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November 23, 2016

Research Notes

Brain model sought for Alzheimer’s, schizophrenia

The Department of Biomedical Informatics in the School of Medicine and biopharmaceutical company Pfizer are working on developing a computational model to help identify the drivers of schizophrenia, Alzheimer’s disease and related brain diseases and enable researchers to better understand and treat the diseases.

Faculty member Kayhan Batmanghelich will be the principal investigator in the one-year study. The goal of the study is to develop a statistical model that relates abnormal anatomical variations of brain structure to the underlying genetic markers of the diseases in order to develop an algorithm that explains causal relationships between such heterogeneous data, and to be able to use the method in similar settings for precision medicine.

Said Batmanghelich: “In addition to the genotype data, measurements from magnetic resonance brain images will be used to characterize abnormal brain variations. By studying brain images and relating the variations of each brain region to the genetics and clinical observations of patients, we provide deeper insight about the underlying biology of the diseases.”

The study will use the publicly available datasets of ADNI (Alzheimer’s Disease Neuroimaging Initiative) and private datasets of the GENUS (Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia) Consortium, both of which contain images, genetic information, biological information and clinical observations of patients, to develop software that can be used to associate the images with gene patterns.

Genetic test aids heart stent patients

A genetic test recently implemented at UPMC Presbyterian can significantly reduce the risk of cardiovascular events by helping to identify more effective medication for some heart patients, according to the results of a study conducted in part at the School of Pharmacy and UPMC. The findings were presented at the American Heart Association’s annual scientific sessions.

The test identifies a genetic deficiency that affects the body’s ability to activate clopidogrel, a common anti-clotting drug given after a coronary artery stent is inserted. About 30 percent of all patients have the genetic deficiency, which can lead to decreased clopidogrel effectiveness and increased risk for adverse cardiovascular events, such as strokes, heart attacks and death.

In the current study from the Implementing Genomics in Practice (IGNITE) Network at the National Institutes of Health (NIH), researchers at Pitt’s pharmacy school and other sites throughout the country analyzed medical outcomes in 1,815 patients who had genetic testing at the time of their cardiac procedure. The testing allows physicians to pinpoint the best anti-clotting medication for each patient.

The study reported significant results: About 60 percent of patients with the genetic deficiency were given a different, more effective medication. Using the genetic data to guide changes in therapy reduced the percentage of deaths, heart attacks or strokes by nearly half compared with those who continued taking clopidogrel, the researchers found. Among those who had the genetic deficiency and continued taking clopidogrel, 8 percent experienced one of those complications.

Significantly fewer adverse events occurred among patients who were switched to an alternative drug, the researchers concluded.

Earlier this year, UPMC Presbyterian became one of the first medical centers in the country to make this test available for patients as part of the PreCISE-Rx (pharmacogenomics-guided care to improve the safety and effectiveness of medications) initiative.

Approximately 10 percent of the study population was analyzed by the team at Pitt and UPMC, one of the affiliates in the IGNITE Network.

Said Philip Empey, pharmacy and therapeutics faculty member and leader of the Pitt team: “This study is a major step forward as it shows applying pharmacogenomics to achieve a precision medicine approach in cardiac stent patients can provide significant benefits.”

Other institutions that participated in the clopidogrel research were the University of North Carolina, the University of Maryland-Baltimore, the University of Alabama-Birmingham, Vanderbilt University Medical Center, the University of Illinois-Chicago, Indiana University-Indianapolis, Sanford Health, Duke University and the University of Pennsylvania.

Patient With Walker While Nurse Assisting Her In Hospital

Patient view part of nursing activity analysis

As the role of technology continues to grow in the health care industry, a UPMC quality improvement project coupled patient surveys with observations, nurses’ self-reports and electronic health record (EHR) data to better understand how nurses allocate their time during a shift.

The findings, published online in the Journal of Nursing Care Quality, are intended to help the health system take additional steps to improve care quality and the patient experience.

Said Linda Higgins, lead author of the project: “UPMC nurses had expressed concerns that they were spending too much time entering information into the EHR and not enough time at the bedside caring for patients. It also was unclear how patients felt about the time they spent with their nurses, so we designed this project to gather multifaceted data that could provide a comprehensive picture of nursing activity and guide future improvements in workflow and patient satisfaction.”

Over five months, 11 trained observers visited four inpatient units, shadowing one shift for each of the 79 nurses involved in the project. The observers chronicled 900 hours of nursing activity and logged it according to predetermined categories. Following the observed shift, nurses filled out a questionnaire, and the observers interviewed the patients cared for by the observed nurses.

In the interviews, patients reported spending an average of 74 minutes with their assigned nurse, and 90 percent rated the amount of time with their nurse as “excellent” or “good.”

However, the observers estimate that the nurses actually spent only about 40 minutes with each patient. This suggests that the quality of the time that nurses spend with their patients may impact the patients’ perceptions of the length of time their nurses spend with them.

The most frequently observed shift activities were: documenting in (11.5 percent) and reviewing (9.1 percent) the EHR; patient assessment and interaction (8.9 percent); in-person communications with health care workers about patients or patient care (7.5 percent); and patient care and bedside procedures (7.2 percent). Overall, nurses were observed to spend an average of 33 percent of their shift interacting with technology.

Other project findings indicate that nurses overestimated the time they spent directly caring for patients and charting in the EHR compared to observations. Nurses also reported mostly positive attitudes toward the EHR and other technology in terms of user experience.

Additional authors were Judith A. Shovel, Andrew L. Bilderback, Holly L. Lorenz, Susan C. Martin and Debra J. Rogers, all of UPMC.

The project was funded by the Masimo Corp. and Pitt’s Health Policy Institute.

Decoding cellular death signals

A multidisciplinary international team of scientists solved the mystery of a recently discovered type of controlled cell death, mapping the path to potential therapies for conditions ranging from radiation injury to cancer. The study, led in part by Graduate School of Public Health faculty, was reported in Nature Chemical Biology.

Ferroptosis is a way the body uses iron to catalyze a reaction that safely destroys and recycles a malfunctioning or damaged cell. Until this study, scientists didn’t know how the body signaled — within the damaged cell and to other cells — that this well-regulated death needed to occur.

Said Valerian E. Kagan, faculty member in environmental and occupational health and lead author of one of the two papers produced from the study: “Our team successfully decoded the signaling language that cells use to trigger ferroptosis. You can think of it like the scanners and radios that policemen use to find and arrest a criminal. The goal is to communicate enough information to neutralize the problem and remove the criminal, or damaged cell, but without creating such a commotion that you disrupt the society, which, in this example, would be other, well-functioning cells.”

Through two years of experiments bridging fields ranging from public health and critical care medicine to basic biology and chemistry, the team analyzed hundreds of molecular combinations generated in the ferroptotic process to discover that only four molecules actually signal for the cell to die. All four are phospholipids, naturally occurring molecules that make up cell membranes.

“Scientists have long known that these lipids were important for encasing the cell and giving it structure,” said Kagan. “What they didn’t know — what we’ve only learned in recent scientific history — is that they do so much more, including communicating and signaling messages like ‘danger’ inside the cell itself, to other cells and to the cellular community as a whole, so that organisms can function in a coordinated way.”

Kagan and Hülya Bayir, faculty member in the School of Medicine’s Department of Critical Care Medicine and senior author of one of the papers, previously worked together to decode another type of more well-known cell death called apoptosis. They then decided to pursue the more esoteric ferroptosis, which had been discovered in 2012.

Kagan and Bayir also study ways to protect people against radiation, such as what would be given off in a terrorist attack. The findings gave them reason to think that ferroptosis may underlie radiation-induced cellular damage as well.

Said Bayir: “More and more, we’re appreciating that the damage from acute radiation is happening to the lining of the intestine, and that damage triggers a cascade of health complications that lead to sepsis, a very deadly syndrome. We believe that the radiation is triggering ferroptosis in the cells that line the intestine. If we can stop that process and get the body to repair, rather than systematically destroy, those cells, we might save the victims of devastating dirty bomb attacks.”

Conversely, in cancer, the body is failing to destroy dysfunctional cancer cells, allowing tumors to grow unchecked. By understanding the ferroptotic pathway, the researchers hope to find medications that can prompt it to recognize and kill cancer cells.

The researchers already have partnered with several UPMC clinicians to explore ways to translate their scientific findings into therapies that could help patients.

The other Pitt leading investigators are Joel Greenberger, Rama K. Mallampalli, Claudette St. Croix and Simon Watkins. Colleagues from Columbia University, Helmholtz Zentrum München and the University of Heidelberg in Germany also contributed.

The research was supported by NIH, Deutsche Forschungsgemeinschaft and the human frontier science program.

Heart care improves; hospitalizations up

Although hospitalizations have increased in recent years for patients with congestive heart failure, survival rates and length of stay have improved, according to research from the School of Medicine and the UPMC Heart and Vascular Institute.

The results, published in Clinical Cardiology and presented at the American Heart Association’s (AHA) scientific sessions, were based on more than 15 million U.S. hospital admissions between 1996 and 2009 due to congestive heart failure.

The prevalence of heart failure is increasing in the U.S. due to its aging population and significant advancements in management of associated co-morbidities, such as ischemic heart disease, diabetes, stroke, peripheral vascular disease and hypertension. More than 5 million Americans are living with heart failure, and close to 500,000 patients are newly diagnosed each year.

Heart failure also is a common cause of hospital admissions, leading to significant costs for the nation’s health care system. A recent report from the AHA estimated the annual direct and indirect costs associated with heart failure in the U.S. at more than $30.7 billion. However, until this study, little was known about recent trends involving those admissions, including length of stay and in-hospital mortality.

Said Muhammad Bilal Munir, faculty member in the Division of General Internal Medicine and corresponding author of the study: “There has been significant progress in heart failure management over the past two decades, but more has to be done. The number of hospitalizations has increased, identifying a need to implement heart failure quality measures stringently to reduce these admissions, therefore reducing heart failure-associated health care costs.”

The number of heart failure hospitalizations increased from 1,000,766 in 1996 to 1,173,832 in 2009, according to study results. The mean length of stay fell from 6.07 days to about 5.26 days, a decrease of 3.41 percent.

Researchers say the findings likely reflect the changes in the management of heart failure across the country, which include numerous advances in care such as new drug therapies and sophisticated devices. Further efforts are needed to curb the cost of heart failure management, experts agreed, with a focus on reducing heart failure hospital admissions and readmissions, especially for patients with less severe symptoms who could be treated with aggressive outpatient management.

Additional Pitt study authors from the UPMC Heart and Vascular Institute were Michael S. Sharbaugh, Floyd W. Thoma, Muhammad Umer Nisar, Amir S. Kamran, Andrew D. Althouse and Samir Saba.

Self-powered soft robot developed

One of the impediments to developing miniaturized, “squishy” robots is the need for an internal power source that overcomes the power-to-weight ratio for efficient movement. An international group involving Pitt, Inha University and the Air Force Research Laboratory (AFRL) has built upon their previous research and identified new materials that directly convert ultraviolet light into motion without the need for electronics or other traditional methods. The research was published in Nature Communications.

The group includes M. Ravi Shankar, co-author and industrial engineering faculty member in the Swanson School of Engineering. The experiments were conducted at the AFRL’s Materials & Manufacturing Directorate at Wright-Patterson Air Force Base in Ohio.

Other investigations have proposed the use of ambient energy resources such as magnetic fields, acoustics, heat and other temperature variations to avoid adding structures to induce locomotion. However, Shankar explained that light is more appealing because of its speed, temporal control and the ability to effectively target the mechanical response. For the material, the group zeroed in on monolithic polymer films prepared from a form of liquid crystalline polymer.

Explained Shankar: “Our initial research indicated that these flexible polymers could be triggered to move by different forms of light. However, a robot or similar device isn’t effective unless you can tightly control its motions. We were able to demonstrate directional control, as well as climbing motions.”

The photomotility of these specific polymers is the result of their spontaneous formation into spirals when exposed to UV light. Controlling the exposure enables a corresponding motion without the use of external power sources attached directly to the polymer itself.

In addition to simple forward movement, the team was able to make the polymers climb a glass slide at a 15-degree angle. While the flat polymer strips are small — approximately 15 mm long and 1.25 mm wide — they can move at several millimeters per second propelled by light. The movement can be perpetual, as long as the material remains illuminated.

“The ability for these flexible polymers to move when exposed to light opens up a new ground game in the quest for soft robots,” Shankar said. “By eliminating the additional mass of batteries, moving parts and other cumbersome devices, we can potentially create a robot that would be beneficial where excess weight and size is a negative, such as in space exploration or other extreme environments.”

Cancer cells hijack DNA repair in order to stay alive

Research by scientists at the University of Pittsburgh Cancer Institute (UPCI) has revealed how cancer cells hijack DNA repair pathways to prevent telomeres, the endcaps of chromosomes, from shortening, thus allowing the tumor to spread. The findings were published in Cell Reports.

The moment a cell is formed, a countdown clock starts ticking that determines how long the cell can live. The clock is the telomere, a series of repeating DNA letters at the ends of each chromosome in the cell.

However, cancer cells cleverly hijack this telomere clock, resetting it and lengthening the telomere every time it shortens. This leads the cell into thinking that it is still young and can divide, thus spreading the tumor.

Most cancers do this by increasing the activity of an enzyme called telomerase, which lengthens telomeres. But approximately 15 percent of cancers use a different mechanism for resetting the clock, called alternative lengthening of telomeres (ALT).

Growing evidence also suggests that tumors that activate the ALT pathway are aggressive and more resistant to treatment. Although ALT was identified almost two decades ago, identifying how this mechanism works has proved elusive.

Said senior author Roderick O’Sullivan, pharmacology and chemical biology faculty member in the School of Medicine and a member of UPCI: “Identifying the parts that the cancer cell tweaks to reset the countdown timer could provide targets for developing new cancer drugs or making existing ones more effective.”

O’Sullivan and his team tackled this problem by using a recently developed technique called proximity dependent biotinylation (BioID), which allowed them to quickly identify proteins that were physically close to, and hence potentially associated with, telomere lengthening in cancer cells.

When comparing cancer cells in which either telomerase or ALT were active, the BioID technique identified 139 proteins that were unique to ALT-activated cells. As the research team took a closer look, one enzyme, DNA polymerase η (Polη), took them by surprise.

Said O’Sullivan: “We expected to see DNA repair proteins, but seeing Polη was really unexpected as it was known to be activated only in cells that were damaged by UV light, which we did not use in our experiments. Its role in the ALT pathway is completely independent of how we think of it normally.” Knowing the molecular players in the ALT pathway opens up a whole new area of research and many potential drug targets, according to O’Sullivan.

Laura Garcia-Exposito, a postdoctoral fellow in O’Sullivan’s lab, is one of the co-first authors of the study.

Other Pitt study authors include Arindam Bose, Simon C. Watkins, Patricia Opresko, Callen Wallace and Justin L. Roncaioli. Also contributing were colleagues from the Cancer Research Center at the University of Toulouse and New York Medical College.

The research was funded by the Competitive Medical Research Fund and Stimulating Pittsburgh Research in Geroscience at Pitt, NIH, Labex Toucan and La Ligue contre le Cancer.

Mature Asian man exercise at gym

Does exercise contribute to brain health?

Improving your memory and brain function as you age might be as simple as investing in a good pair of sneakers, but studies recommending that still are met with skepticism because the exercise/brain-health connection has not been tested to the rigors of a large-scale, Phase III trial. Kirk Erickson, psychology faculty member in the Dietrich School of Arts and Sciences, will conduct such a trial thanks to a five-year, $21.8 million grant from the National Institute on Aging.

Said Erickson, director of the Brain Aging and Cognitive Health Lab: “This study will more definitively address whether exercise influences cognitive and brain health in cognitively normal older adults, as well as understanding the mechanisms of physical activity on the brain.” Erickson’s study, “Investigating Gains in Neurocognition in an Intervention Trial of Exercise” (IGNITE), will be conducted in collaboration with Northeastern University, the University of Kansas and the University of Illinois.

The project will study 639 cognitively normal adults between 65 and 80 years old. Participants will be broken into three groups to test different “doses”: the first group will engage in moderate-intensity exercise — brisk walking — at the public-health recommended dose of 150 minutes a week; the second group will exercise for 225 minutes a week; and the third group will do stretching and toning exercises for 150 minutes a week.

Participants will be examined at the beginning of the study to establish baselines in their cognitive and physical health, using a comprehensive battery of neuropsychological tests as well as measures of physical function, fitness and brain health.

The IGNITE study will explore four main aims:

• whether a moderate-intensity exercise intervention improves cognitive health;

• whether that intervention improves MRI-measured markers of brain health and whether those changes are dose dependent;

• whether changes to the nervous system, heart and metabolism mediate improvements in the brain and in cognition; and • how individual differences such as age and genetics affect the results.

The researchers also hope to discover whether the baseline brain measurements lend insight to participants’ compliance with the intervention, as well as the usefulness of analytical brain imaging in understanding the effects of physical activity on the aging brain. In addition to Pitt, Northeastern and Kansas will serve as intervention sites.

Mechanisms of cancer, aging and inflammation found

A team of researchers from the Graduate School of Public Health and UPCI has uncovered new details about the biology of telomeres, “caps” of DNA that protect the tips of chromosomes and play key roles in a number of health conditions, including cancer, inflammation and aging. The findings were published in Nature Structural and Molecular Biology.

Telomeres, composed of repeated sequences of DNA, are shortened every time a cell divides and therefore become smaller as a person ages. When they become too short, telomeres send a signal to the cell to stop dividing permanently, which impairs the ability of tissues to regenerate and contributes to many aging-related diseases, explained lead study author Patricia Opresko, environmental and occupational health faculty member and a member of UPCI’s molecular and cellular cancer biology program.

In contrast, in most cancer cells, levels of the enzyme telomerase, which lengthens telomeres, are elevated, allowing them to divide indefinitely.

Said Opresko: “The new information will be useful in designing new therapies to preserve telomeres in healthy cells and ultimately help combat the effects of inflammation and aging. On the flip side, we hope to develop mechanisms to selectively deplete telomeres in cancer cells to stop them from dividing.”

A number of studies have shown that oxidative stress — a condition where damaging molecules known as free radicals build up inside cell — accelerates telomere shortening. Free radicals can damage not only the DNA that make up telomeres, but also the DNA building blocks used to extend them.

Oxidative stress is known to play a role in many health conditions, including inflammation and cancer. Damage from free radicals, which can be generated by inflammation in the body as well as environmental factors, is thought to build up throughout the aging process.

The goal of the new study was to determine what happens to telomeres when they are damaged by oxidative stress. The researchers suspected that oxidative damage would render telomerase unable to do its job.

“Much to our surprise, telomerase could lengthen telomeres with oxidative damage,” Opresko said. “In fact, the damage seems to promote telomere lengthening.”

Next, the team looked to see what would happen if the building blocks used to make up telomeres were instead subjected to oxidative damage. They found that telomerase was able to add a damaged DNA precursor molecule to the end of the telomere, but then was unable to add additional DNA molecules.

The new results suggest that the mechanism by which oxidative stress accelerates telomere shortening is through damaging the DNA precursor molecules, not the telomere itself. “We also found that oxidation of the DNA building blocks is a new way to inhibit telomerase activity, which is important because it could potentially be used to treat cancer,” she said.

Opresko and her team now are beginning to further explore the consequences of oxidative stress on telomeres, using a novel photosensitizer, developed at Carnegie Mellon University, that produces oxidative damage selectively in telomeres.

Funding for the research was provided by NIH, the American Cancer Society and the Abraham A. Mitchell Distinguished Investigator Fund.

Additional Pitt collaborators were Elise Fouquerel, Justin Lormand and Arindam Bose. Researchers from Johns Hopkins, the University of Illinois, the University of South Alabama and the University of Kansas Medical Center also contributed.

—Compiled by Marty Levine

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