This thesis seeks to use mathematical and computational models to develop measures of clinically available data to deepen our understanding, and improve our treatments, of cancer. We consider two broad characteristics of cancer: heterogeneity, in the form of differences in cellular phenotype, and the physical microenvironment; and evolution, which has become accepted as a driver of tumour progression. To ensure that the conclusions drawn are as translatable as possible, we will attempt to use data types that are clinically available. Using a hybrid discrete-cell-based model in two spatial dimensions, we focus on these fundamental aspects of cancer, with the hope of generating new understanding and useful hypotheses to benefit current patients and oncologists. First, we model a tumour growing under the rules of the cancer stem cell hypothesis and a neutral model of evolution, and ask if we can infer the underlying biological proliferative structure. Specifically, we work toward predicting the symmetric division probability of our simulated tumours from clincally relevant observables, as this is a key driving parameter of tumour progression and therapeutic response. We focus on measures of clonal diversity, group size and shape, and a suite of statistical measures of the phylogenetic trees resulting from the tumour's evolution in different regions of parameter space. We find strikingly different patterns in these measures for changing symmetric division probability which hinge on the inclusion of spatial constraints. These results give us insight into differences between solid and liquid tumours, and also generate a number of actionable clinical and biological hypotheses. Second, we explicitly consider the physical microenvironment of tumours invading into healthy tissue, and model oxygen transport, uptake and cellular competition. We then explore the effect of spatial organisation of blood vessels within the tumour on tumour growth kinetics and cellularity. Finding wide variability in the distribution of oxygen across tumours dependent on both vascular organisation and density, we proceed to explore the utility of spatial measures of vessels on radiation efficacy. Our results offer a novel hypothesis as to the failure of vascular normalisation therapy and radiation, and a possible clinical solution.

The post-translational modification of histones and their interaction with transcription factors is essential to gene regulation. Furthermore, these targets would greatly benefit from probe molecules to fully elucidate their biological actions and to potentially lead to therapeutics. However, these protein-protein interactions have been considered difficult to inhibit and few high-quality chemical probes currently exist for the study of epigenetic biological systems in particular.

Introduction: Oncology nurses provide end-of-life (EOL) care to their patients daily. Oncology nurses' perceptions regarding how to provide quality care to dying patients could be an important addition to the ongoing research on quality EOL care. The purpose of this study was to determine the impact of specific obstacle and supportive behaviors in EOL care as perceived by hospital-based oncology nurses. This study extended the work of Beckstrand, Moore, Callister, and Bond (2009). Methods: A 69-item questionnaire adapted from previous studies (Beckstrand & Kirchhoff, 2005; Beckstrand, Smith, Heaston, & Bond, 2008) was sent to 1,000 nurses who were members of the Oncology Nursing Society (ONS) and who had provided EOL care to dying oncology patients. Three mailings of the questionnaire yielded 380 usable responses from 907 eligible respondents, which resulted in a 41.9% return rate. Oncology nurses were asked to rate obstacle and supportive items on both size and frequency of occurrence as they related to oncology patients in a hospital setting. Results: Obstacle items which received the three highest perceived impact scores were: (1) dealing with anxious family members, (2) families not accepting what the physician is telling them about the patient's poor prognosis, and (3) being called away from the patient and family because of the need to help with a new admit or to help another nurse care for his/her patients. Supportive behavior items which received the three highest impact scores were: (1) allowing family members adequate time to be alone with the patient after he or she has died, (2) providing a peaceful, dignified bedside scene for family members once the patient has died, and (3) allowing families unlimited access to the dying patient even if it conflicts with nursing care at times. Implications: Oncology nurses are dedicated to providing the best EOL care to their patients and patients' families. This study identified obstacle and supportive behavior items with the largest impact on providing quality EOL care. Recommendations: Results of this research demonstrated the need for more EOL education and guidance in forming teams of nurses, social and palliative care workers, and physicians to support the giving of quality care. Nurses also reported the need for more time to support the dying patient and family.

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<p><strong>Abstract</strong></p> <p><strong>Purpose: </strong>While most children diagnosed with cancer survive their initial disease, the intensive treatments they receive place them at risk for late effects. Long-term follow-up (LTFU) care is recommended for cancer survivors for surveillance and early detection of late effects. Knowledge, or lack thereof, regarding diagnosis, treatment and late effects is an important barrier and/or facilitator for attending LTFU care in adolescent and young adult (AYA) cancer survivors. The purpose of our study was to examine the extent of knowledge in Canadian AYA survivors of childhood and adolescent cancer, and identify factors associated with such knowledge.</p> <p><strong>Methods: </strong>Survivors of childhood and adolescent cancer, between the ages of 15 and 26 years, were recruited from three pediatric oncology centres. Patients were invited to participate in the study through mail and clinic recruitment. A questionnaire booklet, including the Cancer Knowledge Survey that asked questions about cancer, treatment and late effects, was administered to collect necessary information. Clinical data was extracted from hospital records to validate participants’ answers.</p> <p><strong>Results: </strong>250 (response rate= 75.5 percent) out of 331 patients invited to participate completed the questionnaire booklet. 18 (7.2 percent) participants lacked information regarding their type of cancer, whereas 25 (10.3 percent) participants were ‘not knowledgeable’ of their treatment. Lack of knowledge regarding treatment was associated with being non-white [odds ratio= 0.3 (0.2-0.6)] compared with white. Also, 83 (33.5 percent) participants were unaware of their late effects. Lack of knowledge regarding late effects was associated with younger age [odds ratio= 1.2 (1.1-1.3)], and having leukemia compared with embryonal tumour [odds ratio= 3.41 (1.10-10.6)].</p> <p><strong>Conclusion:</strong> Results from this study highlights important knowledge deficits, especially in terms of understanding risk of late effects from cancer treatments. Findings from this study can be used to design programs and interventions aimed at increasing cancer knowledge in AYA cancer survivors.</p> / Master of Science (MSc)

Hepatitis B virus encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to cancer. Thus, experiments were designed to test the hypothesis that HBx contributes to HCC via activation of Hh signaling. HBx expression correlated with up-regulation of Hh markers in human liver cancer cell lines, in HBx transgenic mice that developed HCC and in liver samples from HBV infected patients with HCC. The findings in human samples provide clinical validation of those in the HBx transgenic mice (HBxTg), and underscore the relevance of these transgenic mice to disease pathogenesis. Further, blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage independent growth, HCC tumorigenesis in HBx transgenic mice and tumor growth in xenograft model. These results suggest that the ability of HBx to promote cancer is at least partially dependent upon Hh activation and that activation of Hh signaling appears to be important for the development of HBx associated HCC. HBx also activates pathways that stimulate downstream Hh signaling, such as PI3K/AKT and Ras/Raf/MEK, also referred as non-canonical Hh signaling. Upon canonical Hh inhibition, compensatory activation of these pathways was seen in the presence of HBx in liver cancer cell lines and in HBxTg mice. Individual inhibition of these pathways also down-regulated Gli2 expression in HBx positive cell lines. These data suggests that in addition to canonical Hh signaling, activation of PI3K/AKT and ERK pathways by HBx leads to up-regulation of Gli2 expression in HBV-mediated HCC. This work identifies Hh pathway inhibition as a therapeutic strategy to slow tumor development and this work could lead to combination therapies that target Hh, AKT and ERK pathways, which may prevent or delay the appearance/progression of HCC. / Biology

Chromosomal rearrangements can lead to loss of heterozygosity (LOH) and oncogene activation, both of which represent possible causative events in cancer development. Such outcomes can result from the misrepair of DNA damage arising from a variety of events including DNA double-strand breaks (DSBs), collapsed replication forks, and dysfunctional telomeres. In response to a DSB, chromosomal stability is principally maintained through the two major DNA repair pathways; non- homologous DNA end-joining (NHEJ) and homologous recombination (HR). The objective of this thesis was to identify novel factors functioning in prevention of chromosomal instability in response to a DSB in Schizosaccharomyces pombe. To achieve this, a central aim was to identify the genes mutated in a number of radiation-sensitive mutants in fission yeast, previously isolated by the laboratory. These include the ‘loh’ mutants loh-2, loh-5, loh-6 and loh-7, which were found to harbour mutations in known DNA repair genes rad3, rad17, and rad57. Further, a pan-genomic screen for novel HR repair factors was carried out. The Bioneer Version 2 deletion-library, consisting of 3308 haploid deletion strains, was screened for strains displaying hypersensitivity to the DNA damaging agents MMS, bleomycin and camptothecin. This screen yielded 209 hits which were further characterised, utilising a set of non-essential Ch¹⁶ minichromosomes . The minichromosome Ch¹⁶-LMYAU harbours an HO endonuclease recognition sequence and a centromere-distal ade6-M216 heteroallele. Following break-induction, failed repair of the DSB leads to loss of the ade6 allele, indicated by pink sectoring on low adenine plates. 39 sectoring hits were identified and further characterised to quantify levels of gene conversion via HR in response to a DSB, utilising Ch¹⁶-RMYAH. As a result of this study, a group of novel genes functioning in HR repair were identified. Finally, one of these hits, putative RNA metabolism protein Nrl1, was subjected to further characterisation, associating this protein with DNA damage repair for the first time. The work presented here, documents the approaches taken to successfully identify novel DNA repair factors in fission yeast.

External beam radiation therapy (EBRT) is the most common form of radiation therapy (RT) that uses controlled energy sources to eradicate a predefined tumour volume, known as the planning target volume (PTV), whilst at the same time attempting to minimise the dose delivered to the surrounding healthy tissues. Tumours in the thoracic and abdomen regions are susceptible to motion caused mainly by the patient respiration and movement that may occur during the treatment preparation and delivery. Usually, an adaptive approach termed adaptive radiation therapy (ART), which involves feedback from imaging devices to detect organ/surrogate motion, is considered. The feasibility of such techniques is subject to two main problems. First, the exact position of the tumour has to be estimated/detected in real-time and second, the delay that can arise from the tumour position acquisition and the motion tracking compensation. The research work described in this thesis is part of the European project entitled ‘Methods and advanced equipment for simulation and treatment in radiation oncology’ (MAESTRO), see Appendix A. The thesis presents both theoretical and experimental work to model and predict the respiratory surrogate motion. Based on a widely investigated clinical internal and external respiratory surrogate motion data, two new approaches to model respiratory surrogate motion were developed. The first considers the lung as a bilinear model that replicates the motion in response to a virtual input signal that can be seen as a signal generated by the nervous system. This model and a statistical model of the respiratory period and duty cycle were used to generate a set of realistic respiratory data of varying difficulties. The aim of the latter was to overcome the lack of test data for a researcher to evaluate their algorithms. The second approach was based on an online polynomial function that was found to adequately replicate the breathing cycles of regular and irregular data, using the same number of parameters as a benchmark sinusoidal model.

Growth and metastasis of tumors appear to be dependent on the ability of tumor cells to recruit blood vessels. Integrins are a class of cell adhesion molecules that may have a role in angiogenesis. In this study the effect of the expression of two integrins, α6β1 and α6β4, on microvessel density in human prostate tumor xenografts in SCID mice was evaluated. Five methods (one-person count, two-person count, digital analysis of immunostained tissues, and digital analysis of vascular corrosion casts) were used to measure microvessel density. Results indicate that alpha6 integrin expression correlates negatively with tumor vessel density. and with tumor cell proliferation but not the extent of the tumor burden. β4 integrin expression does not appear to affect tumor vessel density, tumor cell proliferation, nor tumor burden. Comparison of methods of quantitation suggest that computer-assisted vessel counting may offer advantages over optical counting or computer-assisted area measurement.