Medicine and Health Sciences Commons^™

Genomic Predictors Of Drug Response To The Alpha-Specific Phosphoinositol 3-Kinase (Pi3ka-Alpha) Inhibitor Byl719 In Head And Neck Cancers, Giananthony T. Rizzo

Electronic Thesis and Dissertation Repository

PIK3CA is the only frequently mutated, druggable oncogene in head and neck squamous cell cancer (HNSCC), with PIK3CA point mutations and gene amplification rates of 17.5% and 40% respectively, with higher rates in HPV-positive disease. The objective of this research was to determine the effects of BYL719, an α-specific PI3K inhibitor in HNSCC cell lines.

All cell lines with PIK3CA hotspot point mutations or gene amplifications will be sensitive to BYL719.

Twenty-eight HNSCC cell lines were subjected to increasing concentrations of BYL719 and cell viability was measured over time. Cell lines were screened for activating PIK3CA hotspot mutations and amplifications …

Roles Of P2x7 Receptors In Adipose And Skeletal Tissues Of Mice, Kim L. Beaucage

Electronic Thesis and Dissertation Repository

P2X7 is an ATP-gated ion channel in the plasma membrane of a number of cell types. Previous in vitro studies show that P2X7 plays a role in regulating the differentiation of osteoblasts and adipocytes from mesenchymal precursors, as well as cellular metabolism and energy homeostasis. Furthermore, P2X7 has been implicated in mediating the effects of mechanical stimuli in bone. Our objective was to investigate the roles of P2X7, mechanical vibration, and their possible interaction in regulating body composition in vivo. We developed a novel method to monitor body composition during growth and aging in mice using micro-computed tomography (Chapter …

Polycomb Repressive Complex 2 Regulates Mir-200b In Retinal Endothelial Cells: Possible Implications In Diabetic Retinopathy, Michael A. Ruiz

Electronic Thesis and Dissertation Repository

Glucose-induced augmented vascular endothelial growth factor (VEGF) production is a key event in diabetic retinopathy. We have previously demonstrated that downregulation of miR-200b increases VEGF, mediating structural and functional changes in the retina in diabetes. However, mechanisms regulating miR-200b in diabetes are not known. Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process. We hypothesized that, in diabetes, PRC2 represses miR-200b through its histone H3 lysine-27 trimethylation mark. We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation, and that inhibition of …

A Non-Contrast Magnetic Resonance Imaging Technique To Assess Blood-Brain Barrier Permeability, Harini Pandithasekera

Electronic Thesis and Dissertation Repository

The Blood-brain barrier (BBB) regulates the entry of compounds between the blood and the brain, thus plays an important role in brain homeostasis. Studies indicate in disease states such as Alzheimer’s the BBB integrity is compromised. The motive of this project is to investigate the sensitivity of the diffusion-weighted arterial spin labeling (DW-ASL) technique to detect water exchange. Testing the sensitivity requires a reliable method of opening the barrier at specific locations of the brain. Here, a unique technology named focused ultrasound (FUS) has been used to mimic a compromised BBB environment.

A series of experiments were conducted in a …

Mri Relaxation Rates: A Quantitative Approach To Track Tumour Cells Expressing Maga, Anindita Sengupta

Electronic Thesis and Dissertation Repository

Using magnetic resonance imaging, relaxation rate measurements were

performed in cancer cells overexpressing a magnetotactic bacterial gene, MagA.

Measurements of magnetic resonance relaxation rates in this expression

system is important for optimizing cell detection and specificity, for developing

quantification methods, and for refinement of gene-based iron contrast using

magnetosome associated genes. We measured the total transverse

relaxation rate (R2^*), its irreversible and reversible components (R2 and R2^′,

respectively) and the longitudinal relaxation rate (R1) in MDA-MB-435 tumor cells.

Clonal lines overexpressing MagA were cultured in the presence and absence of

iron supplementation, and mounted in a …

Nerve Blood Flow Control In Health & Disease:The Effects Of Type 1 Diabetes And Exercise Training, Terry D. Olver

Electronic Thesis and Dissertation Repository

Peripheral nerve blood flow (NBF) is critical to nerve health. Impaired NBF control may contribute to the progression of diabetes peripheral neuropathy. The purposes of this dissertation were: i) to investigate the acute and chronic effects of hyperglycemia on basal sciatic NBF (measured via Doppler ultrasound), ii) to examine the potential vasodilatory effects of insulin (euglycemic hyperinsulinemic clamp; 10 mµ•kg^-1•min^-1) on NBF control in healthy rats and rats with insulin-treated type 1 diabetes (DS) and iii) to determine if exercise training (~75% VO₂max, 60 min/day, 5 days/wk for 10 wk) improves vasa nervorum reactivity …

Investigating Risk Factors For Pediatric Opioid Morbidity And Mortality, Lauren E. Kelly

Electronic Thesis and Dissertation Repository

Young children are sometimes prescribed opioids and may be exposed to opioids in utero and through breast milk. Clinical and genetic factors create large inter- individual variability in opioid response and have been associated with life threatening and often fatal adverse drug reactions in young children. Genetic factors have been studied in adults but there is little clinical evidence in young children. The focus of this thesis is on three commonly prescribed opioids: codeine, morphine and methadone. The objective of this work was to investigate risk factors associated with opioid related morbidity and mortality in young children. Risk factors were …

Cortisol And Testosterone In Hair As Biological Markers Of Systolic Heart Failure, Justin Chan

Electronic Thesis and Dissertation Repository

Congestive heart failure (CHF) is associated with increased stress and alterations in metabolism, favoring catabolism over anabolism. Hormonal profiles of patients with heart failure have been assessed using serum and saliva as matrices, which are only point measurements and do not provide long-term information. Scalp hair is a novel matrix that allows for measurement of hormones over a period of several months. We aimed to evaluate whether levels of cortisol and testosterone and their ratio (C/T) in hair correlate with severity of heart failure. We conducted a prospective study in ambulatory male patients with a left ventricular ejection fraction (LVEF) …

Deep Learning Via Stacked Sparse Autoencoders For Automated Voxel-Wise Brain Parcellation Based On Functional Connectivity, Céline Gravelines

Electronic Thesis and Dissertation Repository

Functional brain parcellation – the delineation of brain regions based on functional connectivity – is an active research area lacking an ideal subject-specific solution independent of anatomical composition, manual feature engineering, or heavily labelled examples. Deep learning is a cutting-edge area of machine learning on the forefront of current artificial intelligence developments. Specifically, autoencoders are artificial neural networks which can be stacked to form hierarchical sparse deep models from which high-level features are compressed, organized, and extracted, without labelled training data, allowing for unsupervised learning. This thesis presents a novel application of stacked sparse autoencoders to the problem of parcellating …

Tak1 Mediates Tgf Beta-1 Responses In Gingival Fibroblasts, Hanna Kuk

Electronic Thesis and Dissertation Repository

In fibroblasts, transforming growth factor β-1 (TGFβ1) signals via canonical and non-canonical pathways to promote wound healing or hyper-contractile responses resulting in scars. The oral cavity however does not scar and fibrotic responses such as gingival hyperplasia are characterized by a hyper-proliferative response. The involvement of non-canonical, TGFβ-activated kinase-1 (TAK1) - mediated TGFβ1 signaling in gingival fibroblasts has not been previously examined. Here I show that TAK1 selective inhibitor (5Z)-7-Oxozeaenol blocks TGFβ1-induced expression of wound healing and fibrotic marker CCN2 (connective tissue growth factor) in gingival fibroblasts. Genome-wide expression profiling revealed that essentially all TGFβ1 induced genes were in fact …

Development Of Non-Covalent Functionalization Of Carbon Nanotubes For Sirna Delivery, King Sun Siu

Electronic Thesis and Dissertation Repository

RNA interference (RNAi) therapy is promising for treating various diseases but the delivery of small interfering RNA (siRNA) is difficult. To overcome the technical difficulties of siRNA delivery, an efficient and targeted delivery of siRNA is required for efficient RNAi therapy. Single-walled carbon nanotubes (CNT) has been used for nucleic acid delivery such as siRNA delivery. It has been found that CNT can gain entry into the cells by a diffusion-like mechanism which was called “nano-needle”. However, the solubility of CNT is low in most of the solvents including water. Functionalization of CNT can be carried out to enhance the …

Multiparametric Imaging And Mr Image Texture Analysis In Brain Tumors, Harish A. Sharma

Electronic Thesis and Dissertation Repository

Discrimination of tumor from radiation injured (RI) tissues and differentiation of tumor types using noninvasive imaging is essential for guiding surgical and radiotherapy treatments are some of the challenges that clinicians face in the course of treatment of brain tumors. The first objective in this thesis was to develop a method to discriminate between glioblastoma tumor recurrences and radiation injury using multiparametric characterization of the tissue incorporating conventional magnetic resonance imaging signal intensities and diffusion tensor imaging parameters. Our results show significant correlations in the RI that was missing in the tumor regions. These correlations may aid in differentiating between …

Resting State Functional Magnetic Resonance And Diffusion Tensor Imaging Of Hemiplegic Cerebral Palsy Patients Treated With Constraint-Induced Movement Therapy: Predictors And Clinically Correlated Evidence Of Neuroplasticity, Kathryn Y. Manning

Electronic Thesis and Dissertation Repository

Hemiplegic cerebral palsy is characterized by unilateral upper limb impairment and patients often compensate by performing most tasks with their unaffected arm. Constraint-induced movement therapy (CIMT) directly combats this learned non-use by casting the unaffected arm and forcing the patient to repetitively practice skills with the hemiplegic limb. Subjects with hemiplegic cerebral palsy were recruited from Holland Bloorview Kids Rehabilitation Hospital, Thames Valley Children’s Centre and McMaster Children’s Hospital. MRI acquisitions and clinical evaluations were collected at baseline, 1 and 6-months later. The case group participated in a CIMT camp after baseline evaluations and was compared to an untreated control …

Quantitative Susceptibility Imaging Of Tissue Microstructure Using Ultra-High Field Mri, David A. Rudko

Electronic Thesis and Dissertation Repository

This thesis has used ultra-high field (UHF) magnetic resonance imaging (MRI) to investigate the fundamental relationships between tissue microstructure and such susceptibility-based contrast parameters as the apparent transverse relaxation rate (R₂^*), the local Larmor frequency shift (LFS) and quantitative volume magnetic susceptibility (QS). The interaction of magnetic fields with biological tissues results in shifts in the LFS which can be used to distinguish underlying cellular architecture. The LFS is also linked to the relaxation properties of tissues in a gradient echo MRI sequence. Equally relevant, histological analysis has identified iron and myelin as two major sources of …

Pre-Diabetes And Sympathetic Nervous System Mediated Microvascular Dysregulation In Skeletal Muscle, Nicole M. Novielli

Electronic Thesis and Dissertation Repository

Pre-diabetes is associated with impairments in cardiovascular health that manifest prior to the onset of overt type 2 diabetes. Characterized by hyperinsulinemia and insulin resistance, pre-diabetes has been associated with increases in sympathetic nerve activity, which may result in augmented sympathetic control of the peripheral vasculature within skeletal muscle. Currently however, there are no studies investigating the impact of pre-diabetes on sympathetically-mediated vascular control. The primary study of this thesis investigated the effects of pre-diabetes on baseline sympathetic neuropeptide Y Y1 receptor (NPY Y1R) and alpha 1 adrenergic receptor (a1R) control of hindlimb vascular tone. Experiments were carried out in …

The Role Of Oxygen Tension And Insulin-Like Growth Factor Signaling In The Placental Mesenchymal Stem Cell Fate, Amer Youssef

Electronic Thesis and Dissertation Repository

The human placenta of different gestational ages is a readily available source for isolation of adult mesenchymal stem cell (MSC) for potential use in regenerative therapies. The chorionic villous region, the largest component of a placenta that interfaces with the maternal circulation, is a rich source of placental MSCs (PMSCs). To remain multipotent, PMSCs are best maintained in culture conditions that mimic the in vivo microenvironment. Insulin like growth factors (IGFs, IGF-I and -II) and oxygen tension are two of the most important microenvironmental factors in the placenta. They are of low concentration or tension respectively, at early gestation, and …

Mirna Regulation Of Programmed Cell Death-1 In T Cells: Potential Prognostic And Therapeutic Markers In Melanoma, Nathan J. Johnston

Electronic Thesis and Dissertation Repository

Immunoinhibitory cell receptors that can induce a state of T cell exhaustion upon exposure to tumor antigen include Programmed Cell Death-1 (PD1). Although much research has been conducted on PD1, global miRNA regulation of PD1 in a cancer model has not been investigated. We hypothesized that miRNAs exist that can silence PD1 in vitro and revert symptoms of T cell exhaustion. Eleven miRNAs were discovered with altered expression between PD1⁺ and PD1^- CD4⁺ T cells from melanoma-bearing mice. miR-28 and miR-107 mimics were shown to bind to and silence the 3’UTR of PD1, and miR-28, miR-150 and …