Framed patents lining a wall in the newly opened USF Heart Institute Genomics Laboratory contain scientific language like polymorphisms and adrenergic receptors.  But application of the entrepreneurial research described in those patents may lead to new therapies based on an individual’s DNA or predict which patients are most likely to benefit from existing drugs.

“It’s ground breaking,” Stephen Klasko, MD, CEO for USF Health and dean of the Morsani College of Medicine, said of the research behind the patents held by Stephen Liggett, MD, who was recruited last year to lead the university’s genomics and personalized medicine research and who will direct the new laboratory.

L to R: Dr. Stephen Klasko, CEO of USF Health and dean of the Morsani College of Medicine, and Dr. Stephen Liggett, vice dean for research at MCOM, with Hillsborough County Commissioners Ken Hagan (chair), Sandra Murman and Mark Sharpe.

Dr. Klasko welcomed university and community leaders May 14  to the grand opening of the 7,550-square-foot laboratory, built on the fifth floor of the USF Health Byrd Alzheimer’s Institute. The celebration was an opportunity to thank Hillsborough County Commissioners for their forward-thinking support of the transformative space focusing on genomic science within the Heart Institute, and showcase how USF Health is transforming health care.

“A lot of people talk about molecular genomics and regenerative therapies, and a lot of people are doing great clinical research,” Dr. Klasko said. “We’re going to be the first place to bring together all that technology and research to really get something done on behalf of patients.”

Shelled-in space at the USF Health Byrd Alzheimer’s Institute was built out to house the Genomics Laboratory, so that basic science research could begin before construction of the freestanding USF Heart Institute. The cost of the laboratory’s construction, equipment and initial recruitment of researchers, was $2 million, half of which was funded by an economic development grant from Hillsborough County.

Last year, the state and country awarded USF a total of $8.9 million to move forward in creating a Heart Institute that will pursue innovative research to find new diagnostics and therapies for cardiovascular disease – a leading cause of hospitalizations, deaths and lost productivity in Florida and nationwide. The Legislature approved a second appropriation of funding for the Institute this session, and a final appropriation is expected next session.

Dr. Klasko welcomed university and community leaders attending the grand opening of the USF Heart Institute Genomics Laboratory.

The Institute’s proposed location will be in the center of the university’s health campus, which includes Moffitt Cancer Center, the Byrd Alzheimer’s Institute, and the Morsani College of Medicine and James A. Haley Veterans’ Hospital. The research facility will also be near Florida Hospital Pepin Heart Institute, which is collaborating with USF Health on the local arm of a national clinical trial testing a new gene treatment for heart failure.

This proximity of these leading medical institutions will help the Heart Institute create meaningful research collaborations and leverage vital resources “that will make the real difference,” said Leslie Miller, MD, director of the USF Heart Institute.

“It’s an exciting time,” Dr. Miller said. “New drugs and biologic therapies we’ll discover here hopefully will have an immediate impact and translate into a reduction in cardiovascular mortality.”

The 15 patents lining one wall of the Genomics Laboratory were issued to Dr. Liggett and colleagues for genomic research discoveries applicable to diagnosis and treatment.

Dr. Liggett, vice dean for research at the USF Health Morsani College of Medicine, said the genomics laboratory is the “seed” for the larger Heart Institute to come.

The laboratory is equipped with state-of-the-art machines for sequencing DNA.  That and other advanced technology will allow USF researchers to study the differences in DNA among individuals to help unravel how diseases emerge and to discover targeted therapies tailored to the patient’s genetic makeup.

The scientists who work in the lab will address such questions as: Do certain genetic variants predispose an individual to certain diseases?  Do they modify the course, or severity, of particular diseases? Can they predict an individual’s response to treatment?

“This whole concept of one drug fits all, which we know doesn’t really work, is going to stop right here,” Dr. Liggett said.

While the new genomics lab will initially focus on heart research, it will eventually branch out to other diseases. “In fact,” Liggett said, “one cannot study heart disease without also studying atherosclerosis, obesity, diabetes and metabolism, to name a few. So, we will be comprehensive.”

Dr. Miller outlines plans for the freestanding USF Heart Institute, which will be constructed in the center of the USF Health campus near other leading health institutions.

Dr. Liggett, who explained what scientists will do in the new genomics laboratory, holds up a test tube, which he said contains his DNA. “It’s labeled sample #1, because, back in 1991, I was the first person whose DNA I ever studied.”

In March 2012, Dr. Liggett and Dr. Miller joined Dr. Klasko in appearing before the Hillsborough County Commission to lay out the visionary plan for creating the USF Heart Institute.

“Given the importance of the University of South Florida as a key economic engine and its standing as a research leader among universities, it was an easy decision for the Board to support this lab,” said Ken Hagan, chair of the Board of County Commissioners. “When innovative thinking is matched with widespread community support, dramatic change can occur.  It will mean healthier lives for all and a healthier economic environment for Tampa Bay.”

Hal Mullis, vice chair of the USF System Board of Trustees, leads the board’s Health work group.

Hagan credited his fellow commissioner Mark Sharpe with championing the proposal for the institute.

“The transformation of health requires radical thinking and brave disruptors who aren’t afraid to challenge the status quo,” Sharpe said. “Health care and heart care is going to be changing right here in Tampa Bay, and we’re thrilled to be part of it.”

Ken Hagan, chair of the Hillsborough County Commission, said the county was proud to partner with a leading research university and the state to pursue the creation of the USF Heart Institute.

Commissioner Mark Sharpe said transforming health and heart care requires disruptive innovation, and Tampa Bay is ready to meet the challenge.

The commissioners attending the opening donned white lab coats and helped unveil a plaque recognizing the county’s contribution to advancing genomic research at the USF Heart Institute.

While economic development is a critical piece of the Heart Institute’s evolution, Dr. Liggett noted that the ultimate goal of the research is to improve and save lives.

“I’ve been at the bedside of patients with heart disease, asthma, COPD and other diseases,” said Dr. Liggett, a physician with basic science expertise.  “Patents, jobs and spin-off companies will come out of our work here, but in the end we want to help the human condition – and that is what we are going to do.”

 Photos by Eric Younghans, USF Health Communications

TAMPA, Fla. and HARTFORD, Conn. (May 9, 2013) – The University of South Florida (USF) and Aetna (NYSE: AET) are launching a ground-breaking study that will examine the influence genetic testing may have on clinical treatment decisions among breast cancer patients and their doctors. Understanding the connection between genetic risk factors, treatment options and results can guide policies and services that can help patients and doctors make more informed, personalized decisions that lead to better health.

The National Institutes of Health (NIH) awarded funding to USF for the five-year American BRCA Outcomes Among the Recently Diagnosed (ABOARD) study. The study will follow 5,000 Aetna members from across the country who have been newly diagnosed with breast cancer and who are undergoing genetic testing.

Certified genetic counselors can help assess specific cancer risks in families, recommend appropriate genetic tests, and interpret genetic test results. They can also recommend appropriate personalized options for cancer screening, early detection and prevention. Individuals and their doctors can use this information to optimize care. Current research suggests that only a small percentage of breast cancer patients who have an inherited cancer risk actually receive genetic counseling and testing services. Even fewer receive this information at the time of diagnosis when it might be most useful for making surgical and other treatment decisions. 

USF Health’s Dr. Rebecca Sutphen will lead the national collaborative study.

“Research shows that many women who develop breast cancer have inherited a strong predisposition to cancer. However, many of these women are not aware of their genetic susceptibility. They also do not know that they are at high risk to develop another breast cancer or ovarian cancer in the future and that other blood relatives are at increased risk for cancer,” said Rebecca Sutphen, M.D., professor of genetics at the Epidemiology Center, USF Department of Pediatrics.

“This unique academic-industry collaboration will create a new level of research into the impact of genetic information on American cancer patients and their families. Few topics have greater potential for positive public health impact. We appreciate Aetna’s leadership and collaboration to make this important research possible.”

Dr. Sutphen, an American Board of Medical Genetics-certified clinical and molecular geneticist and expert in inherited cancer risk, will lead the national study. The multidisciplinary team will include:

• Dr. Sutphen’s research team at the USF Health Morsani College of Medicine, including co-investigators Kristian Lynch, Ph.D., James Andrews, Ph.D. and Claudia Aguado Loi, Ph.D.
• An Aetna team led by Joanne Armstrong, M.D., M.P.H., national medical director for women’s health and lead for genomic medicine
• An advocacy team led by Sue Friedman of the national non-profit advocacy and awareness organization Facing Our Risk of Cancer Empowered (FORCE)
• Marc Schwartz, Ph.D., director of cancer control, Lombardi Comprehensive Cancer Center, Georgetown University

The project will use patient-reported outcomes as well as medical claims data.  Using information from a variety of clinical settings rather than only academic centers will provide a more “real-world” view of current care. USF and Aetna have developed an extensive research and security infrastructure to ensure the privacy and confidentiality of participant data.

“The research will provide critical information that can help ensure the benefits of advanced genetic testing and genomics can be used to guide safe, effective personalized health care. As more sophisticated tests are developed, we have a responsibility to help patients and doctors understand how to act on the information to improve patients’ health,” Dr. Armstrong says.

The new study builds on an existing research partnership between this multidisciplinary team and researchers from the American Cancer Society. The groups have been working together for the past two years, with support from the Aetna Foundation, to better understand the experiences of individuals who have had genetic tests to determine their inherited risk of cancer. The study also looked at differences in treatment, information and health outcomes among minority patients. Results are expected to be published later this year.

About USF Health
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities. For more information, visit www.health.usf.edu

About Aetna
Aetna is one of the nation’s leading diversified health care benefits companies, serving an estimated 44 million people with information and resources to help them make better informed decisions about their health care. Aetna offers a broad range of traditional, voluntary and consumer-directed health insurance products and related services, including medical, pharmacy, dental, behavioral health, group life and disability plans, and medical management capabilities, Medicaid health care management services, workers’ compensation administrative services and health information technology services. Aetna’s customers include employer groups, individuals, college students, part-time and hourly workers, health plans, health care providers, governmental units, government-sponsored plans, labor groups and expatriates. For more information, see www.aetna.com. 

About FORCE
No one should have to face hereditary breast and ovarian cancer alone. For more than 13 years, Facing Our Risk of Cancer Empowered (FORCE) has been the voice of the hereditary breast and ovarian cancer community. FORCE provides support, education and awareness to help those facing hereditary breast and ovarian cancer know their healthcare options and make informed decisions. The organization is the de facto leader in guiding critical research and policy issues that impact the hereditary breast cancer and ovarian cancer community. For more information about FORCE and hereditary breast and ovarian cancer, please visit www.facingourrisk.org.

When it comes to reproduction, women aren’t the only ones who may need to heed ticking biological clocks.

Newer studies, including one by researchers at the University of South Florida College of Public Health and the University of Rochester, suggest that the offspring of older men may face greater risks of harmful birth outcomes – attributed in part to age-related genetic defects passed along by the father’s sperm. Paternal lifestyle characteristics, like smoking and poor diets, and environmental toxins that lead to mounting epigenetic changes over time may also be part of the mix.

“In general, society has not talked about the age of the dad. The underlying thinking has been, since development occurs in the womb for nine months, that moms are the only ones who matter when it comes to pregnancy and birth outcomes,” said Hamisu Salihu, MD, PhD, professor of epidemiology and obstetrics at the USF College of Public Health. “The recent genetic and epidemiological research indicates that the father’s age may influence the processes of embryo development early in life.”

Dr. Salihu was quoted in the article “Too Old To Be a Dad?” appearing in the April 22, 2013 issue of Time magazine.

Dr. Hamisu Salihu of the USF College of Public Health has studied the effect of paternal age on birth outcomes.

 The Time piece cites a paper by Dr. Salihu and fellow investigators published last year in the American Journal of Men’s Health.

Analyzing more than 755,000 births in Missouri from 1989 to 2005, the researchers found that infants fathered by men in the 40-to-45 age group had a 24 percent greater risk of stillbirth than those fathered by men in the 25-to-29 category. Babies born to fathers older than age 45 were at 19 percent greater risk of low birth weight, 13 percent higher risk of preterm birth, and 29 percent increased risk of very preterm birth.

The exact chemical or physiological mechanisms to explain why advanced paternal age correlates with poorer birth outcomes are not yet known, Dr. Salihu says. But, he emphasized, the latest research points to the need for men to be included in preconception counseling and prenatal care to optimize the odds for a healthy baby.

“Now that we know the father’s age matters, it means we need screening protocols for older fathers, not just older mothers,” he says. “It’s going to change the paradigm of how we practice medicine.”

April 17, 2013  – Researchers from the University of South Florida were members of an international team that has decoded the genome of a creature whose evolutionary history is both enigmatic and illuminating: the African coelacanth.  A sea-cave dwelling, five-foot long fish with limb-like fins, the coelacanth was once thought to be extinct.

A living coelacanth was discovered off the African coast in 1938, and since then, questions about these ancient-looking fish – popularly known as “living fossils” – have loomed large. Coelacanths today closely resemble the fossilized skeletons of their more than 300-million-year-old ancestors. Its genome confirms what many researchers had long suspected: genes in coelacanths are evolving more slowly than in other organisms.

“It has been a highly rewarding experience to be involved in another project of this scope, with such a distinguished international team of scientists,” said Gary Litman, PhD, a USF Distinguished University Professor and Hines Professor of Pediatrics at USF Health.   “As we continue to expand our understanding of genomes, it never ceases to amaze us how many different (evolutionary) solutions there have been for creating a functional immune system.”

Dr. Litman, an international expert in the field of immunogenetics, directs the molecular genetics laboratory at the St. Petersburg-based USF Children’s Research Institute.   He and colleagues John Cannon, PhD, assistant professor of pediatrics at USF, and Gail Mueller,  laboratory coordinator-All Children’s Hospital, are among the authors of a paper on the coelacanth genome, which appears in the journal Nature this week.

Coelacanths can be huge, reaching 5 feet or more and weighing 198 pounds.

Using fish as a good model for human immunity, Dr. Litman’s research has led to the discovery of many novel genes that offer insight into how the immune system develops in children.  He was also a member of the team to first sequence all the gene receptors tht appear to play a critical role in the innate immune protection of zebrafish.  His papers have appeared in other such distinguished journals as Proceedings of the National Academy of Sciences,  Nature Immunology and Science.

In the coelacanth genome project,  the researchers  found that the genes overall were evolving significantly slower than in every other fish and land vertebrate they examined.

“This is the first time that we’ve had a big enough gene set to really see that.”said Jessica Alföldi, a research scientist at the Broad Institute and co-first author of  the Nature paper

Researchers hypothesize that this slow rate of change may be because coelacanths simply have not needed to change: they live primarily off of the Eastern African coast (a second coelacanth species lives off the coast of Indonesia), at ocean depths where relatively little has changed over the millennia.

“We often talk about how species have changed over time,” said Kerstin Lindblad-Toh, scientific director of the Broad Institute’s vertebrate genome biology group and senior author. “But there are still a few places on Earth where organisms don’t have to change, and this is one of them. Coelacanths are likely very specialized to such a specific, non-changing, extreme environment – it is ideally suited to the deep sea just the way it is.”

Because of their resemblance to fossils dating back millions of years, coelacanths today are often referred to as “living fossils” – a term coined by Charles Darwin. But the coelacanth is not a relic of the past brought back to life: it is a species that has survived, reproduced, but changed very little in appearance for millions of years.

“It’s not a living fossil; it’s a living organism,” said Alföldi. “It doesn’t live in a time bubble; it lives in our world, which is why it’s so fascinating to find out that its genes are evolving more slowly than ours.”

The coelacanth genome has also allowed scientists to test other long-debated questions. For example, coelacanths possess some features that look oddly similar to those seen only in animals that dwell on land, including “lobed” fins, which resemble the limbs of four-legged land animals (known as tetrapods). Another odd-looking group of fish known as lungfish possesses lobed fins too. It is likely that one of the ancestral lobed-finned fish species gave rise to the first four-legged amphibious creatures to climb out of the water and up on to land, but until now, researchers could not determine which of the two is the more likely candidate.

In addition to sequencing the full genome – nearly 3 billion “letters” of DNA – from the coelacanth, the researchers also looked at RNA content from coelacanth (both the African and Indonesian species) and from the lungfish. This information allowed them to compare genes in use in the brain, kidneys, liver, spleen and gut of lungfish with gene sets from coelacanth and 20 other vertebrate species. Their results suggested that tetrapods are more closely related to lungfish than to the coelacanth.

However, the coelacanth is still a critical organism to study in order to understand what is often called the water-to-land transition. Lungfish may be more closely related to land animals, but its genome remains inscrutable: at 100 billion letters in length, the lungfish genome is simply too unwieldy for scientists to sequence, assemble, and analyze. The coelacanth’s more modest-sized genome (comparable in length to our own) is yielding valuable clues about the genetic changes that may have allowed tetrapods to flourish on land.

Gary Litman, PhD, one of the world’s top experts in immunogenetics, leads the molecular genetics laboratory at the USF Children’s Research Institute.

By looking at what genes were lost when vertebrates came on land as well as what regulatory elements – parts of the genome that govern where, when, and to what degree genes are active – were gained, the researchers made several unusual discoveries:

 -  Sense of smell. The team found that many regulatory changes influenced genes involved in smell perception and detecting airborne odors. They hypothesize that as creatures moved from sea to land, they needed new means of detecting chemicals in the environment around them.

- Immunity. The researchers found a significant number of immune-related regulatory changes when they compared the coelacanth genome to the genomes of animals on land. They hypothesized that these changes may be part of a response to new pathogens encountered on land.

- Evolutionary development. Researchers found several key genetic regions that may have been “evolutionarily recruited” to form tetrapod innovations such as limbs, fingers and toes, and the mammalian placenta. One of these regions, known as HoxD, harbors a particular sequence that is shared across coelacanths and tetrapods. It is likely that this sequence from the coelacanth was co-opted by tetrapods to help form hands and feet.

- Urea cycle. Fish get rid of nitrogen by excreting ammonia into the water, but humans and other land animals quickly convert ammonia into less toxic urea using the urea cycle. Researchers found that the most important gene involved in this cycle has been modified in tetrapods.

Sequencing the full coelacanth genome was uniquely challenging for many reasons. Coelacanths are an endangered species, meaning that samples available for research are almost nonexistent. This meant that each sample obtained was precious: researchers would have “one shot” at sequencing the collected genetic material, according to Alföldi. But the difficulties in obtaining a sample and the technical challenges of sequencing it also knit the community together.

Researchers from 40 institutions across 12 countries contributed to this work. Many funding agencies around the world provided support, including the African Coelacanth Ecosystem Programme of the South African National Department of Science and Technology, which supported the collection of samples, and the National Human Genome Research Institute, which supported the Broad Institute’s contributions including genome sequencing.

Although its genome offers some tantalizing answers, the research team anticipates that further study of the fish’s immunity, respiration, physiology, and more will lead to deep insights into how some vertebrates adapted to life on land, while others remained creatures of the sea.

Multistate, hospital-based quality improvement programs can be remarkably effective at reducing early elective deliveries of babies, a study published April 8 in the journal Obstetrics & Gynecology reports.

The March of Dimes, which partly funded the study, calls the findings good news, because babies delivered before full-term are at increased risk of serious health problems and death in their first year of life.

In the group of 25 participating hospitals, the rate of elective early-term deliveries (i.e., inductions of labor and Cesarean sections without a medical reason before a baby reaches a full 39 weeks gestational age) fell significantly from 27.8 percent to 4.8 percent during the one-year project period, an 83 percent decline.

Florida did even better than the other four states involved in the March of Dimes national project, said William Sappenfield, MD, MPH, director of the Lawton and Rhea Chiles Center for Healthy Mothers and Babies at the USF College of Public Health.  Dr. Sappenfield, co-chair of the March of Dimes prematurity initiative, and John Curran, MD, an associate vice president at USF Health and executive director of the Florida Perinatal Quality Collaborative (FPQC), were among the authors of the multistate study.

“The initiative coordinated by the FPQC at USF Health and the Chiles Center reduced the (early-term delivery) rate in Florida’s pilot hospitals to the same low national study rate of 5 percent, even though our state’s pilot hospitals started the initiative with a substantially higher rate of 38 percent,”  said Dr. Sappenfield.  “This would not have been possible without our partnership with the March of Dimes and our obstetrical consultants from Florida’s new district of the American Congress of Obstetricians and Gynecologists.”

L to R: USF leaders of the Florida Perinatal Quality Collaborative include Linda Detman PhD, Department of Community and Family Health at the Chiles Center for Healthy Mothers and Babies; William Sappenfield, MD, MPH, director of the Chiles Center; and USF Health’s John Curran, MD, executive director of the FPQC.

“Reducing unnecessary early deliveries to less than 5 percent in these hospitals means that more babies stayed in the womb longer, which is so important for their growth and development,” said Edward R.B. McCabe, MD, medical director of the March of Dimes.  “This project saw a decrease in the proportion of babies born at 37 and 38 weeks and a corresponding increase in the 39-41 week range during the one-year period studied. Additional studies, perhaps over a longer period of time, could clarify whether such quality improvement programs can also bring down a hospital’s overall preterm birth rate.”

The initiative focused on implementation of a toolkit called “Elimination of Non-medically Indicated (Elective) Deliveries before 39 Weeks Gestational Age,” to guide changes in early term delivery practices.  The toolkit was developed in partnership with March of Dimes, the California Maternal Quality Care Collaborative and the California Maternal Child and Adolescent Division within the California Department of Public Health.

This was the first project of a collaborative with perinatal quality improvement advocates from state health departments, academic health centers, public and private hospitals, and March of Dimes chapters from the five most populous states in the country: California, Florida, Illinois, New York and Texas. These five states account for an estimated 38 percent of all births in the United States.

Florida hospitals participating in FPQC pilot study were St. Joseph’s Hospital in Tampa, Lee Memorial Health System in Ft. Myers, Plantation General Hospital in Plantation, Santa Rosa Medical Center in Milton, South Miami Hospital in Miami, and Broward General Medical Center in Ft. Lauderdale.

The study targeted deliveries that were not medically necessary during the 37th and 38th week of fetal gestation. Even babies born just a few weeks early have higher rates of hospitalization and illness compared to full-term infants.

The six Florida hospitals participating in FPQC pilot study were St. Joseph’s Hospital in Tampa, Lee Memorial Health System in Ft. Myers, Plantation General Hospital in Plantation, Santa Rosa Medical Center in Milton, South Miami Hospital in Miami, and Broward General Medical Center in Ft. Lauderdale.  For an earlier story on USF’s role in the statewide, multihospital initiative, click here.

“This study is only the beginning,” said Dr. Sappenfield, a professor in the USF Department of Community and Family Health. “Not only do other hospitals in Florida need to reduce their rates of non-medically indicated deliveries, but this is the first of many needed perinatal quality improvement initiatives in Florida to assure that all our mothers and infants have access to quality health care.”

The FPQC, in coordination with hospitals, obstetricians, pediatricians, nurses and nurse midwives, is developing new statewide initiatives to reduce preterm births, avert infections and prevent maternal deaths.

The March of Dimes urges hospitals, health care providers, and patients to follow the American College of Obstetricians and Gynecologists guidelines that if a pregnancy is healthy, to wait for labor to begin on its own.  The final weeks of pregnancy are crucial to a baby’s health because many vital organs, including the brain and lungs, are still developing.

“A Multistate Quality Improvement Program to Decrease Elective Deliveries Before 39 Weeks,” by Dr. Bryan T. Oshiro and others, appears in the April 8 online edition of Obstetrics & Gynecology.

The March of Dimes is the leading nonprofit organization for pregnancy and baby health. With chapters nationwide and its premier event, March for Babies, the March of Dimes works to improve the health of babies by preventing birth defects, premature birth and infant mortality. For the latest resources and information, visit marchofdimes.com or nacersano.org.

Anne DeLotto Baier of USF Health Communications contributed to this story.
Photo by Eric Younghans, USF Health Communications

Tampa, FL (April 8, 2013) – A new discovery about the malaria-related parasite Toxoplasma gondii — which can threaten babies, AIDS patients, the elderly and others with weakened immune function — may help solve the mystery of how this single-celled parasite establishes life-long infections in people.

The study, led by a University of South Florida research team, places the blame squarely on a family of proteins, known as AP2 factors, which evolved from the regulators of flowering in plants.

In findings published today in the Proceedings of the National Academy of Sciences, the researchers demonstrate AP2 factors are instrumental in flipping a developmental “switch” that transitions the parasite from a rapidly dividing acute form destructive to healthy tissue to a chronic stage invisible to the immune system.   They identified one factor, AP2IX-9, that appears to restrict development of Toxoplasma cysts that settle quietly in various tissues, most commonly the host’s brain.

Michael White, PhD, professor of global health and molecular medicine at USF Health, is one of the world’s leading experts on Toxoplasma parasites.

A better understanding of how the switch mechanism works may eventually lead to ways to block chronic Toxoplasma infections, said study principal investigator Michael White, PhD, professor of global health and molecular medicine at USF Health and a member of the Center of Drug Discovery and Innovation, a Florida Center of Excellence at USF.

White and his colleagues are among the world’s leading experts in T. gondii, combining approaches from biochemistry, genetics and structural biology to look for new ways to combat the parasitic disease toxoplasmosis.

No drugs or vaccines currently exist to treat or prevent the chronic stage of the disease. The T. gondii parasites may remain invisible to the immune system for years and then reactivate when immunity wanes, boosting the risk for recurrent disease.

“The evolutionary story of Toxoplasma is fascinating,” White said. “We were blown away to find that the AP2 factors controlling how a flower develops and how plants respond to poor soil and water conditions have been adapted to work within an intracellular human parasite.”

Ages ago the ancestors of malaria parasites genetically merged with an ancestor of plants, and the primitive plant donated its AP2 factors to the future malaria family.

“Our study showed that, like the AP2 factors help a plant survive a stressful environment, the AP2 factors of T. gondii help the parasite decide when the time is right to grow or when to form a tissue cyst that may lie dormant in people for many years,” White said.

http://www.youtube.com/watch?v=XzOwg23EmrU

Time-lapse of Toxoplasma parasites under the fluorescent microscope shows the living single-cell organisms (red) expressing a plant protein, known as an AP2 factor (yellow) in real time.  The video was produced by the laboratories of Michael White (USF) and Boris Striepen (University of Georgia).  The still image below captures the peak expression of the AP2 factor.

Toxoplasmosis, the infection caused T. gondii, is commonly associated with the medical advice that pregnant women should avoid contact with litter boxes.  That’s because infected cats play a big role in spreading the disease. The tiny organism thrives in the guts of cats, producing countless egg-like cells that are passed along in the feces and can live in warm moist soil or water for months.

People can acquire toxoplasmosis several ways, usually by exposure to the feces of cats or other infected animals, by eating undercooked meat of infected animals, or drinking water contaminated with T. gondii.

Up to 30 percent of the world’s population is estimated to be infected with the T. gondii parasite.

In some parts of the world, including places where sanitation is poor and eating raw or undercooked meat is customary, nearly 100 percent of people carry the parasite, White said.

Few experience flu-like symptoms because the immune system usually prevents the parasite from causing illness, but for those who are immune deficient the consequences can be severe.

The disease may be deadly in AIDS patients, organ transplant recipients, patients receiving certain types of chemotherapy, and infants born to mothers infected with the parasite during or shortly before pregnancy. Recently, toxoplasmosis has been linked to mental illness, such as schizophrenia and other diseases of dementia, and changes in behavior.

Joshua Radke, a PhD student in Dr. White’s laboratory, was a first author of the study.

Because it is common, complex and not easily killed with standard disinfection measures, the toxoplasma parasite is a potential weapon for bioterrorists, White added.

The USF-led study was supported by grants from the National Institutes of Health. White’s team worked with researchers at Princeton University, Albert Einstein College of Medicine, and Indiana University School of Medicine. Joshua Radke, a PhD student in the USF Health Department of Molecular Medicine, was a first author of the study.

Article citation:
“ApiAP2 transciption factor restricts development of the Toxoplasma tissue cyst;” Joshua B. Radke, Oliver Lucas, Erandi K. DeSilva, YanFen Ma, William J. Sullivan, Jr., Louis M. Weiss, Manuel Llinas, and Michael W. White; Proceedings of the National Academy of Sciences; www.pnas.org/cgi/doi/10.1073/pnas.1300059110

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities. For more information, visit www.health.usf.edu

Media contact:
Anne DeLotto Baier,  USF Health Communications
(813) 974-3303 or abaier@health.usf.edu

Photo of Michael White by Eric Younghans/USF Health Communications

Tampa, FL (March 20, 2013) – University of South Florida researchers played a key role in an international multidisciplinary project that has yielded a promising new antimalarial drug with the potential to cure the mosquito-borne disease and block its transmission with less costly,  low doses.

Roman Manetsch, PhD, USF associate professor of chemistry, and Dennis Kyle, PhD, USF professor of global health, were co-leaders of the USF team, which helped to discover and develop a series of potent compounds to combat malaria known as the 4-(1H)-quinolone-3-diarylethers, or quinolones.

The USF researchers were part of larger Medicines for Malaria Venture (MMV) project team including Oregon Health & Science University in Portland, Drexel University in Philadelphia, and Monash University in Australia.

Dennis Kyle, PhD, professor of global health at the USF College of Public Health, is a technical advisor to the Medicines for Malaria Venture team preparing the new antimalarial drug ELQ-300 for clincal trials.

The researchers narrowed the most effective drug candidates in the quinolones series to one lead drug – ELQ-300 – now moving toward clinical testing.

The project team’s findings are published today in the journal Science Translational Medicine.  Alexis N. LaCrue, PhD, a research associate in Dr. Kyle’s laboratory, was a co-first author for the paper along with Aaron Nilsen, PhD, of Portland VA Medical Center.

In initial preclinical tests, the lead drug demonstrated impressive preventive and transmission-blocking – and a low likelihood for developing rapid resistance to major strains of malaria parasites.

In addition, ELQ-300 could likely be produced more cheaply than existing antimalarial drugs – a major advantage in treating a tropical disease that kills nearly one million people a year and causes recurring bouts of severe and incapacitating illness, most often among poor people in developing countries.

“This is one of the first drugs ever to kill the malaria parasite in all three stages of its life cycle,” said Dr. Kyle, a member of the Global Infectious Diseases Research team at the USF College of Public Health.  “So, it may become part of a new-generation therapy that not only treats sick people and prevents them from getting ill, but also blocks the transmission of malaria from mosquitoes to humans … If the drug can break the parasite life cycle, we may ultimately eradicate the disease.”

New life from an old class of compounds

The new drug class identified by the researchers were derived from the first antimalarial quinolone, endochin, discovered more than 60 years ago but never pursued as a treatment because it appeared not to work in humans.

Using new technology to optimize the quinolones, the MMV project team demonstrated that these compounds were indeed highly effective against Plasmodium falciparum, the most lethal strain of malaria, and Plasmodium vivax, the major cause of malaria outside Africa.  The quinolones target both the liver and blood stages of the parasite as well as the forms critical for disease transmission.

“This was a very challenging project requiring years of hard work, collaboration across disciplines, and a good portion of luck,” said Dr. Manetsch, whose laboratory specializes in medicinal chemistry, drug discovery and development of novel chemical probes to characterize drug-protein interactions.

Alexis LaCrue, PhD, a research associate at the USF Department of Global Health, Tampa, FL, was a co-first author for the Medicines for Malaria Venture paper detailing a series of potent compounds active against all three stages of the malaria parasite life cycle.

Optimizing drug success against a complex parasite life cycle

In humans, the malaria parasite targets the liver after it enters the bloodstream through the bite of an infected mosquito.  Once inside the liver, the infecting parasites for most types of malaria multiply and rupture liver cells, escaping back into the bloodstream — although sometimes parasites can remain dormant in the liver for extended periods. The parasites, now modified to attack red blood cells, rapidly create more parasites, which spread throughout the bloodstream in waves.

The researchers needed to find and fine-tune a drug with a long half-life both to prevent malaria and to offer long-term protection against reinfection.

“It was a balancing act to optimize an antimalarial drug so that it was soluble and metabolically stable, without compromising its potency,” Dr. Manetsch said.  “We wanted a compound that within an individual would not break down too quickly, remain circulating in the blood for a long enough period to kill the parasites, and be highly active in blocking transmission in rodent models of malaria.”

The antimalarial drug developed needed to be potent enough to work without harmful or bothersome side effects.

ELQ-300 targets a protein complex of the mitochondria that is integral for the energy household of a cell, Dr. Manetsch said.   That’s good when you’re trying to incapacitate a malaria parasite’s powerhouse, but the same hit in a human’s mitochondria could be disastrous, he added.

So, Dr. Manetsch, with the help of Dr. Kyle’s expertise in parasitology, structurally modified the quinolone scaffold so that the drug candidate ELQ-300 would selectively hit only the malaria parasite’s target while sparing the human mitochondria.

Roman Manetsch, PhD, associate professor of chemistry, was co-leader, along with Dr. Kyle, of the USF team that helped to discover and develop a series of potent compounds (quinolone-3-diarylethers)to combat malaria.

Antimalarial drug resistance: A global health threat

With the rapid emergence of multi-drug resistant strains of malaria, the need to find new drugs capable of delaying or preventing drug resistance has become even more pressing, researchers say.

The quinolones, including ELQ-300, target the same biological pathway as atovaquone, the main component of Malarone, one of the newest combination drugs used to treat malaria. But, in repeated experiments ELQ-300 did not generate drug-resistant strains of the malaria parasite – making it a significant improvement over atovaquone.

In addition, the new drug’s design makes it more effective at lower doses, hopefully meaning fewer and smaller pills for patients at a lower cost, said Dr. Kyle, a technical advisor for the MMV team preparing ELQ-300 for clinical trials.

Dr. Kyle and Dr. Manetsch, funded by National Institutes of Health grants totaling more than $2.5 million, continue to collaborate on research to identify and develop novel antimalarial drugs.

Article citation:
“Quinolone-3-Diarylethers: A New Class of Antimalarial Drug,” Aaron Nilsen, Alexis N. LaCrue, Karen L. White, Isaac P. Forquer, Richard M. Cross, Jutta Marfurt, Michael W. Mather, Michael J. Delves, David M. Shackleford, Fabian E. Saenz, Joanne M. Morrisey, Jessica Steuten, Tina Mutka, Yuexin Li, Grennady Wirjanata, Eileen Ryan, Sandra Duffy, Jane Xu Kelly, Boni F. Sebayang, Anne-Marie Zeeman¹, Rintis Noviyanti, Robert E. Sinden, Clemens H. M. Kocken, Ric N. Price, Vicky M. Avery, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Santiago Ferrer, Esperanza Herreros, Laura M. Sanz, Francisco-Javier Gamo, Ian Bathurst, Jeremy N. Burrows, Peter Siegl, R. Kiplin Guy, Rolf  W. Winter, Akhil B. Vaidya, Susan A. Charman, Dennis E. Kyle, Roman Manetsch, and Michael K. Riscoe; Science Translational Medicine, Vol. 5, Issue 177.

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USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities. For more information, visit www.health.usf.edu

Media contact:
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SAN DIEGO, CA (March 14, 2013) – Three studies released today present possible positive news for people with Parkinson’s disease. The studies, which will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013, report on investigational treatments for blood pressure problems, the wearing-off that can occur when people have taken the main drug for Parkinson’s for a long time, and for people early in the disease whose symptoms are not well-controlled by their main drugs.

“All of these treatments are promising news for people with Parkinson’s disease, which is the second most common neurodegenerative disease after Alzheimer’s disease,” said Robert A. Hauser, MD, MBA, professor of neurology at the University of South Florida in Tampa, FL,  and a Fellow of the American Academy of Neurology, who was an author of all three studies.  Dr. Hauser directs the USF Center for Parkinson’s Disease and Movement Disorders.

The first study dealt with the rapid drop in blood pressure that people with Parkinson’s can experience when standing up, which can lead to dizziness, fainting and falls. The problem, which affects about 18 percent of people with the disease, occurs because the autonomic nervous system fails to respond to changes in posture by releasing enough of the chemical norepinephrine.

 In the study, 225 people were randomized to receive either eight weeks of stable dose treatment with a placebo or the drug droxidopa, which converts to norepinephrine. After one week of stable treatment, those who received the drug had a clinically meaningful, two-fold decrease in the symptoms of dizziness and lightheadedness, when compared to placebo. They also had fewer falls, or 0.38 falls per patient per week, compared to 1.73 for those receiving a placebo on average over the entire 10-week study duration.

The second study looked at treatment with a new drug for “wearing-off” that occurs with people who have been taking levodopa for several years. As each dose wears off, people experience longer periods of time where the motor symptoms do not respond to levodopa. For the study, 420 people who were experiencing an average of six hours of “off” time per day received a placebo or one of four dosages of the drug tozadenant in addition to their levodopa for 12 weeks. People receiving two of the dosages of the drug had slightly more than an hour less off time per day at the end of 12 weeks than they had at the start of the study. They also did not have more troublesome involuntary movements during their “on” time, called dyskinesia, that can occur.

The third study looked at 321 people with early Parkinson’s disease whose symptoms were not well-controlled by a dopamine agonist drug. For the 18-week study, the participants took either the drug rasagiline or a placebo in addition to their dopamine agonist. At the end of the study, those taking rasagiline had improved by 2.4 points on a Parkinson’s disease rating scale. In addition, rasagiline was well tolerated with adverse events similar to placebo. 

The blood pressure study was supported by Chelsea Therapeutics. The “wearing-off” study was supported by Biotie Therapies, Inc. The early Parkinson’s disease study was supported by Teva Pharmaceuticals.

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Learn more about Parkinson’s disease at http://www.aan.com/patients.

The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy. 

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.

Media contacts:
Rachel Seroka, American Academy of Neurology, rseroka@aan.com, (612) 928-6129
Angela Babb, APR, ababb@aan.com, (612) 928-6102

Ann Arbor, MI (Feb. 26, 2013) – Lead exposure in early childhood has been linked to lower performance on state achievement tests for many Detroit Public School students in several grades, researchers from the University of Michigan School of Public Health and colleagues report.  The study’s lead author Nanhua Zhang, PhD, currently an assistant professor in the Department of Epidemiology and Biostatistics at the University of South Florida College of Public Health, conducted the research as a doctoral candidate at the U-M School of Public Health.

The researchers also found lower scores for children who had been exposed to lead at levels below the federal threshold. 

In a paper to be published in the March 2013 issue of the American Journal of Public Health, the researchers found a strong relationship between lowered math, science and reading scores on the Michigan Education Assessment Program (MEAP) tests and elevated blood lead levels. High blood lead levels before age 6 were associated with poor academic achievement in elementary and junior high students.  

Further, the researchers found that the higher the blood lead levels, the lower the scores.

“We can clearly see a dose-response relationship. The higher the lead level in the blood, the lower the academic scores,” said Zhang, who conducted the research as a member of STATCOM (Statistics in the Community), a student-led organization that provides pro-bono statistical consulting for governmental and nonprofit organizations.

“Even when factoring in grade level, gender, race, language, maternal education and socioeconomic status, we still found a significant impact of the blood lead level on the probability of scoring low on the tests.”

Study lead author Nanhua Zhang, PhD

 The team also found cognitive impairment with much lower blood lead levels than the current federal reference level. In May 2012, the Centers for Disease Control changed the standard to identify children with blood lead levels that are much higher than most children’s levels from 10 micrograms per deciliter to 5 mcg/dL. 

“In reality, there is no well-documented threshold for acceptable levels of lead in the body, and our research shows that in amounts as small as 2-5 micrograms per deciliter, children had significant cognitive impairment,” said Michael Elliott, PhD, professor of biostatistics at the U-M School of Public Health and a research professor at the Institute for Social Research.

“Our publication really is a document that shows the degree to which childhood lead exposure impacts cognitive function. It’s a real-world issue. These lowered test scores impact students’ ability to move forward in the educational system and on to higher education.”

The study linked lead testing surveillance records to MEAP data for 21,281 children who had a blood test prior to age 6 during the time period of 1990-2008. MEAP scores from 2008-10 were used for the study.

While some other studies have shown the effects of lead exposure on cognitive ability in young children, this one shows the impact on students in grades 3, 5 and 8.

The collaborative research team involved a number of Detroit leaders, including a member of the Detroit Public Schools administration and the Detroit Department of Health and Wellness Promotion.

Harolyn Baker, who represented the health department but now is director of the department of epidemiology and evaluation at Michigan’s Quality Improvement Organization, said that even though campaigns to raise awareness of lead dangers and abatement programs to reduce the threat of contamination have been successful in some areas, more work needs to be done.

 Baker said continued investments in primary prevention such as lead testing, remediation and abatement to sustain success toward the elimination of childhood lead poisoning are needed. Further, investments in research and educational interventions for children who already have been exposed are needed to help them regain cognitive ground lost by lead exposure.

 ”What happens to the children who get exposed? This has been the missing component of the discussion—once a child has been exposed, what do you do to help him or her overcome?” Baker said. “Lead poisoning is preventable. It’s an area in public health that provides a clear pathway to solve the issue. It’s essential that we keep this issue on the education, public health, policy and community agendas.”

Other authors included: Hamisu Salihu, Department of Epidemiology and Biostatistics, University of South Florida College of Public Health; Margaret Tufts, Office of Health Information, Planning, Policy, Evaluation and Research, Detroit Department of Health and Wellness Promotion, Detroit; and Randall Raymond, Detroit Public Schools, Office of Research, Evaluation, Assessment and Accountability.

Media contacts:
Laurel Thomas Gnagey, University of Michigan, (734) 647-1841, or ltgnagey@umich.edu
Anne DeLotto Baier, University of South Florida, (813) 974-3303, or abaier@health.usf.edu

“So when prescribers are faced with choosing a medication to give a patient, which do they pick?” said McLeod, who directs the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina-Chapel Hill. “They often make their decisions based on familiarity with drugs they know best.”

That’s because there is no way to predict with great certainty whether a patient will respond to a drug very well, somewhat, not at all – or perhaps even adversely. The result, for many patients, is a time-consuming, sometimes costly, trial-and-error approach to finding the right drug at the right dose.

Howard McLeod, PharmD, Distinguished Professor of Pharmacogenomics and Individualized Therapy at the University of North Carolina Eshelman School of Pharmacy, was the keynote speaker for this year’s USF Health Research Day.

McLeod is a prominent researcher in the emerging field of pharmacogenomics, which explores how variations in our individual genetic makeup influence how we react to drugs.  The institute he leads is working to integrate personalized into medical practice by providing the tools and tests for physicians to identify patients at high risk for toxic side effects as well as those likely to benefit from a particular treatment.

During his Research Day presentation, McLeod focused on the need to harness the growing body of information obtained from DNA analysis to attain comprehensive and more meaningful understanding of which genes are important in guiding drug therapy.

Easy-to-use informatics solutions must be in place before clinicians and pharmacists can broadly apply complex information about the multitude of genetic variations, and other factors interacting with genetic makeup, to select and dose medicines, McLeod said. Some progress is being made. For example, he said, there is now an iPhone app, called iWarfarin, that can help determine the optimal initial dose of  warfarin, a widely-prescribed anticoagulant drug, based on an individual’s genetic signature. “It’s not as fun as Angry Birds, but almost,” McLeod quipped.

McLeod challenged academic medicine to be more proactive about translating genetic discovery into applied knowledge that will mean safer, more cost-effective care for patients. “We get the grants, do the discovery, validate findings, publish papers… but then what? Are we creating the science that will help grandma?”

Stephen Liggett, MD, vice dean for research at the USF Health Morsani College of Medicine, said that McLeod’s relay race analogy of progressing from basic science discovery to validation to implementation of research and incorporation into medical practice was a good one.

“If at any one of those points, your institution or group of collaborators doesn’t pick up the pace and move the baton forward, then it’s possible all that work will not come to fruition,” said Dr. Liggett, who joined USF Health to lead the university’s personalized medicine and genomics research.

USF, known for its innovation, will move forward with implementation, Dr. Liggett said. Our relay race, he added, “could be helped along by hospital partners willing to be adventurous with us” in tackling the complex challenges and issues of pharmacogenomics and personalized medicine.

Photos by Eric Younghans, USF Health Communications