Fall 2014 - GResearch by Augusta University

esearch Fall 2014

GEORGIA

REGENTS UNIVERSITY

The Fighter Immunotherapy Delivers 2,3 Punch

VOL. 2

NO. 2

D IS C O V E R IES

P R O G R ESS

37 CONTENTS GResearch is produced twice a year by the Office of the Vice President for Research, in conjunction with the Office of Communications and Marketing. PRESIDENT Dr. Ricardo Azziz PROVOST Dr. Gretchen Caughman SR. VP FOR RESEARCH Dr. Mark Hamrick Interim SR. VP FOR COMMUNICATIONS AND MARKETING Jack Evans

EDITOR Christine Hurley Deriso DESIGN AND PRODUCTION P.J. Hayes Design PHOTOGRAPHER Phil Jones WRITERS Toni Baker Christine Hurley Deriso John Jenkins Georgia Regents University does not discriminate on the basis of race, color, national origin, sex, disability, religion, age, veteran status, gender identity or expression, or sexual orientation in its programs and activities as required by Title IX of the Educational Amendments of 1972, the Americans with Disabilities Act of 1990, Section 504 of the Rehabilitation Act of 1973, Title VII of the Civil Rights Act of 1964, and other application statutes and university policies. ÂŠ2014 GEORGIA REGENTS UNIVERSITY

AT A GLANCE

THE FIGHTER

TRUE COLORS

DIRECTIONS, PLEASE

STAT!

QUIETING THE GRUMBLING

Cancer Therapy Pulls Immune System Back Into the Fight

Test Eases Detection of Liver Cancer

Tools Allow for Mapping the Brain

Halting Jaw Destruction a Team Effort

Study Targets Irritable Bowel Syndrome Pain

TOTAL WAR

DOING THE MATH

NAILING THE PROBLEM

Experts Offer Nuance to Studies of Civil Conflicts

Model Adds Precision to Epidemic-Predictions

Study Targets UVA Exposure in Nail Salons

Dear Readers, groundbreaking research into the immune system that it is with much sadness – yet great anticipation – that unfolded right here on campus. How gratifying to see I write my final introductory letter for our research such efforts come full circle. magazine. I hope you enjoy reading about these clinical trials, as I have decided to return full time to my first love of well as the many other exciting initiatives taking place research. Of course, during my tenure as Senior Vice President for Research, I’ve had the inestimable privilege in our labs. That’s where you’ll find me from now on – in my lab – but please know my heart is with each and of guiding and supporting the research of others. every one of you as our research innovations continue This role was doubly fulfilling when our university’s to improve the lives of those in our consolidation enabled state, our nation, and, indeed, the me to delve into not i hope you enjoy world. n only biomedical research, reading about these but liberal arts research as well. I have been so clinical trials, as well gratified to oversee the as the many other amazing work of so many exciting initiatives dedicated faculty, staff, Dr. Mark Hamrick and students. SENIOR VICE PRESIDENT FOR RESEARCH taking place in our But as much as I have labs. relished this role, I’ve looked on with a bit of envy. Yes, I’ve continued my own research, but administrative duties pulled me farther away from my lab than I wanted to be. As much as I have enjoyed the responsibilities entrusted to me, I am champing at the bit to put my lab coat back on full time. As I return to my GRU lab, rest assured that our research operation is in fine and capable hands. Dr. Michael Diamond, Vice President of Clinical and Translational Sciences and Chairman of the Medical College of Georgia Department of Obstetrics and Gynecology, is serving in an interim position as my permanent successor is recruited. He is extremely wellsuited to build the momentum of a research program that is garnering increased recognition nationwide and beyond. (Read more about him and his own research on page 2) I will do everything possible to support and assist him. And I continue to offer my unqualified support and assistance to all GRU researchers. Even the most cursory scan of this magazine makes it clear that their work is second to none. The clinical trials now available to our cancer patients, for instance, stemmed from 1

AT A GLANCE Expanded Roles Dr. Michael Diamond, Georgia Regents University Vice President of Clinical and Translational Sciences and Chairman of the Medical College of Georgia Department of Obstetrics and Gynecology, has been named GRU’s Interim Senior Vice President for Research. He succeeds Dr. Mark dr. michael diamond Hamrick, who has returned to fulltime research. Diamond, who earned a medical degree from Vanderbilt Medical School, studies fertility and other issues associated with women’s reproductive health. He recently chaired an FDA-convened panel on dissecting uterine fibroids to ease their removal. Also, Dr. Abiodun Akinwuntan, Associate Professor of Physical Therapy, Neurology, Ophthalmology, and Graduate Studies, has been named Associate Dean for Research in the College of Allied Health Sciences. He has served as Interim Associate Dean since October 2012. Akinwuntan, also Director of GRU’s Driving Simulation Laboratory, studies rehabilitation for neurological impairments. He received doctoral and master’s degrees in neuromotor rehabilitation from Katholieke Universiteit Leuven (Catholic University of Leuven) in Belgium and a master’s degree in public health from GRU. n

Double Duty A breast cancer drug may be an effective fertility treatment for women with polycystic ovary syndrome. A national study of 750 women with PCOS, a hormonal disorder affecting up to 10 percent of reproductive-age women, showed rates of ovulation, conception, pregnancy, and live birth were all higher in women taking letrozole than in those taking the usual front-line fertility medication clomiphene, according to a study in the New England Journal of Medicine. “A lot of anecdotal evidence and small studies suggested that letrozole could help these patients conceive,” said Dr. Michael Diamond, Chairman of the MCG Department of Obstetrics and Gynecology and GRU’s newly appointed Interim Senior Vice President for Research. “This study comparing it to conventional therapy supports those earlier reports.” Diamond, a study co-author, participated in the trials while at Wayne State University. Dr. Richard S. Legro, reproductive endocrinologist at Penn State College of Medicine, is the study’s corresponding author. Women taking letrozole were 44 percent more likely to conceive than women taking clomiphene, the authors wrote, predicting that letrozole may assume clomiphene’s frontline fertility treatment status for these women. The safety profile on both drugs, including the common infertility treatment risk of multiple pregnancies, is similar. n

dr. abiodun akinwuntan

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dr. adam berman

Stem Cell Treatment “We want to know if stem cell therapy is an option for patients who have essentially run out of options.”

GResearch Fall 2014

Researchers want to know whether debilitating heart failure can be treated with one’s own stem cells injected into the ailing heart muscle. Ischemic dilated cardiomyopathy, an incurable condition resulting from compromised blood flow to the heart as well as heart attacks, leaves the muscle bulky and inefficient. “We want to know if stem cell therapy is an option for patients who have essentially run out of options,” said Dr. Adam Berman, GRU Director of Cardiac Arrhythmia Ablation Services. “It’s a very exciting potential therapy.” Berman is a Principal Investigator on the multisite study in which stem cells are removed from the bone marrow, their

numbers significantly increased by technology developed by Aastrom Biosciences, then injected into multiple weak points in the heart. At GRHealth, the procedure is performed in the Electrophysiology Lab, where a catheter is threaded into an artery from the groin to the heart. Three-dimensional maps of the heart provide a clear picture of its natural geography as well as major sites of damage. Half of the study participants receive the stem cell treatment, called ixmyelocelT, and the remainder a placebo. Researchers will follow all participants for 12 months to assess heart function and quality of life. For more study information, call the Surgical Research Service at 706-721-0193. n

AT A GLANCE Kidney Balancing Act

Transplant Success Patients with high levels of the immune molecule HLA-G appear to have the lowest risk of rejecting a transplanted kidney, researchers report. A study of 67 transplant patients – 50 with no evidence of rejection and 17 with chronic rejection – showed those most tolerant of their kidney had naturally high levels of HLA-G dimer, making two of the immune molecules bind together, said Dr. Anatolij Horuzsko, an MCG immunologist. Knowing which form of HLA-G correlates with optimal transplant success could enable physicians to further tailor the delicate balance of prescribing sufficient immune-suppressive drugs to keep a donated organ without significantly increasing the risk of infection and cancer, said Dr. Laura L. Mulloy, Chief of the MCG Section of Nephrology, Hypertension, and Transplantation Medicine.

“A patient with naturally higher levels of HLA-G dimer might need less immunosuppression, which means less toxicity, less drug complications, and less cost,” said Mulloy, a co-author of the study reported in the Journal of Immunology Research. Conversely, patients with low levels might benefit from higher drug doses. High levels of HLA-G dimer also correlated with lower levels of inflammation, an immune response that can lead to rejection. The most successful transplant patients also had higher levels of HLA-G receptors, noted Horuzsko, the study’s corresponding author. He and several biotech companies are working to develop a more stable version of HLA-G that could one day supplement low levels. The research was funded by the Carlos and Marguerite Mason Trust. n

drs. laura mulloy and anatolij horuzsko

Obese Caucasian females over age 50 with diabetes and on dialysis are among those at highest risk for the rare and deadly condition dr. lu huber calciphylaxis, according to an analysis of the U.S. Renal Data System. Calciphylaxis occurs when calcium and phosphorus bind to form a biological cement that blocks and inflames small blood vessels, risking major infection and skin ulcers, said Dr. Lu Huber, an MCG nephrologist. “It’s all about balance, and our kidneys help regulate that balance,” said Huber, who scoured the national database of 2.1 million patients with failed kidneys to better define incidence and risk factors with the goal of better identifying and managing those at highest risk. Her findings were cited as one of eight best abstracts submitted to the 51st European Renal AssociationEuropean Dialysis and Transplant Association Congress May 31-June 3 in Amsterdam. Huber found the condition occurred in 459, or 0.02 percent, of the high-risk patients. While dialysis is a lifesaver, it does not completely replace all the filtering work of the kidney, never mind other major functions, such as making the active form of vitamin D, Huber said. “In end-stage renal disease, we tend to see low calcium and high phosphorus,” Huber said. The dysregulation prompts the two to bind in the blood. The material deposits in small blood vessels, valves, and soft tissue, contributing to the vascular complications of life on dialysis. n GEORGIA REGENTS UNIVERSITY

Lifetime Achievement Award

dr. darrell brann

Dr. Darrell Brann, Regents’ Professor of Neurology, has received the Georgia Regents University Research Institute’s 2014 Lifetime Achievement Award. Internationally recognized for contributions to women’s health, neuroendocrinology, and reproductive endocrinology, “few have had the impact upon the university and community as Dr. Brann has through his outstanding contributions in research, education, service, and administration,” wrote Dr. Lin Mei, Chairman of the

MCG Department of Neuroscience and Regenerative Medicine, in his nomination letter. Brann has clarified the neuroendocrine mechanisms that underlie steroid hormone positive feedback to control ovulation; helped explain the neuroprotective actions of estrogen in the brain; and provided key support for the “critical window hypothesis” of estrogen replacement therapy, helping elucidate the link between premature menopause and dementia. n

Sickle Cell Double Whammy Low levels of oxygen and nitric oxide appear to have an unfortunate synergy in sickle cell disease, researchers report. Their studies indicate that both factors dramatically increase red blood cells’ adhesion to the lining of blood vessels walls (the defining characteristic of the disease) and the debilitating pain crises that can result. The good news is that restoring normal levels of nitric oxide can substantially reduce red blood cell adhesion, said Dr. Tohru Ikuta, an MCG molecular hematologist. Ikuta and Dr. C. Alvin Head, former Chairman of MCG’s Department of Anesthesiology and Perioperative Medicine, were co-corresponding authors of the study in the journal Blood. The study also points to a potentially new therapeutic target, the self-adhesion molecule P-selectin, which the researchers found plays a central role in increased red blood cell adhesion. Low levels of oxygen and nitric oxide both increase expression of P-selectin. Nitric oxide therapy likely would benefit only patients with intermittent or chronically low levels, he said. “The answer is that some patients may not need this. And, our studies indicate that there is no therapeutic benefit to increasing levels beyond physiologic levels.” The studies were funded in part by the National dr. tohru ikuta Institutes of Health. n

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AT A GLANCE Serving the Underserved The GRU Cancer Center has received a five-year grant from the National Cancer Institute to lead the state’s only cancer research program focused on better access to clinical trials and cancer treatments for minority and underserved patients. Working with the Morehouse School of Medicine, University Cancer and Blood Center, and the Jiann-Ping Hsu College of Public Health at Georgia Southern University, the Community Oncology Research Program Minority/Underserved Community Site at GRU Cancer Center will aim to increase awareness of, and participation in, NCI-sponsored clinical trials and cancer care delivery research throughout Georgia, particularly among minority and underserved populations. As the only site of its kind in Georgia, and one of just 12 selected nationally, the GRU Cancer Center-led consortium will

help design, conduct, and translate the national NCORP research agenda, particularly studies pertaining to minority and underserved populations. Key stakeholders and community partners will help set priorities for community-based cancer research and work to increase the participation of minority and underserved patients in clinical trials and other cancer research.

“We are honored to work with our colleagues from around the state to build on more than a decade of experience serving as a minority-based CCOP,” said Dr. Samir N. Khleif, Director of the GRU Cancer Center. “This grant is in perfect alignment with our shared commitment to serve all Georgians with the best possible cancer care.” n

Cancer Center patient Carolyn Bowen

China at One’s Fingertips GRU and the College of Education, in conjunction with the GRU Confucius Institute, have developed two new apps for Apple products, which introduce users to simplified Chinese language and Chinese culture. “With the opening of the Confucius Institute for Chinese language and culture, we wanted to offer tools to introduce the

concepts to children in the local schools,” said Dr. Cindi Chance, Dean of the College of Education. One app, Hanyu, contains interactive lessons in vocabulary, phrases, conversations, and Chinese characters. The other, Lunar New Year, is a fun tutorial about the celebration, the animals of the Chinese zodiac, and cultural customs. “We’ve been getting great

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Epilepsy Study Georgia Regents University is teaming with GW Pharmaceuticals to study a cannabis-derived product to treat children with medication-resistant epilepsies. Georgia Gov. Nathan Deal recently announced his support for clinical research investigating the use of CBD, a nonpsychoactive component of the cannabis plant, to treat the condition, in which disordered nerve cell activity in the brain causes recurrent seizures. “I have learned the stories of brave Georgia families desperately seeking treatment for their children’s debilitating condition,” Deal said. “I’m confident this publicpartnership will deliver relief and improve quality of life for these children and their families.” The Food and Drug Administration has already authorized physician-sponsored GW programs with Epidiolex at 12 sites nationwide involving over 300 children. n

Gov. Nathan Deal visits the Children’s Hospital of Georgia

feedback,” said Jeff Mastromonico, Director of Educational and Collaborative Technology. “The kids like it, and they’re very honest about what they want.” Mastromonico and his staff – Aaron Burkhart and Lynsey Ekema – worked with Dr. Nai-Cheng Kuo, a Professor of Education originally from Taiwan, to conceptualize and develop the games. “The lessons are very easy to follow, even for beginners,” Kuo said. n

GResearch Fall 2014

FREE download

HANYU itunes.apple.com/us/app/hanyu/id836252975?mt=8

Lunar New Year: itunes.apple.com/us/app/lunar-new-year/id836259278?mt=8

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The

Fighter BY CHRISTINE HURLEY DERISO

Immunotherapy Delivers 2, 3 Punch When Drs. Andrew Mellor and David Munn provided a key puzzle piece about the mysteries of the immune system in the late 1990s, they predicted real-world results for cancer patients about 15 years into the future. Cancer patients in Georgia and beyond are todayâ&#x20AC;&#x2122;s beneficiaries of a prediction that was right on the money. continued

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Sea Change

dr. Andrew Mellor

The therapy the Georgia Regents University researchers have set in motion is nothing less than a sea change in cancer treatment: triggering the immune

de facto bouncer – chasing away viruses, bacteria, and other invaders – it can malfunction with tragic results. For instance, the immune system can accidentally declare war on the body’s own tissues, resulting in autoimmune diseases such as multiple sclerosis or rheumatoid arthritis – or it can inexplicably give a pass to troublemakers such as cancer cells.

Outsmarting the Bouncer

dr. david munn

system to attack cancer cells to supplement the conventional tools of surgery, chemotherapy and radiation. Several clinical trials are unfolding on campus – and elsewhere nationwide – capitalizing on Mellor’s and Munn’s groundbreaking discovery of how a fetus avoids rejection by its mother’s immune system. Mellor, Director of the GRU Cancer Research Center, and Munn, Professor of Pediatrics, in 1998 published their finding that an enzyme called indoleamine 2,3-dioxygenase, or IDO, signals the immune system to leave a fetus undisturbed, despite the fact that it is a foreign body. Now that they had the key to selectively suppress the immune system, the next step was unlocking new treatments for the country’s second-leading cause of death: cancer. As vigilant as the immune system is in serving as the body’s

“Humans are big organisms,” Munn says. “We have trillions of cells. So even if the immune system is 99 percent effective, if you live long enough, some cancer cells will eventually slip through the surveillance.” He and his colleagues’ IDO research uncovered another intriguing dimension to the process: The cancer cells don’t simply slip past the bouncer; they actively outsmart it. “The immune system thinks it’s doing its job,” Munn says. “The tumor basically pushed a button that said, ‘Leave me alone.’ It’s not like the immune system is falling down on the job.” The researchers hypothesized that the tumors hijack existing mechanisms to outsmart the immune system, and their lab results have borne out the theory.

The Ultimate Hijackers “We initially looked at the pregnancy model not because we were interested in the immunology of pregnancy, but because we wanted to figure out how tumors evade the immune system,” Munn says. “That led us to figure out the normal way the body suppresses an immune response. In pregnancy, the immune system is aware of the fetus but holds an immune response in check. Discovering IDO as the mechanism led us to demonstrate that IDO is the mechanism hijacked by tumors.”

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The discovery toppled a huge stumbling block. Researchers have tried since the 1980s to boost the immune system to combat cancer, “but it wasn’t working well,” Munn said. “It was disappointing. The IDO research helped us realize that a tumor doesn’t just sit there invisible to the immune system. That’s why experimental vaccines weren’t working. It’s more complicated than that.” The pregnancy work, he says, led the researchers to debunk the assumption “that the baby must keep itself invisible somehow to avoid an immune response,” Munn says. “It was thought that the placenta must hide the antigens that otherwise would trigger the immune system. But it didn’t make sense that the mother’s bloodstream would be intimately tied to the fetus and placenta for nine months without the immune system catching on. There must be more going on.”

Doing Good Now that he and his colleagues identified IDO as the missing puzzle piece, they went to work developing small-molecule drugs that inhibit IDO. GRU patented the findings that enabled the researchers to partner with NewLink Genetics to expedite the drug development. “They’ve been good partners,” Munn says. “Our mission is to get these discoveries to patients in Georgia and beyond so they can do some good.” The results so far? GRU is conducting clinical trials using IDO-inhibiting drugs on patients who have largely run out of other options. A drug called NLG919, for instance, is targeting the prostate and bladder cancer of a 66-year-old man who has run out of effective chemotherapy drugs. Another IDO-inhibiting drug targets glioblastoma, a brain tumor, and was based on work in

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mice by Dr. Theodore Johnson, who conducted research with Mellor as a GRU MD/PhD student.

Homegrown Talent “Drs. Mellor and Munn were formative influences on me, and my goal is to apply their groundbreaking work to children’s cancer,” says Johnson, who joined GRU’s faculty as an Assistant Professor of Pediatrics after completing a pediatric oncology fellowship at Cincinnati Children’s Hospital. Johnson is combining the IDO-inhibiting drug, indoximod, with standard chemotherapy to treat glioblastoma, which often can’t be fully removed surgically and almost always returns aggressively. The drug being used in the trial seeks not only to provoke an immune response with few side effects, but to battle the resistance tumors build up against chemotherapy agents. The clinical trial, which began accepting

dr. theodore johnson

patients in March, is being used on adult glioblastoma patients, but the next step is tailoring the trial for children with the disease. “We’re very hopeful that we can open the trial for children within one to two years,” says Johnson. “This will fulfill my goal of bringing immunotherapy treatment into clinical use for children with cancer.” No place could have better prepared him for this challenge than GRU, he says. “My education and clinical experience here prepared me greatly for the challenges of a subspecialty fellowship,” Johnson says. “When I went to Cincinnati, I felt very well-prepared for that arduous training experience. And from a research perspective, I’d had the opportunity to work on a groundbreaking project – helping develop the IDO science that is

“We are becoming one of the major centers, if not the major center, for the Southeast in immune therapy and tumor immunology. [The National Cancer institute] looks at strength and uniqueness, both of which we have.” –dr. samir n. khleif ultimately leading to immunotherapy for cancer patients. We’re very excited that this may offer relapsed brain tumor patients the hope for a cure.”

Strength and Uniqueness Other trials on campus are targeting pancreatic cancer and melanoma. These initiatives are drawing worldwide attention, says Cancer Center Director Samir N. Khleif, who will oversee still more clinical trials to advance the two leading

immunotherapies of GRU’s corporate partner, Advaxis: ADXS-HPV for cervical cancer and ADXScHER2 for breast cancer. “Because of those clinical trials,” Khleif says, “we are becoming an international destination. [Immunotherapy] is one of the hottest areas in cancer currently. “We are becoming one of the major centers, if not the major center, for the Southeast in immune therapy and tumor immunology,” he says, adding that the prominence is hastening GRU’s quest for National Cancer Center designation by the National Cancer Institute. “[The institute looks] at strength and uniqueness, both of which we have.” As excited as the researchers are about the potential of IDO-inhibiting drugs – none of which seem to have onerous side effects – Munn emphasizes that the treatment is an adjunct, not a substitute, for existing therapies. “The immune system is already behind the eight ball by the time cancer is diagnosed,” he explains. “The tumor has already won. But the hope is to use existing methods – surgery, chemotherapy, radiation – then use these new drugs to help the immune system attack those last existing cancer cells to prevent relapse or metastasis.” He hopes the additional firepower will enable less-toxic doses of chemotherapy as well. “If the immune system is doing its part of the job, we hope the existing treatment won’t be so damaging,” Munn says. And assuming the clinical trials validate the effectiveness of the drugs in humans, Munn emphasizes that the sooner they’re used in cancer treatment, the better. “Ideally, they’ll be used right up front,” he says. “That’s absolutely our goal. We’re starting with latestage patients because they’re running out of options, but we envision much broader applications in the future.” n GEORGIA REGENTS UNIVERSITY

Another Role for IDO Evidence suggests that IDO-powered stem cell therapy can restore blood flow to an injured limb without causing additional damage. Ischemia reperfusion injury is the heightened inflammation and cell death that can result when blood flow is restored after a condition such as trauma or heart attack. Dr. Babak Baban, a GRU immunologist, and Dr. Jack Yu, Chief of the MCG Section of Plastic and Reconstructive Surgery, are collaborators on a study published in PLOS ONE that shows stem cell therapy appears to help via IDO.

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Drs. babak baban (left), mohamad masoumy, and jack yu

Earlier studies indicate stem cells may improve recovery both by enabling new blood vessel growth and by reducing inflammation, Baban said. The new study shows that IDO plays an important role in regulating inflammation. Stems cells and numerous other cell types are known to express IDO. In mouse studies, IDO boosted stem cell efficacy by about a third. The researchers documented decreased expression of inflammatory markers, swelling, and cell death. That could be just what the doctor ordered for these patients, said Baban,

the study’s corresponding author. “We don’t want to turn off the immune system,” he said. “We want to turn it back to normal.” Next steps include seeing if more is better, by giving more stem cells – the researchers only gave one dose in the studies – as well as IDO-enhancing drugs, Baban said. This will include incubating stem cells with IDO. The researchers note that stem cell therapy isn’t yet used to treat injured limbs, but is being studied clinically to aid stroke and heart attack recovery at MCG and other centers. Currently,

the most physicians can do is restore blood flow and give broadspectrum antibiotics. “Sometimes it works, sometimes it doesn’t,” Yu said. “That is why this kind of pharmacologic intervention could be very, very important.” Dr. Mohamad Masoumy, a fourth-year general surgery resident at MCG and GRHealth, is first author on the study. n

True colors BY TO N I B A K E R

Test Eases Early Detection of Liver Cancer It’s among the fastestgrowing and deadliest cancers in the United States with a 17 percent three-year survival rate. Still, you don’t really hear a lot about liver cancer.

Orphan Cancer “Liver cancer is an orphan cancer. No major group is a voice for it,” says Dr. Ravindra Kolhe, pathologist and Medical Director of the Georgia Esoteric, Molecular Labs LLC at the Medical College of Georgia. In fact, liver cancer itself is typically quiet until a sizeable tumor is taking up significant space previously occupied by healthy liver cells. Such obscurity results from the reality that even with the most experienced eyes peering through a microscope, early liver cancer cells are essentially identical to healthy liver cells. By the time the tumor is large enough to be discernible and cause symptoms, such as abdominal pain and weight loss, the liver is failing. “There isn’t a test for diagnosis of liver carcinoma; rather, what leads us to that diagnosis is failure of liver function,” Kolhe says.

By then, the treatment options – removing the diseased portion of the liver, a liver transplant, freezing or heating cancer cells, destroying blood vessels that feed them – have a high failure rate as well. “The deadly liver cancer cells seek to recapitulate the appearance of normal liver cells,” says Dr. Amyn M. Rojiani, Chairman of MCG’s Department of Pathology. And they are very good at that, the two pathologists agree, which is the frustration they have when trying to give patients definitive, early answers from looking at the tiny core biopsies of their livers under the microscope.

Wanting to Know More “As pathologists, we often find ourselves wanting to know more,” says Dr. Andy Rahardja, a pathology resident. By early next year, the MCG pathologists, in collaboration with BioGenex laboratories, a California company with expertise in cell and tissue testing, should be able to give patients and physicians alike a lot more information by making widely available a new test that dramatically enhances the ability to defi-

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drs. ravindra kolhe (left), amyn m. rojiani, andy rahardja, and Puneeta Vasa

nitely diagnose early liver cancer. She may not be famous in the traditional sense, but Ann Rushton could be a great voice for – or rather against – liver cancer. It’s really more her laugh than her voice, but the two comingle so often that really they seem the same. The native Texan, mother of three (including identical twin daughters), grandmother of seven, and bride of 48 years of Dan Rushton, defines herself as headstrong but happy, even as she sits down to talk about her liver cancer. Calling it a little “blob monster,” Rushton amazingly finds humor in the past year and three months, even the day in May that the side pain she had been feeling for a week got really, really bad. It was a Saturday, and she was at her part-time job at an art glass store. “I am not a big run-to-thedoctor person,” says Rushton, who had readily managed a

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handful of other maladies in her own life and her family’s. But that Saturday, she could barely catch her breath. She learned first what she already suspected, that she had gallstones, but she also learned there was a large tumor on her liver.

ann rushton

Stealth Predator Despite its relative obscurity, Rushton knew that liver cancer was a very bad diagnosis. She went to her primary care doctor, Dr. Robert West, at University Hospital, then to an oncologist, Dr. David R. Squires at Augusta Oncology Associates, and finally to Dr. Edward J. Kruse, a hepatopancreatico-biliary surgeon and Interim Chief of the MCG Section of Surgical Oncology. Husband Dan, who had survived his own serious malady,

a bleed in his brain when he was in his 50s, remains a terrific life partner, but one who is a bit hard of hearing. So best friend Peggie Ruben made this difficult doctor journey as Rushton’s compassionate extra set of eyes and ears. Kruse would tell them the good news was that the cancer appeared confined to her liver and that her best option, really Rushton’s only potentially curative option, was to remove the diseased portion of the organ. He could operate the next week. “I really didn’t have a lot of time to chew my nubs,” Rushton says. “Your best chance of cure is if you can take it out,” says

Kruse, and, as with any cancer, the earlier, the better. But also as with most cancers, patients are dealing with a stealth predator. In this hyper-vascular organ, liver cancer commandeers blood vessels and, when available, feeds on the fat that is itself a risk factor for cancer. It hides behind the cirrhosed cells that also are a cancer risk. The symbiotic relationship appears to build because, later in the disease process, cirrhosed cells also will be hard to differentiate from liver cancer cells. “Dysplasia is the term we use when we are not sure if it’s cancer or cirrhosis,” Rojiana says. At first, liver cancer takes over existing healthy liver tissue; after a while, the already large organ gets bigger, stretching the cellophane-like wrap that encapsulates it and causing some of the pain that Rushton felt that

Saturday. In Rushton’s case, Kruse would remove the 40 percent of her liver that was by then a diseased mass. Chemotherapy to shrink first and operate later was not an option. Adjuvant chemotherapy is not considered very helpful either, says Kruse, who would definitely like an early test that could improve patient survival in such a difficult scenario.

Showing Its Cards Early Despite its covert operation, liver cancer does really show its cards early, if you know where and how to look. Kolhe and his colleagues in collaboration with BioGenex have developed a test that is about 95 percent effective at helping early liver cancer cells stand out by giving them a distinctive red-brown hue when viewed through a microscope.

Normal liver cells, by contrast, are a more classic pink. By not staining cirrhosed cells, the test helps clear up that confusion as well. Their probe detects and stains a microRNA called mir-21, a known biomarker for liver cancer that was previously undetectable in the micron-thin liver biopsies pathologists routinely examine. Normally, DNA coverts to RNA, which makes the proteins that determine and enable cell function. However, microRNA doesn’t make proteins; rather, it helps control proteins that are expressed by RNA. That means it’s more stable and can survive harsh chemicals normally used to prepare the biopsy for microscopic evaluation. This includes using formaldehyde for preservation and replacing natural fluids with paraffin so the tissue can be easily cut and stained

Liver Cancer

is a leading cause of cancer deaths worldwide, accounting for more than 600,000 deaths each year, and the percentage of Americans developing liver cancer has been rising slowly for several decades, according to the American Cancer Society. The cancer, more common in men than women, is diagnosed at the average age of 63. Risk factors include cirrhosis, which can result from alcohol abuse; chronic hepatitis infection; non-alcoholic fatty liver disease, common in obesity; and diabetes. While hepatitis vaccines have reduced liver cancer rates in most other countries, obesity and diabetes are driving up rates in this country, says Dr. Yukai He. Much like chronic hepatitis infections and alcohol abuse, fat is a toxin that irreversibly scars the liver, producing cirrhosis. Fat and diabetes also dramatically increase the workload of the large organ, which has a big role in metabolism, by generating more fat and glucose that need handling, He says. 16

Dr. Edward J. Kruse, an MCG surgical oncologist, and Dr. Ravindra Kolhe, an MCG pathologist, say a healthy liver looks like an oddly shaped loaf of bread that takes two hands to hold. The extremely vascular organ should be a beautiful burgundy color, much like the distinctive maroon that along with white are the school colors of Kolhe’s PhD alma mater, Mississippi State University. In obese patients, the liver can double or triple in size with not only surface fat, but fat packed throughout the sponge-like organ. These livers are cancer-prone and lack the regenerative abilities of a healthy liver. High obesity rates in children portend liver transplants as early as one’s 30s. n GEORGIA REGENTS UNIVERSITY

CANCEROUS LIVER CELLS

NORMAL LIVER CELLS

Strong mir-21 nuclear staining

Negative mir-21 nuclear staining

Their probe detects and stains a microRNA called mir-21, a known biomarker for liver cancer that was previously undetectable in the micron-thin liver biopsies pathologists routinely examine.

GResearch Fall 2014

Discoveries in Progress

with different reagents to help pathologists pinpoint a patient’s problem.

Seeing Red-Brown Rojiani likens their probe to a tag for mir-21. They first used the probe on biopsies of 10 healthy livers and 10 livers with early cancers. In every case of liver cancer, the biopsy took on the redbrown hue. The studies were done retrospectively, so they already knew which patients – all of whom had hepatitis and so were at higher risk for liver cancer – ultimately were diagnosed with the disease. They have since used the test on more than 200 similar cases and found it works consistently. In biopsies where a lot of the now-familiar red-brown hue surfaces, those patients ultimately develop the classic symptoms that are today physicians’ first real proof of cancer. The researchers first presented their findings at the American Society of Clinical Pathology 2013 Annual Meeting and in many professional venues since; they hope the test will be widely available as soon as early 2015. While it took a lot of sophisticated machinery and science to develop, another real plus is that the test should be simple enough to use in less-sophisticated settings, such as Tanzania, where lack of access to the hepatitis vaccines increases the risk for liver cancer. In fact, Kolhe already is working with that country’s government to set up its first pathology oncology laboratory that will eventually enable such testing.

Back home, the group is exploring this approach of identifying other molecules, such as mir-21, that will help other hard-to-detect early cancers show their true colors. In collaboration with BioGenex, they already have about 40 probes in hand, including one based on a molecule for melanoma, which Kolhe worked with pathology resident Dr. Puneeta Vasa to identify. Skin cancer cells look a lot like common mole cells.

‘It’s All Good’ It’s a good thing Rushton really loves her cancer doctors, because, like her grandchildren, they will be part of the rest of her life. Her follow-up visits were every few months that first year, and are now slightly less often as her recurrence risk slowly decreases. As has been true of other major twists in her life, she has not been one to wonder too much about why. She lost an aunt and uncle to liver failure. She doesn’t share their risk factor of alcoholism but – as is true of many Americans – she knows she needs to lose weight. Despite her strong-willed nature, this time, at least, Rushton is doing what she’s told to optimize her health. Her family, friends, and faith in her doctors and her Lord – the Lord first – enable her to continue to fill each day with a lot of laughter. “I didn’t know I was going to see another year, so I figure, it’s all good,” says Rushton, who turns 68 in December. n

Vaccine on the Horizon Tweaking a protein expressed by most liver cancer cells has enabled scientists to make a vaccine that is exceedingly effective at preventing the disease in mice.

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Alpha-Fetoprotein, or AFP – normally expressed during development and by liver cancer cells as well – has escaped attack in previous vaccine iterations because the body recognizes it as “self,” said Dr. Yukai He, immunologist at MCG and the Georgia Regents University Cancer Center. Vaccines help direct the immune system to attack invaders by showing it a representative substance, called an antigen, that the body will recognize as foreign, in this case, AFP for liver cancer. In a process called antigen engineering, He tweaked AFP just enough to get the immune system to recognize it but still keep the AFP expressed by liver cancer cells in the bull’s eye. He and his colleagues reported their findings in the journal Hepatology.

AFP is expressed by about 80 percent of the most common liver cancer cells but not typically by healthy adults. For cancer to flourish, cells must revert to an immature state, called dedifferentiation, which is why liver cancer cells make a protein normally expressed during development and why the immune system can recognize AFP as “self.” The researcher’s modified AFP was delivered in a vehicle with a proven record for infiltrating cells. The lentivector is the backbone of the human immunodeficiency virus, or HIV, minus most of its genes. It is particularly good at targeting dendritic cells, whose job is to show the immune system antigens, then activate T cells to attack. In a proven model where mice are exposed to chemicals known to induce liver cancer, the vaccine blocked cancer about 90 percent of the time. Mice receiving the vaccine had more T cells generally and more that targeted AFP, which could keep an eye out for re-emerging liver cancer. He hopes some version of his vaccine will dramatically improve patient survival and perhaps work to prevent the disease in high-risk populations. He has not yet looked at whether the vaccine could be a first-line treatment. He recently received a $1.6 million grant from the National Cancer Institute to hasten human application of the mouse studies. “Now that we know it works in mice, we have to make sure it works in people,” He said, noting that many promising cancer vaccines have not worked well in humans. The newer studies include taking the blood of healthy individuals and removing monocytes, which are plentiful white blood cells that can

become dendritic cells. They’ll coax dendritic cells to develop, give them the vaccine, then return the armed dendritic cells to mice to see if they will produce AFP-focused T cells. Next steps also include developing a virus-like particle, which retains the efficiency of lentivector without the safety concerns of the HIV-derived delivery system and can be easily reproduced in a factory. These protein-based delivery systems are utilized by a number of vaccines already used in humans. He and his team also are working on a receptor ligand that would cause AFP to draw even more attention from dendritic cells. He is betting that a safer delivery vehicle and ligand packaged with his antigen in a so-called “tripartite” vaccine will be a powerful package. Carcinogen- and hepatitis B-induced liver cancer models are being used for the studies. The U.S. Food and Drug Administration has approved two vaccines classified as cancer preventers: the hepatitis B virus vaccine and vaccines against human papillomavirus types 16 and 18 that cause most cervical cancer. A variety of cancer treatment vaccines, such as the one He is working on, are under development. The FDA has approved one cancer treatment vaccine for some cases of metastatic prostate cancer, according to the NCI. He is a Georgia Research Alliance Distinguished Vaccine Investigator. Postdoctoral Fellow Dr. Yuan Hong is first author on the published study. Co-authors include Yibing Peng and Drs. David Munn and Nahid Mivechi. n

dr. yukai he GResearch Fall 2014

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Toolkit Enables Scientists to Map the Brain A virus and a zebrafish are helping scientists map the living brain. “You can kind of draw a diagram and see how cells within it are connected in a functioning brain,” says Dr. Albert Pan, a Medical College of Georgia neuroscientist. “This will help us see how wiring is laid and how it functions.” Faulty Wiring Miswiring is believed to cause conditions such as mental retardation, autism, and schizophrenia. In autism, as an example, some brain areas may have too many connections and others too few. “We want everything to happen well in the embryo, where a lot of this dividing and migrating and connecting is taking place,” Pan says. He recently received a $1.9 million grant from the National Eye Institute to develop a virus-based toolkit to help scientists understand normal connectivity and, ultimately, what goes wrong in disease. His model organism is the zebrafish and his model system visual function. While the tiny zebrafish may seem an odd choice, the transparent vertebrate is actually a great model, Pan says. The human brain has 70 billion cells compared to 100,000 in the zebrafish, but the brains have the same basic structure. The fact that the fish develops rapidly and transparently are two other huge pluses, he said. continued

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Zebrafish start out as an external egg in a transparent shell, complete embryonic development in two days, and are fullgrown fish by three months. By day 10, Pan compares them to young children who can readily manage most common, important behaviors, such as learning, despite the fact that their brains are still developing.

Fishy Similarities “It fits the timeframe of a scientist. In very small fish, you can look at very interesting behaviors in a vertebrate brain,” says Pan, who is the first to try virus-based brain mapping in zebrafish. Previous efforts to map neural circuits have been done mostly in mice. “The unique thing about using this fish is that we can actually look at the neuronal activity while we are tracing, we can try

different behavior tasks and see which cells are active, which cells are connected, and we can use different techniques to destroy different neurons and see how it affects behavior,” he says. Pan’s use of a mutant, super albino that lacks pigment further enhances his ability to keep his eye on functioning cells. The fish are also transgenic, so firing cells naturally light up, but visualizing the nanometer-scale synapses with a light microscope as they form is another matter. “If a cell fires, we can see kind of a spike of light coming out of those cells. So you can see the firing pattern of these cells. But you don’t know which cells are connected to each other, so it’s difficult to make sense of how the brain is transferring information from one part to another and how this information is processed,” he says. dr. albert pan

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Heavy Lifting That’s where a virus can help “do the heavy lifting.” The vesicular stomatitis virus, which is in the same family as rabies but doesn’t infect humans, has the uncanny propensity to travel across synapses. Pan is using VSV, armed with a fluorescent agent, to fill in the important blanks of when and how cells connect. “What this grant is about is developing a new tool where you can see these connections and how one cell is connected to another cell,” he says. The brain’s basic organizational structure is neural circuits, groupings of brain cells for a common purpose such as sight, smell, or movement. “If you think of it like a computer, it’s different software that does different things,” Pan says. Different circuits also integrate so the brain works as a cohesive unit. The transparency of the zebrafish is enabling him to watch the visual circuit from essentially the beginning, when neural progenitor cells, destined to be neurons, first appear around the donut hole of the neural tube, a hollow tube that forms the brain and spinal cord.

The Brain’s GPS Neural progenitor cells split, then migrate out, with gradients and the distinctive smell of different proteins guiding them – if all goes well – to the right place in the developing brain. Pan uses the analogy of pouring cream in coffee and its natural motion away from that point. “Cells can sense the proteins and know where they are within the body plan. They know what type of cell they should be and where they should migrate,” Pan says. Once in place, neurons wire together and connect by forming

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synapses that enable communication. Synapses can be shortlived – for instance, helping you remember how much apples cost until you leave a grocery store – or long-term, so you always remember your mother’s voice and face. Pan notes that the additional information he learns about the visual neural circuit will better illuminate this important neural circuit as well as related behaviors – such as how the eyes naturally follow a moving car – in

addition to providing a model for studying other circuits. “A lot of what we already understand about the brain comes from vision research,” says Pan. His studies will include eliminating some cells, seeing if the zebrafish, also known for its regenerative ability, will regrow the cells, and if those new cells will integrate into the existing circuitry. n

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Researchers Join Forces to Halt Jaw Destruction Nobody saw it coming. Bisphosphonates have been studied for bone metabolism disorders since the 1960s and are now commonly used to treat osteoporosis and some cancers – but at a high price for a small fraction of patients who suffered a totally unanticipated side effect. “Make no mistake: bisphosphonates are lifesaving drugs,” says Dr. Mohammed Elsalanty, Associate Professor in the College of Dental Medicine Department of Oral Biology. “For those who need them, they aren’t optional. They are very effective.” (See ‘Manage, Don’t Hide,’ page 27.)

Rushing into Action Yet when a small percentage of patients taking the drug – particularly those fresh from dental work such as a tooth extraction – began suffering from a harrowing and unforeseen side effect, researchers rushed into action to get a handle on the problem. Nowhere has that research been more intensive or multifaceted than at Georgia Regents University. The side effect is jaw osteonecrosis – the death of cells that leads to jaw destruction. “It seems that the bone fails to heal,” says Elsalanty. “The jaw can totally disintegrate, and the damage is irreversible.” The side effect can happen spontaneously, but invasive dental work is by far the highest risk factor, Elsalanty says. Other

risk factors include rheumatoid arthritis, smoking, corticosteroid use, and possibly periodontal disease. And those taking bisphosphonates for cancer – multiple myeloma and prostate cancers, among others – are at much higher risk than those taking it for osteoporosis. “This drug is given in much higher doses to cancer patients than osteoporosis patients,” Elsalanty says.

Sounding the Alarm It was the link to dental work that first raised the alarm. Craniofacial scientists in the early 2000s began reporting patients whose dental work wasn’t healing, then started documenting the resulting jaw destruction. Once bisphosphonates were identified as the common denominator, Elsalanty was among those who rushed to solve the problem. Elsalanty, who joined the faculty in 2007, began working with Dr. James Borke, then a faculty member in the Department of Oral Biology and Maxillofacial Pathology, to better understand the jawbone destruction. “We learned that the blood supply to jawbone was diminished in rats treated with lowdose bisphosphonates,” Elsalanty says. Their follow-up studies pursued their hunch that bone changes cause, rather than result from, the vascular impairment. “There is a change in the bone that makes it less viable and less

caroline lewis

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dr. mohammed elsalanty

inviting to the blood supply,” he says. In tackling the problem from another vantage point, a Medical College of Georgia student recently won a national competition working in the lab of Dr. Paul

McNeil, an MCG cell biologist specializing in cell membrane success, to help determine exactly what that bone change is.

Membrane Repair Caroline Lewis, a junior who spent the summer of 2013 as a participant in the MCG Dean’s Student Summer Research Program, determined with McNeil that bisphosphonates seem to impede a cell’s ability to repair a protective outer membrane that helps determine what enters and exits. “The bottom line is it inhibits cell membrane repair in two distinct cell types,” said Lewis, one of five winners of the 2014 National Medical Students Competition of the American College of Physicians. She and McNeil found that kidney epithelial cells from monkeys and muscle cells from

mice lost the ability to quickly repair their outer membrane after exposure to zoledronate, a common bisphosphonate. Without drug exposure, cells quickly recovered from a microscope laser injury. Lewis cites a video showing a healthy cell experiencing only a brief flicker of fluorescence where hit by a laser. “That is a healthy, normal repair,” she says. On the other hand, zoledronateexposed cells quickly filled with a fluorescent dye the researchers placed in the petri dish.

Lethal Disruption “All this dye coming into the cell means there is still a disruption, and no repair occurred to sort of mend the fence,” Lewis said. “We know these cells are dying. Basically, these videos speak for themselves.” “It’s a paradox,” added McNeil. continued

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“On the one hand, [the drug] is given to people mainly to promote bone health, increase bone density. But in the case of a jaw that has suffered, for example, a tooth extraction, the exact opposite occurs.” He theorized cell membrane repair was contributing to destruction of the jawbone and the lining of the mouth after the Journal of Proteome Research reported in 2012 that bisphosphonates bind to cell membrane proteins vital to membrane repair. Since the severe side effect occurs most commonly following dental work, McNeil made the connection. While it’s not clear whether this failure to repair is happening in other parts of the body, McNeil and Lewis note that cell membrane repair is typically a constant throughout the body.

Breaking the Attachment Meanwhile, Elsalanty’s research continues to unfold as well, including his finding that “bisphosphonates uniquely stay attached to bone for many years. We’re trying to target this aspect of the drugs.” He is working with Dr. Maryka Bhattacharryya in using chelating agents to remove bisophosphonates from the jaw and other bone in lab animals. Elsalanty hopes further studies will demonstrate the effectiveness of the procedure in humans. He hopes this particular avenue of research will preclude the need for the current health care recommendation to forego dental work during bisphosphonate treatment, or to take a drug holiday if the dental work is vital. “We are trying to provide an alternative to those guidelines,” Elsalanty says. “I’d love for those who need bisphosphonates to neither have to stop the drug nor postpone dental work.” He is also working with Dr. Martin Salguiero in the Department of Oral and Maxillofacial Surgery to identify risk factors for bone necrosis after dental procedures in patients receiving bisphosphonates. They are assessing the effectiveness of the current prediction tool (CTX serum levels) and of the current prevention method (a drug holiday).

Survival Pathway

dr. paul mcneil

Constant Friction “Pretty much every day of our life, you are contracting your muscles, the muscle cells rub past each other, and that friction causes microscopic tears in the membrane,” Lewis said. “If those cells can’t repair an injury, they die because they can’t maintain internal homeostasis.” Next steps include more cell studies, including those on jawbone cells, McNeil said. Kidney epithelial cells and muscle cells used in this study are routinely used in cell membrane repair research, and cell repair mechanisms tend to be consistent across cell types, even across different species, McNeil noted. He also is pursuing the potential protective properties of vitamin E for these patients. McNeil reported in December 2011 in the journal Nature Communications that vitamin E, a powerful antioxidant found in most foods, helps repair tears in the plasma membrane.

Their work complements the bone loss research of Dr. Carlos Isales, Vice Chairman of Clinical Affairs in MCG’s Department of Neuroscience and Regenerative Medicine; Dr. William D. Hill, an MCG stem cell researcher; and Dr. Mark Hamrick, who recently stepped down from his role as GRU Vice President of Research to pursue research and education full time. The research is funded by a National Institutes of Health Program Project Grant. One of their recent studies, conducted with Samuel Herberg, a GRU graduate student, identified a survival pathway that helps mesenchymal stem cells stay in place and focused on making bone – a role that can become compromised with age or disease. They hope the findings, reported in PLOS ONE, will lead to better treatments for bone loss in aging and enhance the success of stem cell transplants for conditions including cancer, cerebral palsy, and cancer. “It’s wonderful to work on a campus where I have access to so many different kinds of resources,” says Elsalanty, whose research is funded by a GRU Extramural Success Award, a means of making projects more competitive for extramural funding, as well as Fort Gordon. “The College of Dental Medicine provided me with a lab and major equipment, and my collaborators on the medical side are invaluable. Having that kind of support has been tremendously helpful.” n GEORGIA REGENTS UNIVERSITY

‘Manage, Don’t Hide’ “I’m managing my health. And that’s a personal responsibility,” says Margie Chapin when speaking about her osteopenia, a potential precursor to osteoporosis. When her father was diagnosed with osteoporosis, Chapin took the initiative and requested a checkup, since 80 percent of osteoporosis cases are hereditary. And her instincts were correct: She was diagnosed with osteopenia. She was in her 40s at the time and says, “If I had waited until I was postmenopausal, it could have been ugly.” Shortly after her diagnosis, Chapin consulted Dr. Carlos Isales, Vice Chairman of the MCG Department of Orthopaedic Surgery. He prescribed a daily dose of Fosamax, a bisphosphonate. She took Fosamax daily for approximately 10 years, at which point Dr. Isales placed her on a weekly dose. During this time, she was continuing to receive annual bone density tests for monitoring purposes. A drawback to taking a bisphosphonate over a long period of time is the bone-destruction cells — osteoclasts — can become more prolific, resorbing bone and increasing the risk of fractures. She credits Isales for being in the forefront of the “drug holiday” concept. Due to the possibility of spontaneous femur fractures from the continued use of Fosamax, he placed Chapin on such a holiday. She remains on holiday, and her bone density tests have remained stable. From initial diagnosis, Chapin’s opinion and actions have been: “Manage it; don’t hide from it.” Although she is not a fan of the gym, she walks daily, carrying 1-lb. hand weights. Her husband accompanies her frequently, but even when their schedules conflict, still she takes her walk. “I feel more noble when I accomplish what I set out to do – not necessarily physically better, but I tell myself, ‘Yeah, you were good today,’” she says. She tries hard to share the lessons she’s learned with others. For example, thanks to her mother’s insistence on education, Chapin’s daughter is aware at a young age of her own risk of developing osteoporosis. She follows her mother’s lead in exercising regularly, taking calcium supplements, and monitoring her health. Asked about her obvious enthusiasm regarding her treatment, Chapin replies, “I’ve gotten good care; who wouldn’t be happy to have had the best care they felt was available without having to fly to New York or Texas or California?” n margie chapin GResearch Fall 2014

QUIETING THE GRUMBLING BY TO N I B A K E R

Study Targets Irritable Bowel Syndrome Pain

dr. satish s.c. rao

The newest drug for irritable bowel syndrome has the benefit of relieving the excruciating stomach pain affecting about a third of patients, and researchers want to know how.

Misfired Signals “These patients seem to have a magnification and misfiring of signals from their gut to their brain,” said Dr. Satish S.C. Rao, Chief of the Medical College of Georgia Section of Gastroenterology and Hepatology and founding Director of the GRU Digestive Health Center. “Our hypothesis is that linaclotide dampens and essentially normalizes that communication.”

Physicians don’t fully understand why belly pain affects some patients with IBS, a condition characterized by chronic diarrhea, constipation, or bouts of both. The condition affects about 15 percent of the population, primarily women age 30-50. Interestingly, individuals can have normal bowel habits and be pain-free for years before trouble starts, then problems can subside as mysteriously as they began. Rao has documented how long it takes the brain and gut to communicate, as well as the size of the signals normally received. Sophisticated brain imagery reveals the communication is much faster and bigger in IBS patients. GEORGIA REGENTS UNIVERSITY

Gut/Brain Interaction “We know that these basic mechanics seemed to be disturbed in IBS, based on our previous work,” Rao said. “Let’s see whether the drug truly works by changing how the gut and brain interact with each other.” Linaclotide, or Linzess, is only

agonist, mimics the work of two hormones normally secreted after eating, Rao said. Animal studies, which show a decreased firing of nerves after taking the drug, support Rao’s hypothesis about how it also eases stomach pain. To determine whether it works in humans, Rao is using his safe, well-established model for studying gut-tobrain and brain-to-gut communication. He uses a magnet to stimulate the portion of the brain that controls gut activity, then measures resulting nerve activity in the gut. He then stimulates the anus and rectum and measures the brain’s response. He is assessing this two-way communication in 45 IBS patients, half of whom will get linaclotide and the remainder a placebo, for 10 weeks.

Heightened Sensitivity Previous work has shown that IBS patients also have a heightened sensitivity in the gut. By slowly inflating balloons in the rectum, Rao has found significantly lower pain thresholds in IBS patients than in healthy individuals. “They feel the balloon at thresholds healthy individ-

“These patients seem to have a magnification and misfiring of signals from their gut to their brain. Our hypothesis is that linaclotide dampens and essentially normalizes that

in the gut,” said Rao. “There are secretions; the stomach is churning and smashing up food; the bowel is contracting; nerves are firing. But we don’t feel any of that” unless afflicted with IBS. Those with the disease “start feeling normal things as painful and abnormal,” Rao said. “We all feel a little bloated, a little gassy sometimes, but these people experience the same things with excruciating pain.” (See “You Are What You Eat,” page 30.) One theory of what triggers IBS is some sort of acute gastrointestinal event, such as food poisoning or a viral or bacterial infection. “They get sick; they get better; then three to six months later, they start getting this grumbling sensation that is IBS,” Rao said. He suspects a virus changes the sensitivity of the nerves just behind endothelial cells in the gut that manage the gut’s communication with the brain. Rao was involved in the clinical trials of linaclotide, which was approved by the FDA in 2012. The new investigator-initiated studies are funded by drug developers Forest Laboratories Inc. and Ironwood Pharmaceuticals. n

For more information about IBS studies, call Research Coordinator Amanda Schmeltz at 706-721-1968.

communication.”–DR. SATISH RAO the second drug approved by the Food and Drug Administration for IBS. It latches onto a receptor on the surface of gastrointestinal cells that line the gut, triggering release of secretions that relieve constipation. The drug, a guanylate cyclase

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uals don’t even feel, so they are hypersensitive inside the gut,” he said. Ultramicroscopy and special stains reveal inflammation in the gut lining undetectable with the eye and standard te4sts, Rao said. “As soon as we eat, there is tremendous activity going on

‘you are what you eat’ BY JOHN JENKINS

porsha beasley

Porsha Beasley, 28, holds a psychology degree from Georgia Southern University, works as a manual checks processor for a large corporation, and has a loving Lab-Pit mix to greet her every day when she arrives home. She could be any of us. But Porsha has irritable bowel syndrome – IBS for short – further complicated by a fructose allergy. She sees Dr. Satish S.C. Rao, MCG Chief of the Section of Gastroenterology and Hepatology and founding Director of the GRU Digestive Health Center, for her condition. Says Beasley, “Treatment is going well.” Four simple words she uses to describe the miraculous, considering the journey she’s made to reach this point in her life. Beasley says, “Normally a person will feel the urge to go to the bathroom, and there’s something there; however, not for a person with IBS. I can eat something as small as a pea, get the urge to go, and nothing will be there to eliminate.” What drove her to finally seek treatment was having “constipation on steroids.” Eating small amounts, she would feel like she had “just finished Thanksgiving Dinner. And no matter what I was eating, I was unable to eliminate it.” Seeking answers, she was told to drink more water and that it “was normal to eliminate only once or twice a week.” And for years, she thought her infrequent bowel movements were the norm. In 2010, she decided on a lifestyle change: a vegetarian diet, working out, and running. At the beginning, “I couldn’t make it one-half mile, but I was determined.” After six months, her distance always increasing, she realized she was running up to eight miles. However, the constipation continued; her stomach continued to grow larger; and eliminations occurred only once every two to two-and-a-half weeks. Beasley says, “It got to the point my stomach looked as if I was seven months GEORGIA REGENTS UNIVERSITY

pregnant, and it was as hard as a tabletop. I began drinking prune juice, taking Milk of Magnesia, even taking Epsom salt. Then I began using magnesium citrate and up to two enemas a day … I literally could not leave the house.” She decided she could not continue this way and said: “I need a specialist. I need someone to tell me what the problem is other than, ‘You’re constipated.’” She began seeing Rao in late 2012. “After testing, Dr. Rao was able to quickly pinpoint the problem,” Beasley says. Rao diagnosed her with IBS and a fructose allergy, further tweaking Beasley’s diet. He also enrolled her several months ago in his study of Linzess, a drug she continues to take. Although not back to “normal,” she no longer has to sprint to the bathroom after eating something as small as a pea. However, Beasley says, “Even harder than the elimination diet

they were resistant to it.” Often she was accused by her family of being offensive because she would not eat. While on vacation with them, she succumbed to the pressure. “I took in a tablespoon of this and that, and I became so sick that I became debilitated. I was sick for weeks. They [my family] had to witness this and realized there was nothing they could do to make it better. Once they saw, they began to say, ‘Maybe Dr. Rao has a point.’ They slowly began showing support and understanding. But it’s still a process, because they don’t fully understand: They don’t understand the digestive process – what foods become when they break down and how this can affect me.” Although anti-anxiety drugs have been suggested, Beasley says, “I flat refuse. I want to accomplish this without them. I cannot pop a pill every time life gets overwhelming. I prefer learning coping skills: If I take my

“You are what you eat: cut out things with high preservatives and see how you feel. See if you notice any difference, even in clarity of mind. Try to avoid gluten; pay attention to the difference in your stress level when facing situations that have upset you in the past.”–PORSHA BEASLEY has been the lack of understanding and support; it’s truly been the hardest part of dealing with this.” Getting the support of her family has been “a struggle; it’s still a struggle,” she says. “They thought Dr. Rao was crazy and I was crazy for believing him. It didn’t make sense to them, so GResearch Fall 2014

morning run, but then go through a difficult day, I will run or swim that night, also – if that’s what it takes to cope with the stress.” This creed she also applies to her IBS medication: taking Linzess “does not mean I can get anything out of a vending machine, pop a pill, and be fine. The Linzess helps treat the symp-

toms when I’m doing what I’m supposed to do. A pill is not the answer, and America has to get that; you have to do your part.” She says she truly appreciates Rao’s discussing all approaches with her and not emphasizing anti-anxiety meds. Instead of anti-anxiety medications, she continues to run. Her personal best distance is 17.5 miles. “It’s my therapy,” Beasley says. Running has helped to control her stress, and she says, “It’s discipline to get up and run 16 to 17 miles, so when I return home, my brain is set right: I’m going to be more focused and conscious of what I’m taking in, because you have to properly fuel your body to run – so running is my checks-and-balances . . . and another benefit: You drop a lot of weight.” When asked how her experience with IBS has affected her, Beasley says, “At first, I was angry, but not now: It’s frustrating, alienating, has its complications. But I’m grateful: Now, I pay attention to everything I eat. I don’t shop the inside aisles of the grocery store anymore. I’ve become a more open-minded, educated person. And I emphasize education when talking to others about my condition.” Her message? “Know what you are putting into your body!” She issues a challenge to everyone: “You are what you eat: cut out things with high preservatives and see how you feel. See if you notice any difference, even in clarity of mind. Try to avoid gluten; pay attention to the difference in your stress level when facing situations that have upset you in the past.” Her gratitude to Dr. Rao is immense: Even though she recently moved to Los Angeles, she will be traveling back to MCG to continue her treatment with him. n

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TOTAL WAR BY CHRISTINE HURLEY DERISO

GRU Experts Offer Nuance, Perspective to Studies of Civil Conflicts All or nothing. Those are the stakes that most intrigue Dr. Hubert van Tuyll when studying military history. And all-or-nothing stakes especially apply to a specific kind of conflict: civil war. “Civil war is almost always a total war,” says van Tuyll, who recently completed an eight-year tenure chairing the Georgia Regents University Department of History, Anthropology, and Philosophy. “Total war is defined not so much by violence as by everything being on the table. Rules disappear. Your whole way of life is on the table.” Now returning to full-time scholarship at GRU, van Tuyll recently launched a research project, “Civil War in the AngloCeltic World,” analyzing civil wars in Britain, Ireland, and America. Although the analyses are the purview of history, they far transcend that discipline. “I never really decided what I wanted to be when I grew up,” van Tuyll says with a laugh, noting he earned degrees in economics and law before settling into his niche as a military historian. He draws extensively on his other interests to add new dimensions of insight to his research subjects. For instance, in “Castles, Battles, and Bombs,” the book he co-wrote with GRU Professor of Economics Jurgen Brauer in 2008, he casts key military operations in sharp relief when viewed through an economic prism. The authors cite, for example, Germany’s Schlieffen Plan in 1914 as a cost/benefit miscalculation that tragically escalated an East European squabble into World War I. continued

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On the other hand, van Tuyll says, decisions that at first glance seem impractical or untenable can make sense economically. For example, the cost of building elaborate castles in the High Middle Ages (1000-1300) seems prohibitive until compared to the alternative – maintaining a standing army. Likewise, former British Prime Minister Neville Chamberlain’s seeming appeasement of Hitler during World War II was intended to buy him time to bolster his country’s air power, which ultimately helped secure victory. Cost-and-benefit analyses have informed virtually

every war-related decision ever made, van Tuyll notes. Even the general public engages in such economic reductionism, although they may not be aware of it. For instance, “as the body count rises during a war, people seem to develop – up to a point – a tolerance of the losses,” van Tuyll says. Indeed, they may continue supporting a war because of, rather than despite, those losses, reasoning the casualties otherwise would have died in vain. Van Tuyll also explores military operations in the context of communications. Bad or incom-

“The average family during the Civil War subscribed to 2.5 newspapers. Even if you couldn’t read, you’d show up at the post office and someone would read it out loud.” –DR. DEBRA VAN TUYLL

drs. Debra and Hubert van tuyll

plete information can doom a war effort, and of course, leaders virtually always seize the opportunity to manipulate information to their advantage. “Our side has information; the other side has propaganda,” van Tuyll says wryly. Erroneous and/or incomplete information almost always shrouds military operations in confusion as they unfold, van Tuyll says. “Battle is an inherently chaotic activity,” he says. “No one has a really accurate view of it at the time. During America’s Civil War, for instance, soldiers wrote their families letters asking for

newspapers so they’d know who won. We have a much clearer picture of what happened afterwards. For the people living it, it’s not nearly as clear.” His wife, Dr. Debra van Tuyll, Professor of Communications, explores the topic in depth in her 2012 book, “The Confederate Press in the Crucible of the American Civil War.” She quotes Alexis de Tocqueville as saying, “Nothing but a newspaper can drop the same thought into a thousand minds at the same moment.” And seldom are people as ravenous for news as during wartime, she says, noting, “The average family during the Civil War subscribed to 2.5 newspapers. Even if you couldn’t read, you’d show up at the post office and someone would read it out loud.” Newspapers clearly brought people together – the medium was often the only way for Civil War families to learn their loved ones had died during battle, for instance – but they also illuminated differences. For instance, GEORGIA REGENTS UNIVERSITY

“a peace movement arose in the Confederacy in 1863,” Debra Van Tuyll says. “Those who supported the movement knew if they negotiated a peace then, they’d end up with better terms and a better outcome [than fighting to the bitter end]. And they were right. But most Confederates didn’t agree, and no single Confederate party enforced discipline. No one was saying, ‘This is what it means to be a Confederate,’ and the newspapers reflected the division.” Still, she notes, the example reflects that Confederate citizens – and the public in general – were much more sophisticated than they may appear in retrospect. They clearly sought out dissenting opinions and appreciated nuances, something she considers admirable when contrasted with today’s echo chambers of polarizing views. “We have obligations as citizens of a democracy to find out what the other side is saying,” she says. “We need a broader perspective. That’s what people sought in the 19th century.” Both van Tuylls agree that nothing has changed the landscape of communications as drastically as technology. “A mass military surprise attack like D-Day (America’s invasion of Normandy on June 6, 1944 to defeat Nazi Germany) couldn’t be done today due to technological advances in communications,” Hubert van Tuyll says. “As early as 1946, historians were already saying technology was making this kind of warfare obsolete.” But he attributes the most sweeping technological advances in communications not to the 20th century, but to the 1400s (the invention of the printing press) and the 1800s (the invention of telegraphy). He picks up his cell phone and muses, “This little box right here is a descendant of the telegraph. Wireless telegraphy became the radio [and ultimately

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spawned the cell phone and Internet]. That changed life more radically than what we’ve undergone in the past 20 to 30 years.” So why and how does warfare persist despite technological advances? Hubert van Tuyll notes that the common denominator of any war, in any era, during any stage of technology, is people. And few battles are more impassioned than those where countrymen turn on each other.

His project chronicling civil wars in Britain, America, and Ireland illuminate several commonalities. “There’s no way to negotiate a peace in these wars,” he says, citing slavery as an example. “In America’s Civil War, the outcome was either slavery or no slavery. The South would either retain its way of life or not. All or nothing. Civil wars become bitter because it’s so difficult to negotiate an end.” continued

The “Other” Civil Wars BRITAIN: Britain’s civil war was actually three wars in close succession from 1642-51. The trouble started when Queen Elizabeth I died in 1603, leaving her first cousin twice-removed to ascend to the throne. King James VI, a Scot who united the British and Scottish kingdoms, chafed at having to share powers with Parliament. His son, King Charles I, perpetuated the resentment when he inherited the throne, inciting a war between the Royalists and Parliamentarians. Charles I also enraged Protestants, chiefly Parliamentarian Oliver Cromwell, by enforcing a monopoly of the Church of England on Christian worship. The ultimate outcomes, largely engineered by Cromwell, included the execution of Charles I, the brief replacement of the English monarchy with the Commonwealth of England, and the brief replacement of the Commonwealth of England with a protectorate. The Royalists returned to power in 1660 (too late for Charles I), and Cromwell, who had since died of natural causes, was exhumed to be hung and have his skeletonized skull placed on a spike. IRELAND: The Irish Civil War, which took place from 1922-23, followed the Irish War of Independence seeking to cut its tether to Britain. The Free State forces in Ireland negotiated an end to that war by signing the Anglo-Irish Treaty. This was perceived as a betrayal by the Irish Republic because, although the treaty established a self-governing Irish Free State, the country remained within the British Commonwealth of Nations. The Irish Republic wanted no less than complete independence. The war was ultimately won by the pro-treaty side but led to generations of division and bitterness that persist to this day. It also fomented resentment against the Catholic Church, whose Irish bishops strongly backed the treaty because of British support of the church’s power and stature in Ireland. “Over time,” van Tuyll says, “the sense grew that Ireland did more for the church than the church did for Ireland, and the country has become increasingly secularized ever since.” Ironically, more Irishmen died in the Irish Civil War than its War of Independence. n

And of course, the very fact that fellow citizens are at war tends to quickly impoverish a nation, multiplying the misery and thus the appetite for revenge. “Great bitterness is enhanced by great impoverishment,” van Tuyll says. As is true of other wars, he says, each side in a civil war claims the moral high ground, inflaming the rhetoric and often inflating the body count. “People as a culture begin with a moral perspective,” he says, and nowhere was this factor more starkly played out than in the American Civil War. “Very early on in the founding of America, you got this moral perspective that is stronger than scenes from the 2014 study abroad trip to ireland

you saw in Europe. It began with Thomas Jefferson and Alexander Hamilton.” Moral issues tend to polarize not only by force, but at the ballot box, he says, and “voting behavior can be an immediate trigger of a civil war.” Somewhat chillingly, he notes that “Americans today are probably at about the level of gridlock we saw in 1860 on the eve of the Civil War. People blame Washington, politics, everyone and everything except who is actually to blame for the state of their affairs: voters.” But although every society

has defining characteristics, van Tuyll, a native of the Netherlands, relishes the chance to open his students’ eyes to the fact that wherever one travels, it’s clear that people have many more commonalities than differences. He and his wife annually conduct Study Abroad sessions with GRU students, and this summer, they, along with Dr. Carl Purdy, Instructor of Music, took 22 GRU students to Ireland for three weeks. “Almost invariably, the students will tell you they have been changed by interacting with very different people, but they GEORGIA REGENTS UNIVERSITY

also see similarities,” Hubert van Tuyll says. “In a sense, you learn more about yourself and your own country when traveling than you do about others. When you can compare your own culture with another, you get a very different perspective.” Shannon King, a 2012 graduate who majored in communications and history and now works in communications in the Columbia County Sheriff’s Office, heartily concurs. “Study Abroad was amazing, a life-changing experience,” says King, who participated in two of the Ireland trips, as well as a study-abroad trip in Senegal, Africa during her GRU education. “It was an integral part of my life and my education, and the experience is never-ending. I’ve made a lot of friends and learned so many things I never could have gotten from the classroom. I got a history perspective from Dr. (Hubert) van Tuyll and a journalism perspective from his wife. I’m proud to say I’m not just their former student; I’m their friend. I consider them family.” n

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All the News That’s Fit to Print Dr. Debra van Tuyll’s extensive research of the press during the Confederacy topples many popular stereotypes. For instance: Many newspaper readers in the Confederate South were women and teenagers. Some were so troubled by slavery, despite Confederate newspaper publishers’ fervent attempts to justify it, that they went on to form their own sounding boards. South Carolinian Mary Boykin Chestnut, for instance, published a diary expressing her ambivalence about the institution. Although the North clearly claimed the moral high ground during the Civil War, van Tuyll notes that the Lincoln presidency censored or otherwise suppressed many newspapers with opposing viewpoints, whereas “in the South, not a single paper was shut down [due to censorship],” she says. “[Confederate President] Jefferson Davis thought you shouldn’t mess with the press.” The average Confederate family not only subscribed to multiple newspapers, but newspapers reflecting opposing points of view. “Of course, they read the ones they agreed with, but they always wanted to know what the other guys were thinking,” van Tuyll says. About 1,000 newspapers were published in the South at the outset of the Civil War, and although only about 80 were left standing by 1865, the surviving publishers showed astonishing grit. One publisher, for instance, defiantly managed to publish a newspaper within days of Union Gen. William T. Sherman destroying his press. The Augusta Chronicle also survived the Civil War. “These were publishers who felt they had to keep publishing even if they were losing money because they had to serve the public. It was the only way for people to know what was happening on the battlefield,” van Tuyll says. Nevertheless, “it took decades for the Southern press to get back on its feet after the war. They were shattered.” n

DOING THE MATH BY CHRISTINE HURLEY DERISO

New Model Adds Precision to Epidemic-Related Predictions

Attention, everyone: A deadly new disease has just been reported, and it appears highly contagious. Take every precaution. Um . . . OK. Just one question: How exactly should one go about doing that? Dr. Laurentiu Sega, Assistant Professor of Mathematics at Georgia Regents University, wants to help the public better answer that question. Sega, originally from Romania, thinks math offers unique solutions to seemingly intractable problems, particularly global ones like epidemics or pandemics that topple boundaries and make the planet seem like a very small world indeed. dr. laurentiu sega

A Valuable Combination “We want to be able to predict how fast and how far an epidemic can spread, as well as how the infected population is likely to fare,” says Sega, who recently created a math model with two colleagues to optimize the accuracy of such predictions. The model, published in the Journal of Biological Systems, draws on existing formulas to create something they think can be readily adapted to new epidemics. “There are other models, but we felt they didn’t take into account a couple of features we consider very important,” says Sega, whose collaborators were Dr. Oscar Angulo of the Universidad de Vall-

adolid in Spain and Dr. Fabio Milner of Arizona State University. One existing class of models – the epidemiological models – rely on factors such as recovery and mortality rates to describe the evolution of an epidemic in a population. Another – the immunological models – describe the evolution of a pathogen in an infected host. “These are called compartmental models,” Sega says. “The major problem my colleagues and I had with them was that there’s really no differentiation between individuals. There is valuable insight to be gained from combining the two, as that may lead to a better understanding of the severity of an epidemic.”

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Reams of Data In creating the new model, the researchers focused primarily on human immunodeficiency virus, or HIV, in the San Francisco area, poring through five years’ worth of patient data and medical records. HIV, the virus that can lead to AIDS, exploded on the scene in the 1980s, killing approximately 636,000 Americans to date, according to the Centers for Disease Control and Prevention. Although a cocktail of drugs has made the disease much more treatable than in its early days,

Gray Matter and Persistence Other factors specific to the disease enabled the researchers to drill down deeper still, Sega says. “When you look at, for example, the initial epidemic, what immune status predicts who will recover?” he muses. “You have to look at treatments, treatment efficacy, and the overall course of the disease. For instance, usually, at some point, a class of HIV drugs stops working, so the patient needs to start a new class of drugs. How is that

“If I want to predict anything about a given epidemic, I’ll have to come up with specific parameters – but now we have the framework to do it. The model can be applied to any epidemic. You just need some initial data to get some parameters for the disease.” when it was almost always fatal, more than 50,000 new cases are diagnosed annually in the United States alone. Sega and his colleagues were interested in the disease not only because of its virulence, but because it lends itself to combining population studies with factors specific to individuals. “HIV is disease that attacks the immune system, and different individuals have different immune responses,” Sega says. Therefore, simply pinpointing areas with the highest mortality rates, for instance, wouldn’t necessarily predict the prognosis of an individual with the disease.

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treatment working? The model needed to incorporate how the disease evolves over time and to assess the patients’ health at various points during treatment.” If this sounds dizzyingly esoteric, Sega notes that much of his work – calculating, recalculating, adding new variables, and otherwise crunching a sea of numbers – was done with paper and pencil. “Our calculations led to computer simulations,” he adds, but the essence of math research still relies on gray matter and persistence. The model is proving accurate, and Sega is optimistic it is easily transferrable to other diseases.

The bottom line is better predictions of how epidemics will unfold, including how contagious they are, how many people they will affect, how many of the afflicted will recover, etc. This is exciting, he notes, not only for existing diseases, but for those coming down the pike. “The way we constructed the model was in a very general framework,” he says. “If I want to predict anything about a given epidemic, I’ll have to come up with specific parameters – but now we have the framework to do it. The model can be applied to any epidemic. You just need some initial data to get some parameters for the disease.”

Crunching the Numbers Sega is excited to apply his expertise to biomedical science, particularly because of potential multidisciplinary studies with GRU’s Health Sciences Campus. But GRU’s math faculty stress that math models can inform and advance a whole host of societal needs. For instance, it was math models that scientists used to try to locate Malaysia Airlines Flight 360 when it seemingly disappeared from the face of the earth last spring. If that seems like a weak example – the plane has yet to be located – mathematicians, like other scientists, stress that only good data can yield good results. In other words, garbage in, garbage out. Conflicting information and even the withholding of information by the Malaysian government clouded the landscape, shining a bright spotlight on the need for accurate data. But good data combined with reliable math models produces unassailable results that can enormously benefit society, Sega says, adding, “We want to keep refining our model and make it even more accurate and predictive.” n

NAILING THE PROBLEM BY CHRISTINE HURLEY DERISO

UVA Exposure in Nail Salons Gets Qualified Clean Bill of Health

It reads like a tabloid headline: “Danger Lurking in Your Nail Salon?” Dr. Lyndsay Shipp, who recently completed her dermatology residency at the Medical College of Georgia and GRHealth, made national headlines recently when she reported that the answer is no. Well . . . a qualified no.

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dr. lyndsay shipp

Mini-Tanning Beds Shipp, who earned her medical degree from the University of Mississippi and has moved back to Oxford to begin her practice, seized the opportunity during her residency to conduct some multidisciplinary research on a subject of interest to countless women: potential health risks in nail salons. Specifically, she was interested in the potential cancer risk of exposure to ultraviolet radiation from heating lights that cure shellac and gel polishes. Ultraviolet radiation, the chief culprit in skin cancers, is composed of three wavelengths: UVA (long-range), UVB (short-wave), and UVC, which is not a factor in skin cancer. UVA accounts for up to 95 percent of the solar UV radiation reaching the Earth’s surface and can penetrate into the deeper layers of the skin’s surface, causing aging, wrinkling, and potentially skin cancer. Says Shipp about nail salons’ heat lights, “They’re essentially like mini-tanning beds,” which the International Agency for Research

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on Cancer includes among the most dangerous sources of cancer-causing radiation. “The heat lights emit a very low amount of the same type of light, but no one has gone out and measured exactly how much.”

A $7.5 Billion Industry The information is much more than strictly academic. Nail salons are an approximately $7.5 billion industry in the United States, according to NAILS Magazine, and Georgia is among the country’s most salon-heavy states. “I go to salons myself about three times a year,” Shipp says. “Lots of our patients come in asking about how safe they are, and our interest was sparked by a case report in JAMA Dermatology citing two cases of squamous cell carcinoma on the hands of frequent users of these devices.” Shipp and Dr. Catherine Warner, who graduated from MCG in 2014, visited 16 Augustaarea nail salons last year to measure the UVA radiation of the heat lights. They enlisted the help of Dr. Loretta Davis, Chief of the

MCG Section of Dermatology, and Dr. Frederick Rueggeberg, Professor of Oral Rehabilitation in the GRU College of Dental Medicine. “We couldn’t have done it without Dr. Rueggeberg,” Shipp says. “I have the expertise and equipment to accurately measure all kinds of light,” he says. “Regulations prohibit the use of UVA in dentistry, but at times, dentists use light that falls in the ‘near-UV’ range, around 380 to 400 nanometers. I helped [Shipp and Warner] understand the limitations of the instruments, analyzed the test data, did the statistical analysis, made the graphs, and calculated the exposure duration values and approximate numbers of visits needed to result in specific levels of exposures to clients.”

Eager for Proof Many of the nail salons welcomed Shipp and Warner with open arms. “They believe their instruments are safe and they were eager for proof,” Shipp says. The findings validated that the heat lights are, indeed, safe. “A wide variety of bulbs are used, and higher wattage correlates with higher UVA exposure,” Shipp says. “But even exposure from the higher-wattage bulbs is extremely small. One would have to visit a nail salon very frequently to really see a risk.” Moderation, she says, is key. “We know the risk of UVA exposure is cumulative (see “Skin in the Game,” page 45), but keep in mind you’re exposed to it just by driving your car or walking down the street. I think nail salons are

fine in moderation. I wouldn’t discourage people from going unless they go, say, every two weeks or so.” On the other hand, “we’re definitely seeing a rise in skin cancer, so people need to take precautions. We see lots of skin cancer in older people who wish they hadn’t tanned when they were younger, and in younger patients, we’re seeing lots of skin cancers related to the use of tanning beds.” She also advises people to use sunscreen before using a heat light and/or wear gloves with the fingertips cut out so that only the nails are exposed to the radiation.

A Flood of Interest So will the public heed her message? Shipp thinks so. When her paper was published in the May online version of JAMA Dermatology, she was flooded with calls from the media. To date, she’s been interviewed by the CBS Evening News, the Today Show, Time magazine, the New York Times, Reuters, Shape magazine, and Health and Wellness magazine, among others. “I still get an occasional call,” she says. “The bottom line is that people want to be safe. Skin health is all about educating people.”

And she is heartened that the message is sinking in. “I never use tanning beds, and I wear sunscreen regularly on my face and exposed skin, especially in the summer and during peak [sun exposure] hours,” says Amy Bruno, a mother of three. “I keep it on my kids regularly, too.” She also uses self-applied nail wraps instead of visiting salons. “I’ve always had an aversion to

going about my daily routine. Plus, I don’t get my nails done often, and I never use tanning beds. Everything in moderation is my motto.” Meagan Elsner concurs. “I visit salons a few times a year and I think the risk of UV exposure is negligible.” Still, she’s vigilant about sunscreen, particularly since she lives near the beach in Jacksonville,

“I think nail salons are fine in moderation. I wouldn’t discourage people from going unless they go, say, every two weeks or so.” –DR. LYNDSAY SHIPP

salons because of the fungus risk (see below), so the exposure to UV radiation just adds to my worries.”

Everything in Moderation Others share her concerns but don’t forgo their salon visits. “I love nail salons, and I’ve never had a bad experience,” says Courtney Wolbert. “I try not to worry about UV exposure; I’m exposed to it through sunlight just

Fla. “I do worry about skin cancer, and my daughters and I use lots of sunscreen when we are out in the sun.” Bruno goes one step further, which Shipp applauds. “I get mapped yearly by my dermatologist as a precaution,” she says. “Skin cancer has always been a concern of mine because we spent our entire childhoods at the pool without sunscreen during summers.”

Are Other Risks Lurking in Nail Salons? Radiation exposure in nail salons was the subject of Dr. Lyndsay Shipp’s research, but other health concerns have been documented as well, including bacterial, viral, and fungal infections. In addition to using nail salons in moderation, physicians advise ensuring your nail technician follows safety procedures, including properly soaking and sterilizing all instruments and equipment. Don’t visit a salon when you’re sick, particularly with a nail infection or foot fungus, and don’t shave your legs immediately before going. Nicks and cuts increase the risk of infection. n

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Tina Graham, who visits nail salons occasionally without concern, says, “Tanning beds are always a no-go. Spray-on options are cheaper and better for you.”

Working Collaboratively Shipp and her colleagues are heartened by the heightened awareness and eager for followup research. “We want to do some skin biopsies,” she says. “Working with Dr. Rueggeberg was so nice, having someone who knows a lot about a field you’re unfamiliar with, and vice-versa. We’ve fostered a nice working environment that we hope will continue.” Rueggeberg agrees. “I would love [further studies] with my dermatology colleagues,” he says. “I’ve already spoken to Dr. Davis about a few ideas I have that would greatly enhance the current results and help make them even more practical and relevant. I find a great deal of satGResearch Fall 2014

isfaction working collaboratively in a field outside of my own, especially when the results impact a lot of people. I also like that I learn so much from others, and that they are eager to learn about technologies and issues in other fields.” n

“We see lots of skin cancer in older people who wish they hadn’t tanned when they were younger, and in younger patients, we’re seeing lots of skin cancers related to the use of tanning beds.” –DR. LYNDSAY SHIPP

Skin Cancer at a Glance The three forms of skin cancer are basal cell, squamous cell, and melanoma. About 80 percent of skin cancers are basal cell, which usually develop on sun-exposed areas. These cancers tend to grow slowly and rarely spread to other areas, although left untreated can invade the bone and other tissues beneath the skin. About two out of 10 skin cancers are squamous cell carcinomas, commonly appearing on sunexposed areas or developing from scars or chronic sores elsewhere. They are more likely than basal cell cancers to grow into deeper layers of the skin and spread to other body parts. Melanoma cancers, the most dangerous, develop from the skinâ&#x20AC;&#x2122;s pigment-making cells and can form from moles.

For more information, contact the GR Health Dermatology Clinic at 706-721-6223.

Along with limiting sun exposure and taking precautions outdoors, an annual visit to the dermatologist can help ensure healthy skin and early detection of skin cancers. Periodic self-checks are advisable as well. The American Academy of Dermatology recommends the following steps: n n n n n

Examine the body front and back in the mirror, then look at the right and left sides with arms raised. Bend elbows and look carefully at forearms, upper underarms, and palms. Look at the backs of legs and feet, the spaces between toes, and the soles of feet. Examine the back of the neck and scalp with a hand mirror. Part hair for a closer look. Finally, check the back and buttocks with a hand mirror.

During your self-examination, be on guard for: n n n n

A skin growth that increases in size and appears pearly, translucent, tan, brown, black, or multi-colored A mole, birthmark, or any brown spot that changes in color, size, or texture; has an irregular outline; is bigger than a pencil eraser; or appears after age 21 A spot or sore that continues to itch, hurt, crust, scab, erode, or bleed An open sore that doesnâ&#x20AC;&#x2122;t heal within three weeks n

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Skin in the Game The same enzyme that enables us to walk in the sun without shedding our skin can also enable non-melanoma skin cancer to survive and grow. Dr. Abigail Cline, a Medical College of Georgia student, spent the summer between her freshman and sophomore years learning more about the role of this enzyme, protein kinase D, or PKD1, in skin cell damage and death. She was among 50 recipients of the 2014 national Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship. Cline, already a PhD in biochemistry who is contemplating a career in dermatology, considers an early focus on pervasive non-melanoma skin cancers a great place to start. The National Cancer Institute estimates about 2 million new cases this year in the United States. Cline’s summer mentor, Dr. Wendy Bollag, an MCG cell physiologist, reported in 2010 in the journal Oncogene that ultraviolet light activates PKD1. Her research has also shown that the effects of UV exposure are cumulative and dose-dependent, so more UV exposure equals more PKD1 activity. Resulting problems, including non-melanoma skin cancer, become a particular concern for an aging population. GResearch Fall 2014

drs. abigail cline (right) and wendy bollag

One of PKD1’s roles in the skin appears to be protecting cells from death and helping them recover from minor sun damage. The tradeoff is that it also can enable badly damaged cells to avoid natural self-destruction, called apoptosis, and become

then gauged which tissue experienced the most DNA damage and cell death from UV exposure. Results are pending, but “we are expecting increased damage compared to controls,” Cline says. “Ideally, we will find that the knockout has a ton of damage

“Ideally, we will find that the knockout has a ton of damage and a lot of apoptosis, the inhibitor cream results in less damage, and the control has no damage.”–dr. abigail cline skin cancer. “It protects them to a fault,” says Cline, noting that increased sun exposure increases the risk. Over the summer, Cline and Bollag explored whether reduced levels of PKD1 increase sensitivity to UV light. “We think PKD1 also protects cells from UV damage,” Bollag says. “Cline looked at whether it also helps accelerate UV repair.” In the lab, she shone ultraviolet light on normal skin tissue as well as tissue in which PKD1 is missing from keratinocytes, the most common skin cell type. She also used a topical PKD1 inhibitor on normal skin tissue,

and a lot of apoptosis, the inhibitor cream results in less damage, and the control has no damage.” Another double edge is that PKD1 tends to support cell proliferation rather than differentiation into mature cell types. Even without sun exposure, skin cells are constantly shedding as the body makes new ones. Without differentiation into mature cell types, the proliferation can set the stage for cancer. Part of the solution may be a topical cream, like the one the researchers are using, that reduces PKD1 activity just enough to let seriously damaged cells die. n

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Sarah J. White (left) and Dr. Mark Hamrick

A Glowing Tribute

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GRUâ&#x20AC;&#x2122;s research community surprised Dr. Mark Hamrick with an engraved lamp during an Aug. 21 get-together that doubled as a tribute to Hamrickâ&#x20AC;&#x2122;s tenure as Senior Vice President for Research. Hamrick is stepping down from the post to return full time to his own research pursuits. Dr. Michael Diamond, Vice President of Clinical and Translational Sciences and Chairman of the Medical College of Georgia Department of Obstetrics and Gynecology, will serve as interim as a permanent successor is recruited. Tributes during the gathering included a tongue-in-cheek poem from Sarah J. White, Associate Vice President for Research Administration. An excerpt: Although we could write, far into the night About all the things he has set right, That the bench has been calling him away from the desk Thus to the lab(yrinth) he shall journey. May your hours be well spent with all number of grants and acclaim!