CINCINNATI—A University of Cincinnati expert on posttraumatic stress disorder (PTSD) will play a leading role in a 17-site, $9 million study that will compare the two leading evidence-based treatments for PTSD.

Kathleen Chard, PhD, will be one of three co-principal investigators for the trial, which is expected to launch later this year. She is an associate professor of clinical psychiatry in the UC Department of Psychiatry and Behavioral Neuroscience and director of the department’s PTSD division, based at the Cincinnati Department of Veterans Affairs (VA) Medical Center facility in Ft. Thomas, Ky.

The grant is sponsored by the VA’s Cooperative Studies Program, the division of the VA’s Office of Research and Development that is responsible for the planning and conduct of large multicenter clinical trials and epidemiological studies.

According to the National Institute of Mental Health (NIMH), PTSD is a type of anxiety disorder that some people get after seeing or living through a dangerous event. People who have PTSD may feel stressed or frightened even when they’re no longer in danger. Anyone can get PTSD at any age—including war veterans and survivors of physical and sexual assault, abuse, accidents, disasters and many other serious events.

Symptoms of PTSD fall into three main categories: re-experiencing the event, such as flashbacks or repeated upsetting memories; avoidance, such as feeling detached or having a lack of interest in normal activities; and hyper-arousal, such as difficult concentrating or startling easily.

Two types of treatment for PTSD have been endorsed by the Institute of Medicine, a nonprofit organization that is the health arm of the National Academy of Sciences:

•     Cognitive Processing Therapy (CPT), which focuses on the patient’s thoughts and feelings, with emphasis on how traumatic experiences changed the patient’s thoughts and beliefs and how the patient’s thoughts influence current feelings and behaviors. Patients identify and challenge unhelpful thoughts through structured therapy sessions and practice assignments. (Chard is co-author of the CPT military/veteran manual and the national CPT implementation director for the Department of Veterans Affairs.)

•      Prolonged Exposure (PE), which focuses on allowing the patient to work through painful memories by re-experiencing the traumatic event or events in a safe and supportive environment and engage with activities he or she has been avoiding because of the trauma. PE also emphasizes education about treatment and common reactions to trauma and breathing retraining.

“We’ve been wanting to put these two therapies head to head as a prediction of which does better in certain situations,” Chard says. “It’s our goal to do better patient matching—making sure that patients get into the therapy that fits them best. This study will help us do that.”

The two co-principal investigators in addition to Chard, both employees of the VA National Center for Posttraumatic Stress Disorder, are Paula Schnurr, PhD, deputy executive director, and Josef Ruzek, PhD, director of dissemination and training. They are faculty members at Geisel School of Medicine (Dartmouth University) and Palo Alto University, respectively.

UC is known for excellence in research, and George Deepe, MD, has played a part in that reputation with his contributions to infectious diseases research.

For over 30 years as a faculty member at UC, Deepe, who also served for 15 years as chief of the division of infectious diseases, has been a leading researcher and a world-recognized expert in the study of Histoplasma capsulatum, a pathogenic fungus that causes infection, particularly in the Ohio River Valley.

For his work, he has been selected as UC’s 2013 recipient of the George Rieveschl Jr. Award for Distinguished Scientific Research. He was honored at the All-University Faculty Awards celebration April 17, 2013.

Deepe has consistently received federal and private funding for his research and has been awarded a number of honors, including the Research Career Development Award from the National Institute of Allergy and Infectious Diseases (NIAID) from 1987 to 1992 and the MERIT Award from the NIAID from 1997 to 2007.

In addition to his outstanding research portfolio, Deepe is heavily involved in mentoring graduate students and currently serves as associate director of the UC Medical Scientist Training Program.

He excels in research, education and clinical care but is known among his colleagues and mentees as being a fun, intelligent and caring person—someone you can always come to with a problem.

One of his nominators wrote: “George is well known in our academic community for his great sense of humor, deep literary background, unstinting loyalty and enormous generosity of spirit.”

 
CINCINNATI—For more than 15 years, deep brain stimulation (DBS) surgery has been an important treatment option for people with Parkinson’s disease, a disorder of the nervous system caused by a lack of dopamine in the brain.

Although the treatment is approved by the U.S. Food and Drug Administration (FDA) for patients who no longer respond to medication and who typically have suffered symptoms of the disease for 10 or more years, a European study published this month in the New England Journal of Medicine is causing doctors to ask whether the procedure should be offered earlier in the disease process.

“This new study gives scientific support to the notion that patients may experience the largest amount of benefit from deep brain stimulation surgery if they have the procedure earlier rather than later,” says Fredy Revilla, MD, associate professor of neurology and rehabilitation medicine and director of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the University of Cincinnati Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health.

“In our own experience here at UC we have too many patients with Parkinson’s disease who want to have the surgical procedure but no longer qualify for it because of the presence of cognitive impairment or other co-morbidities that occur with longer duration of disease. In other words, we waited too long. A very careful selection process to determine who is a candidate for surgery is still warranted, but more patients with Parkinson’s disease should be able to access this therapy, based on these recent findings.”

In a typical treatment scenario, a patient has lost 50 percent of his or her dopamine-producing neurons when symptoms first appear and a diagnosis is made. The typical patient is then treated with medications for 10 to 14 years.

During that time, medications can offer symptomatic relief from tremor, slowness of movement, stiffness, and walking problems, but cell loss continues unabated. There is at present no cure for the disease.

“For those who have Parkinson’s disease, medications to restore the needed balance of dopamine quickly become a way of life,” says Ellen Air, MD, PhD, assistant professor in UC’s department of neurosurgery and a neurosurgeon at the Gardner Center and Mayfield Clinic. “For most, these medications are very much a miracle, releasing the stiffness and calming tremors.

“Over time, however, the medications’ effect shortens, becomes less predictable, and leads to large swings in motor function. Daily life becomes a roller coaster, moving from extremes of slow and stiff movement to uncontrolled twisting movements and back, often over just a few short hours.”

DBS surgery becomes an option in patients who experience benefits from dopamine-replacement medication but whose symptoms have become severe. The procedure involves implanting tiny electrodes deep inside the brain and connecting them to a programmable, battery-powered device that creates electric pulses. The device, which resembles a heart pacemaker, is implanted beneath the collarbone. Electrical impulses from the electrodes work by regulating or overriding faulty signals caused by the disease.

“Deep brain stimulation provides effective treatment of Parkinson’s disease for those experiencing these side effects of dopamine therapy,” Air says. “We generally wait to consider DBS until the disease and the medication side-effects are severe and are impairing the patient’s ability to work, socialize and enjoy life.”

Although that timetable is usually a decade or more, the FDA’s approval of DBS for medically refractory Parkinson’s disease does not specify a time course. “We have done surgery on patients within five years of diagnosis because of symptom severity,” says George Mandybur, MD, associate professor in the department of neurosurgery and director of the NeuroRestorative Program at the UC Neuroscience Institute.

Doctors have tended to postpone surgery, Air says, because they want to confirm that the patient has Parkinson’s and not another condition that may mimic Parkinson’s in the early stages but that will not respond to DBS. Doctors also have lacked good evidence about the optimal timing of surgery.

The research by German and French researchers, led by Günther Deuschl, a professor at Christian-Albrechts-University in Kiel, Germany, and published Feb. 14 in the New England Journal of Medicine, provides new evidence that may alter the conventional wisdom of late surgical intervention. The German-French study, known as the EARLYSTIM trial, enrolled 251 patients who had been diagnosed with Parkinson’s disease an average of 7.5 years earlier and had not yet lost occupational and psycho-social function. The participants were randomized to one of two groups: one that received continued medical therapy, and another that received DBS surgery. Over two years of follow-up, those who underwent DBS showed a 26 percent improvement in quality of life compared with no improvements in patients treated with best medical therapy alone.

The study was partially funded by Medtronic, Inc., which makes DBS products.

The EARLYSTIM study’s results were not necessarily surprising. The safety and tolerability of DBS in early Parkinson’s disease has been studied for several years by David Charles, MD, the chief medical officer of the Vanderbilt Neuroscience Institute who lectured about the topic at UC in 2008. Meanwhile, preliminary laboratory research performed at UC http://healthnews.uc.edu/news/?/7426/ found that DBS halts the progression of dopamine-cell loss in animal models. That research grew out of an observation by physicians, including Mandybur, about patients who underwent DBS.

“We noticed that in some patients the disease did not seem to progress as rapidly after surgery as it did before the surgery,” says Mandybur, a neurosurgeon with the Gardner Center and Mayfield Clinic. As a result, he and others theorized that DBS not only alleviated symptoms, but also provided neuroprotection.

Air cautions that DBS is not a cure-all for Parkinson’s disease and that it only improves some symptoms. DBS does not improve the declines in memory and thinking that come with Parkinson’s.

The study reported surgical complications that were no higher than complications in previous studies of patients with more advanced disease, but it did suggest a higher rate of depression among those who underwent surgery. “This highlights the importance of both pre-operative screening for psychiatric disease and post-operative monitoring,” Air says.

Air notes that more study is needed before large-scale changes in practice can be recommended. “However, this study pushes us to rethink when and for whom surgery is suited so that we can help those with Parkinson’s disease maximize their quality of life,” she says.

CINCINNATI—A new oral vaccine that produces a novel two-pronged immune system attack on cancer cells could be effective in preventing breast cancer recurrence, according to findings from a collaborative research team from the University of Cincinnati (UC) Cancer Institute and the National Institutes of Health (NIH).

This is the first scientific report of using oral delivery of a unique virus—known as recombinant adeno-associated virus (AAV)—as a cancer vaccine. First author and UC College of Medicine research assistant professor Jason Steel, PhD, and colleagues reported their findings in the Jan. 8. 2013, issue ofMolecular Therapy, the journal of the American Society of Gene and Cell Therapy.

Although other oral breast vaccines have been studied in animal models, these vaccines raised human safety concerns because they used bacteria known to have potential harm to human health.

In conjunction with NIH researchers, the UC team sought to develop a vaccine using AAV, a virus that has been shown to have minimal negative effects on human health and is currently being investigated as a gene therapy platform for treating inherited genetic disorders.

“AAV is special because the virus survives the stomach,” explains Steel. “Normally, you introduce a virus by mouth and it is broken down in the stomach. This virus is resistant to breakdown, which opened up the possibility of administering it orally as a cancer vaccine.”

In this preclinical animal study, the UC team tested two strains of AAV—one that was able to escape the stomach and move into the bloodstream, the other staying in the stomach. Studies were conducted to show both short-term and long-term impact on the reduction of breast cancer tumors. The team also evaluated which delivery method was more effective—oral versus the traditional intramuscular injection.

“The strain that remained in the stomach was more effective at preventing breast cancer tumors than the strain that traveled systemically—100 percent of study subjects had no tumors for over a year following the treatment,” says Steel. “Additionally, we showed that oral delivery (versus intramuscular injection) was more effective, resulting in a stronger immune response with greater than a 100 percent increase in anti-tumor antibodies at the lower doses and increased survival.”

Researchers say this AAV-based oral cancer vaccine holds potential as a human breast cancer prevention tool in individuals who have been treated for a certain type of breast cancer or those deemed at increased risk for the disease.

“We have done similar studies with different virus strains that have produced an antibody response,” adds Steel. “With this virus, we get both an antibody and a tumor-killer T-cell response. By combining the two mechanisms of action in one vaccine, we are creating a two-pronged immune system attack on the cancer cells that appears to be more effective.”

The UC team expects to begin testing the AAV-based oral vaccine for prevention of other cancers, including lung cancer, in 2013.

The study was funded in part by the National Cancer Institute, National Institute of Dental and Craniofacial Research and startup funds from the UC Cancer Institute. UC postdoctoral fellow Charmaine Ramlogan, MD, and senior author John Morris, MD, UC professor and director of phase-1/developmental therapeutics, collaborated in this study. Giovanni Pasquale, PhD, Vyomesh Patel, PhD, and John Chiorini, PhD, of the National Institute of Dental and Craniofacial Research, also contributed to this study.

About the UC Cancer Institute

The University of Cincinnati Cancer Institute is one of four UC and UC Health partnerships that brings together patient care, research and education initiatives. Many researchers and clinician-scientists at UC are also part of the Cincinnati Cancer Center, a collaborative initiative of the University of Cincinnati, Cincinnati Children’s Hospital Medical Center and UC Health. The center’s ultimate aspiration is to create a world-class comprehensive center leading in innovation to eliminate cancer.

CINCINNATI—The University of Cincinnati will lead a $5.2 million national trial studying removal of both corticosteroids and common immunosuppression treatments from the post-transplant drug regimen for kidney transplant patients.

The Belatacept Early Steroid withdrawal Trial (BEST) seeks to determine if a belatacept-based regimen for post-transplant patients can prevent organ rejection without the harmful side effects posed by corticosteroids and calcineurin inhibitor (CNI) immunosuppressants. Belatacept is a modified version of the drug abatacept, which is used to treat rheumatoid arthritis.

Led by principal investigator and director of UC’s division of transplantation E. Steve Woodle, MD, the $5.2 million trial will be carried out at four other transplant centers across the country: University of Wisconsin, University of Minnesota, California Pacific Medical Center and the Christ Hospital in Cincinnati.

The BEST study is the first large, multicenter trial to remove both corticosteroids and CNIs from a patient’s drug regimen after kidney transplantation. Both drugs place patients at an increased risk of cardiovascular disease, high blood pressure, high cholesterol and diabetes. Additionally, CNIs have shown toxicity to transplanted kidneys.

“Cardiovascular events like stroke and heart attacks are the top cause of death for both the general population and transplant patients,” says Woodle, who also serves as William A. Altemeier Chair in the UC Department of Surgery. “We’ve previously demonstrated that early steroid withdrawal results in reduced cardiovascular events and increased graft survival in transplant patients.”

Rita Alloway, PharmD, research professor of medicine and director of transplant clinical research within the UC Department of Internal Medicine, will direct the coordinating center for the trial. She says belatacept was approved by the Food and Drug Administration in 2011 for prevention of rejection in kidney transplant patients—the first FDA-approved drug to replace CNIs like tacrolimus and cyclosporine.

“This trial is a major step forward in immunosuppression because it provides a means to avoid many of the toxicities of the CNI drugs, particularly kidney toxicity, high blood pressure, and hyperlipidemia,” says Alloway.

Adele Shields, PharmD, associate research professor of surgery with clinical practice at the Christ Hospital, has specialized in quantitating the impact of long-term immunosuppression on cardiac risk factors and cardiac events.

“An important feature of the belatacept-based treatment regimen is that it provides an opportunity to greatly minimize cardiovascular risk in the long term,” she says. “By avoiding both CNIs and corticosteroids, this trial provides an opportunity to substantially impact long-term patient survival following kidney transplantation.”

The trial seeks to enroll 315 new kidney transplant patients across all centers. Enrollment will begin December 2012.

This study is funded by Bristol Myers Squibb. The IND is held by Woodle, however research support for study conduct is provided by Bristol Myers Squib (BMS), manufacturer of belatacept. Woodle and other investigators report no financial interest in BMS. Woodle has previously received consulting compensation from BMS and Genzyme, manufacturer of Thymoglobulin.

Richard Godby has always felt drawn to clinical medicine. However, he’s also enthralled by the scientific discovery process—a more recent interest that developed throughout his undergraduate career.

“I love the intellectual challenges of medicine and the fact that solutions lead to improved health care. When scientists and physicians work together, the power of basic science emerges in clinical practice and seemingly distinct approaches coalesce to yield tangible outcomes,” says Godby, who will graduate this month at the top of his class and serve as the Marshal for the UC College of Engineering and Applied Science’s biomedical engineering (BME) program, entering medical school at UC this fall. “It’s fascinating to read about and observe scientific concepts, study those concepts and come up with your own conjectures about what is reality—and try to prove it in the lab. Then the process continues when others challenge your ideas.:”

His BME undergrad experience ingrained in him the value of translational research—moving promising ideas beyond the lab bench and into clinical application. This, teamed with his interest in medical research, led him to pursue a co-op in the lab of UC Cancer Institute researcher Vladimir Bogdanov, PhD.

Bogdanov specializes in hemostasis—the process that causes bleeding to stop—and specifically, alternatively spliced Tissue Factor (asTF) as a target for diseases including cancer, occlusive diseases, sickle cell and others.

When Godby entered Bogdanov’s lab, he was brimming with enthusiasm, but was an admitted novice when it came to the interworkings of a basic science laboratory.

“I’d never even used a pipette,” Godby recalls, noting that the rapport among him, Bogdanov and the lab staff overcame that obstacle quickly and resulted in a very positive co-op experience.

“Dr. Bogdanov encouraged me to come to grand rounds and shadow in the clinic and basically get a holistic picture of how what we are doing here in the lab influences clinical care. It was just a really good experience.”

Training Scientifically Minded Clinicians
Giving future physicians hands-on experience with and an appreciation for science is very rewarding, says Bogdanov, who has had three co-op students rotate fthrough his laboratory since joining the UC College of Medicine faculty in the summer of 2009.

“Richard was a pleasure to have in the lab. He was hardworking and applied a lot of effort to self-improve in real time. I’ve had the pleasure of working with many talented medical students, but sometimes you really see someone’s potential. In the lab, you learn to think on your heels and become a better critical thinker and strategic risk taker,” says Bogdanov.

“As a faculty mentor, you hope that experience in the research lab with stay with them when they begin practicing medicine so they continue to contribute to the research that ultimately improves care at the bedside.”

Student-Faculty Research Project
During his six-month co-op, Godby worked with Bogdanov to examine the biologic properties of the mouse form of asTF and its usefulness in mouse models. The study goal was to articulate the potential significance of having or not having asTF in an effort to understand the molecule’s role in disease development.

Numerous models exist for studying Tissue Factor, but a comprehensive evaluation of the Tissue Factor system showing the potential significance of having—or not having the asTF molecule—did not previously exist in the scientific literature.

The study, published in July 2012, was recently listed in the Top Ten most read original research articles in Molecular Medicine, an open access journal seeking insight into the cellular and molecular basis of disease.