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Researchers Discover Mechanism Crucial to Brain Cancer Growth

Special to UM News

Brain.Tumor2

From left are Nagi Ayad, Claes Wahlestedt, Chiara Pastori, and Ricardo J. Komotar.

MIAMI, Fla. (July 2, 2015) — A team of Miller School of Medicine researchers has discovered that a previously unappreciated so-called long noncoding RNA mechanism controls tumor growth of Glioblastoma Multiforme cells.

Their findings, which have been published online as “The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation” by the journal Proceedings of the National Academy of Sciences, may lead to the development of new drugs with increased effectiveness against brain tumors.

Glioblastoma Multiforme (GBM) is the most common and deadliest primary brain tumor in adults. Despite aggressive treatment, median survival is approximately 14 months, and there is an urgent need for novel therapies.

“For many years, investigators have been studying conventional genes in brain tumors, but arguably no complete picture has emerged,” said Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, Associate Dean for Therapeutic Innovation, and a principal author of the journal article. “We instead focused on the huge area of so-called ‘dark matter’ of the human genome, which is essentially uncharted territory. Our research team has been building expertise to study these unknown parts of the genome for a long time, and we have found that they play an absolutely crucial role in the growth of these tumors.”

Epigenetic modulators, such as bromodomain proteins, are considered important therapeutic targets in cancers, including GBM. Bromodomain inhibitors suppress proliferation by repressing oncogenes and inducing tumor suppressor genes through largely unidentified pathways.

“We demonstrated that the molecule HOTAIR is often massively overexpressed in GBM, where it is crucial to sustain tumor cell proliferation, and that inhibition of HOTAIR expression by bromodomain inhibitors is necessary to induce cell cycle arrest in GBM cells,” said co-author Nagi Ayad, Ph.D., associate professor of psychiatry and behavioral sciences. “Our study helps understand the mechanism of action underlying the anti-proliferative activity of this new drug class, showing for the first time that the oncogenic long noncoding RNA HOTAIR is a major factor in driving tumor growth.”

This novel study produced completely unexpected results.

“We learned two important things,” said Wahlestedt. “First, that this dark matter of the genome is crucial for the growth of these types of brain tumors. Second, that an important new type of drug currently being tested in patients with brain tumors actually works, at least in part, by modifying this dark matter of the genome.

“We and others can use these findings to develop drugs for brain tumors that are hopefully more effective than the treatments we have today. Our study describes not only HOTAIR, but also other so-called long noncoding RNAs that could conceivably be used as biomarkers by which we and others can monitor the effectiveness of these new drugs.”

Additional Miller School of Medicine authors are first author Chiara Pastori, Ph.D., postdoctoral fellow at the Sylvester Comprehensive Cancer Center; Ricardo Komotar, M.D., Director of Surgical Neuro-oncology at UHealth – University of Miami Health System; Clara Penas, Ph.D., research associate in the Ayad laboratory; Veronica Peschansky, M.D./Ph.D. student; Claude-Henry Volmar, Ph.D., associate scientist in the Department of Molecular and Cellular Pharmacology; and Amade Bregy, M.D., Ph.D., Director of Research Support in the Department of Neurological Surgery.

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Political Scientist to Study New Zealand’s Female Prime Ministers

CORAL GABLES, Fla. (June 30, 2015) — Over the past four decades, the number of women holding national-level political office has steadily increased throughout the world. However, only one country has appointed two women to its top leadership post: New Zealand.

Next year, Louise Davidson-Schmich, associate professor of political science in the UM College of Arts & Sciences, will spend four months there, conducting research on how these two former Prime Ministers – Jenny Shipley, 1997-1999, and Helen Clark, 1999-2008 – represented New Zealand women during their terms, and the lasting effect of their tenures on female Kiwis.

Davidson-Schmich will be based at the Victoria University of Wellington, in New Zealand’s capital city, where she will have access to parliamentary transcripts and news archives, and will be able to meet with individuals who worked closely with these two dynamic but very different leaders.

Davidson-Schmich’s project was inspired by her ongoing research on gender and politics in Germany, and Chancellor Angela Merkel.

“I could not always determine whether Merkel’s policies were inspired by her gender or by some other factor,” Davidson-Schmich says, noting that Merkel grew up in communist East Germany, and was trained as a physicist.

So she set her sights on New Zealand, “a country which experienced two very different female leaders serving back-to-back terms.”

She explains, “If I could identify commonalities in the ways in which two very different women governed, I could better make claims that their gender played a role.”

Davidson-Schmich will travel to New Zealand in February 2016, and conduct her research there through July. She will also teach an undergraduate course on the comparative political economy of post-industrial democracies.

The Fulbright U.S. Scholar Program provides approximately 800 teaching and/or research grants to U.S. faculty and experienced professionals in a wide variety of academic and professional fields each year. Program participants design their own research projects aimed at enhancing their existing scholarly interests.

The fellowship will give Davidson-Schmich “a wonderful opportunity to expand my intellectual horizons beyond the European focus of my research to date,” she says. Her forthcoming book is about gender quotas in Germany, and she has edited a special issue of the journal German Politics focusing on Merkel’s Chancellorship.

Davidson-Schmich served as the Director of the Women’s and Gender Studies Program in the UM College of Arts & Sciences for the 2014-2015 academic year. She received her Ph.D. from Duke University.

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New Study Predicts Variation in Illness Severity

 UM News

UM researcher explains the basis of the Weibull distribution and finds applications in human health and across scientific fields

dose-response functionCORAL GABLES, Fla. (June 23, 2015) – Many of us are familiar with bell-shaped curves that show the distributions of school grades, annual rainfall, and many other quantities. This ubiquitous distribution results when many points for individual non-correlated quantities are added to produce an outcome.

Interestingly, a very differently shaped, highly skewed pattern, often called a power law distribution, is also ubiquitous and often considered a signature of complex systems. But its origin has never been adequately explained.

A new study shows that when individual random quantities, such as reactions in the body, are correlated, and multiplied, the process gives rise to the highly skewed pattern known as the Weibull distribution, and it can be used to describe and predict the pattern of illness severity across a population exposed to different chemicals.

The correlated multiplicative model can potentially explain many types of results in a wide range of areas, and thus lead to better predictions of many types of risk, including human health risk.

“The insight is new and cuts across scientific fields,” said James D. Englehardt, professor of Environmental Engineering at the College of Engineering and author of the study. “The correlated multiplicative, or first-order kinetic, model can explain many different processes, ranging from mortality rates to distributions of incomes, material released into the environment during oil spills, explosions and natural disasters to the magnitudes of solar flares, among many other quantities.”

The Weibull distribution is similar to a power law, which has been observed to describe many aspects of complex systems. But according to the study, the Weibull distribution is superior in explaining these systems.

“In the case of a power law probability distribution, the probability of an outcome size occurring is proportional to a power of the size,” Englehardt said. “However, as a probability distribution, it must necessarily break down at one or both extremes, otherwise over the range zero to infinity there would be a total probability of all possible outcomes greater than one,” he said. “A Weibull distribution does not have this problem,” he said. “It can fit the full range of observed data, and the paper shows it to have better ‘goodness-of-fit’ to illness severity data, and to be predicted theoretically in many complex systems.”

Previous studies have not generally used the Weibull form in place of the power law to describe complex systems, in part because the sizes of the individual multiplicative causes of complex systems outcomes are not often known, and in part because some of these systems are not often analyzed numerically. For instance, illness severities are described by clinical findings, which are generally sets of observed symptoms leading to a yes/no diagnosis.

“Another more technical reason is that the ‘first-order kinetic model,’ used in economics, chemistry, biology, and pathology to describe how many quantities grow or decay over time, has not been recognized to describe the sizes of outcomes of many complex systems, and has not been generally recognized as equivalent to a multiplicative model, and the incremental multipliers of that model have not generally been recognized as correlated and exponentially distributed, though it is known that products of perfectly correlated exponential random variables are Weibull,” Englehardt said.

The study, titled “Distributions of Autocorrelated First-Order Kinetic Outcomes: Illness Severity,” is published in the online journal PLOS ONE. Currently, Englehardt is working on a general dose-response function for chemicals and chemical mixtures, based on the Weibull illness severity distribution that may greatly improve our ability to predict the risk of illness resulting from exposure to extremely low doses of chemicals that we experience in our daily lives.

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Alumnus Makes $1 Million Pledge to UM Athletics

Special to UM News

CORAL GABLES, Fla. — University of Miami alumnus Scott C. Mueller, BBA ’85 and CEO of Dealer Tire, has made a gift of $1 million to establish The Scott C. Mueller Endowed Football Scholarship at the University of Miami.

The gift will help fund an annual scholarship for one student-athlete in the football program in perpetuity.

Mueller, a native of Cleveland, Ohio, who attended the University of Miami on an academic scholarship, earning his Bachelor of Business Administration in 1985, never forgot the opportunity the University gave him.

“I was fortunate enough to earn a scholarship while attending the University of Miami,” Mueller said.  “I always thought it was a great honor and a tremendous break in my life and I want to make sure that I pay back that generosity by helping another student. The hard work and commitment of Miami’s students-athletes is very inspiring to me and I want to ensure the University is positioned for future success.”

Mueller, who lives in the Cleveland area, co-founded Dealer Tire in 2001 with his brother, Dean, and father, Walter, after selling the 84-year-old family business, Mueller Tire & Brake. Dealer Tire supplies tires and accessories to car dealers and manufacturers and is one of the largest tire distributors in the nation.

Mueller has been a fan of Miami football since his days as an undergraduate student in the early 1980s, when the Hurricanes captured their first national championship under head coach Howard Schnellenberger.

“On behalf of the University of Miami, I would like to thank Scott for his unwavering support and generosity to our athletics program,” said Miami Athletic Director Blake James. “This leadership gift will provide an academic and athletic opportunity to a deserving young man who will proudly represent UM on the football field while working toward a degree. Scott truly defines what it means to be a Miami Hurricane and we can’t thank him enough for his passion and support of our student-athletes.”

The Department of Athletics fields 17 varsity sports with 400-plus student-athletes and has won 21 national championships. Nearly 260 student-athletes receive athletic scholarship dollars. For more information or to make a gift, please visit www.uhurricaneclub.com.

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Help Shape the Future of the US 1-Red Road-Sunset Corridor

Join city of Coral Gables officials, staff, and guest speakers for a visioning workshop on the US 1-Red Road-Sunset Corridor Friday, July 17 and Saturday July 18 that will include discussions about the Underline and feature keynote addresses by the School of Architecture’s Charles Bohl, director of the Graduate Program in Real Estate Development and Urbanism, and Elizabeth Plater-Zyberk, the Malcolm Matheson Distinguished Professor of Architecture and director of the Master of Urban Design Program.

View the event page and agenda for more information and RSVP at Planning@coralgables.com or 305-460-5211.

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