Medicine and Health Sciences Commons^™

Translational Study Of Liver Cancer And Hypertrophy: Translich, Mauro Enrique Tun Abraham

Electronic Thesis and Dissertation Repository

Abstract

Background: Associating liver partition with portal vein ligation for staged-hepatectomy (ALPPS) is a technique for inducing accelerated hypertrophy in patients with insufficient future liver remnant (FLR). It remains unknown whether this hypertrophy may lead to rapid cancer cell dissemination and/or alteration of immune cell/function reconstitution in the FLR. We aimed to determine if the rapid hypertrophy during ALPPS procedure results in more circulating tumour cell (CTCs) dissemination and whether the FLR remains immunologically competent in patients with CRLM.

Methods: In our prospective, observational, 2-arm study, we assessed the utility of CTCs as an evaluation tool for disease dissemination. Moreover, …

Characterization Of N-Butyl Cyanoacrylate (Nbca) Glue Polymerization For The Embolization Of Brain Arteriovenous Malformations (Avms), Bill H. Wang

Electronic Thesis and Dissertation Repository

Brain AVMs are abnormal connections between arteries and veins. Endovascular glue embolization with NBCA is an accepted form of treatment. The reported complication rates of NBCA embolization varies widely from 2-15%, and timing of polymerization plays a major role.

Polymerization time was measured for mixtures of lipiodol/NBCA of 50/50, 70/30, 60/40. The influence of pH, temperature and presence of biological catalysts on polymerization time was investigated in-vivo. PVA-C, silicone and endothelium surfaces were compared. High-speed video analysis of glue injection through a microcatheter was performed.

Polymerization rate increases with pH and temperature. A hydrophilic surface such as PVA-C better mimics …

A Non-Canonical Role For Choline Acetyltransferase In Chromatin Organization And The Response To Beta-Amyloid, Warren R. Winick-Ng

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The three-dimensional structure of chromatin is essential for context-dependent regulation of gene expression in post-mitotic neurons. Chromosomal rearrangements have been observed in the aging brain, and proteins involved in chromatin organization have altered expression and/or localization in Alzheimer’s disease (AD). A human- and primate-specific transcript of choline acetyltransferase produces an 82-kDa protein (82-kDa ChAT) that is localized to the nucleus of cholinergic neurons, but is found in the cytoplasm in individuals with mild cognitive impairment (MCI) and AD. The function of the 82-kDa ChAT protein is unknown, though recent evidence suggests it has a role in gene expression changes in …

Multi-Nuclear Magnetic Resonance Imaging Of Obstructive Lung Disease, Khadija Sheikh

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Obstructive lung diseases such as chronic-obstructive-lung-disease (COPD), bronchiectasis, and asthma are characterized by airflow obstruction. They affect over six million Canadians costing the economy $12 billion/year. Despite decades of research, therapies that modify obstructive-lung-disease progression and control are lacking because patient diagnosis, monitoring, and response to therapy are currently made using airflow measurements that may conceal the independent contributions of underlying pathologies. One goal of obstructive-lung-disease research is to develop ways to identify patients with specific underlying pathological phenotypes to improve patient care and outcomes. Thoracic computed-tomography (CT) and magnetic-resonance-imaging (MRI) provide ways to regionally identify the underlying pathologies associated …

Energy Subtraction Methods As An Alternative To Conventional X-Ray Angiography, Christiane S. Burton

Electronic Thesis and Dissertation Repository

Digital subtraction angiography (DSA) is a technique that is widely used to enhance the visibility of small vessels obscured by background structures by subtracting a mask and contrast image. However, DSA is generally unsuccessful for imaging the heart due to the motion that occurs between mask and contrasted images which cause motion artifacts. An alternative approach known as energy subtraction angiography (ESA) exploits the iodine k-edge by acquiring contrast images with a low and high kV in rapid succession to bring the benefits of DSA without motion artifacts. However, it was concluded that image quality for ESA could not compete …

Development Of Anatomical And Functional Magnetic Resonance Imaging Measures Of Alzheimer Disease, Samaneh Kazemifar

Electronic Thesis and Dissertation Repository

Alzheimer disease is considered to be a progressive neurodegenerative condition, clinically characterized by cognitive dysfunction and memory impairments. Incorporating imaging biomarkers in the early diagnosis and monitoring of disease progression is increasingly important in the evaluation of novel treatments. The purpose of the work in this thesis was to develop and evaluate novel structural and functional biomarkers of disease to improve Alzheimer disease diagnosis and treatment monitoring. Our overarching hypothesis is that magnetic resonance imaging methods that sensitively measure brain structure and functional impairment have the potential to identify people with Alzheimer’s disease prior to the onset of cognitive decline. …

Identification Of A Nuclear Localization Signal (Nls) Within The Pleckstrin Homology (Ph) Domain Of Rho Guanine Nucleotide Exchange Factor (Rgnef), Michael V. Tavolieri

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Rho Guanine Nucleotide Exchange factor (RGNEF) is a 180 kDa protein which forms pathological neuronal cytoplasmic inclusions in degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS) and for which the gene (ARHGEF28) is mutated in a subset of cases. Despite having previously been shown to localize to the nucleus and to undergo a nuclear cytosolic shift in response to cellular injury, the mechanism of its nuclear import has yet to be elucidated. Here we use site-directed mutagenesis with a combination of subcellular fractionation and confocal microscopy to identify a functional nuclear localization signal (NLS) within the Pleckstrin …

The Biophysical Alterations To Pulmonary Surfactant During Lung Injury, Scott D. Milos

Electronic Thesis and Dissertation Repository

Pulmonary surfactant is a lipoprotein mixture responsible for reducing surface tension of the lung. In this thesis, we investigate the impact of lung injury on surfactant composition and function, with a specific focus on cholesterol content. First, the impact of a high cholesterol diet on surfactant function was assessed in three models of lung injury. It was hypothesized that serum hypercholesterolemia would increase host susceptibility to surfactant functional impairments. Secondly, the impact of injurious ventilation on intracellular surfactant within the lung was investigated. It was hypothesized injurious ventilation would produce alterations to lamellar body surfactant. Overall, the data suggest that …

Maternal Nutrient Restriction With Fetal Growth Restriction In Guinea Pigs Impacts Brain Development And Neuroimaging Correlates In Neonatal Offspring, Catherine Nevin

Electronic Thesis and Dissertation Repository

Aberrant brain development in utero accompanied by fetal growth restriction (FGR) increases the risk of neurodevelopmental disorders in later life. However there are limited non-invasive biomarkers in the brain for the early identification of said neurodevelopmental disorders in an animal model of FGR. Guinea pig sows were fed either ad libitum (Control) or 70% of the control diet pre-pregnancy, increasing to 90% at mid-pregnancy (MNR) creating appropriately grown (AGA) Control and FGR-MNR neonates, respectively. Three to four weeks corrected post-natal age, neonates were imaged using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques, and were killed 48-72 hours later for …

The Long Non-Coding Rna Malat1 Regulates Inflammatory Cytokine Production In Chronic Diabetic Complications, Andrew D. Gordon

Electronic Thesis and Dissertation Repository

We examined the role of MALAT1, a highly conserved nuclear lncRNA, in chronic diabetic complications affecting the heart and kidneys, specifically with respect to inflammatory cytokine production. Endothelial cells, exposed to various glucose levels, and MALAT1 knockout mice and controls, with or without streptozotocin-induced diabetes were examined. Endothelial cells cultured with high glucose, and renal and cardiac tissue from diabetic mice showed increased inflammatory cytokine (eg. IL-6, IL1β, TNFα) production along with transient MALAT1 upregulation. This was confirmed by both transcript and protein analyses, and such changes were prevented in the MALAT1 knockout diabetic animals. In the malat1 knockout animals, …

Sample Size Formulas For Estimating Intraclass Correlation Coefficients In Reliability Studies With Binary Outcomes, Mengxiao Xu

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Introduction: Measurement errors can seriously affect quality of clinical practice and medical research. It is therefore important to assess such errors by conduct- ing studies to estimate a coefficients reliability and assessing its precision. The intraclass correlation coefficient (ICC), defined on a model that an observation is a sum of information and random error, has been widely used to quantify reliability for continuous measurements. Sample formulas have been derived for explicitly incorporation of a prespecified probability of achieving the prespecified precision, i.e., the width or lower limit of a confidence interval for ICC. Although the concept of ICC is applicable …

Characterizing The Role Of The Neuropeptide Y-Y5r System In Breast Cancer, Jenna Kara

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Studies have demonstrated a correlation between stress and an increased risk of breast cancer. Neuropeptide Y (NPY) is up- regulated in chronic stress and induces proliferation and chemotaxis of 4T1 breast cancer cells via Y5 receptor (Y5R) activation. In the studies performed in this thesis, we characterize NPY-Y5R as a regulatory system that promotes breast cancer metastasis. We compared three cancer cell sublines derived from the same murine mammary fat pad tumour, that greatly differ in metastatic potential (67NR, 168FARN, and 4T1) in addition to a 4T1-Y5R knockdown established in our labs. In this thesis we demonstrate significance of up-regulation …

Is Online Motor Control Really Impaired In Parkinson's Disease?, Kate E. Merritt

Electronic Thesis and Dissertation Repository

Patients with Parkinson’s disease (PD) are thought to be selectively impaired in consciously-mediated online automatic motor control, whereas the ability to perform subconscious online adjustments remains intact. This present study evaluates the hypothesis that the previously alleged deficits in online motor control in PD are not due to the consciousness of the correction, but rather are attributable to aspects of the prior experimental designs disproportionately penalizing patients for PD-related bradykinesia. Here, we implemented a modified traditional double-step paradigm to investigate consciously-mediated online motor control in PD, in a manner that would be unconfounded by disease-related bradykinesia. Further, we investigated the …

Magnetic Resonance Imaging Of Breast Cancer Brain Metastasis Progression And Responses To Radiotherapy, Donna H. Murrell

Electronic Thesis and Dissertation Repository

Introduction: The incidence of brain metastasis due to breast cancer is increasing and prognosis is poor. Treatment is challenging for this disease because systemic therapy has limited efficacy due to the presence of the blood-brain barrier. In addition, it is thought that disseminated dormant cancer cells persist in metastatic organs and may evade treatment, thereby facilitating a mechanism for later recurrence. Methods: In this thesis, we use contrast-enhanced MRI and high resolution anatomical MRI to characterize blood-brain barrier integrity associated with the development of brain metastases due to HER2+ breast cancer in the SUM-190-BR3, JIMT-1-BR3, and MDA-MB-231-BR-HER2 experimental models. We …

Radiomics For Response Assessment After Stereotactic Radiotherapy For Lung Cancer, Sarah A. Mattonen

Electronic Thesis and Dissertation Repository

Stereotactic ablative radiotherapy (SABR) is a guideline-specified treatment option for patients with early stage non-small cell lung cancer. After treatment, patients are followed up regularly with computed tomography (CT) imaging to determine treatment response. However, benign radiographic changes to the lung known as radiation-induced lung injury (RILI) frequently occur. Due to the large doses delivered with SABR, these changes can mimic the appearance of a recurring tumour and confound response assessment. The objective of this work was to evaluate the accuracy of radiomics, for prediction of eventual local recurrence based on CT images acquired within 6 months of treatment. A …

Characterization And Personalization Of Botulinum Toxin Type A Therapy For Upper Limb Tremor In Parkinson Disease And Essential Tremor Patients Using Multi-Sensor Kinematic Technology, Olivia Samotus

Electronic Thesis and Dissertation Repository

Tremor commonly affects the upper extremities in essential tremor (ET) and Parkinson disease (PD) patients where many experience functional disability and ultimately seek therapy. As ET and PD tremor features overlap and clinical assessment is challenging due to its highly complex nature, misdiagnosis is common resulting in unsuitable therapies and prognosis. Current treatment options for ET and PD tremor include pharmacotherapy, focal therapy with botulinum toxin type A (BoNT-A) injections, and surgical interventions which provide modest relief of tremor. However, such therapies are commonly associated with significant adverse events and lack long-term efficacy and tolerability. Hence lack of standardized, objective …

Protective Benefits Of Hydrogen Sulfide Treatment During Renal Transplantation, Ian Lobb

Electronic Thesis and Dissertation Repository

Ischemia/reperfusion injury (IRI) is inherent to renal transplantation (RTx) and is initiated when blood supply is necessarily removed during organ procurement (ischemia) and subsequently restored upon engraftment (reperfusion). During renal ischemia, ATP depletion causes tubular epithelial cell (TEC) injury and subsequent release of pro-inflammatory mediators. Upon reperfusion, influx of O₂ causes reactive oxygen species (ROS) production and infiltration of innate immune cells which release damaging ROS and proteases. Prolonged periods of IRI are associated with increased risk of delayed graft function (DGF) and decreased long-term graft survival. The endogenously produced gasotransmitter, hydrogen sulfide (H₂S), has recently been …

Investigating Stromal Contributions To The Regulation Of Cancer Progression, Krista M. Vincent

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Tumours are not insular masses of proliferating cells, rather tumour cells evolve within a complex local environment complete with matrix, stromal, and immune components. Therefore, successful tumour growth and eventual metastasis is not determined solely by tumour cells themselves, but also by the fitness advantage or disadvantage conferred by their local environment. However, many of our current cancer models are composed solely of tumour cell isolates. As tumour fitness is dependent on the entire local cellular context, we were interested in characterizing the accuracy of cell lines as models of the tumour microenvironment, with a focus on the secreted Frizzled-related …

Beta Blocker Dialyzability And Effectiveness In Chronic Hemodialysis Patients, Alvin Tieu

Electronic Thesis and Dissertation Repository

Of the minimal information describing drug dialyzability, the majority was obtained prior to modern hemodialysis membranes. This study characterized the dialyzability of the most commonly prescribed beta blockers in patients undergoing high-flux hemodialysis. Eight subjects were recruited to a pharmacokinetic, 4-way crossover trial. Drug concentrations were measured using mass spectrometry and dialyzability determined by the arterial-venous difference and recovery clearance methods. A provincial-wide retrospective cohort study was designed to determine the effect of dialyzability on adverse clinical outcomes. Beta blocker efficacy can be hindered if substantial clearance occurs during dialysis. Our results demonstrate atenolol and metoprolol are extensively cleared during …

Digging Deeper With Diffuse Correlation Spectroscopy, Kyle J. Verdecchia

Electronic Thesis and Dissertation Repository

Patients with neurological diseases are vulnerable to cerebral ischemia, which can lead to brain injury. In the intensive care unit (ICU), neuromonitoring techniques that can detect flow reductions would enable timely administration of therapies aimed at restoring adequate cerebral perfusion, thereby avoiding damage to the brain. However, suitable bedside neuromonitoring methods sensitive to changes of blood flow and/or oxygen metabolism have yet to be established.

Near-infrared spectroscopy (NIRS) is a promising technique capable of non-invasively monitoring flow and oxygenation. Specifically, diffuse correlation spectroscopy (DCS) and time-resolved (TR) NIRS can be used to monitor blood flow and tissue oxygenation, respectively, and …

Mechanisms Regulating Stem Cell Phenotype In Infantile Hemangioma, Niamh Richmond

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Infantile hemangiomas (IHs) are benign vascular neoplasms characterized by the differentiation of multipotential stem cells (hemSCs) into endothelial cells during the early proliferative phase, and later into adipocytes during spontaneous involution. Transforming growth factor-β (TGFβ) has been shown to be significantly elevated upon IH involution and this coincides with repression of a developmentally-regulated transcription factor T-box 2 (TBX2). These findings implicate both TGFβ and TBX2 in mediating hemSC differentiation during IH evolution. The aim of my study is to understand the role of TGFβ and TBX2 in hemSC differentiation. I performed immunofluorescence staining to localize TBX2 protein in sectioned IH …

Optimizing Respiratory Gated Intensity Modulated Radiation Therapy Planning And Delivery Of Early-Stage Non-Small Cell Lung Cancer, Ilma Xhaferllari

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Stereotactic ablative body radiotherapy (SABR) is the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC) patients. However, thoracic tumours are susceptible to respiratory motion and, if unaccounted for, can potentially lead to dosimetric uncertainties. Respiratory gating is one method that limits treatment delivery to portions of the respiratory cycle, but when combined with intensity-modulated radiotherapy (IMRT), requires rigorous verification. The goal of this thesis is to optimize respiratory gated IMRT treatment planning and develop image-guided strategies to verify the dose delivery for future early-stage NSCLC patients.

Retrospective treatment plans were generated for various IMRT delivery techniques, including …

Quantitative Pet-Ct Perfusion Imaging Of Prostate Cancer, Adam R. Blais

Electronic Thesis and Dissertation Repository

Functional imaging of ¹⁸F-Fluorocholine PET holds promise in the detection of dominant prostatic lesions. Quantitative parameters from PET-CT Perfusion may be capable of measuring choline kinase activity, which could assist in identification of the dominant prostatic lesion for more accurate targeting of biopsies and radiation dose escalation.

The objectives of this thesis are: 1) investigate the feasibility of using venous TACs in quantitative graphical analysis, and 2) develop and test a quantitative PET-CT Perfusion imaging technique that shows promise for identifying dominant prostatic lesions.

Chapter 2 describes the effect of venous dispersion on distribution volume measurements with the Logan …

Regulation Of Phosphatase And Tensin Homolog Expression And Activity By Transforming Growth-Factor Beta In The Trabecular Meshwork Cells: Implications For Primary Open Angle Glaucoma, Nikoleta Tellios

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Glaucoma is a multifactorial condition caused, in part, by fibrosis of the sieve-like trabecular meshwork (TM) tissue, which impedes drainage of aqueous humor (AH), leading to increased intraocular pressure and associated optic nerve damage and blindness. Fibrosis of the TM is mainly caused by the increased levels of active transforming growth factor-β 2 (TGFβ2) in the AH of glaucoma patients.

Previous reports have shown that TGFβ decreases the expression of Phosphatase and Tensin Homolog (PTEN) gene and that PTEN is a major regulator of ECM deposition. In this study we investigate the regulation of PTEN protein expression and …

Effects Of Prenatal Exposure To Bisphenol A On Fetal Lung Development, Ayten Hijazi

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Prenatal exposure to bisphenol A (BPA), one of the most prevalent endocrine disrupting chemicals, is associated with lung dysfunction and diseases in later life. However, it is unknown if this association has a fetal origin. In this thesis, a series of in vivo and in vitro experiments were conducted to determine the effects of prenatal exposure to BPA on fetal lung development, and define the underlying molecular mechanisms. Environmentally relevant doses of BPA were administered to pregnant mice via diet from embryonic day (E) 7.5 to 18.5. Fetal lungs were analyzed at E18.5 for changes in structure and expression of …

Evaluating The Role Of Intestinal Transporters In Fruit Juice-Drug Interactions, Mandy Mj Li

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Fruit juice-drug interactions (FJDIs) involving non-metabolized oral medications result in decreased drug exposure that may lead to reduced therapeutic efficacy. The effect is thought to be mediated by inhibition of the intestinal drug transporters organic anion transporting polypeptide 1A2 and 2B1 (OATP1A2 and OATP2B1) by fruit juice constituents, however the exact mechanisms remain controversial. We tested the hypothesis that fruit juices limit the absorption of fexofenadine through interactions with specific intestinal transporters. In vitro transport and fruit juice inhibition studies using fexofenadine, a medication involved in FJDIs, revealed that in addition to previously implicated transporters, organic cation transporter 1 (OCT1) …

Acute Kidney Injury Biomarkers: A Prospective Cohort Study In Urological Patients, Daniel Olvera-Posada

Electronic Thesis and Dissertation Repository

Several recent studies have assessed the use of biomarkers of Acute Kidney Injury (AKI), but the information among patients with stone disease and those with obstructive uropathy is limited. For this reason, we conducted a prospective cohort study to determine the urinary levels of KIM-1, Total and Monomeric NGAL in patients with hydronephrosis secondary to renal stone disease, congenital ureteropelvic junction obstruction or ureteral stricture, and in a group of healthy controls in our health care center. Urinary biomarker concentrations were evaluated before and after surgical treatment. Patients with hydronephrosis showed significantly higher baseline levels of KIM-1 compared to those …

Oncolytic Virus Therapy For The Treatment Of Metastatic Ovarian Cancer, Jessica Tong

Electronic Thesis and Dissertation Repository

The management of patients with epithelial ovarian cancer (EOC) faces two major challenges which standard treatments fail to effectively address: 1) Diffuse metastasis as a consequence of late stage diagnosis and 2) intra-tumoral heterogeneity, which fuels tumor evolution and drives the acquisition of chemotherapeutic resistance. In this thesis, we tested new therapeutic strategies using a 3-dimensional in vitro spheroid culture model that mimics key steps of epithelial ovarian cancer metastasis; and another model that mimics both temporal and cellular heterogeneity by establishing multiple cell lines from a single patient over the course of disease progression. Using these models, we investigated …

Markerless Radiostereogammetry Of The Shoulder Joint In Humans: Comparisons Of Scapulohumeral Kinematics Between Individuals With Healthy And Supraspinatus-Impaired Shoulders, Ashley N. Hannon

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The purpose of this collection of studies was to further develop the knowledge of shoulder motion in order to better understand joint function through direct measurement of 3D scapulohumeral joint kinematics using a technique of high accuracy. Markerless, bi-planar fluoroscopic radiostereometric analysis using a generic shoulder model was developed in this thesis, reducing the amount of radiation exposure to subjects. The studies compared kinematic data of the scapulohumeral joint in six degrees of freedom with a precise, in-vivo measuring technique. Data were collected on young and older healthy individuals, individuals with a torn supraspinatus and post-surgical intervention.

Although this generic …

Arthrokinematics Of The Distal Radioulnar Joint In The Normal Wrist And Following Distal Radius Malunion, Braden M. Gammon

Electronic Thesis and Dissertation Repository

Contact patterns in the distal radioulnar joint (DRUJ) are not well understood for normal anatomy or with distal radius deformity. This thesis presents three studies which investigate the arthrokinematics of the DRUJ for these conditions. The first study compared casting and Tekscan, two standard methods for contact measurement, with a novel technique of proximity mapping termed Inter-cartilage Distance (ICD). The relative benefits, limitations and role for ICD in DRUJ contact assessment were examined and discussed. The second study used ICD to characterize contact patterns in the native DRUJ. Contact was found to be maximal in 10 degrees of supination and …