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October 10, 2013

Research Notes

Thyroid cancer detection advances

A new test for genetic markers that can identify which lumps in the thyroid gland are cancerous and which are harmless, potentially preventing unneeded operations, will debut Oct. 1 for patients at the University of Pittsburgh Cancer Center (UPCI)/UPMC Multidisciplinary Thyroid Center (MTC).

According to Yuri Nikiforov, director of thyroid molecular diagnostics at the thyroid center and pathology faculty member in the School of Medicine, the growth of a small mass or nodule of the thyroid gland, which is located in the Adam’s apple area of the neck, is very common, particularly with aging. The nodule is benign 90 percent of the time, but an ultrasound-guided biopsy of the suspicious tissue is needed to confirm it is harmless.

“The test we had been using can distinguish between cancerous and benign nodules about 70 percent of the time, but that means the result is uncertain in nearly a third of cases,” said Nikiforov. “When that happens, the patient has to have the nodule surgically removed so that more extensive testing can be done. If it turns out to be cancerous, yet another operation might be needed to remove the entire thyroid gland.”

Approximately 100,000 thyroid nodule biopsies done annually yield uncertain results, and most of these patients must undergo follow-up testing and diagnostic surgery, even though the likelihood of having a cancer is very low, he noted.

The new test, called ThyroSeq, was designed and developed by Nikiforov and his team and uses a technique called next-generation sequencing. This technology allows pathologists to simultaneously test for multiple genetic markers using just a few cells collected from the nodule and at low cost. The test detects mutations associated with thyroid cancer in nearly 300 sites of 12 genes in the thyroid cells obtained during the biopsy procedure. UPMC will be the first academic institution in the country where next-generation sequencing technology will be used to improve care for patients with thyroid nodules.

Said MTC co-director Sally E. Carty, surgery faculty member: “The ultimate goal of molecular testing is to allow patients to have the initial definitive operation for thyroid cancer and to avoid diagnostic surgery for benign conditions.” Carty added that the new panel is the same price as the earlier one, which was shown to be cost-effective in a 2012 study led by MTC expert and fellow surgery faculty member Linwah Yip.

According to Nikiforov’s research, ThyroSeq findings suggest that certain gene alteration patterns may be associated with more aggressive cancers, so there is potential to develop tailored treatment approaches for specific kinds of tumors.

Said MTC co-director and medicine faculty member Steven Hodak: “If we can distinguish aggressive thyroid cancers from cancers that are growing much more slowly and will not metastasize, we might be able to avoid surgery in these low-risk patients in favor of watchful waiting. That’s really the Holy Grail — finding patients both with and without thyroid cancer for whom surgery is unnecessary and not putting them through the expense and risk of surgeries they don’t need.”

Each year, approximately half of the 25,000 patients assessed at the MTC have thyroid conditions and more than 900 thyroid operations are performed by MTC surgeons. The center aims to provide patients with one-stop evaluation from thyroid experts in a variety of fields, including surgery and endocrinology.

Developing 4-D printing of adaptive materials

Imagine an automobile coating that changes its structure to adapt to a humid environment or a salt-covered road, better protecting the car from corrosion. Or consider a soldier’s uniform that could alter its camouflage or more effectively protect against poison gas or shrapnel upon contact.

Researchers from the Swanson School of Engineering and two other institutions are proposing to advance 3-D printing one dimension further. With an $855,000 grant from the United States Army Research Office, the team hopes to develop 4-D materials, which can exhibit behavior that changes over time.

The principal investigator is Anna C. Balazs, the Robert v. d. Luft Distinguished Professor of Chemical Engineering and a researcher in the computational design of chemo-mechanically responsive gels and composites. Balazs and her colleagues will integrate their expertise to manipulate materials at nano and micro levels to produce, via 3-D printing, materials that can modify their structures over time at the macro level. Three-dimensional printing, also known as additive manufacturing, is the process of creating a 3-D object based upon a digital model by depositing successive layers of material.

Said Balazs: “Rather than construct a static material or one that simply changes its shape, we’re proposing the development of adaptive, biomimetic composites that reprogram their shape, properties or functionality on demand, based upon external stimuli. By integrating our abilities to print precise, three-dimensional hierarchically structured materials, synthesize stimuli-responsive components and predict the temporal behavior of the system, we expect to build the foundation for the new field of 4-D printing.”

Since the research will use responsive fillers embedded within a stimuli-responsive hydrogel, this opens new routes for producing the next generation of smart sensors, coatings, textiles and structural components, such as a fabric that responds to light by changing its color, and to temperature by altering its permeability, or even to an external force by hardening its structure.

Also contributing were researchers from Harvard and the University of Illinois.

Mystery of basic cellular process solved

Pitt scientists report in the Oct. 1 issue of Nature Cell Biology that they have solved the mystery of a basic biological function essential to cellular health.

By discovering a mechanism by which mitochondria — tiny structures inside cells often described as “power plants” — signal that they are damaged and need to be eliminated, the University team has opened the door to potential research into cures for disorders such as Parkinson’s disease that are believed to be caused by dysfunctional mitochondria in neurons.

Said senior author Valerian Kagan, vice chair of the Graduate School of Public Health’s Department of Environmental and Occupational Health: “It’s a survival process. Cells activate to get rid of bad mitochondria and consolidate good mitochondria. If this process succeeds, then the good ones can proliferate and the cells thrive. It’s a beautiful, efficient mechanism that we will seek to target and model in developing new drugs and treatments.”

Kagan likened the process to cooking a Thanksgiving turkey. “You put the turkey in the oven and the outside becomes golden, but you can’t just look at it to know it’s ready. So you put a thermometer in and when it pops up, you know you can eat it. Mitochondria give out a similar ‘eat me’ signal to cells when they are done functioning properly.”

Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion.

Added Charleen T. Chu, the A. Julio Martinez Chair in Neuropathology in the School of Medicine’s Department of Pathology and another senior author of the study: “It’s not just the turkey timer going off; it’s a question of who’s holding the hot mitt to bring it to the dining room?” That turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell.

Together with Hülya Bayir, faculty member in critical care medicine, and nearly two dozen scientists, the three senior authors worked out how the pieces of the mitochondria signaling problem fit together.

“There are so many follow-up questions,” Chu said. “What is the process that triggers the cardiolipin to move outside the mitochondria? How does this pathway fit in with other pathways that affect onset of diseases like Parkinson’s? Interestingly, two familial Parkinson’s disease genes also are linked to mitochondrial removal.”

Bayir explained that while this process may happen in all cells with mitochondria, it is particularly important that it functions correctly in neuronal cells because these cells do not divide and regenerate as readily as cells in other parts of the body.

“I think these findings have huge implications for brain injury patients,” she said. “The mitochondrial ‘eat me’ signaling process could be a therapeutic target in the sense that you need a certain level of clearance of damaged mitochondria. But, on the other hand, you don’t want the clearing process to go on unchecked. You must have a level of balance, which is something we could seek to achieve with medications or therapy if the body is not able to find that balance itself.”

Pitt co-authors on this paper included Jing Ji, Ruben K. Dagda, Jian Fei Jiang, Yulia Y. Tyurina, Alexandr A. Kapralov, Vladimir A. Tyurin, Naveena Yanamala, Indira H. Shrivastava, Dariush Mohammadyani, Kent Zhi Qiang Wang, Jianhui Zhu, Judith Klein-Seetharaman, Krishnakumar Balasubramanian, Andrew A. Amoscato, Grigory Borisenko, Zhentai Huang, Aaron M. Gusdon, Amin Cheikhi, Erin K. Steer, Ruth Wang, Catherine Baty, Simon Watkins and Ivet Bahar.

The study was funded by the National Institutes of Health (NIH).

UPCI presents pulmonary fibrosis therapy research

Two new UPCI studies offer promising research avenues for preventing debilitating lung-scarring in people who undergo radiation therapy for cancer. The findings were presented at the American Society for Radiation Oncology’s annual meeting in Atlanta.

Radiation-induced pulmonary fibrosis occurs in some patients years after radiation therapy has concluded and can have a significant impact on their quality of life. In laboratory studies funded by NIH, UPCI researchers found that genetic differences could be the reason some patients develop severe fibrosis and others are not afflicted.

In a separate study, the researchers found that a sulfoxide compound discovered at Pitt that exhibits antioxidant properties can significantly decrease pulmonary fibrosis in mice exposed to chest radiation, a model comparable to that of patients undergoing cancer treatment.

Said Ronny Kalash, a fourth-year medical student in UPCI’s Department of Radiation Oncology, who presented the research: “More and more people are surviving cancer, so we are increasing our focus on not only curing cancer but also improving quality of life long after treatment. All our work is geared toward making aggressive, targeted radiation therapy a safer treatment option so that patients are free of cancer but also able to breathe comfortably for the remainder of their lives.”

Kalash and his fellow researchers tested two different strains of mice, one that is very prone to fibrosis and another that is not. On examination, the researchers found that several genes activated differently between mouse strains following radiation therapy.

“These differences indicate changes in how cells turn on and off production of protective and damage-repairing proteins in irradiated lungs of fibrosis-resistant, compared to fibrosis-prone, mice,” said Kalash. “This is a stepping stone toward determining which patients may be more prone to fibrosis and creating a therapeutic treatment to help prevent sensitive patients from developing it.”

In the second study, the researchers tested a water-soluble antioxidant, called MMS-350, which was created by Peter Wipf, chemistry faculty member and co-leader of the molecular therapeutics and drug discovery program at UPCI.

Fibrosis-prone mice were given the antioxidant in their drinking water beginning 60-80 days after radiation therapy. Nearly 200 days after radiation exposure — the point at which the mice normally would develop fibrosis similar to a cancer patient — researchers found that these mice developed significantly less pulmonary fibrosis than the control group.

“The antioxidant is water-soluble and easy to administer,” said Kalash. “In general, antioxidants have been shown to have protective effects and help with the healing process. Further investigations will tell us whether MMS-350 could be useful in clinical applications.”

Additional co-authors included Hebist Berhane, Julie Goff, Tracy M. Dixon, Xichen Zhang, Michael W. Epperly and Joel S. Greenberger, all of UPCI’s Department of Radiation Oncology.

In addition, the MMS-350 research was co-authored by Darcy Franicola of UPCI’s Department of Radiation Oncology, and Melissa M. Sprachman and Wipf, both of Pitt’s Department of Chemistry.

Both projects were funded by the National Institute of Allergy and Infectious Diseases; the genetic study also received funding from NIH.

McGowan Inst. to co-direct $75 million regenerative medicine effort

The Armed Forces Institute for Regenerative Medicine (AFIRM) will continue its efforts to apply the latest in tissue engineering and other regenerative medicine techniques to the treatment of battlefield injuries in a $75 million, five-year second phase.

The AFIRM-II consortium of more than 30 academic centers and industry partners will be co-directed by Rocky Tuan, associate director of the McGowan Institute for Regenerative Medicine and director of the Center for Military Medicine Research.

Said Tuan: “For the next five years, AFIRM-II will aim to develop novel therapies for severely damaged limbs, reconstruct facial and skull injuries with tissue engineering approaches, regenerate skin for burns, find new ways to prevent rejection of composite tissues, such as hand transplants, and much more.”

Since its inception in 2008, AFIRM efforts have resulted in clinical studies of face transplantation, minimally invasive surgery for craniofacial injuries, scar reduction treatments, fat grafting for reconstructive surgery and new treatments for burns.

The AFIRM program not only funds scientific research, but also requires that discoveries be tested and compared so that the most promising therapies, which could benefit civilians as well as soldiers, can be brought to clinical trials. The consortium will work with health professionals at the U.S. Army Institute of Surgical Research and Walter Reed National Military Medical Center.

Government sponsors of AFIRM are the U.S. Army Medical Research and Materiel Command, the Office of Naval Research, the Air Force Medical Service, the Office of Research and Development-Department of Veterans Affairs, NIH and the Office of the Assistant Secretary of Defense for Health Affairs.

Mathematical approach forms odor descriptions

Using advanced statistical techniques, Pitt researchers have developed an approach to systematically describing smells.

This work may help guide future studies pertaining to how smells are represented in the brain. The research suggests that there are 10 basic categories of odor including fruity, minty, lemony and sickening.

Senses such as hearing and vision can be discussed in terms that most people understand and that are tied to measurable physical phenomena. But the sense of smell, or olfaction, has thus far not lent itself to such a systematic understanding of what smells we perceive and how those perceptions relate to physical phenomena.

Said Jason Castro, who began the study as a postdoctoral fellow and now is a psychology and neuroscience faculty member at Bates College: “It’s an open question how many fundamental types of odor qualities there are. This is in striking contrast to olfaction’s ‘sister sense,’ taste, where we know that five basic qualities seem to organize sensations.”

Working with a standard set of olfactory perception data, Andrew Dravniek’s 1985 “Atlas of Odor Character Profiles,” the team was the first to apply a mathematical method called non-negative matrix factorization (NMF) to achieve “dimensionality reduction” — the simplification of information into coherent categories, similar to the way compressing a digital audio or image file reduces the file’s size without, ideally, compromising its usefulness.

Castro and Chakra Chennubhotla, faculty member in the Department of Computational and Systems Biology in the School of Medicine, led the research. Said Chennubhotla: “What NMF is good at is dividing a dataset into its constituent parts. You have to give hints for how many parts you may expect to find, but otherwise you let the data decide. NMF has been successfully used in many other areas including the financial world and the processing of still images and videos.”

From the data, the team identified 10 basic odor qualities: fragrant, woody/resinous, fruity (non-citrus), sickening (decayed), chemical, minty/peppermint, sweet, popcorn, sickening (pungent) and lemon.

An intriguing aspect of the work is that the different qualities seem to be associated with different chemical features, although more research is necessary on this front.

In ongoing work, the researchers now are approaching the problem from the other direction, applying the current research to a bank of chemical structures in an attempt to predict how a given chemical is going to smell.

“That’s something that nobody’s really done with any kind of compelling accuracy,” Castro said. “And obviously perfume companies, flavor and fragrance companies are really interested in doing that well.”

The research, completed with a computer scientist at Oak Ridge National Laboratory, was published in the open-access online journal PLoS ONE.

New British charity funds OCD study

Susanne Ahmari, psychiatry faculty member, is a 2013 MQ: Transforming Mental Health Fellow.

The British charity focuses on research aimed at improving the treatment of mental health issues. Each winner receives £225,000 (currently $360,000) over three years.

Ahmari will investigate the causes and mechanisms of obsessive-compulsive disorder (OCD), which affects more than 165 million people worldwide. She will use optogenetics to explore how brain cells interact to cause the repetitive behaviors commonly seen in OCD, and whether this can be averted.

Developing controls for small nuclear reactors

Pitt researchers were awarded an $800,000 grant from the Department of Energy’s Nuclear Energy University Programs (NEUP) to develop advanced instrumentation and control systems for small modular reactors (SMRs).

The team’s research will lead to more effective staffing at these advanced reactors, which generate less than 300 megawatts of electricity but allow for multiple reactors at one site.

Principle investigator is Daniel Cole, mechanical engineering and materials science faculty member and interim director of the Swanson school’s nuclear engineering program. Co-PI is Daniel Mossé, chair of the Department of Computer Science.

Said Cole: “Because SMRs allow for the installation of several reactors inside one facility, you can’t staff each as you would a typical modern reactor and make it economically viable. Rather than duplicating staffing protocols, we’re proposing the development of a supervisory control system that will provide operators with the necessary information needed for reactor, module and plant management.”

Another aspect of the research will investigate condition-based monitoring to better predict fault-tolerance within the plant, as well as in the future change the operating conditions during peak and off-peak loads.

“If you can better monitor how the systems function and improve maintenance schedules, you can enhance operations and allow the supervisory staff to better monitor the entire plant,” Cole said. “The ultimate goal is to predict problems before they occur, provide for the possibility of cogeneration within the plant and adapt to the natural ebbs and flows in the power grid, creating a more economically efficient system.”

Grant funds research that could yield “smart” clothes

A computational “fabric” envisioned by Pitt researchers could lead to the development of clothing that could respond to external stimuli, monitor vital signs of patients or athletes and help the visually impaired “sense” their environment.

The research, funded by a $700,000 National Science Foundation grant, builds on the already-established research of principal investigator Anna C. Balazs, Distinguished Robert v. d. Luft Professor of Chemical Engineering, and Steven P. Levitan, the John A. Jurenko Professor of Computer Engineering at the Swanson School of Engineering. The two are integrating Balazs’ research into Belousov-Zhabotinsky (BZ) gel, a substance that oscillates in the absence of external stimuli, with Levitan’s expertise in computational modeling and oscillator-based computing systems.

“Although BZ gels have been investigated since the 1990s, this research moves in a new direction beyond logic operations — in essence creating materials that compute,” Balazs explained. “The material would be an integrated sensing, computing and responsive device without an external power source that could act as a ‘sixth sense’ for those who wear it.”

Balazs and Levitan propose utilizing the chemo-responsive nature of the BZ gels to create a chemical-based computational fabric that would be lightweight and mechanically compliant, and would be human-centric, sensing and responding to human touch and motion. The material would perform autonomously for up to several hours without connections to an external power supply.

The BZ reactions within the gels would process information  between sets of stored or learned patterns and stimuli in the form of light, pressure or chemistry. This ability for the material to interpret a stimulus, send out a signal and respond in kind will be a key part of the research.

Levitan said: “The real leverage for this project is capitalizing on the gels’ natural oscillation to communicate at a human scale that can sense the surrounding environment, process information and react to complex stimuli. The fabric would most likely require a piezoelectric film to generate an electric field, allowing it to interface with embedded electronics.”

The five-year grant will allow the researchers to further the computational modeling of how such a BZ gel fabric would function, with the goal that others would be able to fabricate the material.

“Imagine this fabric helping a burn patient who has lost the sense of touch know whether he is in contact with a hot or cold material, or the fabric integrated into a jogging suit that can monitor and display your pulse, pressure and respiration,” Balazs said. “By eliminating the need for external wiring or typical computer processors, this sensing fabric could help to change human quality of life.”

Ed school monitors Tenn. schools’ instruction

School of Education researchers have received two grants to monitor instructional quality in classrooms across the state of Tennessee.

The awards, which include a $1.5 million National Science Foundation (NSF) grant and a William T. Grant Foundation grant, will extend ongoing collaboration between the Pitt researchers and educators in that state.

The NSF grant will allow faculty from Pitt’s learning sciences and policy program to partner with officials in Tennessee’s Department of Education to study instructional quality, teachers’ access to resources and student achievement across Tennessee.

Said Mary Kay Stein, faculty member in learning sciences and policy: “The objective of our work is to build an indicator system that will help leaders in Tennessee monitor the impact of all of their work to train teachers and coaches to better help students reach the common core state standards.”

The Common Core State Standards Initiative is a national campaign aimed at increasing the quality of education in English language arts and mathematics.

The research team will design the indicator system to measure two main dimensions.

The first dimension is the extent to which teachers select, and are able to maintain, high-cognitive-demand tasks for their students as part of their mathematics instruction. This will help state educators monitor instructional quality.

The second dimension is the teachers’ access to resources that facilitate their improvement as teachers. This will help officials in the Department of Education decide what resources they need to add to the system to improve instructional quality.

The researchers will use a three-tiered approach to monitoring these two dimensions, Stein said. The first tier focuses on creating an intensive sample.

“Data about cognitive demand and teachers’ access to resources will be collected on 50 teachers in up-close ways by observing classes and interviewing teachers,” Stein said. “These are the measures that we will have a lot of confidence in in terms of how valid they are and their ability to predict student learning.”

But no state can monitor instruction this way, she added, because this method is too labor-intensive. For that reason, an intermediate sample of 100 teachers — the second tier of the approach — will be used to generate less intensive measures, such as having teachers keep logs and collect assignments and samples of student work.

The third tier, known as the scale sample, will collect survey responses from approximately 1,000 teachers by the end of the third year of the project.

“What we’re hoping to do is to refine the less-intensive measures so that they correlate heavily with what we find out in the intensive sample,” Stein said.

By calibrating the design of the logs, assignments, samples of student work and surveys to closely correlate with the observational and interview measures, the researchers intend for their indicator system to offer a less-intensive set of tools that the Tennessee Department of Education can use to accurately monitor teacher performance.

Stein anticipates that the team will require three years to build the indicator system, with researchers working in Tennessee classrooms as well as hiring Tennessee-based individuals to carry out some tasks in the state.

Stein and education school colleagues Richard Correnti and Jennifer Russell will be heading the project. All are scientists in the Learning Research and Development Center.

NIH awards $5.8 million for kidney research

The Pittsburgh Center for Kidney Research has been awarded a five-year grant totaling $5.8 million from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of NIH.

The grant will support research facilities, educational programs and pilot projects to enhance kidney-focused research at Pitt and related institutions.

The Pittsburgh Center for Kidney Research is one of seven George M. O’Brien Kidney Research Core Centers in the United States and also is supported by Pitt’s School of Medicine and the Department of Medicine. Established in 1987 by the NIDDK, the O’Brien centers bring together scientists from multiple institutions to collaborate on basic, clinical and applied aspects of biomedical research in renal physiology and pathophysiology.

The Pittsburgh Center for Kidney Research supports four research facilities encompassing cellular physiology, single nephron and metabolomics, kidney imaging and model organisms at the University; the center also supports a research facility at the Icahn School of Medicine at Mount Sinai in New York.

Center director Thomas Kleyman, who is Sheldon Adler Professor of Medicine at the School of Medicine and chief of the UPMC Renal-Electrolyte Division, said: “Our Center for Kidney Research is designed to facilitate research that advances our understanding of how the kidney works, with a goal of improving how we diagnose and treat kidney diseases.”

Of the 98 investigators who participate in the Pittsburgh Center for Kidney Research, 58 are Pitt faculty members, 35 are at other U.S. institutions and five are at foreign institutions.

$11 million awarded to fight ovarian cancer

More than 14,000 women in the U.S., including 800 from Pennsylvania, died last year from ovarian cancer, a disease that often isn’t detected until later stages when it is significantly more difficult to treat. Now, the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, and Roswell Park Cancer Institute (RPCI) will join forces thanks to an $11 million grant from the National Cancer Institute (NCI) to develop deeper understanding of the disease and identify ways to prevent and cure it.

The five-year grant award comes through NCI’s specialized program of research excellence (SPORE), and will fund three clinical trials evaluating newly developed immunotherapies and an epidemiological study examining strategies to reduce risk in women considered at high risk for developing ovarian cancer.

Robert P. Edwards, a faculty member in the Department of Obstetrics, Gynecology and Reproductive Sciences and executive vice chair of gynecologic services and director of the Ovarian Cancer Center of Excellence at Magee-Womens Hospital, said:  “Our clinical trial is tackling one of the ultimate goals of personalized cancer medicine and will explore the roles of chronic inflammation, cancer development and the body’s immune response, and how the immune response can be used to immunize the patient against her own cancer.”

One of only five ovarian cancer-focused SPORE grants awarded nationally, this is the only one focused exclusively on utilizing the body’s immune system to fight the disease. The goal of the research is to reduce the overall morbidity and mortality of ovarian cancer through “bench to bedside” research.

Kunle Odunsi, director of the Center for Immunotherapy at RPCI and principal investigator of the SPORE grant, said: “There is a need to develop novel and effective ovarian cancer therapies that are nontoxic and harness the body’s immune response to fight ovarian cancer.”

According to Edwards, the UPMC CancerCenter network will play a substantial role by providing access to all three clinical trials, including those that are launched at RPCI, to women across Pennsylvania.


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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