VictorJuiz/thesis huggingface dataset:
Association of Obesity with Breast Cancer

In a literature-based meta-analysis, we reported on the association of obesity at breast cancer (BC) diagnosis with disease-free (DFS) and overall survival (OS) in BC subtypes. We included 26 studies (108,793 patients) and the results showed pooled hazard ratios, HRs, for DFS and OS in obese vs non-obese were worse in all subgroups studied (ER/PgR+ve and HER2-ve; HER2+ve and any ER/PgR; and triple negative, TN), with larger prognostic effects in the ER/PgR and HER2-ve subtype. HRs for OS (but not DFS) were somewhat higher in observational vs interventional studies in ER/PgR+ve/HER2-ve and HER2+ve/ any ER/PgR but not in TN. This differential effect was statistically significant only in the HER2+ve subgroup and it may reflect the selection of healthier patients for intervention trials; obese patients in these studies may not have the same degree of obese physiology as the broader population. We evaluated the association of BMI, metabolic, inflammatory and tumor markers with CTCs in women with metastatic BC prior to a new systemic therapy. 96 patients with metastatic BC were recruited. ≥5 CTCs/7.5mL was detected in 43.8% of patients and those with liver metastases (vs. not) more frequently had an elevated CTC count. Some inflammatory markers were significantly associated with PAI-1, IL6, IL8, hs-CRP. CEA and CA15-3 were significantly higher in the CTC high (≥5 CTCs/7.5mL) versus in the CTC low group (

Keywords: Breast Cancer
Circulating Tumor Cells
Inflammation
Meta-analysis
Obesity
Outcome
Advisor: Goodwin, Pamela J
Positron Emission Tomography (PET) of Breast Cancer Heterogeneous for HER2 and EGFR using Bispecific Radioimmunoconjugates

The human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer (BC) and is the target for immunotherapy with trastuzumab, pertuzumab, and trastuzumab-emtansine (T-DM1). Despite improvements in survival, resistance to HER2-targeted therapies remains a major problem. One resistance mechanism is loss of HER2 and increased EGFR. Additionally, intratumoral HER2 heterogeneity is correlated with a poor response to trastuzumab. The hypothesis was that novel bispecific radioimmunoconjugates (bsRICs) are capable of permit molecular imaging of both EGFR and HER2 receptors simultaneously with positron emission tomography (PET) and deliver more radioactivity to the tumor especially in the presence of receptor heterogeneity. BsRICs was developed by chemically linking trastuzumab Fab (anti-HER2) to human EGF through a 24-mer polyethylene glycol (PEG24) spacer, and radiolabeled with 64Cu. 64Cu-NOTA-Fab-PEG24-EGF demonstrated the ability to specifically bind to EGFR or HER2 both in vitro and in vivo, and exhibited prolonged blood circulation than monospecific agents in mice. PET imaging was performed on NOD-SCID mice bearing tumor xenografts expressing EGFR, HER2, or both receptors. Tumors were clearly visualized by microPET/CT imaging, and biodistribution studies showed significantly better tumor uptake for bsRICs in tumor xenograft expressing both receptors. Human cancer xenograft mouse models with heterogeneous levels of HER2 and EGFR was established by subcutaneous inoculation of mixtures of SK-OV-3 cells and MDA-MB-468 cells. These BC xenografts were more clearly visualized by microPET/CT, and bsRICs exhibited higher tumor uptake and lower degree of heterogeneous uptake than monospecific agents. These results suggest that bsRICs may be useful for imaging of HER2-positive heterogeneous BC consisting of EGFR-positive subpopulations. Thus, bsRICs will be able to address the challenge of HER2 intratumoral heterogeneity in BC.

Keywords: Bispecific Radioimmunoconjugate
Breast Cancer
Copper-64
Human Epidermal Growth Factor Receptor 2
Molecular Imaging
Positron Emission Tomography
Advisor: Reilly, Raymond M
A Wearable Computer Vision System for Monitoring Hand Use at Home

Impairments in hand function lead to reduced independence and quality of life after cervical spinal cord injury (SCI). In order to develop effective rehabilitation interventions for individuals with cervical SCI, it is important to assess hand function throughout the rehabilitation process. Currently, the efficacy of new treatments is measured by assessments limited to a controlled setting or based on self-report; there is currently no viable method to collect quantitative information once the patient has returned to the community. This thesis attempts to solve this gap by developing a computer vision-based wearable camera system for monitoring hand use. Our research involved (1) the collection of egocentric video that represents activities of daily living, (2) the development of an algorithm that captures interactions between the hand and objects in the environment, and (3) the evaluation of the system in both laboratory and home settings. Four studies were executed, involving three video datasets (20 able-bodied participants and 17 participants with SCI in a home simulation laboratory, as well as 3 participants with SCI in their home). We introduced the concept of hand-object interaction detection, defined as a binary decision about whether or not the hand is manipulating an object for a functional purpose. The datasets were used in the development and evaluation of an algorithmic pipeline consisting of hand detection and segmentation, followed by hand-object interaction detection. For this step, a random forest classifier was trained on hand motion, hand shape and scene colour features. The frame-by-frame binary output data over time was further analysed to extract three functional hand-use metrics: (1) the amount of total interaction as a percentage of testing time, (2) the average duration of interactions in seconds, and (3) the number of interactions per hour. The final study investigated the views of participants with SCI on the use of wearable cameras. With appropriate strategies determined by input from individuals with SCI, this thesis demonstrates the potential of a wearable egocentric camera as a unique tool to allow researchers and clinicians to gauge the user's level of independence at home in activities involving upper limb function.

Keywords: Community-based rehabilitation
Egocentric vision
Outcome measure
Rehabilitation engineering
Tetraplegia
Upper extremity
Advisor: Zariffa, José
Conditional Copula Inference and Efficient Approximate MCMC

This thesis consists of two main parts. The first part focuses on parametric conditional copula models that allow the copula parameters to vary with a set of covariates according to an unknown calibration function. Flexible Bayesian inference for the calibration function of a bivariate conditional copula is introduced. The prior distribution over the set of smooth calibration functions is built using a sparse Gaussian Process prior for the Single Index Model. The estimation of parameters from the marginal distributions and the calibration function is done jointly via Markov Chain Monte Carlo sampling from the full posterior distribution. A new Conditional Cross Validated Pseudo-Marginal criterion is used to perform copula selection and is modified using a permutation-based procedure to assess data support for the simplifying assumption. The first part concludes with methods for establishing data support for the simplifying assumption in a bivariate conditional copula model. After splitting the observed data into training and test sets, the method proposed will use a flexible Bayesian model fit to the training data to define tests based on randomization and standard asymptotic theory. I discuss theoretical justification for the method and implementations in alternative models of interest: Gaussian, Logistic and Quantile regressions. The performance is studied via simulated data. The second part of the thesis focuses on approximate Bayesian methods. Approximate Bayesian Computation (ABC) and Bayesian Synthetic Likelihood (BSL) are popular simulation based methods for sampling from the posterior distribution when the likelihood is not tractable but simulations for each parameter are easily available. However these methods can be computationally inefficient since a large number of pseudo-data simulations is required. I propose to use perturbed MCMC versions of ABC and BSL algorithms and attempt to significantly accelerate these samplers. The main idea of the proposed strategy is to utilize past samples with k-Nearest-Neighbor approach for likelihood approximation. This general method works for ABC and BSL and greatly reduces computational cost and number of required simulations for these samplers. Performance and computational advantage are examined via series of simulation examples. The second part concludes with theoretical justifications and convergence properties of the proposed strategies.

Keywords: Approximate Bayesian Computation
Conditional copula
Perturbed MCMC
Simplifying assumption
Single index model
Synthetic Likelihood
Advisor: Craiu, Radu
Theory of Charge and Heat Transport Mechanisms in Nanodevices

In this thesis, we pursue mechanisms in the nonequilibrium transport of charge and heat, to elucidate nanodevice operation, and explore fundamental theoretical questions. The thesis is divided into two parts. Part I explores in detail the role of incoherent effects on the charge transport behaviour of molecular junctions. Such effects, induced by molecular vibrations, solvent or other environmental effects, play a crucial role in many physical setups, but are difficult to simulate explicitly. We apply the Landauer-B\"uttiker probe technique, a phenomenological approach that incorporates incoherent effects at a low computational cost, and demonstrate the applicability of the technique by verifying that it captures a number of pertinent physical features, and achieves semi-quantitative agreement with experimental data. Going beyond this, we apply the probe method to a number of proposed physical setups. In stacked vs. alternating GC-rich ds-DNA, we find the even-odd effect in the experimentally observed conductance can be explained via a mixed coherent-incoherent transport mechanism. We find that in general, environmental interactions are destructive to the operation of molecular charge rectifiers, though in certain circumstances a weak rectifying behaviour might arise from many-body environmental effects. In Part II of this thesis we shift our focus to heat transport, and particularly the operation of quantum heat machines. We begin with a study of the role of so-called noise-induced coherences on the operation of a quantum absorption refrigerator. While in the past quantum coherences have usually been found to boost power in such setups, we observe a complete shutdown of the device when coherences survive to the nonequilibrium steady-state. We then extend our analysis, developing a general approach that one can use to more easily discover the role of coherences in quantum heat machines. We conclude with the development of a new numerically exact approach, the iterative full-counting statistics path integral (iFCSPI), which is suitable for simulations of heat transport in nanodevices. The iFCSPI allows the calculation of the cumulants of heat transport, as well as strong-coupling and non-Markovian effects, provided it can be converged.

Keywords: Buttiker probe
Feynman-Vernon path integral
Molecular junction
Nanodevices
Quantum heat machine
Quantum thermal transport
Advisor: Segal, Dvira
Thinking of You: The Interpersonal Work Meaningfulness Model

A growing literature indicates that people are desired to experience a sense of positive work meaning. Although the topic on the antecedents of work meaningfulness is relatively well studied, we know comparatively little about how other people affect an individual’s sense of it. To deepen our understanding of how other individuals, especially significant others, shape meaningfulness attached to different work aspects and, subsequently, work outcomes, this dissertation proposed an Interpersonal Work Meaningfulness Model and empirically tested it using three types of family members as examples of significant others. Drawing on research of relational goals and relational self, I predicted that thinking of certain relational others influence work meaningfulness attached to certain work aspects, which in turn influence work outcomes. I contribute to our understanding of the antecedents of work meaningfulness by considering the relational nature of human beings and argue that an individual’s interdependent-self construal should be considered in understanding his or her sense of meaning attached to different work aspects. Pilot Test 1 qualitatively studied the content of work meaningfulness. In Pilot Test 2 I explored the relational goals that employees typically held with family members. Four main studies were conducted. The first study adopted a cross-sectional multi-source survey design to test the relationships among chronic thought of family members, work meaningfulness, and work outcomes. The second through fourth studies used experimental design and examined how the activated thought of family members influenced work meaningfulness and behavioral intentions. My findings suggested that thinking of family members could influence work meaningfulness, but the strength and pattern of such influence were not clear. The results of Study 1 through Study 3 suggested the important role of chronic thoughts of family members on work meaningfulness. The results of Study 2 and Study 3 indicated that the strength of interpersonal goal could moderate the effect of activated thought of family member on work meaningfulness. In addition to reporting the results, this dissertation discussed its scholarly contribution.

Keywords: Family member
Social factor
Work meaningfulness
Advisor: Zhong, Chen Bo
Investigating Antipsychotic Drug-induced Impairment of Central Energy Homeostasis

Antipsychotic medications are increasingly linked to the development of insulin resistance and type 2 diabetes. Though antipsychotic-induced weight gain was initially thought to be responsible for these effects, evidence has shown that antipsychotics can impair glucose homeostasis separate from changes in adiposity. The majority of studies investigating the direct effects of antipsychotics on glucose homeostasis have examined peripheral changes; however, the central nervous system (CNS) also plays a vital role in the regulation of whole-body energy homeostasis. A handful of studies have looked at the association between the CNS and antipsychotic-induced glucose dysregulation but have not reported a direct association between CNS insulin and whole-body glucose homeostasis. Furthermore, a mechanism is far from established. Thus, we set out to determine if antipsychotics impair central insulin sensing, and whether this impairment was via action on the central KATP channel, a downstream signal of CNS insulin action. Use of the pancreatic euglycemic clamp technique allowed determination of glucose kinetics, while central infusion allowed determination of specific CNS effects. We discovered that the commonly used antipsychotic, olanzapine, impairs the ability of CNS insulin to suppress hepatic glucose production. We also discovered that olanzapine blocks KATP channel activation, preventing the CNS KATP channel from increasing glucose uptake. These divergent results suggest olanzapine can act on multiple pathways in the CNS to dysregulate whole body glucose homeostasis. We also investigated whether antipsychotics could directly modulate the hypothalamus, the primary brain region involved in energy homeostasis, using immortalized hypothalamic neurons from rats and mice. Use of a neuronal model minimized confounding effects present in whole-body research, such as antipsychotic-induced hyperglycemia and hyperinsulinemia. We determined that the antipsychotics olanzapine, clozapine, and aripiprazole can directly modulate insulin, energy sensing, and inflammatory signals in hypothalamic neurons. Taken together, our findings suggest that antipsychotics can directly modulate the CNS to dysregulate whole body energy homeostasis, via action on insulin and the KATP channel. This underlines the importance of including the CNS in future studies on antipsychotic-induced metabolic effects. Understanding this relationship has the potential to then be leveraged to develop new strategies to improve metabolic outcomes in patients with schizophrenia.

Keywords: Antipsychotic
Diabetes
Hypothalamus
Insulin
Olanzapine
Schizophrenia
Advisor: Hahn, Margaret K
Remington, Gary
Age and Ageism in the Assessment of Witnesses

As Canada’s population ages, an area of related concern is widespread and systemic discrimination against older adults known as ageism. Despite its importance, little is known about the ways age or ageism relate to judges’ credibility decisions in common law trials. This study empirically examines case law to see if there is a relationship between old age and judges’ credibility decisions for a sample of witnesses (N=898). T-tests and probit regressions showed a positive correlation between old age and judges’ assessments of general credibility, where witnesses aged over 60 were more likely to be positively assessed. At the same time, testimony from witnesses who were aged over 60 was also less likely to be positively assessed in terms of weight. The other evidence led by the party that called a witness was the strongest predictor of judges’ assessments. When the inquiry is shifted to the texts of individual cases, there are examples of judges holding stereotypical beliefs about older individuals who testify in their courtrooms. The final part of this dissertation moves beyond credibility decisions and considers the ways the rules of evidence and procedure could disproportionately exclude older adults from participating in trials. While the rules are capable of accommodating witnesses who experience limitations, a case law review finds that these provisions are rarely used for older adults. Through its detailed catalogue of judicial behaviours and analysis of rules and procedure, this study provides insights into the ways age and ageism could affect older witnesses, a conclusion with that has implications for research as well as for those who practice law.

Keywords: Ageism
Aging
Credibility
Judicial Decision Making
Law
Law of Evidence
Advisor: Shaffer, Martha
Normothermic Ex-Situ Liver Perfusion and PPAR-gamma Activation as Strategies to Reduce Liver Ischemia Reperfusion Injury

The liver ischemia-reperfusion injury (IRI) is a significant problem during liver transplantation. IRI leads to hepatocyte damage and a prominent inflammatory response that results in graft dysfunction, and high morbidity and mortality following transplantation. The pro-inflammatory Kupffer cell (KC) polarization and the cold ischemic injury are key factors that initiate and perpetuate the severity of IRI. In this dissertation, I explore strategies that address these factors. First, I aim to modify the pro-inflammatory KC-phenotype in an in-vitro and in-vivo model. Second, I focus on optimizing a model of normothermic ex-situ liver perfusion (NEsLP) as a preservation technique to reduce cold ischemic injury and as a platform to evaluate the liver viability before transplantation. The pro-inflammatory (M1) activation of KCs is thought to initiate the IRI event. In this dissertation, I utilize a peroxisome proliferator activated-receptor-gamma (PPAR-γ) agonist to ameliorate the M1 polarization of KCs. The PPAR-γ activation results in a significant decrease of the M1-Nitric oxide + KC-phenotype in-vitro (Chapter 3) and in-vivo (Chapter 4), which reflects in a significant reduction of hepatocyte injury, apoptosis and necrosis in a mouse model of IRI. As the next step in this dissertation, I aim to optimize NEsLP for its use in donation after circulatory death (DCD) organs. In Chapter 6, I evaluate the different clinical perfusates to identify the most suitable solution for the perfusion of DCD grafts. The use of a human albumin/ dextran solution during NEsLP displays a better endothelial function and reduces the levels of AST, apoptosis, and necrosis after transplantation compared to the other solutions. Finally, in Chapter 7, I evaluate the feasibility of using NEsLP biomarkers to predict liver viability after transplantation with marginal DCD grafts. The model identifies consistent biomarkers of hepatocellular (lactate clearance and urea production) and biliary viability (bile/perfusate glucose and sodium ratio) that reflect in successful liver transplantation. The results of this dissertation highlight the importance of addressing several targets during IRI and suggest that the combination of these strategies evaluated by consistent viability biomarkers during NEsLP might result in a reliable use of marginal DCD grafts in the future.

Keywords: Donation after circulatory death
Ischemia reperfusion injury
Kupffer cells
Liver biomarkers
Liver transplantation
Normothermic ex situ liver perfusion
Advisor: Selzner, Markus
Selzner, Nazia
Word and Image in Alfonso d’Aragona’s Manuscript Edition of the Divina Commedia

The purpose of this thesis is to examine the manuscript edition of the Divine Comedy prepared for Alfonso D'Aragona, known as Yates Thompson MS 36 and preserved in the British Library. This is one of the most famous illuminated manuscript of the Divine Comedy, with over 100 miniature illustrations of great artistic merit. Most of the scholarship available on the manuscript is of a historical nature, concerning as it does the authorship of the illustrations and the historical background of the production of the manuscript itself. Valuable as this scholarship is, it does not explain how the images and verbal text interact in both the aesthetic experience of the reader and the interpretation of the poem to which they lead when they work in unison. My task will be to consider the manuscript from a hermeneutical perspective based on the idea of visibile parlare. My analysis of the manuscript will be simultaneously grounded in the dominant theories of manuscript illumination of the late Middle Ages and in the phenomenology of the reading process for texts consisting of script and images related by reciprocal conditioning. Building on the historical research done so far, my thesis will discuss the visibile parlare of the manuscript in the contexts of the paleographic legacy of the fourteenth and early-fifteenth century scribes and rubricators of each canticle of the Divine Comedy, considered in the light of Husserl's and Dufrenne's phenomenology of the aesthetic experience and in relation to Jacques Maritain's and Umberto Eco's theories of art and scholasticism. The aesthetic and philosophical interpretation of each canticle will then be evaluated against the background of the interpretive process and textual exegesis of the early commentators of the Divine Comedy.

Advisor: Pietropaolo, Domenico