Breslauer, Cori Ann; The University of Arizona College of Medicine - Phoenix; Mickey, Tom; Taylor, Melanie (The University of Arizona., 2015-04)

      Fortin Ensign, Shannon Patricia; The University of Arizona College of Medicine - Phoenix; Tran, Nhan (The University of Arizona., 2015-04-10)
      Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK- Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-B dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.

      Raza, Ali; The University of Arizona College of Medicine - Phoenix; Ernst, Kacey (The University of Arizona., 2015-04-13)
      Background: Dengue fever is the most common mosquito borne viral disease in the world. Its symptoms can be fairly nonspecific and most commonly include fever, rash, headache, and eye pain. Passive surveillance is currently the most prevalent method used to detect dengue cases in the United States. Identification of positive cases can be limited by the public’s awareness of the disease’s symptoms, barriers to healthcare seeking behavior, and by physician approval of laboratory testing. Objective: This study sought to evaluate barriers to dengue reporting, as well as the patient‐ level factors that may limit the efficacy of passive surveillance of dengue in Key West, Florida. Methods: Cross‐sectional surveys were administered across Key West, FL. Subjects were asked if they had a recent fever, additional dengue symptoms, and whether they sought medical care for these symptoms. Also the hypothetical question was posed: would you seek medical care for a fever greater than 102 F? Responses were stratified according to patient characteristics and demographics. Results: In Key West, patient‐level factors that influenced the decision to seek medical care for a high fever were: having a specific doctor call when sick (p<0.006), health insurance status (p<0.037), and ethnicity (p<0.005). Additionally, barriers to dengue reporting were identified. The most impactful were the decision to seek medical care for symptoms consistent with dengue fever, and the doctor’s decision to administer confirmatory dengue laboratory tests. Only one person with a recent fever plus one additional classic dengue symptom received laboratory testing, and this was done outside of the United States. There were four individuals who met the current WHO clinical case definition for dengue, yet none were offered laboratory testing or were diagnosed with the disease. Conclusion: This study shows that both patients and doctors in Key West, Florida underestimate the potential for dengue when there are symptoms consistent with the disease. As such, it is certainly possible that there have been unreported cases in the country.

      Wadas, Erica; The University of Arizona College of Medicine - Phoenix; Graziano, Kathleen; Nigro, John (The University of Arizona., 2015-04-14)
      Purpose: Infants born with Heterotaxy Syndrome (HS) often have intestinal malrotation in addition to severe congenital heart disease (CHD). Given the catastrophic risk of midgut volvulus, where the vascular supply to the gut is cut off causing necrotic bowel and possible future short‐gut syndrome following surgery, an elective Ladd procedure is recommended at the first diagnosis of malrotation. In patients with severe CHD, however, the risk of complications from prophylactic surgery is high, especially in infancy prior to stable cardiac palliation. This study sought to determine whether deferring a Ladd procedure during the first six months of life in infants with CHD is safe by focusing on the incidence of volvulus in the HS population, morbidity of volvulus and morbidity of an elective Ladd procedure. Methods: Medical records of patients with HS and intestinal malrotation at Phoenix Children’s Hospital from 2006‐2011 were reviewed. Stage of heart surgery, severity of heart disease, diagnosis of intestinal malrotation, and timing of Ladd procedure if applicable were recorded. Results: 31 patients with HS and intestinal malrotation were identified. Of the 31, 9 had a Ladd procedure prior to six months of age, 2 for volvulus and the other 7 either electively or for less severe GI symptoms that were not suggestive of volvulus. The other 22 did not have a Ladd procedure prior to six months of age. There was one death (1/22) from a non‐gastrointestinal cause in a patient who had not undergone a Ladd procedure. There were no deaths in the 9 patients who underwent a Ladd procedure (0/9). Conclusions: Given the low overall incidence of volvulus in HS, and with continued vigilance for obstructive symptoms, this study suggests that delaying the Ladd procedure in asymptomatic patients with HS and CHD and intestinal malrotation is safe. Watchful waiting may reduce the incidence of cardiac complications during the Ladd procedure by allowing for stabilizing cardiac surgical palliation prior to elective abdominal surgery.

      Cavallo, Katherine; The University of Arizona College of Medicine - Phoenix; Coles, Sarah (The University of Arizona., 2015-04-09)
      Background: Obesity has transitioned from an individual health concern to being a national problem with almost two‐thirds of the adult population in the United States now overweight or obese1. Television potentially provides a medium in which to model healthy and unhealthy behaviors to millions of viewers each week. Although there is no quick solution to obesity, promoting and normalizing healthy lifestyles in today’s most viewed shows may be one tool to help combat an obesogenic lifestyle. Research Question: To what degree do today’s most popular sitcoms model healthy and unhealthy behaviors? Methods: A scorecard with 11 behaviors (6 healthy and 5 unhealthy) was created using publically published guidelines from the Center for Disease Control (CDC)1,2,3, World Health Organization (WHO)4, and the United States Department of Agriculture (USDA)5,6. The top three sitcoms for the 2013‐2014 season, as determined by TV Guide, were viewed and analyzed by one evaluator. These included The Big Bang Theory, The Millers, and Modern Family7. Results: In total, 898 unhealthy behaviors and 532 healthy behaviors were portrayed. The Big Bang Theory demonstrated the most behaviors overall and had the most favorable ratio of healthy to unhealthy behaviors at 1/1.1, compared to 1/3.8 for The Millers and 1/3.2 for Modern Family. The most common unhealthy behavior viewed was beverage choice with 492 occurrences. One of the least portrayed healthy behaviors was moderate physical activity with only 47 instances. In two of the three shows, there were remarkably few examples of fruit and vegetable consumption. Conclusion: Today’s top three sitcoms expose their viewers to many healthy and unhealthy behaviors during the span of a 22‐minute show. Significantly more unhealthy behaviors were portrayed than healthy behaviors. The most common unhealthy behavior centered on beverage choice. This is a behavior that can easily be adjusted to promote a healthier lifestyle. Additionally, food content could reflect more healthy choices. Television shows reach millions of viewers each week and may prove to be a useful tool in helping to reinforce and normalize healthy lifestyle choices.