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June 12, 2014

Research Notes

Potential breast cancer drug performs well in early trials

A drug previously studied to improve chemotherapy may be effective in treating patients with cancers related to the BRCA 1 or 2 genetic mutations, as well as patients with BRCA-like breast cancers, according to a University of Pittsburgh Cancer Institute (UPCI) clinical trial.

The results of the phase I study were presented at the annual American Society of Clinical Oncology meeting this month.

The drug, veliparib (ABT-888), is a PARP inhibitor, which means it lowers the resistance of cancer cells to treatment by targeting the poly (ADP-ribose) polymerase (PARP) family of enzymes responsible for a wide variety of cellular processes in cancer cells, particularly DNA repair.

“Cancer cells have increased levels of PARP, which we believe may, in part, lead to resistance to chemotherapies and other cancer treatments,” said Shannon Puhalla, a faculty member in the Department of Medicine and a breast oncologist with UPMC CancerCenter at Magee-Womens Hospital.

“Tumor cells in patients with BRCA mutations are particularly sensitive to the effects of PARP inhibitors due to underlying DNA repair abnormalities caused by the BRCA mutation. Veliparib can act as personalized medicine for patients with tumors caused by an inherited BRCA mutation, due to this particular sensitivity.”

The study enrolled 60 patients with a BRCA genetic mutation and 28 patients without a mutation. The objectives of the trial included determining how veliparib affected cancer cells and observing how patients responded to the drug.

“We found that veliparib is well-tolerated by patients, with fewer side effects than what can be seen with chemotherapies,” Puhalla said. “In addition, anti-tumor activity was detected in both our BRCA-positive and our BRCA-negative patients.”

Puhalla and a research team at UPCI have been investigating ABT-888 for five years. Their research began in the laboratory and progressed to human clinical trials. Puhalla currently is leading a phase II clinical trial with ABT-888.

“Many cancer patients with BRCA mutations end up exhausting their treatment options. Veliparib may give them another option,” she said.


Pitt team first to detect exciton in metal

Pitt researchers have become the first to detect a fundamental particle of light-matter interaction in metals, the exciton. The team published its paper, “Transient Excitons at Metal Surfaces,” online June 1 in Nature Physics.

Mankind has used reflection of light from a metal mirror on a daily basis for millennia, but the quantum mechanical magic behind this familiar phenomenon only now is being uncovered.

Physicists describe physical phenomena in terms of interactions between fields and particles, said lead author Hrvoje Petek, Richard King Mellon Professor in the Department of Physics and Astronomy in the Dietrich School of Arts and Sciences. When light (an electromagnetic field) reflects from a metal mirror, it shakes the metal’s free electrons (the particles), and the consequent acceleration of electrons creates a nearly perfect replica of the incident light (the reflection).

The classical theory of electromagnetism provides a good understanding of inputs and outputs of this process, but a microscopic quantum mechanical description of how the light excites the electrons is lacking.

Petek’s team of experimental and theoretical physicists and chemists from Pitt and the Institute of Physics in Zagreb, Croatia, reported on how light and matter interact at the surface of a silver crystal. They observed, for the first time, an exciton in a metal.

Excitons, particles of light-matter interaction where light photons become transiently entangled with electrons in molecules and semiconductors, are known to be fundamentally important in processes such as plant photosynthesis and optical communications that are the basis for the Internet and cable TV.

The optical and electronic properties of metals cause excitons to last no longer than approximately 100 attoseconds (0.1 quadrillionth of a second). Such short lifetimes make it difficult for scientists to study excitons in metals, but also enable reflected light to be a nearly perfect replica of the incoming light.

Yet Branko Gumhalter at the Institute of Physics predicted, and Petek and his team experimentally discovered, that the surface electrons of silver crystals can maintain the excitonic state more than 100 times longer than the bulk metal, enabling the excitons in metals to be experimentally captured by a newly developed multidimensional coherent spectroscopic technique.

The ability to detect excitons in metals sheds light on how light is converted to electrical and chemical energy in plants and solar cells, and in the future may enable metals to function as active elements in optical communications. In other words, it may be possible to control how light is reflected from a metal.

The work was supported by the Division of Chemical Sciences, Geosciences and Biosciences in the U.S. Department of Energy.


Activity prevents loss of mobility in older adults

A 20-minute brisk walk each day could help older adults significantly maintain their ability to walk, according to the results of the longest-running randomized clinical trial evaluating physical activity in the elderly.

Pitt was one of eight field centers that recruited and monitored trial participants. The findings were presented at the annual meeting of the American College of Sports Medicine  and published in the Journal of the American Medical Association.

“Doctors have long suspected that maintaining or starting physical activity is important in promoting good health as we age,” said Anne Newman, principal investigator on the study and chair of the Graduate School of Public Health’s Department of Epidemiology, as well as the Katherine M. Detre Endowed Chair of Population Health Science. “But until this study, we didn’t have the proof necessary to say that daily exercise, sustained over several years, truly can prevent loss of mobility. Doctors can now feel confident that moderate physical activity improves the independence and mobility of older adults.”

Newman and her fellow investigators, coordinated by Marco Pahor, director of the University of Florida’s Institute on Aging, obtained those results through the Lifestyle Interventions and Independence for Elders, or LIFE study. This study recruited and followed 1,635 sedentary men and women — 216 from Pittsburgh — ages 70-89.

Newman, a geriatrician, supervised the Pittsburgh arm of the LIFE study. For the national study, she chaired the ancillary studies review committee and wrote the outcome procedures for cardiovascular events and the procedures for participant medical clearance at enrollment and for return after illness.

The study showed that prescribed daily physical activity would prevent older adults’ loss of mobility, defined in the study as the inability to walk 400 meters, or about a quarter-mile. That is approximately equal to a trip from a parked car to a grocery store or a walk through a neighborhood.

Moderate physical activity helped aging adults maintain their ability to walk at a rate 18 percent higher than older adults who did not exercise. It also resulted in a 28 percent reduction in people permanently losing the ability to walk easily.

Newman said, “This shows that we can repair a deficit through physical activity.”

When recruited to the study, participants could walk a quarter-mile within 15 minutes, but were at risk for losing that ability. Low physical performance can be a predictor of early death and higher hospitalization rates. Patients with low physical performance often are not recruited to large studies, making it difficult to give research-backed medical recommendations.

Pahor said: “These are people who are patients we see every day. This is why this study is so important: It includes a population that is typically understudied.”

The participants were randomly sorted into two groups. For two years, the first group walked 150 minutes per week and did strength, flexibility and balance training. Twice each week, they visited field centers, which kept them on track with their exercise. The second group attended health education classes and performed stretching exercises. This phase of the study occurred between February 2010 and December 2013.

Research technicians assessed study participants every six months, checking their ability to walk, their body weight, blood pressure and pulse rate, among other measurements. The staff was not told which participants were assigned to physical activity or to the education classes.

At Pitt, nearly two dozen researchers, students, technicians, nurses and exercise physiologists ensured that the trial and data collection ran smoothly. All eight field centers regularly communicated with one another to share tips for encouraging participants to stay in the study.

The researchers noted that there is still a vast amount of data available from the study that needs to be analyzed, including the effects of physical activity on the participants’ cognitive function.

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


Simple change to Medicare Part D would yield $5 billion in savings, study finds

The federal government could save over $5 billion in the first year by changing the way it assigns Part D plans for Medicare beneficiaries eligible for low-income subsidies, according to research from the Graduate School of Public Health.

The results of the study, funded by NIH and the U.S. Department of Health and Human Services, is being published in the June issue of the journal Health Affairs.

Medicare Part D provides assistance to beneficiaries below 150 percent of the federal poverty level. In 2013, an estimated 10 million beneficiaries received subsidies, and 75 percent of the total Part D federal spending of $60 billion is for low-income enrollees.

Since 2006, the government has randomly assigned low-income enrollees to stand-alone Part D plans, based upon the region in which they live.

“Random assignment is suboptimal because beneficiaries often are assigned to plans either not covering or charging higher costs for their medications,” said Yuting Zhang, the study’s lead author and a faculty member in the Department of Health Policy and Management. “We found that most people are not in the least expensive plans that satisfy their medication needs.”

Zhang and her colleagues say an “intelligent reassignment” that matches beneficiaries to their medication needs would yield substantial savings.

Using real data from 2008 and 2009 for a 5 percent random sample of all Medicare beneficiaries who qualified for the low-income subsidy program, Zhang and her team simulated potential medication costs to the beneficiaries and the government under each alternative plan available in the region. They then compared the simulated costs with the actual costs of each plan. They found that if low-income enrollees were assigned to the least expensive plan instead of a random plan, the government and beneficiaries could save more than $5 billion in the first year.

In addition to the savings under the proposed change, beneficiaries would have fewer restrictions when filling their prescriptions. Some common restrictions used by Part D plans include quantity limits, prior authorization and step therapy.

The Pitt researchers noted that assigning beneficiaries to plans could be implemented relatively easily each year, with the largest savings in the first year but additional savings annually thereafter.


$1.5M grant awarded to educate, retain science students

The Howard Hughes Medical Institute (HHMI) has awarded Pitt a $1.5 million, five-year grant to continue, develop and create new lab-based biology courses aimed at retaining students in the sciences.

Pitt is one of 37 schools to receive funding through the HHMI’s sustaining excellence competition, aimed at improving science teaching nationwide. More than 170 applicants underwent three rounds of peer review before HHMI decided on the 37 recipients.

Graham Hatfull, the University’s Eberly Family Professor of Biotechnology as well as an HHMI professor, is leading the charge to expand and develop course-based research experiences in the Department of Biological Sciences within the Dietrich School of Arts and Sciences. The effort will build upon science educational activities funded by HHMI for the past eight years.

“In the past, and this will continue, students learned to ‘do’ science through an apprentice-based approach, working with a faculty member or a graduate student,” Hatfull said. “What HHMI is aiming at is the sort of approach where you can develop a course-based research experience that can engage many more students and can do so at an early point in their college career — in other words, freshmen.”

HHMI reported that nearly 40 percent of the 3 million students who enter college annually intend to study science or engineering, but 60 percent of that cohort fail to earn their degree in a science or engineering field. Hatfull is optimistic that the HHMI funding will help reverse this national trend.

“Research indicates that it is effective to get students involved in lab work,” he said. “If we can get to students in their freshman year and get them invested in research, that will promote retention in the sciences. The earlier we get them, the bigger the impact it will have.”

Nancy Kaufmann, assistant program director in the Department of Biological Sciences for the HHMI-supported work, said a portion of the grant will be used to expand offerings of the Hatfull-created SEA-PHAGES course, in which students find, identify and sequence the DNA of bacteriophages, the most abundant life form on Earth.

SEA-PHAGES has been implemented at 70-plus colleges and universities around the country and a study reporting its success was published in mBio this year. Another course, already being piloted in Pitt’s biology department and ready to be expanded, delves into the intricacies of aquaporins, proteins that control fluid levels in cells.

Kaufmann said the grant also will allow Pitt biology faculty to develop new lab-based courses, pay for summer research fellowships for undergraduates after their freshman year as well as the salaries of graduate teaching assistants and teaching postdoctoral students, and fund an existing research hub lab where undergrads can do independent research.


Dad’s alcohol consumption could influence sons’ drinking

Even before conception, a son’s vulnerability for alcohol use disorders could be shaped by a father who chronically drinks to excess, according to a new animal study from the School of Medicine. The findings, published online in PLOS ONE, show male mice that were chronically exposed to alcohol before breeding had male offspring that were less likely to consume alcohol and were more sensitive to its effects, providing new insight into inheritance and development of drinking behaviors.

Previous human studies indicate that alcoholism can run in families, particularly father to son, but to date only a few gene variants have been associated with alcohol use disorder and they account for only a small fraction of the risk of inheriting the problem, said senior investigator Gregg E. Homanics, a faculty member in the Department of Anesthesiology.

“We examined whether a father’s exposure to alcohol could alter expression of the genes he passed down to his children,” Homanics said. “Rather than mutation of the genetic sequence, environmental factors might lead to changes that modify the activity of a gene, which is called epigenetics. Our mouse study shows that it is possible for alcohol to modify the dad’s otherwise normal genes and influence consumption in his sons, but surprisingly not his daughters.”

He and lead author Andrey Finegersh, a student in anesthesiology, chronically exposed male mice over five weeks to intermittent ethanol vapor, leading to blood alcohol levels slightly higher than the legal limit for human drivers. Then, they mated them to females who had not been exposed to alcohol.

Compared to those of ethanol-free sires, adult male offspring of ethanol-exposed mice consumed less alcohol when it was made available and were less likely to choose to drink it over water. Also, they were more susceptible to alcohol effects on motor control and reduction of anxiety.

“We suspected that the offspring of alcohol-exposed sires would have an enhanced taste for alcohol, which seems to be the pattern for humans,” Finegersh said. “Whether the unexpected reduction in alcohol drinking that was observed is due to differences between species or the specific drinking model that was tested is unclear.”

The researchers plan to examine other drinking models such as binge drinking, identify how alcohol modifies the genes, and explore why female offspring appear to be unaffected.


$3 million grant awarded for fundamental particle research

Sergey Frolov, a faculty member in the Department of Physics and Astronomy, has received a $3 million Office of Naval Research basic research challenge grant to explore ways of transforming quantum computing through the use of an unusual particle. Frolov will be the primary investigator for the study on the Majorana fermion, a long-posited but elusive elementary particle that Frolov and colleagues discovered in 2012.

Frolov said, “We may be adding a new, third class of fundamental particles to fermions and bosons.”

On a more practical level, he said, Majorana fermions could be used to create a novel and incredibly powerful quantum computer. “A Majorana fermion quantum computer would be rather unusual,” he says. “It would process information differently because of the manner in which the particles are interchanged. Logical operations are undertaken by the physical swapping of Majorana fermion particles. There would be thousands of them, and they’d shuffle around; that’s how computation would proceed.”

Majorana fermions were first theorized in the 1930s, when physicist Ettore Majorana mathematically proved that there could be a particle that lived on the boundary of matter and antimatter, a particle that is also its own antiparticle. Frolov and colleagues were the first to create them in a lab.

Their paper, “Signatures of Majorana Fermions in Hybrid Superconductor-semiconductor Nanowire Devices,” made the cover of Science in 2012. Frolov worked on the project as a postdoctoral fellow at Delft University of Technology in the Netherlands.

The American Association for the Advancement of Science dubbed the paper the best research article published in Science in 2012, honoring Frolov and his colleagues with the Newcomb Cleveland Prize.

—Compiled by Alex Oltmanns


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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