University Times

Cancer data-sharing software developed

Researchers at the School of Medicine, UPMC and the Pittsburgh Supercomputing Center have created a software resource to help investigators wade through a colossal amount of genomic cancer data in search of better methods of prevention, diagnosis and treatment. The open-source, freely available software, which processes data generated by The Cancer Genome Atlas (TCGA) project and is called TCGA Expedition, is described in PLOS ONE.

Said lead author Rebecca Jacobson, biomedical informatics faculty member: “Starting with TCGA, our goal is to make large data sets available to the average researcher who would not otherwise be able to access this information. There’s a growing understanding that further advances in health care are going to require a previously unseen level of data-sharing, which will require new tools. That’s particularly true in cancer research, as recognized by the major focus on data sharing in Vice President Joseph Biden’s recently announced Cancer Moonshot initiative.”

Funding for the new software was provided by IPM and the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

Fundamentally, all cancers are caused by an overgrowth of cells due to an error in DNA. Examining a cancer’s complete set of DNA, or genome, can provide insights into many aspects of tumor biology. The goal of TCGA, a collaborative effort of the National Cancer Institute and the National Human Genome Research Institute, is to collect and share genomic data from cancers with poor prognoses and the greatest impacts on public health. To date, the project has profiled 33 different cancers from more than 11,000 patients, and the resulting data has been used in more than 1,000 cancer studies.

Jacobson said: “These very large data sets are incredibly hard to work with because they are enormous, not only in terms of the amount of digital storage space they need, but also in terms of the complexity of software and computational processing power that they require. Right now, our institutions are choking on data.”

The new software continuously downloads, processes and manages TCGA data, allowing researchers to take the tools that they need and apply them to making cancer discoveries.
The team then puts the new software to work, creating an information technology framework called the Pittsburgh Genome Resource Repository to allow approved Pitt researchers to use TCGA data much more effectively. While initially designed for TCGA data, the new software also can be used with other large data sets.

Jacobson hopes the benefits of TCGA Expedition will extend well beyond Pittsburgh.

Additional Pitt collaborators on the project include Adrian Lee, Uma Chandran, Olga Medvedeva, M. Michael Barmada, Anish Chakka, Soumya Luthra, Antonio Ferreira, Kim Wong, Jeremy Berg and Annerose Berndt. Colleagues from Carnegie Mellon University also contributed.

Fat injections combat foot pain

Patients who suffer from pedal fat pad atrophy, or the loss of fat in the ball of the foot, may benefit from a new procedure that involves restoring the lost padding by grafting fat from other areas of the body, according to a clinical trial in the School of Medicine’s Department of Plastic Surgery, published in Plastic and Reconstructive Surgery.

Said lead author Jeffrey Gusenoff, a department faculty member: “The fat pads in the foot act as a shock absorber when we walk, cushioning the structures around them. People with pedal fat atrophy face tremendous pain with each step they take. The loss of this important natural padding of fat, which can be triggered by age, obesity, high-heeled shoes or abnormal foot mechanics, among other causes, gives the sensation of walking on bone, making even standing for a short period nearly impossible.”

Gusenoff led a multidisciplinary team that included podiatry and plastic surgery clinicians as they examined 25 patients divided into two groups. One group was treated immediately with fat grafting, with follow-up after one year. The minimally invasive procedure allowed them to leave the office on their feet with the help of padded sneakers.

Strenuous activity was restricted for four-six weeks, and no barefoot walking was permitted during that time.

A second group was treated with conservative management of symptoms for a year.

The study found that, after one year, patients in the first group demonstrated improved foot function and reduced pain with no change in tissue thickness or foot pressure. The conservatively managed group experienced a decrease in tissue thickness with an increase in foot pressure. Ultimately, fat injections to the foot may prevent worsening of the condition compared to going without treatment, the study found, and continuing analysis will determine long-term effects.

Additional Pitt authors on the study were Beth Gusenoff, Ryan Mitchell, Kwonho Jeong and Dane Wukich.

The research was supported by The Plastic Surgery Foundation and the Department of Plastic Surgery.

Model may predict brain dynamics

For as long as scientists have been listening in on the activity of the brain, they have been trying to understand the source of its noisy, apparently random, activity. In the past 20 years, “balanced network theory” has emerged to explain this apparent randomness through a balance of excitation and inhibition in recurrently coupled networks of neurons. A team of scientists has extended the balanced model to provide deep and testable predictions linking brain circuits to brain activity.

Lead investigators at the University of Pittsburgh Brain Institute (UPBI) say the new model accurately explains experimental findings about the highly variable responses of neurons in the brains of living animals. Their paper, “The Spatial Structure of Correlated Neuronal Variability,” was published in Nature Neuroscience.

The new model provides a much richer understanding of how activity is coordinated between neurons in neural circuits. The model could be used in the future to discover neural “signatures” that predict brain activity associated with learning or disease, the investigators believe.

Said Brent Doiron, UPBI member, mathematics faculty member in the Dietrich School of Arts and Sciences and senior author on the paper: “Normally, brain activity appears highly random and variable most of the time, which looks like a weird way to compute. To understand the mechanics of neural computation, you need to know how the dynamics of a neuronal network depends on the network’s architecture, and this latest research brings us significantly closer to achieving this goal.”

Earlier versions of the balanced network theory captured how the timing and frequency of inputs — excitatory and inhibitory — shaped the emergence of variability in neural behavior, but these models used shortcuts that were unrealistic biologically, according to Doiron.

“The original balanced model ignored the spatial dependence of wiring in the brain,” he said, “but it has long been known that neuron pairs that are near one another have a higher likelihood of connecting than pairs that are separated by larger distances. Earlier models produced unrealistic behavior — either completely random activity that was unlike the brain or completely synchronized neural behavior, such as you would see in a deep seizure. You could produce nothing in between.”

In the context of this balance, neurons are in a constant state of tension. According to co-author Matthew Smith, ophthalmology faculty member in the School of Medicine and a member of UPBI: “It’s like balancing on one foot on your toes. If there are small overcorrections, the result is big fluctuations in neural firing, or communication.”

The new model accounts for temporal and spatial characteristics of neural networks and the correlations in the activity between neurons — whether firing in one neuron is correlated with firing in another. The model is such a substantial improvement that the scientists could use it to predict the behavior of living neurons examined in the area of the brain that processes the visual world.

After developing the model, the scientists examined data from the living visual cortex and found that their model accurately predicted the behavior of neurons based on how far apart they were. The activity of nearby neuron pairs was strongly correlated. At an intermediate distance, pairs of neurons were anti-correlated (when one responded more, the other responded less), and at greater distances still they were independent.

“This model will help us to better understand how the brain computes information because it’s a big step forward in describing how network structure determines network variability,” said Doiron. “Any serious theory of brain computation must take into account the noise in the code. A shift in neuronal variability accompanies important cognitive functions, such as attention and learning,” and is a signature of Parkinson’s disease and epilepsy.

While the scientists examined the visual cortex, they believe their model could be used to predict activity in other parts of the brain, such as areas that process auditory or olfactory cues, for example. And they believe that the model generalizes to the brains of all mammals. In fact, the team found that a neural signature predicted by their model appeared in the visual cortex of living mice studied by another team of investigators.

Said Nathan Urban, associate director of UPBI: “A hallmark of the computational approach that Doiron and Smith are taking is that its goal is to infer general principles of brain function that can be broadly applied to many scenarios. Remarkably, we still don’t have things like the laws of gravity for understanding the brain, but this is an important step for providing good theories in neuroscience that will allow us to make sense of the explosion of new experimental data that can now be collected.”

Other Pitt contributors to the study were Jonathan Rubin and Robert Rosenbaum (a former postdoctoral scholar now at the University of Notre Dame). A colleague from the Albert Einstein College of Medicine also participated.

The research was funded by National Science Foundation’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, the National Eye Institute, Research to Prevent Blindness, the Eye and Ear Foundation of Pittsburgh and the Simons Foundation.

Program boosts adult vaccine rates

A newly developed program boosts vaccination rates in adult patients seen at primary care offices, two recent studies demonstrated.

Physician offices participating in the 4 pillars practice transformation program had nearly three times the increase in patients getting the Tdap vaccine for protection against pertussis (whooping cough) compared to nonparticipating offices, according to research published in Vaccine.

Another study, published in the Journal for Healthcare Quality, demonstrated that certain characteristics already embedded into some primary care practices, such as open leadership and staff communication, organizational flexibility and experience with quality improvement, predicted which practices would garner the most vaccination rate improvement from the 4 pillars program.

Said Richard K. Zimmerman, faculty member in the school’s Department of Family Medicine and one of the authors on the two studies: “Vaccination is the single best way to prevent communicable diseases. In recent years, we’ve seen surges in cases of whooping cough, which can be deadly in newborns, who can contract it from unvaccinated adults. And we recently learned from federal health officials that the rate of people getting vaccinated against the flu — another virus that kills hundreds annually — fell last season. We need to find ways to get more people immunized.”

The 4 pillars program is a step-by-step guide, backed by decades of research, for increasing adult immunizations at primary care clinics by using an online tool that tracks vaccination rates. It’s based on four key pillars: convenient vaccination services; communication with patients about the importance of immunization; enhanced office systems to facilitate immunization; and motivation through an office “immunization champion” who is charged with implementing the strategies and maintaining the program.

In a study focusing on increasing Tdap immunization rates, following its recommendation for all adults by the federal advisory committee on immunization practices in 2012, the researchers enrolled 25 primary care practices in Pittsburgh and Houston. Half received the 4 pillars program in the first year, while the other half acted as a control group and didn’t receive the program until the second year.

At the beginning of the study, the practices had Tdap immunization rates ranging from a low of 6.8 percent to a high of 79.5 percent. With the 4 pillars program, the practices increased their immunization rates by an average of 7.6 percent in the first year compared to a national increase of about 3 percent. One practice increased by 17 percent in the first year.

In a different analysis using the same enrolled practices, Mary Hawk, faculty member in behavioral and community health sciences at the Graduate School of Public Health, examined factors that made the program more effective at some practices. Those that had the highest implementation of the 4 pillars program strategies, resulting in the best immunization rate improvement, were those with:

• Extensive experience with previous quality improvement initiatives.

• Two-way communication in which information between physicians and staff members flowed in both directions, reflecting a mutual respect for ideas.

• An immunization champion who was respected for his or her leadership and was able to guide and motivate staff in making office systems changes.

• An organizational flexibility that was nimble and amenable to embracing positive changes.

Hawk said: “The ability to implement change within primary care settings requires more than simply intent to participate, especially when it comes to improving immunization rates. Even with a proven, research-backed program like 4 pillars, practices also may need to make internal adjustments for the program to work to its full ability.”

The work was supported by the U.S. Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH).

Additional Pitt researchers on both studies are Mary Patricia Nowalk, Krissy K. Moehling, Jonathan M. Raviotta and Edmond E. Ricci. Colleagues from Baylor College of Medicine also participated.

The vaccine study also included Chyongchiou J. Lin, Song Zhang, Jeannette E. South-Paul and Donald B. Middleton of Pitt, as well as colleagues from the CDC.

Visual hallucinations induced, measured

Many people have experienced the sensation of seeming to see something that isn’t there: a visual hallucination. But studying the phenomenon of hallucinations is difficult: They are irregular, transitory and highly personal — only the person experiencing the hallucination knows what he or she is seeing, and representations of what’s being seen are limited to verbal descriptions or drawings.

A research team of Bard Ermentrout, Distinguished University Professor of Computational Biology and mathematics faculty member in the Dietrich School, and Joel Pearson from The University of New South Wales in Australia have come up with a way to create hallucinations that could make them easier to be studied objectively, potentially leading to new treatment methods. Ermentrout and Pearson outlined their discovery in a paper, “Sensory Dynamics of Visual Hallucinations in the Normal Population,” which was published in eLife.

Most visual hallucinations are associated with illnesses such as schizophrenia, Parkinson’s disease, migraines and some forms of dementia, but healthy people also can experience hallucinations from drugs, sleep deprivation or loss of vision.

Ermentrout and Pearson displayed a white ring that flickered against a black background between two and 30 times per second. The subjects, college students with no history of migraines or psychiatric disorders, uniformly “saw” what they all described as pale grey blobs rotating around the ring, first in one direction, then the opposite direction.

Said Ermentrout: “Because the pale grey blobs are much simpler and uniform than more complex hallucinations that people generally see, they are much easier to study objectively.”

To measure the hallucinations, Ermentrout and Pearson created a second ring with actual grey blobs inside the white ring, and participants were able to convey the relative strength of the hallucinations by indicating whether the hallucinated blobs were lighter or darker than the real blobs. The researchers also were able to have participants gauge the relative speed of the hallucinated motion by placing fixed lines at the top and the bottom of the white ring and noting how quickly the blobs passed the lines.

The researchers found that both the real blobs and hallucinations seemed to be perceived in the visual cortex, and they created a computer model of the visual cortex.

They hope this model will help to explain both normal vision and hallucinations and lead to the next step, determining whether the experimental method can be used to model hallucinations produced by psychiatric disorders.

Stewart Heitmann of Pitt also participated in the study, as did other colleagues from New South Wales.

New therapy prevents skin radiation damage

School of Medicine researchers have demonstrated that a newly developed topical therapy applied before or after radiation exposure prevents skin damage in both animal and human models.

The results, published in the Journal of Investigative Dermatology, are expected to accelerate efforts that will lead to clinical studies and licensing of the technology, noted Louis Falo, chair of the Department of Dermatology and corresponding author for the study.

The skin is the largest human organ and protects the body from physical, chemical and environmental exposures. Radiation-induced skin damage ranges from photo-aging and ultraviolet sun exposure to radiation dermatitis, a treatment-limiting condition caused by radiation therapy, as well as skin radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents.

Falo had teamed with Joel Greenberger, chair of the school’s Department of Radiation Oncology, and Peter Wipf, Distinguished University Professor of Chemistry in the Dietrich school, in 2008; Greenberger and Wipf were exploring treatments to mitigate radiation poisoning caused by an accident at a nuclear power facility or from a so-called “dirty bomb” device. Together, they determined that the approaches being developed and investigated could potentially benefit the approximately 1 million people annually in the U.S. who undergo radiation therapy to the skin for breast, head and neck and other cancers.

Said Falo: “During the course of radiation therapy, patients can develop irritating and painful skin burns that can lead to dangerous infections and diminished quality of life. Sometimes the burns are so severe that patients must stop their treatment regimen. Our results show that topical treatment with this therapeutic agent prevents skin damage at the source.”

Wipf’s lab developed the molecule that targets the formation of oxidative free radicals in the cell’s mitochondria, thereby preventing inflammation and cell death.

Joshua Pierce, a former student of Wipf’s who is now at North Carolina State University, is credited with synthesizing the molecule, named JP4-039. Said Pierce: “This provides for potentially improved treatment options for patients undergoing radiation therapy with the prospect for more simplified treatment regimens and reduced concern about quality of life post-treatment.”

Falo said he is optimistic about the therapy’s performance in clinical trials because the treatment appears to be effective in a model that uses human skin obtained from cosmetic procedures.

Looking beyond treating radiation therapy, he and his team are pursuing studies of the molecule’s ability to reduce skin damage from sun exposure, including sunburns and the molecular changes that lead to skin cancer, as well as cosmetic applications to prevent skin changes caused by the oxidative stress associated with normal skin aging.

Additional Pitt authors on this study were Rhonda M. Brand, Michael W. Epperly, J. Mark Stottlemyer, Xiang Gao, Erin M. Skoda, Song Li, Saiful Huq and Valerian E. Kagan.

This research was funded by National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases and the Coulter Foundation.

Can at-risk cerebral aneurysms be predicted?

Although cerebral aneurysms affect a substantial portion of the adult population, the risk of treatment including open brain surgery often outweighs the risks associated with rupture. With increasing numbers of unruptured aneurysms detected using noninvasive imaging techniques, there is an urgent need for a reliable method to distinguish aneurysms vulnerable to impending rupture from those that are robust and can be safely monitored. An international research team led by the Swanson School of Engineering received a grant from NIH to improve risk assessment and treatment of this devastating disease.

Principle investigator of the five-year, $2,950,622 grant is Anne M. Robertson, the William Kepler Whiteford Professor of Engineering at the Swanson school. The grant is funded through NIH’s National Institute of Neurological Disorders and Stroke.

Said Robertson: “The cells in our blood vessels have a remarkable capacity for rebuilding and maintaining the collagen fibers that give the artery walls their strength. Unfortunately, this natural process can be derailed by the abnormal fluid flow in brain aneurysms, leading to vulnerable walls and rupture. Understanding the factors that discriminate between robust aneurysm walls with well-organized collagen fibers, and fragile aneurysm walls with diverse changes to the collagen architecture, is essential for improving risk assessment and developing new treatments to prevent rupture.”

To support their work, Robertson and a multidisciplinary team of world leaders in aneurysm research from Pitt, Allegheny General Hospital, George Mason University and the University of Illinois-Chicago, as well as Helsinki University Central Hospital and Kuopio University Hospital in Finland, will analyze brain tissue donated from patients with cerebral aneurysms. Using biomechanical analysis and bioimaging, the investigators will look specifically at how and why some patients naturally are able to maintain a healthy aneurysm wall while the walls in other patients weaken, leaving them vulnerable to rupture. They will use computational mechanics to explore the possible multiple mechanisms by which hemodynamics alters the wall and study the mechanisms of structural failure.

Added Robertson: “Because of the critical importance and delicate nature of the brain, surgical treatment of cerebral aneurysms is avoided unless absolutely necessary. That’s why doctors and surgeons need a more effective way to determine whether a patient with a cerebral aneurysm is at risk for rupture. We expect that by understanding the differences in the vulnerable and robust aneurysm wall, we will be able to improve risk assessment, identify biomarkers of wall fragility and provide essential knowledge for developing pharmacological treatments to harness and augment the natural repair process of the aneurysm wall.”

Co-investigators from Pitt are Spandan Maiti and Simon C. Watkins.

Children’s ED sees hike in headaches among patients

Research shows that the pediatric emergency department at Children’s Hospital is seeing a steady increase in the number of children with headaches. The findings were presented at the American Academy of Pediatrics national conference and exhibition.

Researchers from Children’s Hospital examined the electronic medical record of patients ages 4-20 visiting the emergency department at Children’s, 2007-14.
During this time, pediatric emergency department visits for headaches doubled from 2 percent to more than 4 percent. In addition, the admission rate for children with headaches more than doubled from 10 percent in 2007 to nearly 25 percent in 2014. Females were more likely to be admitted for headache pain than males.

Said Michelle Perry, study author and pediatric resident at Children’s Hospital: “The results are intriguing because this is the first study to report a current trend in pediatric headache visits and to characterize pediatric patients with headache within a pediatric emergency department.”

Added Regina Toto, study co-author and pediatric chief resident at Children’s Hospital: “Our study confirms that headaches are an increasingly common reason for children to be admitted to our hospital, in accordance with national trends. Despite more patients receiving pharmacologic treatment, more and more children with headaches are being hospitalized. The reasons why remain unclear to us and represent a key next step in pediatric headache research.”

The research team hopes to determine why this is occurring and how clinicians can more effectively treat patients with headaches in emergency departments and outpatient settings to avoid hospital admissions whenever possible.

African drought decreasing

The notion that the African continent has been getting progressively drier over time is being challenged by new research that finds that drought actually has decreased over the past 1.3 million years and that the continent is on a 100,000-year cycle of wet and dry conditions. These new findings add a wrinkle to one of the keys to human evolutionary theory, the savannah hypothesis, which states that the progressively drier conditions in Africa led to prehuman ancestors migrating from forests and moving into grasslands.

Josef Werne, Pitt faculty member in geology and environmental science in the Dietrich School of Arts and Sciences, along with colleagues from other universities in the United States, Australia, Chile and the Netherlands, made the discovery by examining core samples extracted from the bottom of Lake Malawi, one of the world’s largest lakes, located between Malawi, Mozambique and Tanzania in southeastern Africa.

Their paper, “A Progressively Wetter Climate in Southern East Africa Over the Past 1.3 Million Years,” was published in the journal Nature.

Previous studies of Africa’s climate focused on the northern part of the continent, Werne explained, and were responsible for the origin of the savannah hypothesis that the continent was getting drier. The 100,000-year cycles the researchers found correspond with the beginnings and endings of the great ice ages.

Lake Malawi had not been explored previously because the depth of the waters — 700 feet — exceeded researchers’ ability to get core samples from the bottom.

The researchers were able to overcome that limitation by using a barge and modifying oil rig equipment to obtain a 380-meter-long sediment core sample. The core was dated using a combination of radiocarbon, volcanic ash and magnetic polarity reversals and examined for molecular fossils indicating changing temperature and rainfall.

Temperature was derived by studying the distribution of the membrane lipids of a single-celled microbe, which was analyzed by mass spectroscopy. The aridity and rainfall were measured by calcium content and the distribution and carbon isotope composition of fossil leaf waxes. There is a difference between fossil leaf waxes that originate in trees and shrubs, which thrive in wetter conditions, and those that originate in grasses, which can outcompete trees in dry conditions.

By noting the changes in temperature records and especially rainfall, the team determined that the continent was getting wetter over time in southern East Africa; the team also identified the 100,000-year climate cycles.

The research project was more than 20 years in the making; the solution to obtaining the core samples wasn’t completed until 2005.

Werne was in charge of analyzing the molecular fossils from these cores.

—Compiled by Marty Levine