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Introduction: Long–standing disparities in colorectal cancer (CRC) outcomes and survival between Whites and Blacks have been observed. A person–centered approach using latent class analysis (LCA) is a novel methodology to assess and address CRC health disparities. LCA can overcome statistical challenges from subgroup analyses that would normally impede variable–centered analyses like regression. Aim was to identify risk profiles and differences in malignant CRC survivorship outcomes. Methods: We conducted an LCA on the Surveillance, Epidemiology, and End Results data from 1975 to 2016 for adults ≥18 (N = 525,245). Sociodemographics used were age, sex/gender, marital status, race, and ethnicity (Hispanic/Latinos) and stage at diagnosis. To select the best fitting model, we employed a comparative approach comparing sample-size adjusted BIC and entropy; which indicates a good separation of classes. Results: A four–class solution with an entropy of 0.72 was identified as: lowest survivorship, medium-low, medium-high, and highest survivorship. The lowest survivorship class (26% of sample) with a mean survival rate of 53 months had the highest conditional probabilities of being 76–85 years–old at diagnosis, female, widowed, and non-Hispanic White, with a high likelihood with localized staging. The highest survivorship class (53% of sample) with a mean survival rate of 92 months had the highest likelihood of being married, male with localized staging, and a high likelihood of being non-Hispanic White. Conclusion: The use of a person–centered measure with population-based cancer registries data can help better detect cancer risk subgroups that may otherwise be overlooked.

Thesis (Ph.D. (Biochemistry)) -- University of Limpopo, 2021 / Cancer remains one of the leading causes of morbidity and mortality worldwide with an estimated 9.9 million deaths in 2020. Cancer treatment regimens such as chemotherapy and radiotherapy have over the years fallen short due to drug resistance, toxicity, damage to normal healthy cells and tissues surrounding the treatment area. Moreover, they have shown very limited survival benefits for most advanced staged cancers such as colorectal cancer, which in 2020 was responsible for 3 728 deaths with a 6.8% incidence rate. Despite the many efforts in developing alternative chemotherapeutic strategies, cancer of the colon and cancer, in general, remains a burden. For centuries, plants and plant derivatives have been exploited for their nutritional and medicinal properties and now serve as chemical scaffolds or templates for designing and synthesising products with pharmacological importance. Herbal medicines are claimed to enhance therapeutic effects and are often used in combination with chronic medication. However, the concurrent use of herbal medicines and synthetic drugs may affect the pharmacokinetic profile of therapeutic drugs or trigger unexpected and undesirable effects. This study aimed to characterise the leaf extracts (crude water and crude methanol) of Momordica balsamina and investigate their potential anticancer activity on HT-29 colon cancer cells. The study also aimed to asses the effect of the extracts on drug metabolising enzymes (CYP450), specifically those which metabolise 5-Fluorouracil (5-FU) prodrugs or are inhibited by 5-FU since it is one of the first-line treatments for colon cancer. Dried powdered leaves were extracted using water and absolute methanol to obtain crude water and crude methanol extracts, respectively. For characterisation, the extracts were spotted on thin-layer chromatography (TLC) plates and further screened using chemical tests. The ferric ion reducing power assay and Liquid chromatographymass spectrometry were used to determine the antioxidant activity of the extracts and to identify prominent or abundant compounds in each extract, respectively. To assess the cytotoxic effect of the extracts and 5-FU, HT-29 colon cancer cells and C2C12 muscle cells, which were used as a model for normal cells, were exposed to concentrations that ranged from 0 to 2000 µg/ml for the water (H2O) extract, 0 to 300 µg/ml for the methanol (MeOH) extract or 0 to 100 µg/ml of 5-FU for 24 and 72 hours, and subjected to the MTT assay. The effect of the extracts on the efficacy of 5-FU was xxi assessed using the MTT assay by combined treatments of the extract and 5-FU. Genotoxicity of the extracts was assessed on the C2C12 cells using the Muse™ MultiColour DNA Damage kit. The generation of intracellular reactive oxygen species (ROS) was assessed by flow cytometry using the DCFH-DA assay. The JC-1 and acridine orange (AO)/propidium iodide (PI) staining assays were used to assess the effect of the extracts on the mitochondrial potential as well as cell and nuclear morphology, respectively. Apoptosis was quantified by flow cytometry using annexin V/PI and caspase activation assessed using the Caspase-8 and Caspase-9 colourimetric assay kits. The pro-apoptotic mechanism(s) was determined by assessing the expression profiles of selected apoptosis regulatory proteins using the human apoptosis antibody array kit. Cell cycle analysis by flow cytometry was conducted to determine the effect of the extract on the cell division cycle. Moreover, to determine the potential of herb-drug interactions, the Vivid® CYP450 Screening kits and P-gp-GloTM Assay Systems with P-glycoprotein were used to assess the effect on the activity of drug metabolising enzymes and drug transportation, respectively. The results showed that the MeOH extract possessed fewer polar compounds, higher ferric iron-reducing power, and a relative abundance of flavonol glycosides, cucurbitane-type triterpenoid aglycones, and cucurbitane-type glycosides than the H2O extract. The MeOH extract was further selectively cytotoxic to the HT-29 colon cancer cells at 24 hours of treatment and selectively induced genotoxicity in HT-29 cells. The H2O extract, however, was not cytotoxic to the HT-29 cells at all the tested concentrations at 24 and 72 hours of treatment. Analysis of nuclear and cell morphology suggested that the decrease in the percentage viability of MeOH extracttreated cells was associated with apoptotic cell death. Apoptosis was further confirmed by the loss of mitochondrial potential, increase in ROS production, caspase-8 and -9 activities as well as Annexin-V/PI-stained cells. Cell cycle analysis revealed cell cycle arrest at the S phase in MeOH extract-treated cells. Analysis of protein expression profiles revealed that the extract modulated various proteins that play a role in the promotion or inhibition of apoptosis. Moreover, the MeOH extract was shown to inhibit the activity of CYPs 1A2, 2A6, 2C8, and 2C9, while the H2O extract showed no significant inhibitory effects on the activity of all tested CYPs and 5-FU only significantly inhibited the activity of CYP2C9. However, combinatory treatments with 5-FU and the MeOH extract were shown to have no additive or diminishing effects on the efficacy of 5-FU on the activity of all the tested CYP enzymes. Treatment with 5FU (0.008 – 32 μg/ml) and the H2O extract (0.02 – 200 μg/ml) was shown to stimulate the ATPase activity of P-gp, while the MeOH extract significantly inhibited its activity with concentrations of 0.2, 2, and 20 μg/ml. In conclusion, the MeOH extract selectively induced cancer cell toxicity, genotoxicity as well as S phase cell cycle arrest and apoptosis via the intrinsic and extrinsic pathways. The anticancer activity of the MeOH leaf extract of M. balsamina as well as its antioxidant potential may be attributed to the presence and relative abundance of flavonol glycosides, cucurbitane-type triterpenoid aglycones, and cucurbitane-type glycosides. Although the MeOH extract may potentially reverse the effects of P-gp multidrug resistance by decreasing its activity, its inhibition of the activity of CYPs 1A2, 2A6, 2C8 and, 2C9, which are involved in the metabolism of more than 80% of the drugs in clinical use may suggest that co-administration of the MeOH extract may still result in increased plasma levels of drugs, thereby resulting in toxicity. The H2O extract, although not pro-apoptotic as the MeOH extract may still have the potential to be developed as a nutraceutical as it was shown to exhibit no adverse drug interactions and because this species is known to possess a wide variety of nutritional and medicinal values. / South African Medical Research Council (SAMRC) Research Capacity Development Initiative.

Hippo signaling is a tumor suppressive signaling pathway that controls organ size by regulating cellular proliferation, apoptosis, and differentiation during development, regeneration, and homeostasis. The Hippo pathway inhibits transcriptional co-activators and Hippo pathway effectors YAP/TAZ, activation of which is often seen in cancer. Within the adult mammalian intestine, homeostasis of which requires intricate reciprocal interaction between the gut epithelium and adjacent mesenchyme, the Hippo-YAP pathway is crucial for intestinal epithelial homeostasis and regeneration. However, its role in adult mesenchymal homeostasis remains poorly understood. Here, I genetically dissect the role of mesenchymal Hippo-YAP signaling in adult intestinal homeostasis. I find that deletion of core kinases LATS1/2 or YAP activation in mesenchymal progenitor cells, but not terminally differentiated cells, disrupts signaling in the stem cell niche and mesenchymal homeostasis by inducing mesenchymal overgrowth and suppressing smooth muscle actin expression. Furthermore, inhibition of Hippo signaling in Gli1+ mesenchymal progenitors, the main source of Wnt ligands within the stem cell niche, stimulates Wnt ligand production and subsequent epithelial Wnt pathway activation, thereby driving epithelial regeneration following DSS-mediated injury as well as exacerbating APC-mediated tumorigenesis. Altogether, our data reveal a previously underappreciated requirement and the underlying mechanism for stromal Hippo-YAP signaling in adult intestinal homeostasis.

A primary reason geospatial approaches are important in cancer research is that health and disease are shaped not only by factors such as age, race/ethnicity, genes, and clinical care but also by the environment where individuals work and act. While the use of geospatial approaches in cancer research is growing, several limitations remain. For example, for most population-based studies, cancer patients' neighborhood environments are based on only a single location derived from the residence at the time of diagnosis.This dissertation aimed to address this limitation by using a unique dataset of colon cancer patients diagnosed in New Jersey that include residential histories obtained through a data linkage with LexisNexis, a commercial data collection company. By incorporating residential histories, I moved beyond a cross-sectional approach to examine how residential histories and socio-spatial mobility can change a patient’s geographic context over time and influence survival. To demonstrate the application of these data in this dissertation, I completed three case studies. In the first case study, I compared whether including residential histories changed the risk of death estimates by neighborhood poverty compared to the traditional approach when including only the location at the time of diagnosis. Results suggested that the risk of death estimates from neighborhood poverty were generally similar in strength and direction regardless of residential histories inclusion. This finding was likely a result of minimal socio-spatial mobility of colon cancer patients (i.e., patients generally moving to census tracts with similar poverty levels). The second study aimed to compare the geographic risk of death estimates when using single location and residential histories in spatial models. Results overall showed that the geographic patterns of the risk of death estimates were generally similar between the models. However, not accounting for residential mobility resulted in underestimated geographic risk of death in several areas. This finding was related to the fact that approximately 35% of the colon cancer patients changed the residency, and 12% of the initial study population left New Jersey after the diagnosis. In the third case study, I examined whether landscape characteristics (e.g., built environment) were associated with the risk of death from colon cancer independent of individual-level factors, residential mobility, and neighborhood poverty. The results indicated that an increasing proportion of high-intensity developed-lands substantially increased the risk of death, while an increase in the aggregation and connectivity of vegetation-dominated low-intensity developed-lands reduced the risk of death. These findings suggested that places lacking greenspaces could have worse access to recreational sites that promote physical activity. Overall, this dissertation expands our knowledge about the geographic disparities in colon cancer in New Jersey. It also provides specific examples of integrating residential histories and remote sensing-based products into cancer disparities research. Including residential histories opens up new avenues of inquiry to better understand the complex relationships between people and places, and the effect of residential mobility on cancer outcomes. Combining multiple socio-demographic and environmental domains to estimate the neighborhood effects on cancer outcomes will increase our potential to understand the underlying pathways. / Geography

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Colonoscopy provides a minimally invasive tool for examining and treating the colon without surgery, but current endoscope designs still cause a degree of pain and injury to the colon wall. The most common colonoscopies are long tubes inserted through the rectum, with locomotion actuators, fiber optic lights, cameras, and biopsy tools on the distal end. The stiffness required to support these tools makes it difficult for the scopes to navigate the twisted path of the colon without damaging the inside wall of the colon or distorting its shape. In addition, little is known about how sharp and forceful endoscopes can be without accidentally cutting into tissue during navigation. In order to solve the requirements of stiffness (to support tools) and flexibility (to navigate turns), we expanded on a design by Zehel et al. [49], who proposed surrounding a flexible endoscope with an external exoskeleton structure, with controllable stiffness. The exoskeleton structure is comprised of rigid, articulating tubular units, which are stiffened or relaxed by four control cables. The stiffened or locked exoskeleton structure aids navigation and provides stability for the endoscope when it protrudes beyond the exoskeleton structure for examination and procedures. This research determined the design requirements of such an exoskeleton structure and simulated its behavior in a sigmoid colon model. To predict just how pointed an endoscope can be without damaging tissue under a given force, we extrapolated a strength model of the descending colon from published stress-strain curves of human colon tissue. Next we analyzed how friction, cable forces, and unit angles interact to hold the exoskeleton structure in a locked position. By creating two- and three-dimensional models of the exoskeleton structure, we optimized the dimensions of the units of an exoskeleton structure (diameter, thickness, and leg angle) and cable holders ( cable attachment location) to achieve the turns of the sigmoid colon, while still remaining lockable. Models also predicted the loss of force over the exoskeleton structure due to curving, further determining the required cable angles and friction between units. Finally we determined how the stiffness of the endoscope stem affected locking ability and wear inside the exoskeleton structure. / Ph. D.

Colorectal cancer is the third most common cancer and the leading cause of cancer deaths in Western industrialised countries. Despite recent advances in the screening, diagnosis, and treatment of colorectal cancer, an estimated 608,000 people die every year due to colon cancer. Our current knowledge of colorectal carcinogenesis indicates a multifactorial and multi-step process that involves various genetic alterations and several biological pathways. The identification of molecular markers with early diagnostic and precise clinical outcome in colon cancer is a challenging task because of tumour heterogeneity. This Ph.D.-thesis presents the molecular and cellular mechanisms leading to colorectal cancer. A systematical review of the literature is conducted on Microarray Gene expression profiling, gene ontology enrichment analysis, microRNA and system Biology and various bioinformatics tools. We aimed this study to stratify a colon tumour into molecular distinct subtypes, identification of novel diagnostic targets and prediction of reliable prognostic signatures for clinical practice using microarray expression datasets. We performed an integrated analysis of gene expression data based on genetic, epigenetic and extensive clinical information using unsupervised learning, correlation and functional network analysis. As results, we identified 267-gene and 124-gene signatures that can distinguish normal, primary and metastatic tissues, and also involved in important regulatory functions such as immune-response, lipid metabolism and peroxisome proliferator-activated receptors (PPARs) signalling pathways. For the first time, we also identify miRNAs that can differentiate between primary colon from metastatic and a prognostic signature of grade and stage levels, which can be a major contributor to complex transcriptional phenotypes in a colon tumour.

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<p><strong>Purpose</strong></p> <p>Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer death among Canadians. Little is known about the types of supportive care needs (SCNs) that patients with colon cancer experience during the diagnostic phase or whether these needs are met. To inform the development of population specific healthcare services, a needs assessment of patients with newly diagnosed advanced colon cancer was conducted to identify the types, prevalence, severity, and importance of unmet SCNs, as well as to identify any gaps between patient priority needs and their use of supportive care services.</p> <p><strong>Patients and Methods </strong></p> <p>A descriptive cross-sectional survey was conducted. Over one year, all newly diagnosed patients with colon cancer at the Juravinski Cancer Centre were screened for eligibility. Sixty-two of 80 eligible patients completed a self-report written questionnaire prior to starting treatment (response rate = 77.5%). The questionnaire included the Supportive Care Needs Survey-Short Form, Functional Assessment of Cancer Therapy-Colorectal and Health Service Utilization Questionnaire.</p> <p><strong>Results</strong></p> <p>‘Fears about the cancer spreading’ was the most prevalent unmet SCN (n = 52/62 or 84%). Unmet SCNs experienced by 65% or more of participants related to lack of control about treatment outcomes, the uncertain future, and concerns about family member well-being. Patients also rated these needs as being most severe.</p> <p>The two most severe CRC-specific concerns were related to ‘body appearance’ (Mean = 1.77, SD = 1.37) and ‘bowel control’ (Mean = 2.28, SD = 1.37). The most important or priority unmet needs were related to uncertainty about the future (43.5%), fatigue (24.2%), and information (22.6%). Less than 12% of participants had used existing supportive care services in the community.</p> <p><strong>Conclusion </strong></p> <p>Prevalent and priority unmet needs were related to psychosocial support and information. Recommendations for designing colon cancer-specific services are provided along with strategies to improve patient use of existing resources.</p> <p><strong> </strong></p> / Master of Science (MSc)