• Targeting the Hippo Signaling Pathway in Atypical Teratoid Rhabdoid Tumor

      Norris, Gregory; The University of Arizona College of Medicine - Phoenix; Bhardwaj, Ratan (The University of Arizona., 2017-05-26)
      Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant pediatric central nervous system tumor. The prognosis is often poor, with a 2‐year survival rate estimated at 15%. This dismal prognosis highlights the need to develop new treatment modalities for this devastating pediatric tumor. Recently, a tumor suppressing signaling pathway known as Hippo has emerged as a possible cancer treatment target. The Hippo signaling pathway is involved in organ growth and maintenance, and is dysregulated in many diverse cancers. We used quantitative real‐time PCR to evaluate the mRNA expression profile of Hippo pathway genes. We then used determined the protein expression of various Hippo components using Western blots. The results of this study suggest that Hippo plays a definite role in atypical teratoid rhabdoid tumor.
    • Training of Community Health Workers: Recognition of Maternal, Neonatal and Pediatric Illness

      McCabe, Chris; The University of Arizona College of Medicine - Phoenix; Yoblonski, Lara (The University of Arizona, 2017-05-11)
      This systematic review focuses on improving recognition and treatment of acute medical conditions in pregnant women, infants and children in low and middle income countries by Community Health Workers (CHWs). By examining critically selected articles from different electronic databases, this review seeks to organize and present the important characteristics of a training program aimed at reducing maternal, neonatal and childhood mortality. Data in the form of peer‐reviewed and published articles were collected using three public databases – PubMed, Ovid and EMBASE – using specific search terms. Greater than 300 articles where found using the specific search terms. Those articles were then processed through a series of inclusion and exclusion criteria resulting in a cohort of papers which were then individually analyzed for content. After critical analysis of all 15 publications included in the study, it becomes clear that training programs are incredibly diverse. These four aspects of training programs appear to be the most variable between the studies: size of the training program, length of the training program, training assessment and follow‐up refresher courses. Training programs that are shorter in duration or greater in class number do not seem to be any less effective than longer programs with fewer participants. Future studies should be performed in which one training program with identical training techniques, lengths, and focuses is taught in different regions. The impact that this study has on the literature is as follows: Training programs of shorter duration seem to be as effective as their longer counterparts. Finally, there is a clear need for more robust, standardized and geographically and culturally diverse training programs to more effectively study training methods.
    • Triage of Trauma Patients Injured By Large Animals: Do Urban Doctors Undertriage?

      Stevenson, Justin; The University of Arizona College of Medicine - Phoenix; Katz, Eric (The University of Arizona., 2017-05-19)
      In the United States the responsibility to develop criteria for trauma patient’s triage status rests upon individual hospitals rather than the American College of Surgeons. Traumatic injuries from large animals represent a potential need for expanded hospital resources. Urban emergency departments are less likely to regularly see patients with large‐animal related injuries and might be expected to underestimate the predicted injuries. There is scarce research on the topic of initial triage designation for large‐animal related injuries. The aim of this study is to investigate the adequacy of the initial triage designation given to patients presenting with injuries from animals larger than themselves at an urban, safety net, academic Emergency Department and Trauma Center (ACS Level 1 Adult, Level 2 Pediatric). A retrospective chart review was performed on patients presenting to the emergency department (ED) from Jan 2006 until September 2015 with injuries resulting from animals larger than the patient. A total of 213 patients met the inclusion criteria. Our study found that trauma patients injured by large animals who are triaged as low priority have dispositions that are not statistically different from those with higher initial prioritization.
    • Tumor Associated Antigens Harbor Readily Defined and Universally Immunogenic Regions Relevant For Cancer Immunotherapy

      McCurry, Dustin; The University of Arizona College of Medicine - Phoenix; Cohen, Peter; Gendler, Sandra (The University of Arizona., 2017-05-11)
      Recent advances in cancer immunology, highlighted by immune checkpoint inhibitors, have demonstrated that immunotherapy is a viable option in the oncologist’s armamentarium. Despite these advances, many patients are nonresponders. Preliminary studies have suggested that non-responders lack a de-novo anti-tumor antigen immune response that can be unmasked by checkpoint blockade; thus, strategies to induce anti-tumor immune responses are needed. We hypothesized that many tumor associated antigens (Ag) are readily susceptible to immune attack, but only in the context of identifying the tumor antigen epitopes that can reliably initiate an immune response, regardless of individual patient human leukocyte antigen (HLA) haplotype restrictions. We further hypothesized that epitope prediction strategies which seek to identify pan- or highly promiscuous-HLA binding epitopes would reduce the number of potential candidates and be more likely to accurately identify high-priority tumor Ag epitopes. Utilizing known HLA-serotype frequencies and setting a threshold of ninety percent of population coverage, regardless of race or ethnicity, twenty-nine different HLA-DRB1 haplotypes were chosen for antigen prediction utilizing the open source epitope prediction algorithm netMHCIIpan. Predictions were also performed for HLA-A serotypes utilizing the open source algorithm netMHCpan. Predicted epitopes were synthesized in the form of synthetic long peptides and tested in immune system sensitization assays involving unfractionated peripheral blood mononuclear cells (PBMC). Briefly, PBMC were subjected to a two-step culture, first synchronizing their exposure to the long peptides with aggressive surrogate activation of innate immunity, followed by IL-7-modulated T-cell hyperexpansion. Predictions resulted in identification of highly promiscuous-HLA binding epitopes. Unexpectedly, these epitopes clustered together forming high priority regions: unique “hot spots” with high densities of promiscuous HLA-binding epitopes from the widely expressed oncoproteins MUC1, HER2/neu and CMV-pp65 (p<0.0001, for predicted HLA-DRB1 binding affinities, compared to non-hot spot regions). Added synthetic long peptides (>20aa) derived from “hot spot” regions of MUC1, HER2/neu, and CMVpp65 reliably produced selective and sustained expansion of both CD4+ and CD8+ peptide-specific, interferon-γ (IFNγ)-producing Tcells when synchronized with step 2 exposure to exogenous IL-7 (p<0.0001 and p=0.0048, for CD4+ and CD8+ Ag-specific T-cells, respectively, compared to T-cells directed against peptides from non-hot spot regions). “Hot spot” peptide Ag-specific T-cells preferentially recognized endogenous tumor derived MUC1, either in MUC1 expressing tumor cell killing assays (p=0.038, compared to non-peptide Ag-specific T-cells) or as MUC1 tumor lysate when pulsed onto restimulatory PBMC (p=0.022 and 0.025, for CD4+ and CD8+ T-cells, respectively, compared to T-cells directed against peptides from non-hot spot regions). This mechanistically rational antigen selection sequence, effective even for unvaccinated donors, regardless of HLA-haplotype, enables rapid identification of tumor protein regions relevant for cancer immunology, including adoptive immunotherapy, vaccines, and even identification of tumor neo-antigens unique to each patient.
    • Underreporting of Fatigue in Gynecologic Oncology Patients

      Chavez, Marin; The University of Arizona College of Medicine - Phoenix; Chase, Dana (The University of Arizona., 2017-04-27)
      Cancer‐related fatigue (CRF) is a well‐documented symptom among gynecologic oncology patients. However, there is little known about the etiology, and treatment options are currently suboptimal. While the lack of knowledge surrounding the intricacies of CRF impedes effective care, there is arguably a more serious barrier to delivering adequate treatment. Fatigue symptoms are highly underreported to physicians making it impossible to offer treatment to a large subsection of patients. This study will focus specifically on gynecologic oncology patients, a population with a staggering prevalence of CRF. The purpose of this study is to identify clinical, psychosocial, and lifestyle characteristics that may be associated with the underreporting of fatigue specifically in gynecologic oncology patients. The design of this study is a cross‐sectional survey. 89 subjects were recruited from three outpatient sites. Inclusion criteria included: (a) women age ≥18 years old with a known ovarian, uterine, cervical, vaginal, vulvar, or primary peritoneal cancer; (b) Currently attending physician’s office hours and/or undergoing chemotherapy at one of the above listed centers. This study will focus specifically on the reporting of CRF in gynecologic oncology patients. Results showed that barriers to reporting fatigue were significantly correlated with the chemotherapy cycle a patient was undergoing. Additionally, the date of last treatment, a patient’s weight, and the cancer stage was associated with higher levels of underreporting in this population. The prevalence of cancer related fatigue is staggering; however, there is limited research as to why patients are underreporting such a significant symptom to their health care team. With the knowledge from this study, screening for fatigue can become more efficient by targeting women in specific chemotherapy cycles. Practitioners can also use this data to identify patients with high‐risk characteristics that might contribute to their unwillingness to discuss fatigue symptoms.
    • Understanding Severe Acute Malnutrition in Children Globally: A Systematic Review

      Kellerhals, Sarah; The University of Arizona College of Medicine - Phoenix; Caputo, Grace (The University of Arizona., 2017-06-19)
      Severe acute malnutrition (SAM) affects 13 million children under the age of 5 worldwide, and contributes to 1‐2 million preventable deaths each year. Malnutrition is a significant factor in approximately one third of the nearly 8 million deaths in children who are under 5 years of age worldwide. There have been many revolutions in treatment of SAM over time; however, the exact etiology of this preventable condition is not well understood. This review serves to identify the most common risk factors for the development of SAM in children and to identify the most effective treatment for the disease. There are many factors that contribute to developing and surviving SAM as a child, and this systematic review serves to highlight the most common variables that lead to this cause of mortality. An exhaustive review of PubMed was conducted to complete this review. The literature review demonstrates that the most common risk factor for the development of SAM is low maternal literacy.
    • Understanding the Effect of Morphine on the Accuracy of Nuclear Hepatobiliary Imaging Through a Case Study

      Dhadvai, Sandeep; The University of Arizona College of Medicine - Phoenix; Verma, Nishant (The University of Arizona, 2017-05-08)
      Many patients present with upper abdominal pain and receive some type of pain relieving therapy prior to gallbladder imaging. The physiologic effect of morphine and other analgesics on gallbladder function has been well‐studied. What hasn’t been studied as much are the implications on clinical practice and the decision about whether morphine is the best option to use in suspected chronic gallbladder disease. This case study serves to illustrate the influence of morphine in a patient who underwent both inpatient and outpatient hepatobiliary scintigraphy with dramatically different results. This case study perfectly shows the considerations that must be taken when using morphine because it eliminates many confounding variables; the only difference in the patient at the time of initial and subsequent presentation was the presence of morphine.
    • The Use of Pulmonary Dead Space Fraction to Identify Risk of Prolonged Mechanical Ventilation in Children after Cardiac Surgery

      Siddiqui, Muniza; The University of Arizona College of Medicine - Phoenix; Willis, Brigham (The University of Arizona., 2017-05-18)
      Children with prolonged mechanical ventilation after cardiac surgery have a higher risk for poor outcome due to a variety of ventilator‐associated morbidities. It therefore becomes essential to identify these children at higher risk of prolonged mechanical ventilation as well as find methods to identify children ready to be extubated as early as possible to avoid these complications. One physiological variable, the pulmonary dead space fraction (VD/VT), has been suggested as a possible indicator of prolonged mechanical ventilation. VD/VT essentially measures the amount of ventilated air that is unable to participate in gas exchange. Can VD/VT be used successfully in children undergoing cardiac surgery to identify those at risk for prolonged mechanical ventilation and identify those ready for extubation? Retrospective chart review of 461 patients at Phoenix Children’s Hospital in the Pediatric Cardiac Intensive Care Unit since the initiation of standard application of the Philips NM3 monitors in October 2013 through December 2014. From the 461 patients screened, only 99 patients met all the inclusion criteria. These 99 patients consisted of 29 patients with balanced single ventricle physiology and 61 patients with two ventricle physiology. Initial postoperative and pre‐extubation VD/VT values correlated with length of mechanical ventilation for patients with two ventricle physiology but not for patients with single ventricle physiology. Additionally, pre‐extubation VD/VT values of greater than 0.5 indicated higher rates of extubation failure in two ventricle patients. Conclusion: For children with two ventricle physiology undergoing cardiac surgery, VD/VT should be used clinically to estimate the length of mechanical ventilation for these children. VD/VT should also be checked in these patients before attempting to extubate. If VD/VT is found to be higher than 0.5, extubation should not be attempted since the patient is at a much higher risk for extubation failure.
    • The Vaginal and Gastrointestinal Microbiomes in Gynecologic Cancers: A Review of Applications in Etiology, Symptoms and Treatment

      Goulder, Alison; The University of Arizona College of Medicine - Phoenix; Chase, Dana (The University of Arizona., 2017-05-26)
      The human microbiome is the collection of microorganisms in the body that exist in a mutualistic relationship with the host. Recent studies indicate that perturbations in the microbiome may be implicated in a number of diseases, including cancer. More specifically, changes in the gut and vaginal microbiomes may be associated with a variety of gynecologic cancers, including cervical cancer, uterine cancer, and ovarian cancer. Current research and gaps in knowledge regarding the association between the gut and vaginal microbiomes and the development, progression, and treatment of gynecologic cancers are reviewed here. In addition, the potential use of probiotics to manage symptoms of these gynecologic cancers is discussed. A better understanding of how the microbiome composition is altered at these sites and its interaction with the host may aid in prevention, optimization of current therapies, development of new therapeutic agents and/or dosing regimens, and possibly limit the side effects associated with cancer treatment.