VictorJuiz/thesis huggingface dataset:
Calcineurin Inhibitor-induced Endothelial Cell Injury - A Role for Complement

Calcineurin inhibitor (CNI) use significantly reduced acute rejection rates and revolutionized early allograft and patient outcomes post-transplantation. However, known nephro- and vascular toxicity preclude its use and contribute to chronic allograft injury, negatively impacting longer term outcomes. Evolving evidence suggest a role for complement dysregulation in the pathogenesis of CNI-induced endothelial injury. In an in vitro model using Blood Outgrowth Endothelial Cells (BOEC) isolated from healthy donors and a donor with a pathogenic MCP/CD46 variant, we showed that cyclosporine resulted in a dose and time dependent increase in complement deposition, enhanced by anti-CD59 sensitization. We showed for the first time that MCP/CD46 deficient BOECs were genetically predisposed to be more susceptible to cyclosporine-induced complement deposition (multiple-hit hypothesis). We found complement factor H surface dysregulation to play a key role in cyclosporine-induced complement activation on BOEC surfaces, with glycocalyx abolishment possibly being the key mechanism leading to alternative pathway dysregulation.

Keywords: Calcineurin inhibitor
Calcineurin inhibitor toxicity
Complement
Endothelial cell
Transplantation
Advisor: Licht, Christoph
Robinson, Lisa
Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence

Bupropion and varenicline are effective, first-line prescription-only pharmacotherapies for smoking cessation; however, their real-world use is limited by affordability and accessibility. Using a novel internet-based randomized design, we evaluated the real-world effectiveness of mailed bupropion and varenicline, as well as the roles of nicotine metabolism (NMR) and medication adherence, in a sample of interested smokers using web-based recruitment and follow up. Quit rates at end of treatment (EOT) were significantly higher for varenicline (30.2%) compared to bupropion (19.6%). Quit rates at 6 months (14.0%) and 12 months (12.1%) were not significantly different between bupropion and varenicline. Increased medication compliance significantly improved cessation outcomes at EOT. NMR was associated with nicotine dependence. Varenicline benefited Slow Metabolizers of nicotine whilst bupropion benefited Normal Metabolizers. Even though real-world quit rates were comparable to clinical trials, improving medication compliance and implementing personalized pharmacological and behavioral interventions are promising approaches to increase efficacy of smoking cessation pharmacotherapies.

Keywords: adherence
bupropion
nicotine metabolism
pharmacotherapy
smoking cessation
varenicline
Advisor: Zawertailo, Laurie A
Neural Correlates of Delusions in Patients with Alzheimer's Disease

The neural correlates of delusions in Alzheimer's disease (AD) remain unclear. This thesis examined the neuropathological, structural volumetric, and resting-state functional connectivity (rs-fc) correlates associated with delusions in AD. We hypothesized that delusional AD patients will have greater disease severity characterized by higher AD pathology load and increased atrophy, as well as altered rs-fc compared to non-delusional patients. We found that delusions were associated with Lewy body pathology, vascular pathology, and vascular risk factors, but were not correlated with increased AD pathology. Patients who developed delusions showed increased atrophy of regions within the default mode network (DMN) following the onset of delusions, while the cohort that did not develop delusions did not exhibit significant atrophy in the DMN over a similar time frame. We found that decreased connectivity within the DMN, in particular disintegration of the inferior parietal lobule with the overall network, may be associated with delusions in AD.

Keywords: Alzheimer's disease
Delusion
MRI
Neuropathology
Psychosis
Resting-state
Advisor: Schweizer, Tom A
Exploring Pain Self-Management Behaviours in Breast Cancer Survivors: A Mixed-Methods Study

Objective: To describe pain self-management behaviours (PSMB), and barriers and facilitators to PSMB in breast cancer (BC) survivors following primary cancer treatment. Methods: This study used a sequential explanatory mixed-methods design. BC survivors (n=53) who were 6 months (ď ą2 months) post-treatment for BC completed measures assessing pain catastrophizing, fear of cancer recurrence (FCR), and pain self-efficacy. Participants also completed the Barriers Questionnaire II (BQ-II) to assess barriers to pain management, and the Pain Self-Care Behaviours Questionnaire (PSCBQ) to assess engagement in PSMB. Interviews were conducted with a subset of participants (n=10) to further describe PSMB and barriers and facilitators to PSMB. Results: The most common PSMB participants reported via the PSCBQ were walking, distraction strategies, other exercise, and relaxation. Barriers and facilitators to PSMB included those identified by the BQ-II, as well as novel barriers and facilitators such as pain acceptance, information, and social support. Conclusion: BC survivors engage in a variety of PSMB and encounter many barriers and facilitators to PSMB not identified by existing quantitative measures. Future research should acknowledge the importance of barriers and facilitators such as pain acceptance, information (on what to expect and on PSMB in general), and social support.

Keywords: Breast Cancer
Pain
Self-Management
Advisor: Jones, Jennifer M
Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A (α-gal A). Enzyme replacement therapy (ERT) consists of regular infusions of recombinant α-gal A. Fabry disease patients commonly develop IgG antibodies against this enzyme and there is a concern that they may reduce the efficacy and safety of ERT. We developed an ELISA to measure anti-α-gal A IgG antibodies and found that 61% of patients on ERT were seropositive. We also designed a fast, single-chromatography purification protocol for α-gal A from the supernatant of a human embryonic kidney 293T cell line engineered to stably overexpress a 6xhis-tagged human α-gal A. We obtained 0.342 mg/L with the expected molecular weight but lower enzymatic activity than expected. This α-gal A is bound by antibodies from seropositive patients and not by those from healthy individuals, which suggests that it may serve as antigen in our ELISA to measure anti-α-gal A antibodies.

Keywords: alpha-galactosidase A
antibodies
ELISA
Fabry disease
lysosomal storage disorder
protein purification
Advisor: Medin, Jeffrey A
The Neural Correlates of Mental Flexibility in Children with Neurodevelopmental Disorders

Mental flexibility is an important executive function, facilitating flexibility in thought and action. Neurodevelopmental disorders represent a heterogeneous group of disorders, characterized by impaired brain development and function. Despite shared impairments in mental flexibility, it is not known whether the various neurodevelopmental disorders share the same aberrant neural correlates. To investigate, children [total n=110, ages 8-15 years; 22 typically developing, 38 autism spectrum disorder (ASD), 28 attention deficit hyperactivity disorder (ADHD), 22 obsessive-compulsive disorder (OCD)] completed a mental flexibility task in a magnetoencephalograph (MEG). Results revealed that typically developing children generally relied on the expected fronto-parietal network. However, all clinical groups showed an atypical reliance on the parietal regions, while patterns of delayed and atypical frontal activity differentiated the three clinical groups. This is the first neuroimaging study to elucidate the similarities and differences in the spatio-temporal profiles of neural regions involved in mental flexibility in children with neurodevelopmental disorders.

Keywords: ADHD
ASD
Child
Magnetoencephalography
Mental Flexibility
Neurodevelopmental Disorders
Advisor: Pang, Elizabeth W
Knee Tissue Strains and Effectiveness of a Novel Functional ACL Knee Brace during Dynamic In-Vitro Loading

Functional knee braces are commonly prescribed to help stabilize and protect the knee after an ACL injury or reconstruction. Newer brace designs employ a dynamic tensioning system to apply directional forces to the knee. The purpose of this thesis was to characterize meniscal loading under dynamic loading conditions and test the efficacy of a functional knee brace equipped with a dynamic tensioning system to reduce ACL and meniscal strain. A combined in-vivo/in-silico/in-vitro testing method was used to quantify tissue strains and the effect of the brace on cadaveric specimens. Tissue strains were quantified and validated before and after reconstruction, and the brace was found to lower tissue strains during most conditions. This work provides supportive evidence for the use of braces with a dynamic tensioning system for patients who are ACL deficient or following reconstruction.

Advisor: Whyne, Cari
Oculomotor Function Testing and White Matter Integrity in Patients with Post-Concussion Syndrome

Objectives: To assess self-paced saccadic (SPS) eye movements in patients with postconcussion syndrome (PCS), and use diffusion tensor imaging (DTI) to determine the white matter (WM) neural correlates of these eye movements. Methods: Fifty-nine PCS patients with at least two concussions performed the SPS task. We evaluated the relationships between the number of SPS and the number of self-reported symptoms and integrity of major WM tracts involved in visual processing (uncinate fasciculus (UF), cingulum (Cg), superior longitudinal fasciculus, and corpus callosum). Results: Number of SPS was negatively correlated with the total number of symptoms patients reported (r=-0.419, p=0.026). Positive correlations were seen between number of SPS and fractional anisotropy of left UF and left Cg (r=0.421, p=0.013; and r=0.452, p=0.008; respectively). Conclusion: SPS testing may reflect symptom burden in patients with PCS and since it is associated with WM integrity, it could be a diagnostic biomarker in patients with PCS.

Keywords: Concussion
Post-concussion syndrome
self-paced saccades
Advisor: Tartaglia, Carmela
Characterizing effects of small molecule inhibition of WDR5 in colorectal cancer

Abstract WDR5 is a core subunit of the MLL-WRAD methyltransferases, NSL-MOF acetyltransferases and MYC-MAX transcription factors. Dysregulation of these complexes has been implicated in numerous cancers. Despite links between colorectal cancer (CRC) and WDR5, little is known about its role. Using OICR11824, an internally developed novel chemical antagonist of WDR5, we investigated the biological effects of targeting the arginine binding pocket of WDR5 in CRC. Firstly, we evaluated the ability of OICR11824 to bind and disrupt WDR5-MLL interaction in cells. We then utilized OICR11824 and shRNA knockdown to investigate effects of WDR5 inhibition on proliferation in CRC cell lines. In addition, Western blot and RT-PCR were performed to confirm modulation of H3K4 methylation and expression of MYC-transcriptional targets. Finally, flow cytometry was used to evaluate effects of WDR5 inhibition on cell cycle. Our research shows that OICR11824 binds and inhibits the WDR5-MLL interaction. As well, OICR11824 displays a range of anti-proliferation potencies in CRC cell lines with the greatest sensitivity seen in COLO205 demonstrating a G1 accumulation and S-phase depletion. Finally, OICR11824 affects the actions of WDR5-complexes in MYC-WDR5 gene targets and H3K4 trimethylation. Our research provides new insights into the role of WDR5 in CRC and will contribute to not only developing new therapeutics against CRC, but will also help elucidate the role of WDR5 complexes in cancer.

Keywords: Colorectal Cancer
Epigenetics
WDR5
Advisor: Al-awar, Rima
Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, triggering many biological effects typified by induction of cytochrome P450 1A1 (CYP1A1). Interestingly, little is known about their effects on human CYP3A4, despite this enzymeâ s clinical relevance. Controversially, studies have reported both inductive and suppressive effects of PAHs on CYP3A expression. The current study used 3-methylcholanthrene (3-MC) to study the effects of PAHs on CYP3A4 activity and expression in humanized PXR-CAR-CYP3A4/3A7 mice. Adult mice were treated by intraperitoneal injection with 3-MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours later. Basal hepatic CYP3A4 activity and expression was significantly higher in female vs. male mice. 3-MC decreased CYP3A4 activity and expression in female mice at 72 hours, whilemales showed similar, but non-statistically significant, trends. This mouse model will facilitate further in vivo studies of the mechanisms and consequences of CYP3A4 suppression by PAHs.

Keywords: aryl hydrocarbon receptor
Cyp3a11
drug metabolism
drug metabolizing enzyme
P450
polycyclic aromatic hydrocarbon
Advisor: Riddick, David S
Social Information Processing after Mild Traumatic Brain Injury

Deficits in social information processing, including emotion perception, theory of mind, and social behavioral control, have been shown in individuals with moderate to severe Traumatic Brain Injury (TBI). However, little is known about social information processing after mild TBI. The current study aims to address this knowledge gap. 47 mild TBI subjects and 30 healthy controls (HC) were tested in three social information processing domains: social perception, social cognition, and social regulation. Non-social cognition was also assessed. Mild TBI subjects performed significantly worse than HC in executive function (p = 0.039), but not in any of the social information processing domains. However, those with mild global non-social cognitive impairment also performed poorer in social cognition domain (p = 0.028). The current results contrast with findings from moderate to severe TBI patients, and suggest that deficits in social information processing in mild TBI may arise secondary to non-social cognitive impairment.

Advisor: Feinstein, Anthony
Evaluating Pre-existing Cognitive Impairment and Anticholinergic Burden as Predictors of Post-operative Delirium following TAVI (Transcatheter Aortic Valve Implantation)

Post-operative delirium (POD) is common following Transcatheter Aortic Valve Implantation (TAVI) and is associated with adverse health outcomes. We hypothesized that cognitive impairment and anticholinergic burden may exacerbate risk of POD in TAVI due to their effects on cholinergic pathways underlying delirium. Cognitive deficits were screened using the Mini-Cog test before TAVI and anticholinergic burden assessed using the Anticholinergic Cognitive Burden (ACB) scale. Logistic regression adjusted for age, history of stroke, atrial fibrillation, diabetes and anesthesia found that neither the Mini-Cog (OR: 6.62, p=0.09) nor the ACB scale (OR: 1.62, p=0.17) were significant independent predictors of POD when assessed individually. When assessed together, patients screening positive on the Mini-Cog and with a high ACB scale score (OR 6.94, p=0.01) predicted increased risk of POD in a significant model (Ď 2 (6) =29.1, p

Keywords: cardiology
geriatric
pharmacology
psychiatry
treatment optimization
Advisor: Lanctot, Krista L
Development and Characterization of a Polyester-Based Implant for Controlled Drug Release

There is tremendous interest in developing IDDSs that improve the efficacy of drugs at the target site while sparing off-target tissues from toxicity. PVL is an attractive yet unexplored polyester for preparing IDDSs since the valerolactone monomer can be alkylated (PAVL) in good yield to afford a pendant arm on the polymer backbone that can be functionalized to tailor the physicochemical properties to suit the application of interest. This thesis describes the first preparation and characterization of polyester-based implants based on PVL-co-PAVL that are capable of sustained release of a library of drugs of varying physicochemical properties. Drug release was found to be controlled by diffusion but influenced by the properties of matrix, the state of the drug, and drug aqueous solubility. Finally, the system proved to be highly biocompatible, illustrating the potential of PVL-co-PAVL as a long-term IDDS.

Advisor: Allen, Christine J
Determining the Natural History of Men with Initially Negative Prostate Biopsies

Prostate biopsies have significant false negative rates. Thus, men with negative results may undergo continued evaluation for prostate cancer. Long-term prostate cancer diagnosis, mortality, and treatment rates are currently unknown in North American men with a negative prostate biopsy. We thus aimed to determine the long-term rates and predictors of these outcomes. Using linked health administrative data, we identified 95,655 men with a single negative prostate biopsy. The outcomes cumulative rates were determined under a competing risk setting and regression analysis was used to assess potential predictors. The 20-year prostate cancer diagnosis and mortality cumulative rates were 23.7% and 1.8%, respectively. Older patients had higher cancer diagnosis and mortality risks; whereas men of higher socioeconomic status and urban residence had increased cancer diagnosis, yet lower cancer mortality risks. These results will allow physicians to inform patients of their cancer-specific outcomes and identify men at higher risk of adverse long-term outcomes.

Keywords: Diagnosis
Population Health
Prostate Biopsy
Prostate Cancer
Sensitivity and Specificity
Survival
Advisor: Fleshner, Neil E
The Role of Family Physicians in Palliative Care: Perspectives of Patients with Advanced Cancer

Introduction: Early palliative care is recommended for advanced cancer patients and can be provided by family physicians(FPs). This study examines patient perspectives of FPs’ palliative care involvement. Methods: Advanced cancer patients attending an Oncology Palliative Care Clinic(OPCC) completed a survey about FP involvement. Eligible patients were English-speaking, ≥18years old, had >1prior OPCC visit, passed a cognitive screen, and had a FP within 5years. Results: Of 79 patients, 58%(46/79) were female; mean age was 58.25±13.11. Seventy-seven(97.5%) currently had a FP and 33%(26/79) had seen them recently for palliative care. As hypothesized, most patients preferred to receive palliative care from their palliative care physician. Possible barriers to FP-provided palliative care included lack of knowledge of FP services, timely access to care, and perceived role of the FP. Conclusion: Patients were overall engaged with their FPs but many had not seen their FP for palliative care. Possible barriers to this care were identified.

Keywords: Early Palliative Care
Family Physicians
General Practitioners
Palliative Care
Palliative Care Physicians
Supportive Care
Advisor: Zimmermann, Camilla
Resting-state functional MRI predictors and correlates of response to rTMS in major depression

Major depressive disorder (MDD) is a debilitating and prevalent psychiatric illness for which an emerging treatment is repetitive transcranial magnetic stimulation (rTMS). Several recent studies have used functional brain imaging modalities to characterize neural predictors and correlates of rTMS response in MDD. Specifically, responders to rTMS may exhibit varying functional abnormalities among brain regions that play roles in cognition, attention, or reward response. Here, using a cohort of 303 patients who received one of two rTMS stimulation protocols, we aimed to identify functional MRI predictors and correlates of response to left dorsolateral prefrontal cortex (dlPFC)- rTMS. Based on baseline and post-treatment change in whole-brain functional connectivity to a selection of cortical, striatal, and network-wide seed regions, we identified several predictors and correlates of treatment response that comprise a ventromedial and orbitofrontal functional loop. This study represents a step to understanding maladaptive network interactions in MDD, the impact of non-invasive brain stimulation on improving inter-network function, and the role of functional brain networks in motivation, valuation, and behaviour.

Keywords: fMRI
major depression
rTMS
salience network
ventromedial network
Advisor: Downar, Jonathan
Examining Brain and Body Correlates of Cerebrovascular Reactivity Among Adolescents with and without Bipolar Disorder

Cardiovascular disease (CVD) is excessive and premature among individuals with bipolar disorder (BD). Cerebrovascular reactivity (CVR), a marker of cerebrovascular health, is the capacity of the brainâ s blood vessels to vasodilate when induced by vasoactive substances. We examined this topic for the first time in BD. CVR was measured in 25 adolescents with BD and 25 age and sex-matched psychiatrically healthy controls (HCs). Whole-brain analyses showed that BDs have lower CVR in the posterior cingulate gyrus and periventricular white matter. When controlling for differences in body mass index (BMI), additional between group CVR differences were observed in the temporal poles, supramarginal gyrus and lingual gyrus. There were no significant clusters of the brain that were BD>HC. Our results suggest that CVR may be a proxy for future risk of CVD and/or cerebrovascular disease, given the location of anomalous CVR within regions where cerebrovascular pathology occurs in mid-life.

Keywords: adolescents
bipolar disorder
blood-oxygenation-level dependent
breath-hold
cerebrovascular reactivity
magnetic resonance imaging
Advisor: Goldstein, Benjamin I
Investigating the central role of astrocytes in mediating postanesthetic memory deficits

Anesthetics cause postanesthetic memory deficits in animal models, and similar deficits may contribute to postoperative delirium and cognitive dysfunction in patients. We previously showed using a mouse model that etomidate-induced persistent memory deficits result from increased tonic GABAA receptor-mediated inhibitory current in the hippocampus, through an astrocyte-mediated mechanism. However, the underlying mechanisms are uncertain. The aims of this study were to: 1) determine whether widely used anesthetic and sedative agents persistently increase tonic GABAA current; 2) determine whether human astrocytes mediate the increase, and 3) identify the underlying mechanisms. The results show that several GABAergic drugs persistently increase tonic current and human astrocytes release soluble factors that mediate etomidateâ s effect on tonic current. Furthermore, etomidate and sevoflurane act through astrocytic GABAA receptors to trigger a pro-inflammatory signaling pathway, which underlies the persistent increase in tonic current. These results increase the mechanistic understanding of postanesthetic memory deficits and delineate treatment targets.

Keywords: Anesthesia
Astrocytes
Electrophysiology
Memory
Îł-aminobutyric acid
Advisor: Orser, Beverley A