Medicine and Health Sciences Commons^™

Serotonergic System And Gait: Dorsal Raphe Nucleus As A Control System For Gait, Nahal Farhani

Electronic Thesis and Dissertation Repository

In advanced stages of Parkinson Disease (PD), gait and postural abnormalities emerge. These symptoms are not prominent at early stages of PD despite significant dopaminergic neuronal loss. Gait abnormalities are largely not responsive to levodopa. Therefore, other types of neurons might be responsible for gait abnormalities of the PD.

Since the reticulospinal tract (RET) is mainly implicated in the control of axial muscles, the degeneration of this pathway or populations of neurons controlling this pathway might be responsible for axial symptoms. However, there is limited data about the neurons controlling the RET. Our aim in this study is to delineate …

Intracellular Acidification In Brain Tumors Induced By Topiramate : In-Vivo Detection Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging, Kamini Y. Marathe

Electronic Thesis and Dissertation Repository

Glioblastoma Multiforme (GBM) is the most aggressive and malignant form of primary brain tumor. In many tumors, increased intracellular pH (pH_i) is a hallmark of aggressiveness. This increased pH_i has been shown to be related to cell proliferation and evasion of apoptosis as well as resistance to chemotherapy. As such, monitoring pH_i and the tumor pH_i response to pharmacologic challenge, may aid in treatment planning and patient management for this deadly cancer. A magnetic resonance imaging (MRI) method called Chemical Exchange Saturation Transfer (CEST) has been used to detect changes in pH_i. Our group …

Intracellular Trafficking Governs The Processing Of The Amyloid Precursor Protein And The Secretion Of Beta-Amyloid, Joshua Hoi Ki Tam

Electronic Thesis and Dissertation Repository

One of the hallmarks of Alzheimer’s disease (AD) is the pathological accumulation of β-amyloid (Aβ) in the brains of AD patients. Oligomeric and fibrillar aggregates of Aβ have been shown to be neurotoxic to neurons and hippocampal slices. Therefore, limiting Aβ production is an important area of research in order to delay or stop AD progression. Aβ is produced by amyloidogenic cleavage of amyloid precursor protein (APP). Amyloidogenic cleavage requires ectodomain removal by β-secretase and intramembrane γ-cleavage by γ-secretase to release Aβ products ranging from 38-43 residues. Work from our lab has shown that APP and γ-secretase are resident proteins …

Pathophysiologic Mechanisms Of Immune-Mediated Drug Hypersensitivity Reactions To Sulfonamides, Elham A. Sultan

Electronic Thesis and Dissertation Repository

As sulfonamide hypersensitivity reactions are serious clinical problem, it is necessary to determine which patients tolerate therapy and which patients are at risk. Although the exact pathogenesis of these reactions remains unclear, the imbalance in the production and detoxification of reactive sulfamethoxazole (SMX) metabolites appears to be important in the propagation of these reactions. It is known that these reactive metabolites can cause lymphocytes toxicity and produce reactive oxygen species (ROS) which can damage proteins, lipids, and DNA. The hypothesis of this research is that there are differences in cytotoxicity and expression of oxidative stress to reactive SMX metabolites in …

Pulmonary Imaging To Better Understand Asthma, Sarah Svenningsen

Electronic Thesis and Dissertation Repository

Asthma is characterized using the spirometry measurement of the forced expiratory volume in one second (FEV₁). Simple and inexpensive, FEV₁ provides a global estimate of lung function but this metric cannot regionally identify airways responsible for airflow limitation, asthma symptoms or control. Work that brought about an understanding that airway abnormalities are heterogeneously distributed within the lung in asthma patients has motivated the development of pulmonary imaging approaches, such as hyperpolarized helium-3 (³He) and xenon-129 (¹²⁹Xe) magnetic resonance imaging (MRI). These methods provide a way to visualize and quantify lung regions accessed by …

The Development And Validation Of A Molecular Imaging Probe Targeted To Cathepsin D For The In-Vivo Detection Of Alzheimer Disease, Jonatan Snir

Electronic Thesis and Dissertation Repository

Background: Currently there is no widely accepted test to diagnose AD. The involvement of the lysosomal system in Alzheimer’s disease (AD) progression provides an opportunity to develop associated biomarkers. The lysosomal enzyme Cathepsin D (CatD) has been shown to be over-expressed in the AD brain before clinical onset. We have developed a dual modality contrast agent (CA) to detect CatD activity which consists of an HIV-1 Tat Cell Penetrating Peptide (CPP) conjugated to a CatD cleavage sequence and two imaging moieties consisting of a fluorescently- tagged probe and a DOTA cage for chelating Gallium-68. The purpose of this work was …

Feasibility Of Using Arterial Spin Labeling For Detecting Longitudinal Changes In Cerebral Blood Flow, Tracy Ssali

Electronic Thesis and Dissertation Repository

The ability of the perfusion MRI technique, arterial spin labeling (ASL), to quantify cerebral blood flow (CBF) makes it attractive for longitudinal studies of changes in brain function, such as those related to chronic pain. However, ASL's poor spatial resolution makes image alignment between sessions difficult, leading to increased variance and greater Type-I errors. In addition, variability due to differences in basal blood flow between sessions and confounding effects such as the arterial transit time (ATT) have the potential to reduce reproducibility over time. The focus of this thesis is to investigate the ability of ASL to detect long-term changes …

Hyperpolarized 129xe Magnetic Resonance Imaging Of Radiation-Induced Lung Injury, Ozkan Doganay

Electronic Thesis and Dissertation Repository

Lung cancer is the largest contributor to cancer-related mortality worldwide. Only 20% of stage III non-small cell lung cancer patients survive after 5-years post radiation therapy (RT). Although RT is an important treatment modality for lung cancer, it is limited by Radiation-Induced Lung Injury (RILI). RILI develops in two phases: (i) the early phase (days-weeks) referred to radiation pneumonitis (RP), and (ii) the late phase (months). There is a strong interest in early detection of RP using imaging to improve outcomes of RT for lung cancer. This thesis describes a promising approach based on ¹²⁹Xe gas as a contrast …

A Randomized Clinical Trial To Compare The Effect Of Non Operative Treatment With And Without Autologous Conditioned Plasma (Acp) On Healing And Function In Patients With Achilles Tendon Ruptures, Tyler M. Pratt

Electronic Thesis and Dissertation Repository

The purpose of this study was to determine whether there is evidence to support conducting a larger randomized control trial (RCT) to compare the non-operative treatment of Achilles tendon (AT) ruptures with or without Autologous Conditioned Plasma (ACP®). Twenty-four patients were randomized to receive an ACP® or saline injection within seven days and again at two weeks post-rupture. Tendon healing was longitudinally evaluated using ultrasound (US) and magnetic resonance imaging (MRI). Functional and patient-reported quality of life measures were also assessed. A small sample size limited our ability to detect statistically significant differences. The mean rankings of healing were slightly …

Role Of Cerebrovascular Abnormality In Neurodegenerative Disease And Subcortical Ischemic Disease: Ct Perfusion And Pet Imaging, Jun Yang

Electronic Thesis and Dissertation Repository

Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical …

A Unified Framework For The Prioritization Of Variants Of Uncertain Significance In Hereditary Breast And Ovarian Cancer Patients, Natasha G. Caminsky

Electronic Thesis and Dissertation Repository

A significant proportion of hereditary breast and ovarian cancer (HBOC) patients receive uninformative genetic testing results, an issue exacerbated by the overwhelming quantity of variants of uncertain significance identified. This thesis describes a framework where, aside from protein coding changes, information theory (IT)-based sequence analysis identifies and prioritizes pathogenic variants occurring within sequence elements predicted to be recognized by proteins involved in mRNA splicing, transcription, and untranslated region binding and structure. To support the utilization of IT analysis, we established IT-based variant interpretation accuracy by performing a comprehensive review of mutations altering mRNA splicing in rare and common diseases.

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Interpretation Of Mutations, Expression, Copy Number In Somatic Breast Cancer: Implications For Metastasis And Chemotherapy, Stephanie Dorman

Electronic Thesis and Dissertation Repository

Breast cancer (BC) patient management has been transformed over the last two decades due to the development and application of genome-wide technologies. The vast amounts of data generated by these assays, however, create new challenges for accurate and comprehensive analysis and interpretation. This thesis describes novel methods for fluorescence in-situ hybridization (FISH), array comparative genomic hybridization (aCGH), and next generation DNA- and RNA-sequencing, to improve upon current approaches used for these technologies. An ab initio algorithm was implemented to identify genomic intervals of single copy and highly divergent repetitive sequences that were applied to FISH and aCGH probe design. FISH …

Mapping The Impact And Plasticity Of Cortical-Cardiovascular Interactions In Vascular Disease Using Structural And Functional Mri, Udunna C. Anazodo

Electronic Thesis and Dissertation Repository

There is growing interest in the role of vascular disease in accelerating age-related decline in cerebrovascular structural and functional integrity. Since an increased number of older adults are surviving chronic diseases, of which cardiovascular disease (CVD) is prevalent, there is an urgent need to understand relationships between cardiovascular dysfunction and brain health. It is unclear if CVD puts the brains of older adults, already experiencing natural brain aging, at greater risk for degeneration. In this thesis, the role of CVD in accelerating brain aging is explored. Because physical activity is known to provide neuroprotective benefits to brains of older adults, …

Characterization Of The Atsr/Atst Global Regulatory Pathway In Burkholderia Ceocepacia, Maryam Khodai-Kalaki

Electronic Thesis and Dissertation Repository

Phosphorylation cascades governed by two-component signal transduction systems provide key signalling mechanisms in bacteria, simple eukaryotes and higher plants, allowing them to translate signals into adaptive responses. These regulatory pathways consist of a transmembrane sensor protein that responds to an environmental cue leading to autophosphorylation, followed by the transfer of the phosphate to a cytoplasmic response regulator. Here, I study AtsR, a membrane-bound hybrid sensor kinase of Burkholderia cenocepacia, that negatively regulates quorum sensing related virulence factors such as biofilm, type 6-secretion and protease secretion. B. cenocepacia is a Gram-negative opportunistic pathogen which causes severe, chronic respiratory infections in …

The Role Of Cytoplasmic Polyadenylation Element Binding Protein-2 (Cpeb-2) In Breast Cancer, Asma Hasan

Electronic Thesis and Dissertation Repository

Over-expression of inflammation associated enzyme cyclo-oxygenase (COX)-2 promotes breast cancer progression, metastasis and sustains cancer stem-like cells (SLCs) by activating prostaglandin E₂ receptor EP4. Two COX-2 induced oncogenic miRNAs, miR-655 and miR-526b, target and down-regulate the cytoplasmic polyadenylation element binding protein (CPEB)-2. Hypothesis: Down-regulation of CPEB2 promotes an aggressive breast cancer phenotype through SLC induction and epithelial to mesenchymal transition (EMT). We found that high COX-2/miRNA expressing cell lines MDAMB231 and MCF7-COX-2 had significantly lower expression of CPEB2 than MCF7 cells (low COX-2/miRNA). CPEB2 knockdown in CPEB2-high MCF7 cell line resulted in increased migratory and invasive capacity in …

Atrial Fibrillation Promotion By Intermittent Hypoxia In The Rat, Sara Bober

Electronic Thesis and Dissertation Repository

Obstructive sleep apnea (OSA) is a significant risk factor for developing atrial fibrillation (AF) in clinical populations, but the underlying mechanisms are unknown. Intermittent hypoxia (IH), as elicited by nocturnal airway obstructive events in OSA patients, has been implicated as the mediator of OSA-related cardiovascular outcomes. However, the role of IH in OSA-related atrial arrhythmogenesis has not been reported. For the first time, this thesis demonstrates AF promotion in a rodent model of OSA using IH to mimic hypoxic events, and investigates the underlying vulnerable substrates of induced AF. Rats exposed to IH for 7 days had significantly enhanced AF …

The Kinetics Of Cystatin C: A Marker For Dialysis Adequacy, Huang S. Shih-Han

Electronic Thesis and Dissertation Repository

When 90% or more of native kidney function is lost, renal replacement therapy must be initiated to sustain life. Renal transplantation is the preferred method, but availability is limited. The ideal dialysis prescription remains elusive. Small molecular weight molecules (such as urea and creatinine) have been used as markers of both kidney (native and transplant) and dialysis toxin clearance (function), but there are pitfalls in using these markers to assess total ‘renal’ dose (kidney plus dialysis). Body weight, gender and other factors also affect the concentrations of these small molecules, but not cystatin C. Furthermore, cystatin C has been shown …

A Clinically Relevant Relevant Post-Traumatic Osteoarthritis Mouse Model, Chantel P. Arce

Electronic Thesis and Dissertation Repository

Osteoarthritis affects 13-20% of Canadians with the majority being under 65years of age. Post-traumatic osteoarthritis (PTOA) is of great concern in young athletes following knee injury. Current research attempts at modeling the disease fall short. This study aimed to incorporate two important aspects of injury, the nature of the injury and the post-injury standard of care in humans, to a model of PTOA in mice. The study validated a non-invasive protocol to elicit an anterior cruciate ligament (ACL) injury at varying loading speeds addressing the closed capsule nature of an ACL injury that occurs in humans. Secondly, we proposed a …

Kidney Injury Molecule-1 Signalling In Ischemic Acute Kidney Injury And Phagocytosis, Ola Z. Ismail

Electronic Thesis and Dissertation Repository

Acute kidney injury (AKI) is defined by the rapid loss of kidney function due to tissue damage. It affects 10-30 % of hospitalized patients and is independently associated with increased morbidity and mortality. Ischemia-reperfusion injury (IRI) is the most common pathoetiological mechanism of AKI, whereby tissue injury is mediated by reactive oxygen species. Ischemic AKI leads to the rapid upregulation of a transmembrane protein, kidney injury molecule-1 (KIM-1) on the apical membrane of proximal tubular epithelial cells (TECs). Previous work from our group and others demonstrated that the extracellular domain of KIM-1 specifically binds to phosphatidylserine on apoptotic cells, thereby …

Towards Adaptive Radiotherapy Through Development Of Treatment Response Prediction, Anthony V. Lausch

Electronic Thesis and Dissertation Repository

Despite modern treatment advances, overall survival (OS) remains poor for many cancers such as liver and brain. Cancer is a fundamentally heterogeneous and adaptable disease and therefore personalized adaptive treatment strategies may be a key towards improving OS. Radiotherapy, a commonly used cancer treatment technique which employs ionizing radiation to kill tumours, holds promise for delivering adaptive treatment. However, effective adaptation requires the ability to assess and predict tumour treatment response. Therefore development of treatment response prediction tools represents a critical first step towards improving patient outcomes via treatment adaptation. The overall goal of this thesis is to develop treatment …

Characterization Of The Nicotine-Induced Endoplasmic Reticulum Stress Response In The Rat Placenta In Vivo And In Vitro, Michael Ka Chun Wong

Electronic Thesis and Dissertation Repository

Nicotine exposure during pregnancy leads to adverse health outcomes, including compromised placental development. Although the molecular mechanisms remain elusive, recent studies identified that endoplasmic reticulum (ER) stress may underlie poor placentation. Therefore, we were interested in investigating the effects of nicotine exposure on the ER stress response in the placenta. A well-established maternal nicotine exposure rat model and Rcho-1 trophoblast giant cell model were utilized to address the research questions. Maternal nicotine exposure in vivo led to elevated ER stress in association with impaired disulfide bond formation and hypoxia. Nicotine exposure in vitro further differentiated that ER stress may be …

Molecular Characterization Of Herc5: A Novel Multifunctional Antiviral Protein, Matthew W. Woods

Electronic Thesis and Dissertation Repository

Interferon (IFN)-induced proteins serve as one of the first lines of defense against viral pathogens such as Human Immunodeficiency Virus (HIV)-1. IFN treatment has been shown to restrict multiple stages of HIV-1 replication. The identities and functions of IFN-induced proteins involved in the inhibition of HIV-1 and other viruses are not fully understood. Homologous to the E6-AP C-terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain (RLD) containing protein 5 (HERC5) is strongly upregulated by the Type I IFN response. HERC5, a member of the small HERC family, is composed of an N-terminus RLD domain and a C-terminus HECT …

Analyzing A-Series Gangliosides In Neurons Following Exposure To Glutamate, Dae Hee Park

Electronic Thesis and Dissertation Repository

Neurons within different brain regions have varying levels of vulnerability to external stress and therefore respond differently to injury. A potential reason to explain this may lie within a key lipid class of the cell’s plasma membrane called gangliosides. These glycosphingolipid species have been shown to play various roles in the maintenance of neuronal viability. The purpose of this study is to use electrospray ionization mass spectrometry (ESI-MS) technique and immunohistochemistry to evaluate the temporal changes in the expression profiles of various ganglioside species during the course of neurodegeneration in rat primary cortical neurons exposed to glutamate toxicity. Primary embryonic …

Investigation Of Endogenous In-Vivo Sodium Concentration In Human Prostate Cancer Measured With 23na Magnetic Resonance Imaging, Justin C. Peterson

Electronic Thesis and Dissertation Repository

Prostate cancer (PCa) is the most common malignancy in men. Aggressive prostate tumours must be identified, differentiated from indolent tumours, and treated to ensure survival of the patient. Currently, clinicians use a combination of multi-parametric magnetic resonance imaging (mpMRI) contrasts to improve PCa detection. While these techniques provide very good spatial resolution, the specificity is often insufficient to unequivocally identify malignant lesions.

Utilizing specialized MRI hardware developed for sensitive in-vivo detection of sodium, this work has investigated differences in sodium concentration between healthy and malignant prostate tissue. Patients with biopsy-proven PCa underwent conventional mpMRI and sodium MRI followed by radical …

Development Of A Small Animal Conformal Irradiator With Dual Energy X-Ray Computed Tomography Imaging For Kilovoltage Dosimetry, Michael D. Jensen

Electronic Thesis and Dissertation Repository

External beam radiotherapy has become technically sophisticated with image guided radiation therapy (IGRT) and intensity modulated radiation therapy (IMRT). These technologies allow for precise delivery of radiation to geometric targets in cancer patients. However, many questions remain on how to best define targets based on biological information, such as functional imaging, and how to combine radiation with other cancer therapies. To help answer these questions, small animal preclinical studies are needed to generate data to inform clinical trials. However, the precise radiation delivery capabilities of IGRT and IMRT have not been available in the preclinical labs. To enable translational experiments …

Characterization Of Maga Expression And Iron Uptake In P19 Cells: Implications For Use As A Gene-Based Contrast Agent, Linshan Liu

Electronic Thesis and Dissertation Repository

Magnetic resonance imaging (MRI) is one of the non-invasive imaging modalities used in longitudinal cell tracking. Previous studies suggest that MagA, a putative iron transport protein from magnetotactic bacteria, is a useful gene-based magnetic resonance contrast agent. Hemagglutinin (HA)-tagged MagA was stably expressed in undifferentiated embryonic mouse teratocarcinoma, multipotent P19 stem cells to provide a suitable model for tracking these cells during differentiation. Western blot and immunocytochemistry confirmed the expression and membrane localization of MagA-HA in P19 cells. Elemental iron analysis using inductively-coupled plasma mass spectrometry revealed significant iron uptake in both parental and MagA-HA-expressing P19 cells, cultured in the …

Evaluation Of Radiation Dose-Response In A Breast Cancer Brain Metastasis Model, Niloufar Zarghami

Electronic Thesis and Dissertation Repository

The second incidence of brain metastases is from breast cancer. Radiotherapy, a standard treatment for brain metastasis, limits cancer division by inducing DNA double-stranded breaks (DSBs). Currently, identical radiation doses are prescribed for all types of brain metastases but little is known about their histological responses. In this thesis, we initiated a radiation dose-response study in a triple-negative human breast cancer brain metastasis mouse model using a custom designed 3D-printed restrainer to assist half-brain irradiation. We quantified the amount of DSBs in tumors and mouse brain tissues using γ-H2AX marker at 30 minutes (acute) and 11 days (longitudinal) after treatment …

The Role Of Bone Sialoprotein In The Tendon-Bone Insertion, Ryan M. Marinovich

Electronic Thesis and Dissertation Repository

Tendons and ligaments insert into bone through a transitional tissue termed the enthesis which is susceptible to injury and difficult to repair. Entheses contain a region of calcified fibrocartilage (CFC), however mineral-associated proteins in this tissue remain poorly characterized. Bone sialoprotein (BSP) is a phosphoprotein associated with mineralizing tissues. In these studies BSP was identified in the CFC of entheses by immunohistochemistry. Analysis of the entheses of Bsp^-/- mice indicate abnormalities in the CFC. Compared to controls, the CFC of the quadriceps tendon enthesis is 28% and 41 % longer in 15 week and 14 month old Bsp^{-/- …}

The Ctcf Chromatin Organizer Is Required For Hindlimb Development, Katherine L. Rabicki

Electronic Thesis and Dissertation Repository

Mutations in chromatin organizer CTCF were identified in patients with intellectual disability and skeletal defects. Previous studies demonstrated that depletion of CTCF in murine limb mesenchyme results in apoptosis in the forelimb. The role of CTCF in the hindlimb, however, is unknown. My objective was to investigate effects of CTCF deletion on chondrogenesis and skeletal development in the hindlimb. In vitro wild-type micromass cultures demonstrate that chondrocyte gene expression is delayed in the hindlimb when compared to forelimbs. Embryonic Ctcf^Fl/Fl;Prx1Cre mice were investigated, and qRT-PCR and histology were performed on limb buds and long bones. Results show that …

Contribution Of The Dorsolateral Prefrontal Cortex To Attentional And Mnemonic Processes In Visual Search, Brandon Belbeck

Electronic Thesis and Dissertation Repository

A key characteristic of selective visual attention is that it may be deployed on the basis of our knowledge or goals of the task at hand. Here, we used cryogenic deactivation to investigate the contribution of the dorsolateral PFC to cognitive flexibility and working memory, as well as their relation to the deployment of attention. Macaque monkeys performed visual search tasks requiring them to foveate a target in an array of stimuli. These included a feature search, a constant-target conjunction search, a variable-target search and variable-target with delay search task, with each being more cognitively demanding than the last. Bilateral …