Elisa Beshero-Bondar, English faculty member, Pitt-Greensburg;

• “Lombards Abroad: Aesthetics, Abstraction and Identity Across the 12th-century Alps” by Shirin Fozi, faculty member in the history of art and architecture, Dietrich school;

• “Genealogies of the Transgender Child: Sex, Race and Organic Form” by Julian Gill-Peterson, English faculty member, Dietrich school;

• “Advancing the Birkbeck/Pittsburgh Collaboration: Summer Workshop on Urban Change” by Randall Halle, Klaus W. Jonas Professor of German film and cultural studies and chair, German, Dietrich school;

• “Between Religious Aesthetics and State Discipline: The Islamic Artistic Scene in the U.K.” by Jeanette Jouili, religious studies faculty member, Dietrich school;
• “Cave Canem Oral History Project” by Dawn Lundy Martin, English faculty member, Dietrich school;

• “Déjà vu Blue” by Michael Morrill, studio arts faculty member, Dietrich school;

• “Little Hands and Mouths: Children’s Literature, Commerce and Relationality in the Early Atlantic World” by Courtney Weikle-Mills, faculty member and director of the children’s literature program, English, in the Dietrich school.

Annual PCP visits should include skin cancer screenings

School of Medicine/UPMC research suggests that if full body skin cancer screenings became a part of routine annual primary care visits, significantly more skin cancers would be discovered and at earlier stages.

The results of the study, led by Laura Ferris, Department of Dermatology, and John Kirkwood, Department of Medicine, Division of Medical Oncology, were published in JAMA Oncology and follow a similar melanoma screening program done in 2004 in Germany.

About half of all skin cancers are found by patients and half by physicians. However, those skin cancers found by patients tend to be more advanced than those detected by physicians.

“Skin cancer can be detected by the naked eye,” said Ferris. “We hope to gather enough data to develop a uniform recommendation for screening guidelines so melanoma, the deadliest form of skin cancer, can be detected earlier.”

UPMC-employed PCPs were offered access to a web-based training program on skin cancer identification. Patients were considered eligible for the screening if they were age 35 or older and saw a UPMC PCP during 2014.

The study examined the electronic health records of more than 300,000 patients who visited a UPMC PCP in 2014 and found approximately 53,000 patients who were in the eligible category were screened for skin cancer, and more than 280,000 were not.

Researchers found the incidence of melanoma in the screened population was more than double that of the unscreened population, and the melanomas discovered in the screened patients were thinner than those of the unscreened patients.

“The thickness of a diagnosed melanoma is the most important predictor of the risk of dying from this cancer,” said Ferris. “So finding thinner tumors has the potential to reduce melanoma deaths.”

Researchers expect more patient and physician participation as they continue to study the screening process.

Additional Pitt researchers who worked on the study were Melissa Saul, Yan Lin, Fei Ding, Jian-Min Yuan, Erica Neuren, Spandana Maddukuri and Francis X. Solano.
Colleagues from Brown University and Harvard also contributed.

The National Cancer Institute and the Melanoma Research Alliance provided support.

—Compiled by Marty Levine


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