VictorJuiz/thesis huggingface dataset:
Medical Image Processing Techniques for the Objective Quantification of Pathology in Magnetic Resonance Images of the Brain
Keywords: Medical image processing
Magnetic Resonance Images
White matter lesion
Fluid Attenuation Inversion Recovery

This thesis is focused on automatic detection of white matter lesions (WML) in Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) of the brain. There is growing interest within the medical community regarding WML, since the total WML volume per patient (lesion load) was shown to be related to future stroke as well as carotid disease. Manual segmentation of WML is time consuming, labourious, observer-dependent and error prone. Automatic WML segmentation algorithms can be used instead since they give way to lesion load computation in a quantitative, efficient, reproducible and reliable manner. FLAIR MRI are affected by at least two types of degradations, including additive noise and the partial volume averaging (PVA) artifact, which affect the accuracy of automated algorithms. Model-based methods that rely on Gaussian distributions have been extensively used to handle these two distortions, but are not applicable to FLAIR with WML. The distribution of noise in multicoil FLAIR MRI is non-Gaussian and the presence of WML modifies tissue distributions in a manner that is difficult to model. To this end, the current thesis presents a novel way to model PVA artifacts in the presence of noise. The method is a generalized and adaptive approach, that was applied to a variety of MRI weightings (with and without pathology) for robust PVA quantification and tissue segmentation. No a priori assumptions are needed regarding class distributions and no training samples or initialization parameters are required. Segmentation experiments were completed using simulated and real FLAIR MRI. Simulated images were generated with noise and PVA distortions using realistic brain and pathology models. Real images were obtained from Sunnybrook Health Sciences Centre and WML ground truth was generated through a manual segmentation experiment. The average DSC was found to be 0.99 and 0.83 for simulated and real images, respectively. A lesion load study was performed that examined interhemispheric WML volume for each patient. To show the generalized nature of the approach, the proposed technique was also employed on pathology-free T1 and T2 MRI. Validation studies show the proposed framework is classifying PVA robustly and tissue classes are segmented with good results.
Evaluating Human Endogenous Retrovirus and LINE-1 Retrotransposable Element Antigens as Novel Targets for T cell Based HIV-1 Vaccine Strategies
Keywords: HIV vaccines
Retrotransposable elements

The global HIV-1 pandemic is new only in the sense that it is the latest iteration in a conflict between humans and retroviruses that has spanned millions of years. Bearing witness to this, our genomes are littered with the DNA remnants of ancient retroviruses. These ‘human endogenous retroviruses’ (HERVs) are generally thought to be inert. In this thesis, I explore the hypothesis that HIV-1 has had to make a compromise in order to avoid extermination by a class of cellular defence factors that our cells evolved long ago in order to defend against ancient retroviruses. In disabling these defence factors to allow for its own replication, I posit, that HIV-1 enables the expression of the ancient retroviruses, as well as LINE-1 retroelements, in our genome. I propose to use this against the virus by targeted immune responses against HERV/LINE-1 antigens as a way of killing HIV-1-infected cells.
The Effect of the Colon Cancer Check Program on Colorectal Cancer Screening in Ontario
Keywords: Health care evaluation
Colorectal cancer screening
Interrupted time series

Background: This thesis is composed of three studies testing the effect of the Colon Cancer Check (CCC) program, the organized screening program for colorectal cancer in Ontario, on screening participation. In the first paper, we described the trends of participation to Fecal Occult Blood Test (FOBT) and endoscopy, and the trend of ‘up-to-date’ consistent with guidelines, overall and stratified by demographic characteristics between 2005 and 2011. In the second paper, we tested the effect of physician’s recommendation on FOBT participation and disparities in participation. In the third paper, we measured the effect of the CCC program on FOBT participation using an interrupted time series. Methods: We identified six annual cohorts of individuals eligible for CRC screening in Ontario between 2005 and 2011 by linking the Registered Persons Database to Ontario Health Insurance Plan and 2006 Census from Statistics Canada. We used descriptive statistics to describe the trends of participation. The effect of physician’s recommendation on screening participation was tested using multiple logistic regression analysis. The effect of the CCC program on FOBT participation was tested using segmented regression analysis. Results: An increasing trend in FOBT participation and ‘up-to-date’ status was observed across all demographic characteristics. The disparity gaps persisted over time by gender, income, recent registrant and age. The rural/urban gap was removed. Physician’s recommendation tripled the likelihood of FOBT participation (prevalence rate ratio=3.23, CI= 3.22-3.24) and mitigated disparities. The CCC led to a temporary increase in level (8.2‰ person-month) in FOBT participation followed by a decline in trend and then a plateau. The increase in level was significant across all population sub-groups. Conclusions: We found that CRC screening has increased in Ontario across all subgroups of the population but remained suboptimal. Disparities in screening participation were identified. Proposed strategies to improve performance include interventions to increase the rate of physician’s recommendation at the practice level, tailored interventions to motivate under-users and public media campaigns.
Record Linkage for Web Data
Keywords: Data Management
Databases
Record Linkage
Entity Resolution
Link Discovery
Data Integration
Data Quality

Record linkage refers to the task of finding and linking records (in a single database or in a set of data sources) that refer to the same entity. Automating the record linkage process is a challenging problem, and has been the topic of extensive research for many years. However, the changing nature of the linkage process and the growing size of data sources create new challenges for this task. This thesis studies the record linkage problem for Web data sources. Our hypothesis is that a generic and extensible set of linkage algorithms combined within an easy-to-use framework that integrates and allows tailoring and combining of these algorithms can be used to effectively link large collections of Web data from different domains. To this end, we first present a framework for record linkage over relational data, motivated by the fact that many Web data sources are powered by relational database engines. This framework is based on declarative specification of the linkage requirements by the user and allows linking records in many real-world scenarios. We present algorithms for translation of these requirements to queries that can run over a relational data source, potentially using a semantic knowledge base to enhance the accuracy of link discovery. Effective specification of requirements for linking records across multiple data sources requires understanding the schema of each source, identifying attributes that can be used for linkage, and their corresponding attributes in other sources. Schema or attribute matching is often done with the goal of aligning schemas, so attributes are matched if they play semantically related roles in their schemas. In contrast, we seek to find attributes that can be used to link records between data sources, which we refer to as linkage points. In this thesis, we define the notion of linkage points and present the first linkage point discovery algorithms. We then address the novel problem of how to publish Web data in a way that facilitates record linkage. We hypothesize that careful use of existing, curated Web sources (their data and structure) can guide the creation of conceptual models for semi-structured Web data that in turn facilitate record linkage with these curated sources. Our solution is an end-to-end framework for data transformation and publication, which includes novel algorithms for identification of entity types and their relationships out of semi-structured Web data. A highlight of this thesis is showcasing the application of the proposed algorithms and frameworks in real applications and publishing the results as high-quality data sources on the Web.
Defining the Mechanisms By Which Transplanted Neural Precursor Cells Mediate Functional Recovery Following Spinal Cord Injury
Keywords: spinal cord injury
neural precursor cell
transplantation
neural repair

Spinal cord injury (SCI) is uniquely devastating. Cellular transplantation strategies for SCI are showing promise. Little, however, is known about how transplanted neural precursor cells (NPCs) enhance functional recovery or the mechanisms by which they interact with the host spinal cord. Better understanding of these critical issues may lead to improved strategies to enhance recovery after SCI. Given this background, I hypothesized that NPCs mediate functional recovery by a number of mechanisms including trophin production, neuroprotection, modulation of the host inflammatory response or glial scarring, and/or remyelination. I thus endeavored to characterize trophin production by NPCs in vitro and in vivo in rats with clip compression SCI of the thoracic spinal cord, to determine if preservation of host cells and tissue contribute to functional recovery and to determine how NPC transplantation influences the host inflammatory response and glial scarring. Here I present unique and novel insights into NPC-host interactions following SCI. We show that NPCs are poised to provide trophic support to the injured spinal cord. We also show that the combination of NPCs, pharmacotherapy and trophin infusion is associated with sparing of grey and white matter, enhanced numbers of oligodendrocytes but not axons as well as an increased inflammatory response. To assess the potential impact of myelination as a mechanism underlying NPC-mediated functional recovery after SCI, experiments were undertaken using NPCs derived from shiverer mutant mice unable to produce central myelin. These experiments showed that while NPCs from wild-type mice generate myelin and mediate functional recovery after SCI; transplanted shiverer NPCs impede neurobehavioural recovery. In summary, my work provides unique insights into the functional effects of NPC transplantation after SCI. Of importance, this thesis provides novel evidence that remyelination is a key mechanism of action by which NPCs mediate recovery after SCI. Hence, this work has important implications for patients with SCI.
Effects of Chronic Maternal Stress on Behaviour and Hypothalamo-pituitary-adrenal Function in Offspring
Keywords: Maternal Stress
Hypothalamo-Pituitary-Adrenal Axis
Behaviour
Endocrinology
Environmental Enrichment
Programming
Amphetamine

Maternal stress during the perinatal period has been linked to attention and behavioral problems and increased adrenocortical activity in children. Underlying this relationship is thought to be exposure to excessive glucocorticoids during development. The aim of this set of studies was to determine the effects of chronic maternal stress (CMS) during the perinatal period on behaviour and endocrine function in male and female guinea pig offspring at the juvenile and adult life stage. Environmental enrichment was investigated as a potential therapeutic tool to reverse changes induced by CMS. Pregnant guinea pigs were exposed to a sequence of stressors every other day over the second half of gestation until weaning on postnatal day 25. Offspring were tested for ambulatory activity, attention, cognitive function, sex-steroid levels and adrenocortical function. One cohort of animals were housed in an enriched environment, the remaining offspring were housed in standard conditions. A separate cohort was administered amphetamine (1 mg/kg) prior to behavioural testing to determine influence of CMS on dopaminergic function. Juvenile male and female offspring of mothers exposed to stress exhibited increased basal and decreased stress-induced salivary cortisol, and male offspring displayed reduced activity and a phase shift in their circadian rhythm of activity. Adult male offspring of CMS mothers exhibited increased activity in a novel environment and decreased activity in a familiar environment. Female adult offspring of CMS mothers exhibited reduced attention and increased activity in a novel environment. Enrichment acted independently of CMS, increasing plasma testosterone and attention in adult male offspring and reducing the adrenocortical response to stress and decreasing attention and activity in female offspring. Amphetamine decreased activity in a novel environment and increased activity in a familiar environment in both sexes, regardless of age or maternal treatment. Amphetamine improved attention in juvenile and adult males. The current studies demonstrated a strong effect of CMS on behaviour in juvenile and adult offspring. Enrichment was not effective for attenuating the effects of CMS. These studies clearly demonstrate behavioural changes as a result of CMS emerge over the lifetime of the offspring and have begun to uncover the underlying mechanisms of programming.
Early Immune Responses to SARS Coronavirus in Ferrets
Keywords: Immunology
Infectious diseases
SARS
Ferret
Chemokines
Interferon

Severe acute respiratory syndrome (SARS) was defined as an invasive respiratory disease in 2002, which originally came from China and rapidly spread all over the globe. Acute pneumonia and lower respiratory tract involvement most affected the middle aged individuals and elderly with a mortality rate of 11%. While SARS Corona virus (SARS-CoV) has maintained its potential capacity to reemerge, clinical study of the immune system of SARS patients, as well as controlled studies may lead to application of new treatment strategies in future. Throughout this work, I have focused on early immune responses to SARS-CoV in humans and in ferrets. CXCL0 has been associated with alterations in the clinical course of several infectious diseases, including SARS and influenza. Here I have cloned ferret CXCL10 gene and have expressed its recombinant protein. I demonstrate that the CXCL10 plasma level in SARS patients is associated with the severity of disease. I also show that endogenous ferret CXCL10 exhibits similar mRNA expression patterns in the lungs of deceased SARS patients and ferrets experimentally infected with SARS-CoV. Type I interferons (IFNs) are indispensable parts of the innate immunity during early stages of infection. A clear distinction between genes upregulated by direct virus-cell interactions and genes upregulated by secondary IFN production has not been made yet. Here, I have investigated differential gene regulation in ferrets upon subcutaneous administration of IFN-a2b and during SARS-CoV infection. In vivo experiments revealed that IFN-a2b causes upregulation of abundant IFN response genes (IRGs), chemokine receptors, and other genes that participate in phagocytosis and leukocyte migration. SARS-CoV infection of ferrets leads to upregulation of varieties of IRGs and a broad range of genes involved in cell migration and inflammation. This work allowed dissection of several molecular signatures present during SARS-CoV infection, which are part of a robust IFN antiviral response. Since localization of CD8+ Tcells may contribute to tissue injury, I have characterized ferret CD8 gene and have generated reagents that can be used in future studies with the aim of evaluating CD8+ T cells localization in the ferret lung during infection with SARS-CoV.
Biological Roles of the Vitamin D Receptor in the Regulation of Transporters and Enzymes on Drug Disposition, Including Cytochrome P450 (CYP7A1) on Cholesterol Metabolism
Keywords: Vitamin D Receptor (VDR)
transporters
enzymes
calcitriol or 1,25(OH)2D3
P-glycoprotein (P-gp)
cholesterol metabolizing enzyme
CYP7A1
short heterodimer partner (SHP)
farnesoid X receptor (FXR)
physiologically based pharmacokinetic (PBPK) model
multidrug resistance protein 1 (MDR1)
multidrug resistance assoicated protein (MRP)
bile acids
cholesterol
homeostasis
nuclear receptor

Nuclear receptors play significant roles in the regulation of transporters and enzymes to balance the level of endogenous molecules and to protect the body from foreign molecules. The vitamin D receptor (VDR) and its natural ligand, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], was shown to upregulate rat ileal apical sodium dependent bile acid transporter (Asbt) to increase the reclamation of bile acids, ligands of the farnesoid X receptor (FXR). FXR is considered to be an important, negative regulator of the cholesterol metabolizing enzyme, Cyp7a1, which metabolizes cholesterol to bile acids in the liver. In rats, decreased Cyp7a1 and increased P-glycoprotein/multidrug resistance protein 1 (P-gp/Mdr1) expressions pursuant to 1,25(OH)2D3 treatment was viewed as FXR effects in which hepatic VDR protein is poorly expressed. In contrast, changes in rat intestinal and renal transporters such as multidrug resistance associated proteins (Mrp2, Mrp3, and Mrp4), Asbt, and P-gp after administration of 1,25(OH)2D3 were attributed directly as VDR effects due to higher VDR levels expressed in these tissues. Higher VDR expressions were found among mouse hepatocytes compared to those in rats. Hence, fxr(-/-) and fxr(+/+) mouse models were used to discriminate between VDR vs. FXR effects in murine livers. Hepatic Cyp7a1 in mice was found to be upregulated with 1,25(OH)2D3 treatment, via the derepression of the short heterodimer partner (SHP). Putative VDREs, identified in mouse and human SHP promoters, were responsible for the inhibitory effect on SHP. The increase in hepatic Cyp7a1 expression and decreased plasma and liver cholesterol were observed in mice prefed with a Western diet. A strong correlation was found between tissue Cyp7a1 and P-gp changes and 1,25(OH)2D3 plasma and tissue concentrations, confirming that VDR plays an important role in the disposition of xenobiotics and cholesterol metabolism. Moreover, renal and brain Mdr1a/P-gp were found to be directly upregulated by the VDR in mice, and concomitantly, increased renal and brain secretion of digoxin, a P-gp substrate, in vivo. The important observations: the cholesterol lowering and increased brain P-gp efflux activity properties suggest that VDR is a therapeutic target for treatment of hypercholesterolemia and Alzheimer’s diseases, since beta amyloid, precursors of plague, are P-gp substrates.
TRADD Mediates Inflammatory Responses in the Cytoplasm and Tumor Suppression in the Nucleus
Keywords: Inflammation
Cancer

TNF is a proinflammatory cytokine whose pleiotropic biological properties are signaled through the receptor TNFR1. Activation of this signaling pathway has been implicated in a broad range of biological functions, including host defense, inflammation, apoptosis, autoimmunity, and cancer. TRADD is an adaptor protein that is recruited to TNFR1 upon receptor engagement. Using a Tradd-deficient murine model, we demonstrated that TRADD is essential for both TNF-mediated apoptosis and inflammatory responses. In addition to refining the role of TRADD in TNFR1 signaling, we have also identified a novel function of TRADD in TLR3 and TLR4 pathways, which are key drivers of the innate immune response. We showed that TRADD is involved in NF-κB activation upon TLR3 and TLR4 stimulation, and Tradd-deficient macrophages showed impaired inflammatory cytokine production in response to TLR ligands in vitro. These data reveal the multifaceted functions of TRADD in immune signaling pathways. Beyond its role in the immune response, TNF has also been shown to play a crucial, cell-non-autonomous role in driving tumor growth in various models of cancer. We initially sought to determine whether TRADD is essential for this aspect of TNF function by employing the use of a chemical induced skin carcinogenesis model in which the tumor-promoting role of TNF is very well established. In this model, H-Ras is the major driving oncogene. We found that Tradd deficiency accelerated tumor formation in mouse skin, in strong contrast to what was observed in Tnfr1-deficient mice. Further in vitro analyses revealed that upon expression of oncogenic H-Ras, Tradd-deficient murine fibroblasts displayed both reduced cell cycle arrest and repression of Ras induced cellular senescence. Importantly, the level of p19Arf induced by H-Ras expression was reduced in Tradd-deficient fibroblasts in a post-translational manner. Our biochemical evidence suggests that TRADD can shuttle dynamically between the cytoplasm and the nucleus; in doing so, nuclear TRADD interacts with ULF, a newly identified E3 ubiquitin ligase for p19Arf. Interaction between nuclear TRADD and ULF sequesters ULF away from p19Arf, leading to p19Arf stabilization and tumor suppression. Together, these data demonstrate the functional diversity of TRADD in different compartments of the cell.
Mechanisms Controlling the Distribution of Two Invasive Bromus Species
Keywords: species distribution
invasive species
plant physiology and reproduction
temperature
tolerance limits
photosynthesis

In order to predict future range shifts for invasive species it is important to explore their ability to acclimate to the new environment and understand physiological and reproductive constraints controlling their distribution. My dissertation studied mechanisms by which temperature may affect the distribution of two of the most aggressive plant invaders in North America, Bromus tectorum and Bromus rubens. While Bromus tectorum is dominant in the “cold desert” steppes of the Intermountain region of western North America, B. rubens is one of the severe grass invaders in the “hot deserts” of southwestern North America. I first evaluated whether winter freezing tolerance is the mechanism responsible for the distinct northern range limits of Bromus species. Bromus rubens has a slower rate of freezing acclimation that leads to intolerance of sudden, late-autumn reductions in temperature below -12°C, Bromus tectorum, by contrast, cold hardens rapidly and is not impacted by the sudden severe late-autumn cold. Photosynthetic response to temperature does not explain their current range separation. Bromus species differ little in their photosynthetic temperature responses and the acclimation pattern of photosynthesis. Both species acclimated to a broad range of temperature through the amelioration of Pi regeneration limitation at sub-optimal temperatures and improved carboxylation capacity above the thermal optimum which probably resulted from increased thermostability of Rubisco activase. The effect of elevated temperatures during flowering on the seed yield of Bromus species demonstrates that neither species produces seed at 36°C and above. These thresholds are close to temperatures encountered during flowering in their natural environment. In summary, climatic changes will cause northward range expansion of Bromus species due to less severe autumn and winter, while reproductive failure could cause range contraction at their southern margins.