The Medical I.B.I.S., Issue 4, 2016

Spring 2016 The Medical I.B.I.S. 1

From the Dean: I am proud to present the fourth issue of The Medical I.B.I.S., the University of Miami Miller School of Medicine’s student-produced research publication, which showcases the innovative research conducted by our extraordinary students.

At the University of Miami, we transform lives through education, research, and service. Discoveries in our laboratories advance prevention, diagnosis, treatments and cures for the diseases and conditions that afflict humankind. They also advance what is taught in our classrooms, because medical students – just like practicing physicians – must have access to the latest knowledge. Under the guidance and mentoring of our faculty, our students take their first important steps in the career to which they have been called. The breakthrough research presented in this issue is truly impressive. The 13 articles span a

wide range of interests, including orthopedics, hematology/immunology, neurology, infectious diseases, public health and ophthalmology. Additional articles provide an overview of different types of biomedical research and another profiles a team of M.D./M.B.A. students and their award-winning project.

Our students are just entering the field of medicine, yet they are already making significant contributions to medical knowledge. Their research is an important element in our mission to transform lives every day, and we know there will be more great work to come. As the Dean, it makes me proud to see our students excel in research, as their work will bring great value to our community in South Florida, the U.S., the Americas and the entire world.

Pascal J. Goldschmidt, M.D. Dean, University of Miami Miller School of Medicine 2 The Medical I.B.I.S. Spring 2016

From the Editor-in-Chief:

person behind the microscope. These students embody the difference we all wish to make.

As medical students, we constantly question our abilities. In a campus filled with true professionals who effortlessly practice what we struggle to learn, we all go through moments of doubt. Can we actually learn all this? Can we apply the things we’ve learned? Will we be able to one day make the difference we’ve hoped to?

At The Medical I.B.I.S. Magazine, we applaud these researchers. Our magazine started humbly with four medical students who shared a passion for research and creativity. Today, we have the support of Student Government, Medical Education, Alumni Association, and an army of thirty students who – in spite of rough deadlines and an oft overbearing Editor-in-Chief – pulled together and created a product in which we take great pride in and that we are excited to share with the Miller community.

Welcome to the fourth edition of The Medical I.B.I.S. Magazine. The students featured in this magazine represent the wayward dreams of the preschooler who pretended to be a doctor during naptime to save his beloved teddy bear’s life, and the thirst for knowledge of the college senior who spent nights scribing in the emergency room trying to absorb every piece of information she had written down. This magazine is not simply full of cut-anddry research articles; each article holds a story of one such medical student. Each story includes weeks and sometimes years of dedication – of pipetting, of visualizing under light microscopy, of rotating in the hospital, and of studying into the wee hours of the night. As a student-run research magazine, The Medical I.B.I.S. seeks to explore the

Reshma Muppala Editor-in-Chief

Nikesh Doshi Managing Editor

I hope the stories in this magazine serve as inspiration to keep those innocent dreams of making a difference alive. The hard work we put in as medical students today will give us the foundation we need to change the world as physicians and researchers tomorrow. Through medical research, we open doors the generations before us have never seen, and each one has the power to not only serve our patients but also to alter the timeline of scientific discovery. Reshma Muppala Laura Bloom Senior Editor

Kevin Moore Senior Editor

Richa Taneja Senior Editor

Spring 2016 The Medical I.B.I.S. 3

VOL. 4

ISSUE 1

SPRING 2016

Editor-In-Chief Reshma Muppala Managing Editor Nikesh Doshi Senior Editors Richa Taneja Laura Bloom Kevin Moore Selection Committee Chair Nikesh Shah

Richa Taneja, Nikesh Doshi, Reshma Muppala, Laura Bloom

Selection Committee Michelle Caunca Mike Durante Matt Field Josh Parker Lee Onn Chieng Layout & Production Editors Lily Zhang Ladan Afifi Director of Photography Felix Chen

Nikesh Shah, Michelle Caunca

Publishing & Advertising Editor Aarabhi Rajagopal Director of Communications Adam Jaffe Cover Illustrator Ladan Afifi Lily Zhang

4 The Medical I.B.I.S. Spring 2016

Adam Jaffe, Ladan Afifi, Jennifer Rodriguez, Aarabhi Rajagopal, Lily Zhang, Felix Chen

Section Editors Houda Boucekkine Cathy Cichon Cory Patrick Devon Cohen Olivia Gardner Miguel Montana

Olivia Gardner, Miguel Montana, Devon Cohen, Cathy Cichon, Cory Patrick

Writers Steven Lord Naiomi Gunaratne Genevieve Wiehl Jennifer Rodriguez Emily Chen Tom Boyle John Paul Kolcun Saradadevi Thanikachalam David Feldman Faculty Advisor Emmanuel Thomas, M.D., Ph.D. Advisory Board Pascal Goldschmidt, M.D. Alex J. Mechaber, M.D.

Steven Lord, John Paul Kolcun, Emily Chen, Naiomi Gunaratne, Saradadevi Thanikachalam, Genevieve Wiehl, David Feldman, Tom Boyle

The Medical I.B.I.S. 2016 Masthead

The Medical I.B.I.S. is published by the University of Miami Miller School of Medicine Student Government. We reserve the right to edit any submissions, solicited or unsolicted, for publication. This magazine is the work of University of Miami medical students, and the University of Miami is not responsible for its contents. Perspectives expressed by authors do not necessarily reflect the opinions of the University of Miami. We retain the right to reprint contributions, both text and graphics, in future issues as well as a non-exlcusive right to reproduce these in electronic form. The Medical I.B.I.S. welcomes comments and feedback. Please send questions and comments to medical.ibis@gmail.com.

Spring 2016 The Medical I.B.I.S. 5

the university of miami’s medical student research publication

8

Engineering Biomimetic Materials for Islet Transplantation

ETHAN YANG

17

Blood Transfusions, Increased Rates of Surgical NEC, and Survival: A Propensity-Score Matched Analysis

ARASH SAYARI

Ankle range of motion, leg pain and leg edema improvement in patients with Venous Leg Ulcers

10

SHIRIN RAZDAN

9

COREY GREGG

Qualitative Effect of Care Groups in a Maternal and Child Health Project in the Guatemalan Highlands

18

JOSHUA FOX

Gender Disparity in the Regulation of CD4+ FoxP3+ T Regulatory Cells in Mice

20

Neurologic Manifestations of Sports Related Concussion

22

Hispanic Immigrants Developing Inflammatory Bowel Disease are More Likely to Eat American Food

Finding the Role of CT694 in Chlamydial Invasion of Host Cells

Preventing Age-Related Macular Degeneration: GSTP1 in the Retinal Epithelium

12

DEVON COHEN

13

MARY MCKUEN

14

JEAN-PIERRE OBEID

16

KATYAYINI ARIBINDI

Probing the Mechanisms of Gene Expression Regulation in Endocrine Cancers and Neurological Disorders

Sphingolipids and Ceramides of Mouse Aqueous Humor: Comparative Profiles from Normotensive and Hypertensive DBA/2J Mice

6 The Medical I.B.I.S. Spring 2016

PAIGE FINKELSTEIN

Pancreatic Neuroendocrine Tumors (PNETs): Survival Analysis Comparing Surgical Resection VS. Non-Surgical Management

24 26

DEREK ESTES

MATTHEW DONOVAN

ALISON MOODY, ERRYN TAPPY, STEPHANIE BLANKENSHIP

Overall Survival, Disease-Free Survival, Local Recurrence, and Nipple–Areolar Recurrence in the Setting of Nipple-Sparing Mastectomy: A MetaAnalysis and Systematic Review

27

TAKING A YEAR OFF FOR RESEARCH

Advice on the reasons behind and the logistics of making this important decision

28

WHAT TYPE OF RESEARCH IS BEST FOR YOU?

A simple guide to help understand the vast opportunities at UMMSM

30

MEDITICK THE SOLUTION FOR THE LEADING CAUSE OF CAUTI, THE MOST EXPENSIVE HOSPITAL ASSOCIATED INFECTION

The unique and simple way three M.D./M.B.A. students hope to create efficiency in the hospital and save lives

Special thanks to

UMMSM

Executive Student Government Spring 2016 The Medical I.B.I.S. 7

Ethan Yang, M.D./Ph.D. Candidate, Class of 2017

Engineering Biomimetic Materials for Islet Transplantation By Jennifer Rodriguez

Type 1 Diabetes (T1D) is a chronic condition of insulin deficiency resulting from autoimmune T cell-mediated destruction of the insulin-producing beta cells of the pancreas. Allogeneic transplantation of insulin-producing Islets of Langerhans cells is one technique that has given rise to improved glucose control in patients with T1D. Though successfully able to restore glucose control, the transplant’s duration is limited by mechanical stress and immune attack through the host’s innate and adaptive immunologic pathways. Many researchers, including Biomedical Engineer, Dr. Cherie Stabler, Ph.D, have attempted to mitigate the inflammatory and immunological responses to the islet surface through biomaterial encapsulation. Thrilled by the translational nature of Dr. Stabler’s lab, Ethan Yang, a M.D. Ph.D candidate, has been searching for pathways to regenerative tissue engineering. Dr. Stabler has a collection of biomaterials expressing unique chemical handles, which permit ease in tethering proteins, antibodies or other agents via the bio-orthogonal Staudinger Ligation reaction. Ethan sought to engineer biomaterial strategies to lessen immunological attack and improve transplant outcomes using this technology to activate regulatory T cells (Tregs).

The release of a soluble form of cytokine transforming growth factor–β1 (TGF-β1) has been known to activate local Tregs, but also induces unwanted fibrosis. Taking a cue from naturally found membrane-bound form of TGF-β1 on the surface of Tregs, Ethan hypothesized

8 The Medical I.B.I.S. Spring 2016

that the insoluble form could create antigen-specific tolerance without the scarring effects.

Ethan first was able to demonstrate in vitro Treg differentiation by tethering TGF-β1 onto 2D and 3D model surfaces. To generate specific tolerance, he created an environment where a model antigen, chicken ovalbumin (OVA), was presented in close proximity to immobilized TGF-β1 and OVA-specific Tregs were produced. This tethering platform was amazingly competent, as demonstrated by the suppression of T cell proliferation compared to endogenous Tregs.

The long-term goal of this work is to eventually create an islet allograft transplant niche protected from rejection; however, additional studies with animal models and human cells are still required to validate these findings in vivo. The flexibility of the ligation chemistry could also translate into developing innumerable immunomodulatory biomaterial platforms that could enhance viability and function in traditional and future 3D printed transplants.

Ethan’s goal is to become a vascular surgeon and hopes that this work and future investigations will boost our understanding and ability to address the issue of immunological rejection in transplants across all fields. His ongoing adventures into regenerative medicine have created a springboard to new technologies forward. Until then, he stands with the pioneers of bioengineers to tackle one of the most exciting problems of our era: tissue generation.

Blood Transfusions, Increased Rates of Surgical NEC, and Survival: A Propensity-Score Matched Analysis

By Naiomi Gunaratne Premature infants are at risk for several post-natal complications, one of the most significant being necrotizing enterocolitis (NEC). This condition involves the inflammation and necrosis of portions of the bowel, and can lead to severe consequences that may require surgery (known as SNEC). In addition, prematurity makes these infants susceptible to other complications, such as anemia and jaundice, both of which may require blood transfusions. However, Arash Sayari and his mentor, Dr. Jun Tashiro, noticed that premature infants receiving blood transfusion were subsequently developing SNEC, and decided to examine this possible connection.

After spending a year doing orthopaedic surgery research, Arash had plenty of database research experience under his belt. When his resident, Dr. Tashiro, offered this research opportunity into SNEC, Arash thought that it was the perfect chance to put his database experience to work and get involved in a fascinating research project. Starting in February 2015, Arash worked with Dr. Tashiro to analyze the association between blood transfusions and the rates of necrotizing enterocolitis requiring surgical intervention (SNEC). Dr. Tashiro had begun to notice a pattern in his patients, in which some premature infants with SNEC had received a blood transfusion shortly before. He wanted to analyze the correlation and predictors of morbidity and mortality between the association of blood transfusions and SNEC. Arash and Dr. Tashiro queried the Kids’ Inpatient Database for cases of premature infants that had or had not received blood transfusions (BT vs. non-BT). Then, they further filtered the patients into SNEC patients and non-SNEC patients; patients were only considered if they had received specific surgical interventions and and a blood

Arash Sayari, M.D. Candidate, Class of 2016

transfusion during the seven days prior to surgery. Analysis was done to compare SNEC in the BT vs. non-BT groups and to find prognostic indicators of mortality.

After analysis, Arash and Dr. Tashiro’s study found that patients who had a blood transfusion had a significantly higher rate of SNEC than patients that had not received a blood transfusion. Patients that were in the BT group with SNEC had a lower survival rate of those with SNEC in the non-BT group. Interestingly, SNEC in the BT group had a lower length of stay when compared to the SNEC in the non-BT group. A few mortality prognostic indicators were found among the male gender, African Americans, infants with lower gestational age, and those with certain associated comorbidities. The study has been accepted for publication in the Journal of Pediatric Surgery, and will open the door to many subsequent studies. Arash says “Now that we have made the association between blood transfusions and SNEC, we can now look at the pathophysiogical mechanisms on a molecular level.” Arash thoroughly enjoyed working on the project, especially researching and understanding the work that has been done in the field thus far.

Spring 2016 The Medical I.B.I.S. 9

Gender Disparity in the Regulation of CD4+ FoxP3+ T Regulatory Cells in Mice By Jennifer Rodriguez

Organ and tissue transplant has become one of the most influential and possibly curative treatments of modern medicine. Some of the key areas for transplant medical management and research deal with the problem of graft rejection and Graft Versus Host Disease (GVHD), a condition in which donated tissues see the host cells as foreign and mount an immunological attack against them. In some cases, these complications can be reduced through serotyping, a process of finding the most appropriate donor-recipient match and the administration of immunosuppressant drugs. However, the search is on to discover more effective ways to prevent rejection complications through immunological tolerance. Anyone who has sat through an Immunology lecture by Professor Robert Levy, Ph.D could tell you how excited he is about T cells, GVHD following hematopoietic stem cell transplantation, and potential interventional strategies. It was his passion for the topic that led second year UMMSM student, Shirin Razdan, to enter the Pathway of Immunology and Infectious Disease and pursue research in his laboratory.

Dr. Levy’s lab has established a novel strategy to expand the T regulatory (Treg) subpopulation of CD4+ T cells, which play a key role in mediating peripheral tolerance to self-antigens, to 5-8x their normal amount in mice models. Preliminary findings indicated a difference in the extent of expansion between male and female mice, with female mice showing greater expansion of the Treg compartment. Consequently, the focus of Shirin’s project was to investigate if estrogen plays a role in inducing Treg expansion in mice. She conducted a threepart experiment to compare differences in Treg expansion between male and female mice of different strains, mice that had received ovariectomies versus normal female mice, and male and female mice transplanted with donor female bone

10 The Medical I.B.I.S. Spring 2016

Shirin Razdan, M.D. Candidate, Class of 2018

marrow leading to development of Tregs (thereby being chimeric mice). Shirin has worked on preparing donor bone marrow and has assisted in transplantation and management of the developing chimeric recipient mice. Prior to each Treg expansion protocol, Shirin first obtained baseline Treg levels from each animal mice by analyzing peripheral blood samples through Flow Cytometry. Then over the span of one week, the time frame identified for maximal Treg expansion, she injected two reagents, one a fusion protein and the other a cytokine-based stimulatory compound to each mouse to induce Treg expansion. Following 7 days, she would again collect peripheral blood samples and stain for lymphocyte populations via CD4, CD8, and CD19 and use Flow Cytometry to calculate the new Treg levels within the mice. In this way, Shirin was able to track the baseline and post-expansion Treg levels in all three arms of her experiment: in non-chimeric male and female mice of different strains, in ovariectomized and non-ovariectomized mice, and in male and female chimeras. After the expansion protocol was completed, spleen and lymph nodes were also removed to measure the Treg levels in each of these compartments. Results to date demonstrate significantly higher levels of Tregs in female mice versus male mice and interestingly, higher levels in female chimeric versus male chimeric mice each containing female Treg cells. In male chimeras the Treg population (normally 8-10% of the total CD4⁺ T cell compartment) expanded to 40-50% whereas in non-chimeric females it expanded to 60-80% of the compartment. This result from the chimera experiments suggests that a factor native to the host is driving increased expansion. Interestingly, Treg levels were also higher in the non-ovariectomized group compared to ovariectomized group, suggesting that perhaps estrogen production by the ovaries may be that factor. Shirin is currently working on increasing her pool of chimeric and ovariectomized mice to increase sample size and

to generate chimeras with male Tregs in male and female recipients. Plans to add back estrogen following ovariectomy to directly test the hypothesis that estrogen plays a role are underway. One potential application of Shirin’s research is by expanding the native Treg levels in patients suffering from an autoimmune disease, the hope is that they would become less likely to suffer from autoimmunity. In the same vein, by increasing the amount of donor Tregs in a transplant recipient, that patient would also theoretically be less likely to experience GVHD because the donor Tregs would suppress unwanted immune responses against the recipient. If estrogen is a key, the next step in this research would be to figure out the mechanism by which estrogen receptors and Tregs interact to cause the potentiated expansion. When asked what her favorite part of working on her Treg project was, Shirin replied, “granted, there is nothing too sexy about injecting and bleeding mice, but being able to work with intelligent and funny people definitely makes following a protocol more fun.” She also likes having Dr. Levy as a mentor, because of his vast knowledge of immunology, medicine, pop culture, and sports.

When she is not studying or conducting research, Shirin dedicates her time to projects she’s passionate about. She was one of the Logistics Coordinators of the Hialeah Health Fair. She also is the Co-Coordinator for the George Paff Teaching Awards Ceremony and an active participant in her Pathway of Immunology and Infectious Disease. While Shirin is unsure whether she will pursue a career in the field of immunology, she feels that her research and interests are applicable to any medical specialty. And if all else fails, she will follow her childhood dreams of becoming an actress or becoming part owner of Bayern Munich.

Spring 2016 The Medical I.B.I.S. 11

Neurologic Manifestations of Sports Related Concussion By Emily Chen

Anyone exposed to the media is aware of the ongoing concussion controversy. Though the focus has been on professional sports, these athletes started at an early age. Pediatric neurotrauma is an under-acknowledged epidemic among youth athletes due to inconsistencies in protocol with which athletes are evaluated. The impact of concussions on the developing pediatric brain remains to be elucidated. Student researcher Devon Cohen has always had a passion for both neurology and sports, so she approached sports neurologist and NFL consultant Dr. Francis Conidi about concussion research. In addition to working with former NFL players on the long-term effects of repeated traumatic brain injury, Devon began evaluating sports- related pediatric concussions. Under the guidance of Dr. Conidi, Devon assessed clinical manifestations and concussion-specific neurologic exam findings to uncover better prognostic indicators of concussion within the pediatric population.

Concussion is defined as a pathophysiological process affecting the brain induced by mechanical forces. Concussion and sub-concussive events may be caused by direct blows to the head, face, neck, or elsewhere on the body where the force may be transmitted to the head. Symptoms often manifest as rapid onset transient impairment in neurologic function, headache, dizziness, nausea, and coordination problems. Devon assessed concussion-specific neurologic exam findings in addition to cognitive symptoms (attention deficit, poor academic performance, and short term memory loss), sleep disturbances, psychological manifestations, and responses to pharmacologic treatment for post-traumatic headaches. Her study revealed headache and cognitive symptoms to be the most common manifestations of concussions. Vestibular symptoms, sleep difficulty, and psychological manifestations were also exhibited by patients. Positive findings on extensive vestibular testing were determined to serve as prognostic indicators, associated with delays in both symptom resolution and return to play. These neurologic exam findings resolved concurrently with symptom improvement. Devon conducted another study characterizing the headache phenotypes in 25 pediatric patients following sports related concussions, which revealed symptoms consistent with migraine in two thirds of the patients.

12 The Medical I.B.I.S. Spring 2016

Devon Cohen, M.D. Candidate, Class of 2016

Broader implications of these retrospective and longitudinal studies reinforce the need for proper neurologic evaluation of athletes following concussion, in order to elucidate the often subtle manifestations on exam. Doing so should preclude premature return to play, thereby preventing secondary concussive or sub-concussive events. In addition to providing patient and parent education, the prognostic indicators improve management and return to play timelines. Headache characterization facilitates proper treatment of debilitating symptoms. Future studies should include multi-center evaluations of concussion manifestation, progression, and management. Devon has enjoyed participating in this research immensely, having the chance to work with both professional and pediatric athletes, while helping to shape our understanding of concussion’s impact on the developing brain. Devon has had the opportunity to give both platform and poster presentations of her research at the American Academy of Neurology as well as the American Headache Society in 2015. Devon’s experience has furthered her excitement for the future of neurology, the field into which she hopes to match this spring.

Mary Mckuen, M.D./Ph.D. Candidate, Class of 2016

Finding the Role of CT694 in Chlamydial Invasion of Host Cells By Sarada Thanikachalam

Chlamydia trachomatis infection is the number one reported sexually transmitted disease in the U.S., with more than one million cases annually. An often silent but serious infection, Chlamydia infects up to 70% without causing symptoms. Almost 40% of untreated women can develop pelvic inflammatory disease (PID) and other severe complications leading to ectopic pregnancy and infertility. Similarly, men can be become infertile if not treated for Chlamydia infection. Currently, there is no chlamydial vaccine.

Since 2010, Mary McKuen, who will be completing her MD this spring and received her PhD in 2014, has been working to discover potential vaccine targets for Chlamydia. This is a particularly important field of work, as many infected individuals in developing countries do not have access to treatments. Under the mentorship of Dr. Ken Fields, Ph.D, Mary is currently targeting a protein that Chlamydia utilize inside the host cell called CT694. An intracellular pathogen, chlamydiae species use the contact-dependent type III secretion system (T3SS), a needle shaped syringe, to translocate effector proteins across the host cell membrane, allowing for pathogen invasion. CT694 is one such effector protein that the researchers studied. To study this protein, HeLa cell cultures were grown, and Chlamydia was added to infect the cell line. Different timed assays were conducted and the

cell cultures were stained with various colors to visualize the interactions of various proteins. The data were analyzed using fluorescent, confocal, and transmission electron microscopy. In addition, proteins from both the cell line and chlamydiae were harvested; western blotting was utilized to further study protein-protein interactions. CT694 was found to block host cell AHNAK, a scaffolding protein that acts to form the actin cytoskeleton. This resulted in break down of the actin cytoskeleton and host cell recovery. Therefore, CT694 may be an important factor for chlamydial invasion and could be a potential target for vaccine therapy development, as it is immunogenic. The next step in the research is to study mouse models that lack AHNAK and evaluate their response to chlamydial infection. Similarly, studying Chlamydia that lack CT694 may yield powerful insights concerning the significance of CT694 interaction with AHNAK. Until now, Mary has presented her findings at multiple conferences, including ESRF and Chlamydial Basic Research Society. In fact, she won the Dr. San-pin Wang Memorial Endowment award for best student oral presentation at the Chlamydial Basic Research Society conference. Having worked on this research long-term, Mary is now interested in OB/GYN, where her clinical and research goals can be aligned with infectious disease and the reproductive microbiome.

Spring 2016 The Medical I.B.I.S. 13

Probing the Mechanisms of Gene Expression Regulation in Endocrine Cancers and Neurological Disorders By Tom Boyle In most tissues, cells can invoke two copies of every gene. That redundancy is crucial for avoiding symptoms of recessive disorders and managing the genetic damage that tends to accumulate with age. In certain tissues, however, the body may only use gene copies inherited from a particular parent. In those arenas, where there is no backup script, gene errors can be immediately devastating. Such is the case in neural tissue where cells depend exclusively on the maternal copy of the UBE3A gene. When that copy is deleted or damaged, individuals are born with Angelman Syndrome, a severe developmental disorder with cognitive, motor, and psychological manifestations. The product of the UBE3A gene is called E6-Associated Protein, or E6AP for short. E6AP is particularly important in modeling neurological disorders because mutations in E6AP are sufficient to induce Angelman syndrome. Moreover, UBE3A and E6AP have been implicated in a wide array of

Jean-Pierre Obeid, M.D. Candidate, Class of 2017

14 The Medical I.B.I.S. Spring 2016

neurological disorders ranging from Parkinson’s Disease to Autism Spectrum Disorder. While various associations between E6AP and neurological disorders have been well established, the specific roles for this protein in these diseases remain elusive. Thus far, at least two separate and distinct functions of this protein have been discovered. E6AP has been known for many years to mark certain proteins for degradation. For example, the insidious oncovirus HPV makes use of it to degrade the tumor suppressor protein p53, releasing the breaks on proliferating cancer cells. In 1999, the Miller School’s own Dr. Zafar Nawaz, Ph.D. demonstrated a second function – that the protein also works as a transcriptional coactivator with steroid hormone receptors. This discovery opened new doors in neuroendocrine research. In the years since, his laboratory has been working on identifying what genes are regulated by these receptor/E6AP complexes in the hope of unlocking clues to a number of disorders.

Jean-Pierre Obeid began working in the Nawaz laboratory while he was still an undergraduate at the University of Miami. Now a third-year medical student at UMMSM, he readily demonstrates an impressive understanding of a new and rapidly-evolving area of study: neuroendocrine cancers. For Obeid, the complexity is a large part of his interest. “Neuroendocrine cancers are some of the most devastating, and some of the least understood.” His love for physics and passion for cancer research have led him to seek a residency in Radiation Oncology. In fact, he’s surprised that realization didn’t come sooner. “I love physics, I love oncology, but it took my roommate to suggest Rad Onc.” Recently, Obeid has worked under the guidance of Jimmy El Hokayem, Ph.D. to investigate if and how E6AP uses its coactivator abilities to regulate the transcription of Protein Kinase A, a potent actor in a vast array of cellular processes. “PKA works in so many ways, you can’t even discuss it in one sitting,” says Obeid, although he probably wouldn’t mind trying. If he were able to outline a connection between those two molecules, it could lead to a better understanding of many neurological disorders and even elucidate new targets for therapies. Entering last year, Obeid had preliminary evidence suggesting that estradiol (E2) and E6AP were both necessary for PKA transcription. To confirm that relationship, Obeid cultured cells that could not make E6AP. As he suspected, those cells were severely hindered in their ability to make PKA. Given the functions that Dr. Nawaz had discovered years earlier, it seemed plausible that E6AP and the estrogen receptor work together to activate PKA transcription. If that were the case,

the DNA in the promoter region for PKA should feature a special binding site for the estrogen receptor. Obeid began using databases to compare the promoter region of PKA with the estrogen receptor’s documented binding sites, known as estrogen response elements.

After careful examination, Obeid was able to identify four possible estrogen response elements. The next step was to test each sequence’s promoting ability with reporter genes. With a luciferase reporter assay, you place a potential promoter upstream of a bioluminescence gene and then measure the luminal output of your culture. In Obeid’s experiment, two of the candidate estrogen response elements that he inserted managed to promote transcription of the reporter gene when the cells were incubated with estradiol. “Call your mom, call your grandma…” he recalled, laughing. After years working with Drs. ElHokayem and Nawaz, Obeid was crossing a major hurdle. “I’d say we went from there being a 10% chance that our hypothesis was right, to like an 80% just with this result.”

That success doesn’t mean that he’s finished. Next, Obeid has to demonstrate that E6AP and the estrogen receptor are actually binding to the DNA where he suspects. He’ll use an electrophoretic mobility shift assay (EMSA) to do that. As a third year who’s also involved in other research, he knows it will be a challenge to advance the project this year. Still, the passion makes it worthwhile. “I like to come in here after rotations, pop my headphones in and just…” His voice trails off, but he begins pipetting in the air outside the Gautier Research Building, where most people have already left for the weekend.

Spring 2016 The Medical I.B.I.S. 15

Sphingolipids and Ceramides of Mouse Aqueous Humor: Comparative Profiles from Normotensive and Hypertensive DBA/2J Mice By Sarada Thanikachalam

Glaucoma is the second leading cause of blindness in the world, affecting over 60 million people. Glaucoma usually results from increased eye pressure that damages the optic nerve. Unfortunately, those who have lost vision due to glaucoma cannot regain their sight- there is no known cure. However, with early detection, patients can protect their eyes against severe vision loss.

Katyayini Aribindi , M.D. Candidate, Class of 2017

A fundamental step in advancing treatment for glaucoma is to understand the pathophysiology of the interactions between lipids and proteins. Katyayini Aribindi, a third year medical student, has been trying to develop an effective method of characterizing ocular lipids under the guidance of Dr. Sanjoy Bhattacharya, Ph.D. Her involvement in eye research began years ago as an undergraduate when she first began working in Bascolm Palmer Eye Institute; her passion and expersise have grown considerably over the years. In this project, Katyayini aimed to identify and quantify the aqueous humor (AH) sphingolipid class profiles in the intraocular pressures (IOP) of both normotensive and hypertensive mice (DBA/2J). First, researchers extracted AH using paracentasis and then extracted the lipids from AH using organic phase extraction methods. Mass spectrometry analysis of the lipids in AH showed that the changes of sphingolipid classes occur with elevation in IOP. These results were presented at the International Society for Eye Research (ISER) in 2014 and published in the peer-reviewd journal Biochimie.

The next step in Katyayini’s research is to re-analyze the lipids on a high resolution mass spectrometer confirming isomers of specific lipids present in the AH. Currently, Katyayini is continuing the characterization of the lipid classes and working to improve the mass spectrometric methods.

16 The Medical I.B.I.S. Spring 2016

In the future, she hopes to combine the practice of science with the clinical aspect of medicine, in order to improve both fields. She hopes that synergism between basic science and clinical medicine may help her and her team find better solutions for patients suffering from glaucoma. As for residency plans, she is undecided but hopes to go back to Illinois, her home state.

Qualitative Effect of Care Groups in a Maternal and Child Health Project in the Guatemalan Highlands By Naiomi Gunaratne

Patients often hear medical advice from their friends or family first. Information - and sometimes misinformation - about health travels by word of mouth, especially in rural communities. How can this form of communication be used for good? Can it actually have an impact on mortality and morbidity? Corey Gregg asked these questions when he joined USAID for a project in the rural region of Huehuetenango, Guatemala.

communication. The first methodology, known as Census-Based, Impact-Oriented Methodology, involved venturing into the community and asking who was living, sick, or deceased; this identified the problems in the community. The second methodology, known as the Care-Group Approach, involved a pyramid of volunteers to disseminate the information to the community. The combined version involved both methods for the final project: a six-level pyramid of female volunteers who both disseminated and collected information. For his research, Corey gathered evaluation data through individual and group interviews with volunteers at the three base levels of the pyramids - Community Facilitators, Communicadoras, and Self-Help groups. This program was conducted for 4 years, beginning in 2011 and ending this year. Corey and his mentors, Dr. Ira Stollak, Dr. Henry Perry, Dr. Mario Ramirez, Dr. Nicolas Cuttriss, and the staff at the facility in Guatemala, all focused on analyzing the results of this program. They performed quantitative analysis to find themes in the transcripts of the interviews done with the pyramid of volunteers.

Corey Gregg, M.D. Candidate, Class of 2016

After taking a year off to pursue a Master’s Degree in Public Health, Corey wanted to implement his new knowledge and simultaneously foray into the global health arena. Corey had travelled to Guatemala twice previously and had fallen in love with the region. The project’s goals, combined with his desire to live in the region and improve his Spanish led to a perfect match. The study focused on an established maternal and child survival project that was implemented by the Guatemalan organization Curamericas Guatemala and funded by the USAID. This project combined two different methodologies in order to spread health information via word-of-mouth

The analysis elucidated several themes that focused on health beliefs, behaviors, and changing attitudes, especially in female empowerment. The team also provided recommendations for sustainability and logistical improvements of the project. These were sent to USAID for review. Unfortunately, the project was stopped by the USAID, but Corey has high hopes that the project’s lasting impacts will allow the project to continue amongst the people in Guatemala. Corey felt that the project was an incredible experience. Not only was it one that helped his future goals of pursuing a Med/Peds residency and practicing global health work, but it also showed how community-based epidemiological research and action can make a huge impact on an entire community for years to come. The study is a fascinating way to show that word-of-mouth communication truly can be an effective way of providing health information to the community.

Spring 2016 The Medical I.B.I.S. 17

Ankle Range of Motion, Leg Pain and Leg Edema Improvement in Patients with Venous Leg Ulcers By David Feldman

When identifying clinical and public health problems in the United States, chronic cutaneous ulcers (CCU) do not commonly top the list. But should they? Researchers at the Wound Healing Research Center in the Department of Dermatology and Cutaneous Surgery at UMMSM say they should. Part of this team is 4th year medical student, Joshua Fox. Joshua has conducted clinical and basic science research through the Dermatology Department on specific types of CCUs, such as diabetic foot ulcers and venous leg ulcers (VLU), and he continues to play an active role in research areas including wound healing, dermoscopy, and patient satisfaction.

Extremely dedicated to his research, Joshua took time off between his 3rd and 4th year of medical school to become a wound healing research fellow with the UMMSM Dermatology Department. He worked under mentors Dr. Robert S. Kirsner, M.D., Ph.D., Interim Chairman and Harvey Blank Chair in the Department of Dermatology and Cutaneous Surgery, Dr. Marjana Tomic-Canic, Ph.D., Director of the Wound Healing and Regenerative Medicine Research Program, and Dr. Irena Pastar, Ph.D., Research Assistant Professor in the Dermatology Department. Joshua was attracted to wound healing because he identified it as a unique and exciting field that required additional research and attention. Joshua Fox, M.D. Candidate, Class of 2016

18 The Medical I.B.I.S. Spring 2016

Historically, medical education and clinical training dedicates minimal time to CCUs, and only seven United States medical schools, including UMMSM, offer wound healing electives. His interest led him to his current mentor, Dr. Kirsner, with whom he conducted clinical wound healing research, and to Dr. Tomic-Canic and Dr. Pastar, with whom he conducted basic science wound healing research. Joshua and the clinical wound healing research team sought to determine how compression therapy impacts associated symptoms like ankle range of motion (AROM), pain, sensation and swelling in patients suffering from VLUs. A VLU is a long-lasting leg wound that is the end result of chronic venous insufficiency (a pathologic phenomenon of the veins in the legs). With current therapies (primarily compression bandages), only 33-66% of VLUs heal by 24 weeks. Joshua and the wound healing research team hypothesized that patients receiving compression therapy who experience an improvement in AROM would also experience improvement in their pain, leg swelling, and neuropathy. Currently, VLUs, diabetic foot ulcers (DFU), pressure ulcers, and other CCUs affect more than 6 million individuals annually with a total estimated medical cost upwards of $25 billion, not including additional quality of life costs. Despite these alarming numbers,

CCU research is disproportionately underfunded compared to less common, less costly and less debilitating diseases like Lyme Disease. In fact, the FDA has only approved 1 drug and 2 class III devices for treating patients who currently suffer from CCUs, and no new drugs have been FDA approved in nearly 20 years. Targeting research in order to improve care for patients with severe CCUs is critical; patients with DFUs, for example, have a 5-year mortality risk of 45-55%, a value that is significantly higher than many common cancers including Hodgkin’s disease, breast cancer and prostate cancer. In addition to the morbidity and mortality risk associated with CCUs, patients who suffer from these conditions face constant pain, malodor, fluid leakage, decreased mobility, social isolation, and depression. To aid patients suffering from VLUs, Joshua and his colleagues began a trial in the summer of 2014 to determine whether compression therapy can affect AROM, pain, swelling, and sensation in the legs. In this 4-week prospective pilot trial, the team enrolled 10 subjects with VLUs and provided each with compression therapy. They measured baseline values of AROM, pain, leg swelling, and neuropathy, and then compared those baselines to measurements performed at 4 weeks. In the end, they concluded that improvements in AROM correlated with a reduction in leg swelling and pain for patients with VLUs, but it had no significant independent effect on reducing the wound size or improving sensation in the legs. While these results are exciting for VLU patients and align with findings from previous studies, solidifying the mechanism will require a longer and larger trial.

“I hope that this is simply the beginning of my contributions to the world of wound healing research and clinical trials.”

Recently, Joshua and his dedicated team of clinicians and researchers had their pilot clinical trial manuscript accepted for publication in the Journal of the American Medical Association: Dermatology. This is one of seventeen manuscripts Joshua has published.

Joshua and colleagues are eager to begin the next phase of this research in order to determine whether dedicated physical therapy, aimed at improving AROM, will impact wound healing, pain, swelling, sensation, quality of life, and inflammatory and histological markers in patients with VLUs. “I hope that this is simply the beginning of my contributions to the world of wound healing research and clinical trials,” said Joshua, who is applying for residency in Dermatology. Joshua hopes to pursue a career that combines caring for patients, teaching and conducting research. “Under the leadership of faculty and colleagues in the Department, I have learned a great deal regarding wound healing and translational and clinical research design, which I hope to utilize to care for patients and lead fu-

Spring 2016 The Medical I.B.I.S. 19

Pancreatic Neuroendocrine Tumors (PNETs): Survival Analysis Comparing Surgical Resection vs. Non-Surgical Management By Steven Lord

Pancreatic cancer carries the lowest survival rate of all the major cancers and is the fourth leading cause of cancer mortality in the United States. Because of its location deep in the abdomen, pancreatic tumors are not usually discovered until they are already at an advanced stage. Oncologists and surgeons will sometimes forgo surgery on these deep masses, especially smaller masses classified as a subset of pancreatic tumors called neuro-endocrine tumors (PNET), because of the possibility of surgical complications and the uncertainty of whether removing the tumor improves survival. As it stands right now, the National Cancer Institute has not set the standard of care treatment because of this lack of consensus. Paige Finkelstein, a second year M.D./M.P.H. student at UMMSM, aims to abolish the uncertainty surrounding the treatment of PNETs with her research on survival outcome after surgical removal of these tumors. She is working on this endeavor with her mentor Dr. Danny Yakoub M.D., Ph.D., a surgical oncologist at the Sylvester Comprehensive Cancer Center.

PNETs are a specific form of pancreatic cancer in which the endocrine cells of the pancreas that produce hormones like insulin or glucagon proliferate out of control and form masses. Sometimes these masses will be functional and produce extra hormones which will cause symptoms like hypoglycemia if insulin is over-produced or hyperglycemia if glucagon is over-produced. In other cases, the tumor will not over-produce hormones, and the patient could go

years without knowing that a tumor is growing inside one of their chief digestive organs.

Surgeons can attempt to remove the mass, or they may decide to forgo surgery in favor of medical care and chemotherapy because of the complications that accompany surgical resection of PNETs. The decision of whether or not to resect the mass is a crucial one, and it is one that Paige and Dr. Yakoub hope to guide.

Paige first became interested in surgical oncology after learning about her own family history with it. Paige’s great grandmother was afflicted with pancreatic cancer, so when she met her mentor Dr. Yakoub, she took an immediate interest in his work. Paige’s initial interest grew into a passion as she saw more of the field. When asked what drove her to pursue this work so avidly, Paige responded, “It’s amazing work. You’re literally watching someone remove a cancer, this horrible disease, from a person’s body.” Paige said she also loved the collaborative environment at the Sylvester Cancer Center, the staff she worked with on this research, and the people she met at the Israel Cancer Research Foundation. With their goal set out before them, Paige, Dr. Yakoub, and the rest of their team performed a systematic review and meta-analysis on the current literature comparing the overall patient survival following the surgical removal of a PNET to that of patients who received non-surgical management.

Dr. Danny Yakoub M.D., Ph.D and Paige Finkelstein, M.D./M.P.H. Candidate, Class of 2018

20 The Medical I.B.I.S. Spring 2016

A meta-analysis is an epidemiological study that uses sophisticated mathematical modelling and statistical analysis to sift through current studies in the field, total up all those studies’ results, and determine whether these studies come to the same conclusion. Paige went through extensive literature on the subject, found eligible studies on PNET management, and weighed their results as a whole to see whether surgical removal improved overall survival rates in patients with PNET.

The results showed that surgical removal of a PNET benefits patients and improves one-year, three-year, and five-year survival rates when compared to patients who do not have their PNET removed or are treated with medical therapy. The results also showed that these benefits hold true even for smaller masses and non-functional tumors as well, providing strong support for the idea that surgery should not be excluded from PNET treatment, no matter the characteristics of the PNET. While this research provides strong evidence in the surgical management of pancreatic cancer, Paige and Dr. Yakoub hope further studies in the field establish even stronger evidence. Paige and her mentor believe that the next step should be a prospective randomized-controlled trial (RCT) to elaborate on all subtypes and management protocols for treatment of these tumors. Paige hopes that presenting this research at the 2016 Society of Surgical Oncology’s Annual Cancer Symposium will gain support for further research and inspire people to work towards better treatments for

all types of pancreatic cancer. In the meantime, Paige will continue working with Dr. Yakoub and their team at the Sylvester Cancer Center to improve the lives of those afflicted with this horrible disease.

When Paige isn’t analyzing studies for her work in surgical oncology, she is working on establishing her company, ERinfo.me. ERinfo.me is designed to expedite the identification of unknown patients coming into the Emergency Room via novel facial recognition software. In doing so, the medical staff may be able to bypass the challenges of identifying an unknown patient and avoid potential identification errors. Furthermore, a faster identification means a faster patient history and hopefully a faster diagnosis.

Paige plans to incorporate all of these experiences into her future medical career by continuing to pursue pharmaceutical development in the field of oncology. Her work in surgical oncology with Dr. Yakoub was an invaluable learning experience, and she couldn’t be more grateful to have the opportunity.

Spring 2016 The Medical I.B.I.S. 21

Hispanic Immigrants Developing Inflammatory Bowel Disease are More Likely to Eat American Food By Genevieve Wiehl

Inflammatory bowel disease (IBD) is an illness causing severe inflammation of the intestines. It includes the diagnoses of Crohn’s disease and ulcerative colitis. These painful diseases affect roughly 1.3 million people in the United States, and are more common in developed countries overall. However, as developing countries become more “westernized,” there is an increasing incidence of IBD. Epidemiologic data also demonstrates an increasing incidence in immigrants who have moved from low prevalence countries to areas with a higher prevalence of Inflammatory Bowel Disease. Given that the pathogenesis and risk factors for IBD are unclear, IBD epidemiology is an especially important area of research.

UMMSM student Derek Estes was inspired to conduct research on inflammatory bowel disease and the increasing incidence in immigrants by a very personal connection—his own diagnosis of Crohn’s disease. Derek was introduced to his mentor, Dr. Oriana Damas, M.D., a Gastroenterologist at the University of Miami Crohn’s and Colitis Center by an upperclassman and from then on eagerly pursued research on IBD. Derek’s project was a retrospective case control study that sought to determine whether there is a difference in fat intake between Hispanic immigrant patients with IBD and those without IBD— and whether there was any difference in their level of acculturation. In other words, Derek and Dr. Damas wanted to see if an “Americanized” diet was affecting the development of IBD in Hispanic immigrants. To conduct the study, participants were given multiple surveys, including a 24-hour dietary recall, a Stephenson Multigroup Acculturation Scale, and a questionnaire detailing aspects of their immigration. The 24-hour dietary recall was a very detailed survey designed to elicit details about everything participants had eaten over the past 24 hours. The research team then looked at differences in the total grams of fat, unsaturated fat, proteins, carbohydrates and specific micronutrients in the participant’s reported diets. The Stephenson Multigroup Acculturation Scale is a standardized survey that attempts to determine the level of adoption of American customs by an immigrant group. The survey asks participants

22 The Medical I.B.I.S. Spring 2016

Derek Estes, M.D. Candidate, Class of 2016

to agree or disagree with statements pertaining to both their native country—“I am informed about current affairs in my native country” and “I like to speak my native language”— and their adoption of American practices—“I know how to prepare (Anglo) American foods” and “I think in English.” The surveys were administered to 29 IBD patients and 22 controls. The data was then compiled and analyzed. Derek administered many of these surveys to the participants, was extensively involved in the data collection, helped write an abstract, and created the poster for presentation. The major findings of the study were that the Hispanic immigrants with IBD ate more American foods, but consumed less saturated fat than Hispanic immigrants without IBD. Derek presented the study at the American College of Gastroenterology Annual Scientific Meeting 2015 in Hawaii, and the team is currently in the process of submitting their

“Research can both be rewarding personally and make a difference in the understanding of disease pathogenesis.� work for publication. Derek and his mentor, Dr. Damas, wish to further investigate the finding that immigrants with IBD reported eating less saturated fat than other immigrants without IBD. They also want to separate the patients by their specific inflammatory bowel disease (Crohn’s disease or ulcerative colitis) to see if there is a difference between those specific patient populations. For Derek, working with patients was his favorite part of the project. In talking with them and administering the surveys, he found he got to know them personally, beyond the data collected for the

study. Derek describes the patients as very receptive to participating in research, and eager to volunteer their time.

Derek is currently applying for a residency in Internal Medicine, and is interested in completing a GI fellowship in the future. He hopes to stay at an academic medical center and continue doing research. His participation in the project helped him realize that research can both be rewarding personally and make a difference in the understanding of disease pathogenesis.

Spring 2016 The Medical I.B.I.S. 23

Preventing Age-Related Macular Degeneration: GSTP1 in the Retinal Epithelium By John Paul Kolcun

Age-related macular degeneration (AMD) is a black box in modern ophthalmology. AMD affects the macula (the center of the visual field) through damage to the light-sensitive cells of the retina, which are the front-line units of the visual system. Patients over 65 are at highest risk for AMD, and those affected can develop progressively blurred vision in one or both eyes. Over time, the blurred areas may progress to visual blank spots. Studies have found that smoking can dramatically increase the risk of developing AMD. While its incidence, presentation, and long-term effects are understood, the underlying mechanism of AMD is still unknown. Worse still, the few treatments currently available to patients do little more than slow the disease progression. Matthew Donovan, an MD candidate in the class of 2016, worked with Dr. Wen-Hsing Lee, M.D., Ph.D. at the Bascom Palmer Eye Institute, to give physicians and patients another tool to prevent – or potentially reverse – AMD. Matthew has been interested in ophthalmology since his undergraduate years at the University of Miami, where he conducted clinical research in the field.

24 The Medical I.B.I.S. Spring 2016

When he began his studies at UMMSM, he joined the Ophthalmology Student Interest Group, where he was put in touch with Dr. Lee. “I wanted to conduct basic research – benchwork – and I’m interested in retinal cells,” Matthew said, “so it was a perfect fit.”

Matthew’s project targeted an enzyme found in cells of the retinal pigment epithelium (RPE): Glutathione S-transferase pi isoform (GSTP1). RPE cells supply the light-sensitive cells of the retina proper, which is itself avascular, and GSTP1 – a phase II detoxification enzyme - is responsible for neutralizing and eliminating chemically reactive species in these cells. Dr. Lee has focused on this enzyme in the past as a key player in the development of AMD, and possible therapies to prevent or reverse its symptoms. Previous studies have found that GSTP1 levels are reduced in mice and humans with AMD, and that over-expression of the enzyme protects RPE cells from UV light damage.

Beginning in June of 2013, Matthew sought to extend these past findings, and measured changing GSTP1 levels in response

“No one knows how AMD happens, or how we can reverse its effects.”

to introducing toxins to the RPE cell environment. In so doing, he was able to determine a dose-response relationship between these toxins and GSTP1 expression, as well as analyze the levels of GSTP1 found in the cells after exposure to toxin. The toxins used were hydrogen peroxide (H2O2, an oxidative agent) and hydroquinone (HQ, a common component of cigarette smoke).

Matthew established several cultures of human RPE cells for manipulation by toxin exposure. Half of the cultures were exposed to H2O2, and the other half to HQ. Within each toxin group, cultures were grouped into triads, which were each assigned doses of 50, 100, or 200μM. Thus, sub-groups of three cultures shared a particular toxin/exposure profile, covering each combination of toxin and dose (for example, 3 cultures received 100μM of HQ, another 3 received 50μM of H2O2, etc.). He also maintained a separate culture as a control group, which received no toxin. The cultures were exposed to toxin for 24 hours, after which time the number of surviving cells was counted for each group using a typical staining assay.

Matthew then wanted to analyze the amount of GSTP1 found in surviving cells. In order to have sufficient levels of enzyme for analysis, he selected the single culture from each toxin/exposure sub-group which had the highest number of surviving cells as a representative sample of that sub-group. He then measured levels of GSTP1 using a standard Western blot. The results were straightforward: for both toxins, increasing doses resulted in decreased cell survival and decreased levels of GSTP1, revealing a direct linear relationship between toxin exposure and GSTP1 levels. Matthew concluded that introduction of toxins consumed GSTP1 at a rate faster than the cell could produce it, as the enzyme fought to reduce the accumulating intracellular toxin. He believes that these reduced levels of GSTP1 predispose retinal cells to damage by further toxin exposure, which could lead to effects seen in AMD development.

Matthew concluded: “So now we can ask, can we do anything to increase GSTP1 levels? Could we introduce the enzyme therapeutically, or stimulate its production? We

don’t know what kind of treatments could come from this work, preventative or therapeutic. There’s more work to do here.”

The project was presented as a poster at the Association for Research in Vision and Ophthalmology (AVRO) in April of 2014, in Orlando, FL. Since then, Matthew has conducted clinical research in pediatric retinal care under Dr. Audina Berrocal, M.D., also of Bascom Palmer. Of the experience, Matthew said “the best part of doing this was working with Dr. Lee. She’s a great mentor and a great teacher. It really paved the way to where I am now.” Matthew is applying for residency positions in Ophthalmology, and hopes to extend the project at the end of this year if the time constraints of applications and interviews allow. He would like to look into the therapeutic and protective effect of increased GSTP1 levels in retinal cells, and try to identify agents that could increases cellular levels of the enzyme.

Matthew Donovan, M.D. Candidate, Class of 2016

Spring 2016 The Medical I.B.I.S. 25

Overall Survival, Disease-Free Survival, Local Recurrence, and Nipple–Areolar Recurrence in the Setting of Nipple-Sparing Mastectomy: A Meta-Analysis and Systematic Review By Steven Lord

As of 2010, breast cancer affects more than 1,600,000 women worldwide and is the most common form of cancer among women in the United States. Thankfully, due to improved diagnostic techniques, breast cancer is being found earlier in its course, and an earlier diagnosis means surgical resection has a better chance of being curative. However, this surgical resection can have lasting effects on a woman’s identity and body image. Modified radical and skin-sparing mastectomy, two surgical treatments for breast cancer, are current mainstays of breast cancer therapy, and both usually remove the nipple-areolar complex of the breast. The nipple-areolar complex is oftentimes integral to female identity, and its removal may be unnecessary if Alison Moody, Erryn Tappy, and Stephanie Blankenship have anything to say about it. Stephanie, Erryn, and Alison are all M.D./ M.P.H. candidates at UMMSM who have worked with Dr. Lucy De La Cruz, M.D., Chief Resident of General Surgery at the

University of Miami Regional Medical Campus, and with Dr. Eric Hecht, M.D./M.S.P.H, to perform a systematic review and meta analysis of the current literature on a third type of procedure: nipple-sparing mastectomy (NSM).

In NSM, the nipple-areolar complex is maintained, along with its innervation and blood supply, while the tumor and affected breast tissue are removed. Despite its seeming advantages for a woman’s quality of life, hospitals are less willing to offer NSM as a treatment option for fear of cancer recurrence in the tissue surrounding the nipple. Alison, Erryn, Stephanie, and Dr. De La Cruz wanted to see whether choosing NSM as a treatment warranted this concern about recurrence.

To that end, these researchers performed a systematic review of twenty studies analyzing NSM as an alternative to skin-sparing or radical mastectomies. They performed a meta-analysis on eight of those studies that had direct comparisons between NSM and the other procedures.

Erryn Tappy, Alison Moody, and Stephanie Blankenship, M.D./M.P.H. Candidates, Class of 2016

26 The Medical I.B.I.S. Spring 2016

Their analysis found that NSM does not put these patients at a higher risk of cancer recurrence and supports the use of NSM in women diagnosed with early stage breast cancer.

This research is already making waves across the surgical world, and, in 2015, the team received the award for “Greatest Scientific Impact” from the American Society of Breast Surgeons at their 16th annual meeting in Orlando. Their manuscript was then published in the Annals of Surgical Oncology. Upon reflecting on her experiences, Alison said that her favorite part of this project has been that, as students, she, Stephanie, and Erryn could actually make an impact. “It was an amazing feeling to see that what we were doing would have actual clinical impact and that we could make a meaningful contribution to clinical science.” Thanks to Stephanie, Erryn, Alison, Dr. De la Cruz, and Dr. Hecht, women are more empowered to advocate for their choice of treatment as well as their quality of life.

"It prepares you for being at the cutting edge of your field...you begin to wonder what is on the horizon."

-Adam S. Aldahan, Class of 2017

"Get advice from as many people as possible...and make a decision that you are most comfortable with. After you have decided, try to never look back."

Taking Time Off for Research

-Ladi Afifi, Class of 2017

"It's a great opportunity if there is something you are truly passionate about." -Rishi Raj Rikhi, Class of 2018

By Emily Chen & Reshma Muppala

As students begin their journey through medical school, at some point, they may ask themselves, “Should I be taking time off to try and strengthen my application for residency or for personal growth?” Not uncommon, a portion of students will choose to defer one year or more to, among many other reasons, delve into a passionate area of research, obtain an MBA, or pursue a doctoratoral degree. This question has become increasingly discussed since residency spots have become more competitive, especially in certain specialties. Students are seeking ways to put themselves in optimal positions to obtain a residency spot in their field of choice and taking time off for research may be a great option. The argument for taking time off includes the chance to boost one's residency application by becoming more familiar with research in a field the student may be seeking a residency in. According to the National Residency Matching Program, matched U.S. seniors in 2014 reported to have a mean of 2.7 research experiences, with more research-heavy fields like radiation oncology and otolaryngology having an average of 4.6 and 4.7, respectively. Plastic surgery had the highest number of average research experiences at 4.8. Although this data may seem daunting, it should be noted that these numbers include only self-reported research experiences, which can range from weeks of research with no publications to years of research with publications. If students feel their grades or scores are not outstanding enough for very competitive specialties or residency programs, a year dedicated to research in the field of interest with abstracts, presentations, and, ideally, publications can show commitment to residency directors.

Third-year Ladi Afifi's connection to research in her home state of California was a deciding factor for her to take a year off. With the opportunity to be co-mentored by two dermatologists and the chance to work on a wide variety of subjects, she explained, “it was an opportunity [she] could not turn down.” Adam S. Aldahan is currently taking a year off for research and offered his own advice on what he would have done differently; as someone who switched to a research-heavy specialty later on during third year, he wished he had shadowed more specialties earlier on and approached the subject of taking a year off for research earlier during third year. Both Ladi and Adam believe talking to upperclassman that took a year off, faculty advisors, and even the residents and attendings in the hospitals can give valuable insight into choosing whether or not to take a year off for research for a specific field of medicine. Pursuing research in any field will undoubtedly show future employers and colleagues that a student is a dedicated and driven scholar.

Research is not only for residencies though. In fact, research can be the stepping-stone to discovering one’s own interests. Second-year Rishi Raj Rikhi shared that among the reasons why he decided to take time off was that he was unsure of what specialty of medicine he wanted to pursue. He knew he had a passion for politics, collaboration, and women's health and thus, during his time off, found two different physicians who shared his interests and pursued research focusing on breast cancer and hepatoblastoma in children. Rishi believes, “taking time off for research is a great opportunity if there is something [the student] is truly passionate about;

however there are several opportunities in medical school, residency, fellowship, and beyond to participate in research so there should not be any rush to pursue research until the student is truly inspired.”

The argument against taking time off becomes a matter of personal preference. Students will not get to graduate with the medical school class they began with and some students may prefer more clinical specialties that don't need research. Perhaps the more pressing reason, though, is the financial consequence of taking a year off. An extra year off for many students is an extra year of accrued interest from student loans and another year of living expenses that may not be covered by student loans. If this becomes a problem, most academic programs will allow students to defer loans and looking for research programs that offer stipends or are near home so they can keep these costs at bay.

Most people recommend taking time off between 3rd and 4th year, which allows students to begin rotations with their original class and allows the student to obtain some clinical skills that could be used for clinical research projects. However it is also common to take time off between 2nd and 3rd years to pursue both research and other degrees. Ultimately it becomes an independent decision, and it should be time used for a meaningful experience. Moreover, it's important for students to know that they are not alone; there is a wealth of faculty mentors and academic deans to help guide them through the decision of whether or not this might be the right choice for them.

Spring 2016 The Medical I.B.I.S. 27

Which Type of Research is Best for You? By Aarabhi Rajagopal

Adapted from an article by Jennifer Rodriguez and Michelle Caunca

CASE REPORTS

As a dynamic field, medical science is constantly developing and evolving, producing new discoveries around every corner. This is especially true at the University Of Miami Miller School Of Medicine, where medical students are vastly involved in various research projects on campus. However, many students seeking to perform research during medical school are often unaware of the various types of research that are available. Although students may consider the specific fields that they are interested in as a project topic, they may not think about the breadth of research in that area, from basic science benchwork to case reviews to retrospective studies. To aid these students, this article outlines the different types of research, along with their pros and cons, time commitment, and publication potential. When deciding what type of research to get involved in, students should first ask themselves these questions: 1) what field are you interested in, 2) how much time do you intend to spend conducting research, and 3) what kind of outcome do you want to gain from a project. After pondering these questions, the next step is to search for projects that seem interesting to the student and reach out to the researchers in charge, especially the principal investigator (PI), about getting involved. Research experience is not only a way to impress residency programs, but also a way to perform highly rewarding work that can impact the scientific and medical field.

28 The Medical I.B.I.S. Spring 2016

Case reports are formal write-ups of a single patient with a unique manifestation of a medical condition. Unlike basic science or clinical research, case reports are solely motivated by observations of patients, rather than a hypothesis and a follow-up experiment. Usually, patients mentioned in case reports have unique clinical presentations or have been treated with a new therapy. It is possible for students to write up and submit a case report for publication in a short time period, thus boosting their resumes. However, case reports do not necessarily indicate their ability to design an experiment or demonstrate hypothesis-driven thinking. Time Commitment: low Publication Potential: if a student is assigned to the project, high. There is also a good chance of first authorship. Pros: great writing experience; good way to publish quickly; opportunity to observe unique variations of a condition within a patient population Cons: not gaining true scientific experience; not beneficial to reach rigorous conclusions

EPIDEMIOLOGICAL CLINICAL RESEARCH BASIC SCIENCE

Basic scientific research typically involves systematic studies, where the general knowledge obtained is used to answer a large number of practical problems and/ or advance the knowledge regarding a phenomenon. Generally, basic science research includes all branches of science and engineering and can be performed in a variety of ways, including method development, animal experiments, tissue and cell studies, and genetic, physiological, biochemical, and biological investigations. Overall, basic scientific research involves a lot of lab time, creativity, and intellectual rigor, since a goal isn’t defined from the beginning, and the expected results may not always occur. For this reason, basic science research can take years to complete. If a student’s motivation to perform research is to gain knowledge, then doing basic science research is ideal. However, if the motivation is to get published, then applied research may be the better route. Time Commitment: high Publication Potential: low Pros: precise procedures and experimental designs can be specified and implemented; projects are highly regarded and considered very valuable when completed; shows the ability to perform hypothesis-driven thinking Cons: results are unpredictable; may take longer than expected to reach significant data

Clinical research involves studies with human subjects and helps to translate the basic science research from labs into new treatments and information for patients. Clinical research includes: •Interventional studies – seek insight into the effects of new drugs, therapies, medical devices, and various procedures, including surgical, physical, or psychotherapeutic. •Patient-oriented research – explore the mechanism of human disease, therapeutic interventions, clinical trials, and the influence of various prognostic factors on the course of a disease. •Behavioral studies – examine how people make health-related decisions, the factors that affect health, the distribution of disease, etc. •Outcomes and health services research – identify attributes related to patient satisfaction and the most effective treatments and services.

As a whole, clinical research requires an integration of medical and research skills, such as scientific writing, familiarity with experimental designs, protection of human subjects, knowledge of bioethics, and an understanding of the clinical condition. While it can be exciting to work directly with patients, clinical research tends to be tedious since it adheres to strict protocols and regulations and may involve copious amounts of paperwork. Time Commitment: medium (6+ weeks) Publication Potential: high for authorship in general; medium for first authorship Pros: work directly with patients; translate basic science research into a practical, medical context Cons: tedious and strictly regulated

Epidemiological studies are mainly done to investigate the distribution and historical changes of various diseases, including their frequency and causes. Epidemiological research includes: •Experimental studies – seek insight into certain interventions for disease prevention within specific populations. Depending on the population, it can be classified as a field study (the patient population is from a large region or a country) or a group study (the patient population is a specific group) •Cross-sectional studies – seek insight into the prevalence of various health outcomes and their distribution •Retrospective studies – evaluate the factors leading to a health outcome by studying the past information from a cohort. This longitudinal type of study is especially useful to establish risk factors and potential causes of diseases.

Generally, students can perform these studies in a timely manner if their research group has a well-established data set, cohort, study design, and protocol. On the other hand, these studies may demand a great amount of time and money, as new data may need to be acquired. Students usually also need to have experience with epidemiological data analysis and training in statistical analysis programs. Time Commitment: medium to high, depending on the student’s dedication and training, as well as the PI’s investment in the research and the student Publication Potential: low to medium for first authorship, but medium to high for authorship overall Pros: gain knowledge and experience in statistical analysis, which is helpful in any field; these studies also give students an introduction into epidemiology and public health Cons: data entry and analysis may be involved, which can be time consuming; no bench work

Spring 2016 The Medical I.B.I.S. 29

Erica Barrios, Phi Ho, and Iman Rabizadeh, M.D./M.B.A. Candidates, Class of 2016

MediTick - The Solution for the Leading Cause of CAUTI, the Most Expensive Hospital Associated Infection By Genevieve Wiehl & Tom Boyle

The demand for business credentials in medicine is rising quickly as management of the field continues to evolve. Both medical students and tenured physicians look to M.B.A. programs to help straddle two realms that are often considered dichotomous. Sitting down with a group of UMMSM’s dual degree students, however, makes it readily apparent how much synergy is possible between business and medicine. Erica Barrios, Phi Ho, and Iman Rabizadeh, all fifth years in the M.D./ M.B.A. program, recently took home the top prize among graduate students in last year’s University of Miami Business Plan Competition for their project, which seeks to reduce hospital-acquired infections. By focusing on an area that they thought would help the highest number of patients, they also carved out a massive potential market - and the judges took notice. Iman recalls asking two questions when brainstorming their business plan: “What’s the most common preventable infection?” and “What’s the

30 The Medical I.B.I.S. Spring 2016

biggest cause of that infection?” That dialogue led them to consider catheter-associated urinary tract infections (CAUTI). CAUTI accounts for as much as a third of all hospital-acquired infections, often taking hold in acute care settings when urinary catheters are not changed on schedule. Considering these infections are preventable, and seeking to incentivize their reduction, the Center for Medicare & Medicaid Services stopped reimbursing hospitals for CAUTI follow-up care in 2008. That non-payment policy contributes to the economic foundation of the team’s business plan. With their bottom lines suffering, hospitals are likely willing to invest in technology that prevents CAUTI. “Now more than ever, quality improvement is really important in any healthcare facility,” notes Erica. After passing on more complex interventions, the team devised MediTick, a small, adhesive vessel that changes color over a designated time thanks to the careful calibration of osmosis rates and membranes. For example, if a catheter should be changed after 5 days, MediTick will turn from clear to a big red X on the fifth day. Stuck easily to a collection container, this universal signal can

alert patients, family, and even the busiest staff members that it’s time for a new catheter. The team’s major revelation was to consider low-tech options. For a unit costs of only around $0.08, hospitals may be able to prevent follow-up care that averages around $900. With those margins, even a modest reduction in infection rates would save the hospital money.

The simplicity behind MediTick is a testament to their ingenuity, but also their broad experiences. Phi, for instance, began his managerial career running an orphanage in Malaysia. During that time, he learned how solutions with low costs and durable construction tend to have much better global reach. From spending time at bedsides, all three team members were also familiar with the alarm fatigue that providers suffer in hospitals—an insight that an ordinary group of business students might have missed.

The team spent an incredible amount of time preparing to present their project at the Business Plan Competition, and faced many hurdles along the way. Iman described how their idea was “destroyed” many times - people recommended it would be better to give up, encouraged the team to drop out of the competition, and told them their idea was unoriginal and unnecessary. One mentor suggested that their product would not make a difference, and would just be one more thing ringing in a hospital, unnecessarily bothering a nurse. However, the team stuck with it, and used the criticism to improve the project. In the end, their simple design meant that it would not take a nurse’s skill level to alert the patient, a family member or friend that the catheter should be changed. In the face of all these criticisms, it would have been easy

for the team to give up, but they were passionate about their idea, and persevered. The team suggests that others facing similar hurdles learn from criticism, and be able to answer questions and defend the project. In the end, they were awarded first place and received a $10,000 award. The judges were so impressed with the product that they recommended the team not limit the scope of the project to catheters. The product could possibly be used in wound care or central lines. It could also be used outside the healthcare industry for perishable foods or other time sensitive goods. The next step for the team is working with other students and a manufacturing company to create a prototype. Their long-term goals include establishing the practicality of the product through pilot tests and randomized control studies, and bringing the product to market. The team envisions their product as a low-cost solution that would both improve patient care and a hospital’s bottom line.

As Erica, Phi, and Iman prepare to graduate medical school and begin their residencies, they intend to take the lessons learned from their M.B.A. degrees, and this project, and implement them in their practices. “Entrepreneurship and healthcare go hand-in-hand,” says Erica. Phi describes how the project “was a great exercise in looking at nitpicky details and figuring out an innovative solution to solve a problem.” For Iman, the project was a way to “practice healthcare on a larger scale… preventing infections, decreasing cost” and combining their medical and business training into a practical solution for a real-world problem.

Spring 2016 The Medical I.B.I.S. 31

32 The Medical I.B.I.S. Spring 2016