Medicine and Health Sciences Commons^™

Characterizing Human Papillomavirus Associated Oral Epithelial Dysplasia, Damir Rosic

Electronic Thesis and Dissertation Repository

The role of high-risk human papillomavirus (HR-HPV) is well documented in oropharyngeal squamous cell carcinoma and cervical cancer. Although a subset of oral dysplastic lesions have been associated to HPV infection as well, there is currently limited data characterizing these lesions. We identified HPV-associated oral epithelial dysplasia (HPV-OED) through screening for histopathological features of HPV and p16INK4a immunoreactivity. Transcriptionally active infections were confirmed by performing RT-qPCR to identify E6 mRNA expression. We identified 82 cases of confirmed HPV-OED that showed a strong predilection for male patients and anatomical sites such as floor of mouth and ventral tongue. This group had …

The Molecular Landscape Of Early-Stage Breast Cancer With Lymph Node Metastasis, Farhad Ghasemi

Electronic Thesis and Dissertation Repository

Axillary lymph nodes (ALNs) are the primary site of metastasis in breast cancer, and their involvement has implications in disease staging, prognostication, and treatment decisions. A non-invasive modality of assessing the risk of ALN metastasis can improve care in patients with early-stage breast cancer by omitting the morbidity and costs associated with axillary surgery.

This thesis explores the molecular landscape of early-stage breast cancers with ALN metastasis and shows the potential of tumour molecular signatures in predicting ALN involvement. After a systematic review of the literature, we use data from The Cancer Genome Atlas (TCGA) to develop molecular signatures correlated …

The Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

Incidence Of Cancer And Stage At Diagnosis Among People With Recent-Onset Psychotic Disorders, Jared C. Wootten

Electronic Thesis and Dissertation Repository

Evidence on cancer incidence in people with psychotic disorders, compared to the general population, is equivocal, although those with psychotic disorders so have more advanced stage of cancer at the time of diagnosis. The objective of this thesis was to compare cancer incidence and stage at diagnosis for people with psychotic disorders, relative to the general population. Our systematic review did not observe a significant difference in overall cancer incidence among people diagnosed with psychotic disorders (RR = 1.08, 95% CI: 1.00 to 1.16), however people with psychotic disorders were more likely to be present with advanced stage cancer at …

Differential Effects Of Kim-1 In Subcutaneous And Orthotopic Renca Models Of Kidney Cancer, Demitra M. Yotis Dy

Electronic Thesis and Dissertation Repository

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The …

Characterizing The Role Of Tdg In Fxr-Dependent Signaling, Oladapo A. Onabote

Electronic Thesis and Dissertation Repository

Thymine DNA Glycosylase (TDG) plays a key role in active demethylation by excising intermediates of 5-methylcytosine. The function of TDG is required for embryonic development, as Tdg-null embryos die at E11.5. To bypass this embryonic lethality, our lab generated conditional Tdg knockout (TDG_CKO) mice. These mice develop late-onset hepatocellular carcinoma (HCC), partly due to impaired Farnesoid X Receptor (FXR) signaling. Interestingly, Fxr-knockout mice display a similar phenotype and transcriptional profile to TDG_CKO mice, prompting us to investigate a role for TDG in FXR signaling. To this end, we generated Tdg/Fxr double-knockout (DKO) mice. …

Evaluating The Utility Of Protein Biomarker, S100a7, And Diagnostic Test, Straticyte, In Predicting The Progression Of Oral Dysplasia, Lachlan Mclean

Electronic Thesis and Dissertation Repository

Five-year survival of oral cancer has remained relatively unchanged despite advancements in treatment, mostly because diagnosis is often made at an advanced stage of disease. The progression of dysplasia to oral cancer often follows a stepwise progression. Histopathology is considered the ‘gold standard’ for diagnosing dysplasia and lesions at a high risk of progression to oral cancer, but lends itself to subjectivity. The protein biomarker, S100A7, in oral dysplasia and squamous cell carcinoma has shown some predictive value for the transformation of dysplasia to cancer. Straticyte, a diagnostic test utilizing S100A7 to predict the probability of progression of oral dysplasia …

The Role Of Kidney Injury Molecule-1 In The Metastasis Of Renal Cell Carcinoma, Jasper Lee

Electronic Thesis and Dissertation Repository

Over 30% of patients with renal cell carcinoma (RCC) present with metastases, with median survival of 2 years. Kidney injury molecule 1 (KIM-1) is a cell-surface glycoprotein expressed by >90% of RCC tumours. Preliminary data mined from The Cancer Genome Atlas RNA-sequencing database indicates that KIM-1 overexpression predicts overall survival in patients. Here we sought to determine if tumour KIM-1 plays a role in RCC cell extravasation and metastasis to the lungs. In vitro invasion and in vivo metastasis assays were performed to investigate the metastatic potential of KIM-1-expressing cells, and RNA-seq was conducted to identify differentially expressed genes between …

Angiogenesis And Neo-Microcirculatory Function In Diseased Tissue Revealed By Intravital Microscopy, Giovanni-Michele Arpino

Electronic Thesis and Dissertation Repository

Angiogenesis is the process of generating new blood microvessels. In adults, angiogenesis is fundamental to tumor biology and also to tissues rendered ischemic from vascular occlusion. Despite a promising appeal, strategies designed to simulate or otherwise modify the angiogenic process in adult tissues have yet to realize significant therapeutic potential. Importantly, understanding the structure and function of new microvascular networks formed in adult, diseased tissues is limited. In fact, it remains unknown if a new or regenerated microcirculation can effectively deliver oxygen to the tissue. The purpose of this thesis was to seek out novel determinants of functional angiogenesis and …

Investigating E2f Independent Cell Cycle Control And Tumor Suppression By Prb, Michael J. Thwaites

Electronic Thesis and Dissertation Repository

Cellular division is primarily controlled at the G1 to S-phase transition of the cell cycle by the retinoblastoma tumor-suppressor protein (pRB). The ability of pRB to restrict S-phase entry is primarily attributed to the repression of E2F transcription factors required to upregulate cell cycle target genes necessary for cellular division. Interestingly, while pRB is disrupted in the vast majority of human cancers, mutations typically target upstream regulators of pRB leading to inactivation through hyperphosphorylation. The rarity of direct pRB mutations suggests that the regulation of the cell cycle by pRB may involve additional mechanisms outside of E2F repression, as this …

Longitudinal Evaluation Of Patient Concerns After Surgery For Head And Neck Cancer, Isabel Wozniczka

Electronic Thesis and Dissertation Repository

The primary purpose of this study was to investigate and describe the longitudinal effects of shoulder and neck mobility, strength, and quality of life (QOL) following neck dissection (ND) surgery and identify the concerns of head and neck cancer (HNC) patients. ND is one of the standard procedures for treating HNC, which results in many complications and dysfunctions that can have an effect on a patient’s QOL.

The study had 27 eligible HNC participants who underwent ND, of which eight participated in the shoulder range of motion (ROM) and strength and 12 participated in the QOL patient-reported outcomes analysis. The …

Women's Stories Of Breast Cancer: Sharing Information Through Youtube Video Blogs, Jenna Kressler

Electronic Thesis and Dissertation Repository

Breast cancer is one of the most prevalent chronic diseases among North American women. Individuals need accessible and reliable health information for self-care and self-health promotion. Increasingly, individuals are contributing to and accessing information about cancer, using interactive online resources such as YouTube. The purpose of this research was to investigate the personal YouTube video blogs of women with breast cancer and their portrayed messages. This study used a narrative inquiry to examine the video blogs of four women with breast cancer. The women talked about having cancer as a transformative experience. Information about breast cancer from healthcare providers was …

Indoleamine 2,3-Dioxygenase Confers Resistance To Chemotherapy And Γ Radiation To Cancer Cells, Independent Of Direct Immune Involvement, Saman Maleki Vareki

Electronic Thesis and Dissertation Repository

Indoleamine 2,3-dioxygenase-1 (IDO) is an immunosuppressive molecule expressed by most human tumours. IDO levels correlate with poor prognosis in cancer patients and IDO inhibitors are under investigation to enhance endogenous anticancer immunosurveillance. Little is known regarding the immune-independent functions of IDO relevant to cancer therapy. In this thesis I show, for the first time, that IDO mediates human tumour cell resistance, in a cell-autonomous fashion, to single and combination treatment with a diverse group of chemotherapy drugs and g radiation. These drugs include a PARP inhibitor (olaparib), a DNA cross-linking agent (cisplatin), a folate antimetabolite (pemetrexed), a nucleoside analogue (gemcitabine), …

Folate Receptor-Targeting Liposomes For The Delivery Of Antisense Molecules To Cancer Cells, Colin J. Way

Electronic Thesis and Dissertation Repository

RNAi (RNA interference) is emerging as a promising tool for cancer therapy. Small interfering RNA (siRNA) molecules are activated in that pathway to reduce specific tumour cell RNAs that mediate malignancy. SiRNA treatment has been primarily limited to in vitro studies: lack of efficient, preferential in vivo delivery to target cells remains a major obstacle. Many human tumours overexpress folate receptors (FR), and siRNA-mediated reduction of thymidylate synthase (TS) sensitizes tumour cells to anti-TS drugs. I developed a folate-containing cationic liposome to preferentially deliver anti-TS siRNA to FR-expressing human tumour cells. I show, in vitro, that liposome-encapsulated siRNA (but …

From Isolated Tumour Cells To Overt Lymph Node Metastases: Biological And Imaging Studies On The Development Of Experimental Lymph Node Metastases, Michael M. Lizardo

Electronic Thesis and Dissertation Repository

Metastatic colonization and establishment of overt lymph node (LN) tumours indicates poor prognosis for cancer patients. However, the basic biology that influences the development of LN metastasis is poorly understood due to the lack of basic animal models. The following work provides a new lymph node experimental metastasis assay (LEMA) that permits the assessment of tumour cell fate after they arrest in draining LNs. In using this new model, we discovered that only 8% of the tumour cells that arrive in the LN are successful in forming overt tumours. This work also explored the use of imaging approaches to monitor …