Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder characterized by a mutation of the neurofibromin 1 (NF1) gene, resulting in increased susceptibility for multiple tumors, namely, gastrointestinal stromal tumors (GISTs)-the most common types of mesenchymal neoplasms in the gastrointestinal tract. Despite these tumors' predilection for the stomach, it seems to be the least likely part of the gastrointestinal (GI) tract to be affected in cases of neurofibromatosis. Herein, we report a case of a 61-year-old male patient with known neurofibromatosis, who presented with acute blood loss anemia due to a recurrent gastric GIST, requiring partial gastrectomy due to its size and multiple recurrences.

Estimates for 2017 indicate that 20% of cancers globally are gastrointestinal tract (GIT) cancers, with oesophageal cancer being the 8th most common cancer. Oesophageal squamous cell carcinoma (OSCC) occurs in the upper to mid oesophagus and is present at high incidence in developing countries including South Africa. There are no early symptoms, resulting in late diagnosis and poor prognosis. In this study, tumour and blood DNA was obtained from 35 OSCC patients and subjected to whole genome sequencing (WGS). Bioinformatics analysis pipelines were designed to identify the possibility of novel viral insertions, investigating Human Endogenous Retroviruses (HERV's) insertions alongside the presence of somatic mutations in patient samples. The aims being to identify integration of any foreign DNA, to investigate if there is any linkage between HERV insertion and somatic mutations, and to identify any somatic mutations of potential interest in the OSCC cohort. The novel virus investigations however, proved to be inconclusive and there appeared to be no link between HERV insertions and somatic mutations present in the patients. Very significantly, it was determined that numerous somatic mutations were present in the MUC3A gene of the patient cohort, an interesting observation as no such previous association with OSCC has been recorded. MUC3A is a membrane-bound glycoprotein component of mucous gels, and its aberrant expression has been correlated with invasion and metastasis in a variety of other cancers. However, due to the complexity of the particular gene sequence and the known inconsistencies of variant calling performed on complex data sets, these mutations should be viewed with extreme caution as they are likely to be false positives. Analysis of RNA-seq data showed a 4.6 log2 fold increase in MUC3A expression in the tumour samples of these OSCC patients, with a P-adjusted value of 7.05e-06, suggesting highly significant differential gene expression. Functional enrichment analysis further showed that MUC3A was significantly associated with one of the top 5 gene ontologies (extracellular matrix structural constituent) for molecular function ontology class together with a number of collagen (COL) and MMP genes known to play a role in oncogenic progression and membrane stiffness. GSEA and KEGG analysis indicated predominantly chemokine/cytokine pro-inflammatory enriched pathways. Immunohistochemistry staining showed 10 out of 13 of the samples had no detectable levels of MUC3A protein, suggesting that the production of a non-functional truncated protein may lead to the upregulation of MUC3A expression that could possibly play a role in downstream pro-oncogenic signalling.

Background: Psychiatric patients have been well documented to have higher rates of physical illness compared to the general population. Treatments of chronic illnesses such as functional gastrointestinal disorders are beginning to incorporate integrated care models to simultaneously address psychiatric and physical symptoms. This is based on recent research emphasizing the importance of the gut-brain axis. However, the intricacies of connections between infectious diseases and mental illness remain unclear. Diarrheal disease and depression account for a disproportionate amount of the total global burden of disease, being the second and fourth greatest contributors respectively. This highlights the need to investigate the possible links between the two, and interactions along the gut-brain axis in general. Objectives: The objectives of this scoping review and thematic analysis was to explore what is known about infectious acute gastrointestinal illness and its relationship to depressive and anxiety symptoms. Ultimately, this review was intended to act as a case study of novel connections between infectious illnesses and mental illness. Methodology: Following Arksey & O’Malley’s framework, five databases (EMBASE, MedLine, PsychInfo, Global Health, HealthStar) were searched resulting in 1156 titles and abstracts. These were screened for inclusion and produced a total of 17 articles included for review and synthesis. Results: Three major themes were identified: 1) Connections between physical and mental status within this context can occur via i) the microbiome, ii) the immune system, iii) the nervous system, and iv) the endocrine system; 2) Bidirectionality of the gut-brain axis is key in understanding cross-talk between symptoms; 3) Integration of care options might result in improved health outcomes. Conclusion: These findings demonstrate that holistic and integrated interventions must be considered not only for chronic and mental illnesses, but also for infectious and mental illnesses, based on the connections between AGI and depressive and anxiety symptoms. More research is required, particularly with human subjects, in order to further understand the connections between the gut and brain. Incorporation of this knowledge into new treatment plans will allow clinicians to deliver more effective care to their patients who suffer from a dual burden of disease. / Thesis / Master of Science (MSc)

Upper gastrointestinal symptoms can be caused by many different diseases and can present themselves in many different forms and range in intensity depending on the person. In previous research, upper gastrointestinal symptoms have been correlated with stress, smoking, alcohol intake, and nonsteroidal anti-inflammatory drugs (NSAIDs), among others. The purpose of this study will be focusing on finding any association between these risk factors mention and symptoms of upper gastrointestinal disease among college students. The study will utilize an Izumo scale questionnaire for the assessment of abdominal symptoms and Quality of Life (QOL). The questionnaire was built using Survey Monkey and distributed via email to students at the University of Central Florida (UCF). The main hypothesis was that the more the student’s advancement in their college career, stress load, alcohol consumption, smoking, poor diet and a high consumption of some over the counter medication (specifically Non-Steroidal Anti Inflammatory Drugs), the more prone the students will be to present symptoms of upper gastrointestinal disease. The results were analyzed using Statistical Package for the Social Science (SPSS), and Analysis of Variance (ANOVA) were used to find any associations. The One-Way ANOVA tests showed an association between gender, ethnicity, student status, major, cigarette smoking habits, alcohol consumption, binge drinking, diet, stress, sleeping, and overall health. The results of this study present clear evidence that among college students, their demographics as well as lifestyle and school choices have significant associations to the amount of gastrointestinal symptoms they present with.

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Many bacterial species exist in nature as part of highly structured multicellular communities known as biofilms. Amyloids, proteins with a conserved β-sheet quarternary structure, show high resistance to many chemical and enzymatic processes including proteinase K and SDS treatments and are produced as essential adhesins during biofilm formation. Curli fibers expressed by Enterobacteriaceae family members including E. coli and S. Typhimurium are the most studied amyloids to date. Curli-like fibers are also produced by members of the predominant phyla found in the host gastrointestinal microbiota in environmental biofilms. Curli fibers are the predominant microbial-associated molecular pattern (MAMP) on enteric bacteria recognized by the Toll-like receptor (TLR) 2/1-heterodimer complex. Interestingly, the TLR2/1 complex has been implicated as a key player in modulating gastrointestinal homeostasis. The focus of the current studies centered on the innate immune recognition of curli fibers by cells of the gastrointestinal tract and how that contributes to gastrointestinal homeostasis. In the first phase of our studies, utilizing intestinal epithelial cells polarized on semi-permeable tissue culture inserts (Transwells®), we observed that the recognition of curli fibers on Salmonella enterica serovar Typhimurium by intestinal epithelial cells led to the augmentation of the intestinal epithelial barrier in a PI3K-dependent manner. We also observed that bacterial translocation of S. Typhimurium from the apical side to the basolateral side of the Transwell system was limited when curli fibers were present. Furthermore, infection of mice with S. Typhimurium showed that translocation of bacteria from the intestinal lumen into the cecal tissue and mesenteric lymph nodes was limited in C57BL/6 mice as compared to TLR2 knockout mice. In the second phase of our studies, we sought to further investigate the effect that curli fibers exert on gastrointestinal homeostasis through the induction of immunomodulatory cytokines such as Interleukin 10 (IL10) from subepithelial lamina propria cells. IL10 has been shown to contribute to the maintenance of the intestinal epithelial barrier and IL10-deficient mice develop lethal colitis within the first 2-3 months of life. 6-8 week-old female C57BL/6 and TLR2-/- mice were given 5mg/kg of curli fibers via intraperitoneal injection. Subsequent RT-PCR analysis of the small intestine showed a significant expression of Il10 in C57BL/6 that was absent in TLR2-/- mice. Interestingly, no changes in Ifnγ or Tgfβ mRNA were observed in these mice. This response was gut-specific, as Il10 was not detected at all in the spleen. Furthermore, in a chemically-induced colitis model, we observed that the administration of curli fibers to 8-week old Balb/c mice ameliorated disease severity as compared to colitic mice that received mock treatments. Interestingly, Il10 was also induced in the colons of colitic mice that received curli and which were euthanized 6 days after colitis was induced. Our results suggest that curli fibers induce IL10 production via a TLR2-dependent manner to dampen inflammation in the gastrointestinal tract. Overall, our results partially describe a novel role for curli amyloid fibers produced by commensal bacteria in modulating gastrointestinal health and homeostasis. We propose that the induction of immunomodulatory cytokine such as IL10 by amyloid fibers is an important mechanism utilized by commensal bacterial to confer beneficial effects that benefit both the host and microbe. We also propose curli fibers as a potential alternative in the treatment of inflammatory bowel disease. / Microbiology and Immunology