VictorJuiz/thesis huggingface dataset:
Autophagy as a Survival Mechanism for Tumor Cells Exposed to Chemotherapy or Hypoxia, and its Inhibition by Pantoprazole to Improve Outcome of Treatment

Chemotherapy is widely used as treatment for patients with metastatic cancer, and is also used to prevent disease recurrence and metastatic spread after local treatment. Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. The clinically used proton pump inhibitor (PPI) pantoprazole inhibits proton pumps, and is reported to inhibit autophagy. This thesis aims to gain insight as to whether pantoprazole inhibits autophagy to improve penetration and activity of anticancer drugs in solid tumors, thereby enhancing chemotherapy effectiveness. The first objective was to evaluate effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel and underlying mechanisms. I found that autophagy is a mechanism of resistance to docetaxel that modified by pantoprazole to improve therapeutic index. The second objective addressed whether induction of autophagy is a general mechanism of resistance to chemotherapy, whether autophagy hence drug resistance can be inhibited by pantoprazole. It was found that seven clinically-used anti-cancer drugs induced autophagy in vitro and in vivo. Induction of autophagy was inhibited by pre-treatment with pantoprazole. The third objective determined whether autophagy is a survival mechanism for hypoxic cells. I found that hypoxia induced autophagy in vitro and inhibited by pantoprazole. Hypoxia-induced cell death was more rapid for autophagy deficient cells. Xenografts generated from autophagy-deficient cells grew more slowly than wild type tumors and the proportion of hypoxia cells was markedly decreased in xenografts generated from knockdown tumors. The work presented here highlights the importance of the tumor- microenvironment in determining response to chemotherapy and suggests that induction of autophagy is a common mechanism of drug resistance. Effects of anti-cancer drugs might be improved by using PPIs to inhibit autophagy. Based on these data, a phase I trial of pantoprazole +doxorubicin has been undertaken in patients with advanced solid tumors and a phase II study of pantoprazole + docetaxel is underway in men with castrate-resistant prostate cancer.

Keywords: Autophagy
chemotherapy
drug resistance
immunohistochemistry
proton pump inhitors
tumor microenvironment
Advisor: Tannock, Ian F
Analyzing and Improving the Performance of Spatial Database Processing

Spatial databases have become increasingly important, due to the advent of popular geospatial Web services such as Google Maps, GPS navigation systems, and a host of accompanying location-based services. Spatial databases are used in a variety of real-world applications involving complex data analytics: land surveying, urban planning, environmental assessments, or new BigData application domains like biomedical imaging. As uses of spatial databases become more widespread, there is a growing need for high performance solutions that provide efficient spatial processing. Prior to this work, spatial database processing was not well studied, especially in the current computational landscape. This work focuses on spatial processing in relational database systems, from a performance standpoint. We identify the performance problems involved in spatial data processing, study the nature of spatial queries in terms of resource utilization, and target optimizations for improving performance at both stages of spatial processing. To achieve these goals, we design a spatial benchmark (Jackpine), which provides comprehensive coverage of spatial functionality. We gain insight into spatial workload characteristics by classifying spatial queries in terms of their resource usage, and determine that computations are the main performance bottleneck. Next, we explore avenues for improving spatial query execution, in both the filtering and refinement stages. Given the computational nature of spatial queries, we leverage GPUs for spatial co-processing support in the refinement stage, resulting in considerable speedups. For the filtering stage, where efficient spatial indexes play a crucial role, we take a different approach. We identify the sources of slowdown in a current state-of-the-art RDBMS, which are in great part attributed to unnecessary features and indexing framework abstractions. We propose a new modular data processing framework (Slingshot), which aims to balance performance and generality by drawing abstraction lines differently: decoupling, for each logical database component, the functionality (fixed in the component’s interface) from the implementation (flexible and independently-optimizable for individual application types). We show that overall, Slingshot outperforms traditional RDBMSs, and is comparable to dedicated single-purpose solutions on their target workloads, on both spatial and general database domains. Furthermore, Slingshot’s flexibility allows for easy and efficient integration of GPU support for spatial refinement.

Keywords: Database redesign
GPU processing
Performance Analysis
Relational DBMS
Spatial databases
Spatial indexing
Advisor: Demke Brown, Angela
The Discovery of Music Pedagogic Culture: Music Teaching as Communication Process

This qualitative study introduces the concept of music pedagogic culture, and explores this phenomenon, as a pedagogic communication process in a variety of educational and social contexts. Within the framework of a popular discourse on multiculturalism in music education, the issues related to the multiplicity of world musics have been covered extensively. However, many theorists tend to disregard the fact that multiculturalism suggests the multiplicity of the instructional approaches, as well. The diversity of music teaching practices has not been perceived as a multicultural issue, and as a result has been excluded from the discussion. This study sought to develop a methodical approach to the investigation of music teaching as a social and cultural phenomenon, and Bartel’s Lens of Pedagogy (2010) were employed as an analytical tool to examine music pedagogic culture at a variety of levels. Four highly qualified and experienced music educators participated in this research project. Data were collected over four—month period through participant observation and semi–structured interviews before and following each observation. The concept of music pedagogic culture has emerged as an attempt to understand and explain the complexity of music educators’ communicative behavior in different educational contexts. Using a combination of micro–ethnography and a constructivist grounded theory methods, this study aimed: 1) to identify the key components and functions of a music pedagogic culture; 2) to determine what identifiable characteristics and qualities can be regarded as properties of a culturally distinctive music pedagogic model; 3) to examine how participants’ pedagogical beliefs and values are reflected and expressed in their mu-sic pedagogic culture; 4) to examine how cultural/subcultural context is manifested in the music pedagogy; 5) to identify and explain some of the factors that might have an impact on the process of decision making related to the transformation of professional values and revision of routine instructional methods of the internationally educated music teachers in a new educational milieu.

Keywords: communication
culture
culture and communication
music education
music teaching
music teaching and culture
Advisor: Bartel, Lee
Learning Generative Models Using Structured Latent Variables

Recent machine learning advances in computer vision and speech recognition have been largely driven by the application of supervised neural networks on large labeled datasets, leveraging effective regularization techniques and architectural design. Using more data and computational resources, performance is likely to continue to improve in the future. Despite these nice properties, supervised neural networks are sometimes criticized because their internal representations are opaque and lack the kind of interpretability that seems evident in human perception. For example, detecting a dog hidden in the bushes by looking at its exposed tail is a task that is not yet solved by discriminative neural networks. Another class of challenging tasks is one-shot learning, where only one training example for a new concept is available to the model for training. It is widely believed that learned prior knowledge must be utilized in order to tackle this problem. My dissertation tries to address some of these concerns by introducing domain-specific knowledge to standard deep learning models. This domain-specific knowledge is used to specify meaningful latent representation with structure, which forces the model to generalize better under certain scenarios. For example, a generative model with latent gating variables that will ``switch off" noisy pixels should perform better when encountering noise at test time. A generative model with latent variables representing 3D surface normal vectors should do better at modeling illumination variations. These are the kinds of relatively simple domain-specific modifications that we explore in this thesis. It is true that we should not rely too much on manual engineering and learn as much as possible. This principle is taken seriously and we strike a balance between using too much laborious engineering on the one hand and learning everything from scratch on the other. Adding structure to deep generative models is not only helpful for computer vision applications, but it is also very effective for unsupervised density learning tasks.

Keywords: Computer Vision
Deep Learning
Machine Learning
Probabilistic Models
Advisor: Hinton, Geoffrey
Salakhutdinov, Ruslan
The Role of Dental Treatment in Welfare-to-Work

Background: Social assistance recipients in Canada receive limited dental care in order to meet health needs and to promote the move from welfare-to-work. Policy advocates argue for the expansion of such services for similar reasons. However, the hypothesis that dental care can improve the chances of employment has been rarely tested. This project was designed to provide policy makers better understanding about the relationship between dental treatment and employment outcomes among social assistance recipients of Ontario, Canada. Methods: First, we conducted a systematic review of the relevant existing literature. Then we designed a retrospective cohort study using large administrative data (total n = 8742) from five Ontario regions and from the province’s social assistance ministry. We also conducted an exploratory pilot study of a convenience sample of assistance recipients (n = 30) using a pre- and post-dental treatment survey. Results: Systematic review revealed minimal and weak evidence concerning the idea that dental services can improve employment outcomes. Our retrospective cohort study showed no significant difference in employment outcomes between treatment and no-treatment group (adjusted odds ratio = 0.93; 95% CI: 0.83-1.03). However, over the one year, people who received treatment (124% increase) had significantly better trajectory (p=0.0014) of leaving assistance as compared to their counterparts (83% increase). Our pilot study revealed that both oral health related quality of life (OHRQoL) and job-seeking self-efficacy (JSS) improved significantly after receiving dental care and there was a significant correlation between these two outcomes. Conclusion: Our research suggests that at one year, dental treatment does not appear to be significantly associated with leaving social assistance for employment. However, people who received dental treatment appeared to be particularly disadvantaged and dental treatment may have helped to level them up in terms of employment outcomes over time. Also, our results indicate that OHRQoL and JSS are correlated.

Keywords: Employment
Oral health
Self-efficacy
Social assistance
Advisor: Quiñonez, Carlos
Tenenbaum, Howard
Integration of Novel Mathematical and Statistical Techniques to Support Model-based Water Quality Management

Environmental modelling has been an indispensable tool for addressing water quality problems in freshwater ecosystems. A variety of data-oriented and process-based models have been used to examine the impact of external stressors to ecosystem integrity and to set water quality goals. The main objective of this thesis is to introduce methodological refinements of the current generation of water quality models that can strengthen their foundation as a scientific/predictive tool. One of the central water quality issues revolves around the elucidation of the mechanisAms that shape the composition of phytoplankton assemblages and their capacity to predict the occurrence of harmful algal blooms. My research proposes the introduction of an extra layer of causality into plankton models by connecting algal metabolic processes with species-specific morphological features (cell volume, surface-to-volume ratio, shape). This strategy can effectively delineate model parametric uncertainty, and may be an excellent solution to the identifiability problem of complex over-parameterized model. The motivation of this approach was provided by a meta-analysis of 122 models published in the peer-reviewed literature, which provided ample evidence that our ability to reproduce the observed aggregated and compositional phytoplankton variability is limited, despite the plethora of mathematical expressions aiming to describe different ecophysiological facets of species populations. Hierarchical Bayesian inference offers an appealing ad-hoc strategy to gradually increase model complexity and subsequently enhance their mechanistic underpinning, whenever possible and relevant. The advantages of hierarchical Bayes are illustrated with phosphorus loading models and with the development of risk assessment tools of cyanobacteria dominance. The central message of my dissertation is that the integration of process-based and empirical models offers an appealing methodological prospect, as it allows combining our best mechanistic understanding of ecosystem processes and feedback loops, while remaining within the bounds of data-based parameter estimation and therefore facilitating rigorous error analysis.

Keywords: Allometric theory
Bayesian Hierarchical Modelling
Cyanobacteria
Ecological diversity
Phytoplankton Functional Group Modelling
Total Phosphorus
Advisor: Arhonditsis, George B
Music, Communications, Place: Udo Kasemets and Experimentalism in 1960s Toronto

This dissertation examines the connections between experimentalism, space, and place as they materialized through the work of Estonian-born composer Udo Kasemets (1919-2014) in 1960s Toronto. Arriving in Hamilton, Ontario in 1951, Kasemets became an integral part of postwar Canada’s musical climate. Kasemets offered a mordant view on the pervasive conservatism that characterized art music performance in Toronto as a critic for The Toronto Daily Star, and frequently wrote of the need for more support for Canada’s modernist composers. After reading John Cage’s Silence in 1961, Kasemets became an ardent proponent of experimental and mixed media performance, and undertook several initiatives to introduce radically new forms of performance situations in Toronto. Targeted by his (former) fellow critics as a charlatan, Kasemets polarized reviewers with his writing, music, and concert organizing. This thesis argues that experimentalism acts as a catalyzing force in configuring place in 1960s Toronto. Like many avant-garde practitioners during this time, Kasemets was influenced by the larger cultural implications of Marshall McLuhan’s spatial theory of communication; namely, that post-print media technologies offered the possibility of sensory and social transformation. In the first half of this thesis, I evaluate experimental music as communication through a reading of McLuhan’s use of sound and orality, and also address methodological challenges of doing historical ethnography, reconciling the dissonances between memory and archive. I propose that examining the tensions between experimentalism and conservatism that became manifest in music criticism in 1960s Toronto allows us to account for a listening culture—the attitudes, assumptions, and expectations that informed how audiences interacted with music that helped define the contours of place. The second half of this dissertation is organized into three case studies of Udo Kasemets’ activities in Toronto: Men, Minds, and Music, the first “all avant-garde” concert series held in Toronto, in 1963; The Isaacs Gallery Mixed Media Concerts of 1965-67; and the Canavangard series of graphic scores curated by Kasemets and published by BMI Canada. In sum, I conclude that the efficacy of experimental practices lies in how notions of place can be articulated, reinforced, and made vivid in the face of postwar placelessness.

Keywords: 20th Century
Canada
Communications
Experimentalism
Mixed Media
Toronto
Advisor: Elliott, Robin
Colouring Problems of Erdős and Rado on Infinite Graphs

The aim of this thesis is to provide solutions to two old problems on infinite graphs. First, we investigate vertex partitions of edge coloured complete graphs into monochromatic paths. Our main result here is an answer to a question of R. Rado from 1978: we prove that every finite edge coloured infinite complete graph can be partitioned into disjoint monochromatic paths of different colours. We also show that analogous results hold for partitions into powers of paths and for hypergraphs in the countably infinite case. Second, we turn to the theory of uncountably chromatic graphs and obligatory subgraphs. We mainly focus on the question whether every graph with large chromatic number contains highly connected subgraphs. With the aid of a special sequence of countable elementary submodels (called Davies-trees or ω1-approximation sequences), we present a new and highly simplified proof of Komjáth’s theorem: every graph with uncountable chromatic number contains an n-connected subgraph with uncountable chromatic number (for each n ∈ N). We outline multiple new applications of Davies-trees to combinatorial problems. Finally, our most important contribution to the theory is an answer to a popular problem of A. Hajnal and P. Erdős from 1985: we construct a graph of chromatic number ω1 without an uncountable infinitely connected subgraph. A general and rather flexible method is introduced which uses ladder systems on non special trees in ZFC. This machinery is applied again to present an example of a triangle-and Hω,ω+2-free graph with uncountable chromatic number.

Keywords: chromatic number
connected graph
decomposition
edge colouring
infinite graph
path
Advisor: Weiss, William
Comparative and Cost-effectiveness of Stroke Prevention Treatments in Atrial Fibrillation: A New Generation of Drugs

Objectives: To develop a state-transition model evaluating the cost-effectiveness of all antithrombotic treatments for atrial fibrillation (AF) patients, at varying risks for stroke and bleeding, and to generate high-quality effectiveness and cost data to inform the model. Methods: Bayesian network meta-analyses (NMA) were conducted to determine the comparative effectiveness of the following treatments: no treatment, aspirin, aspirin+clopidogrel, warfarin, dabigatran (110mg and 150mg), rivaroxaban, apixaban, and edoxaban (low-dose [LD] and high-dose). Cost data were generated from a cohort of real-world AF patients identified through administrative data, to estimate the costs associated with clinical events corresponding to health states in a state-transition model. The resulting model evaluated the cost-effectiveness of treatments in patients at varying CHADS2 and HAS-BLED scores. Patients were stratified into six risk groups, denoted as stroke/bleeding risk. The analysis was undertaken from the Canadian payer perspective using a lifetime horizon. Cost-effectiveness was measured in quality-adjusted life-years (QALYs) using the net health benefit (NHB) framework. Results: At a willingness-to-pay of $50,000/QALY, the most cost-effective strategy was edoxaban LD for patients in all groups, except those at Moderate/Low and High/Low risk, for which apixaban was more cost-effective. The incremental NHBs (INHBs) of the first and second most cost-effective strategies for each group are presented. The INHBs of edoxaban LD versus apixaban were: Low/Low=0.01 QALYs, Moderate/Low= -0.03 QALYs, Low/High=0.25 QALYs, Moderate/High=0.21 QALYs, and High/High= 0.10 QALYs. The INHB of apixaban versus dabigatran 150mg in patients in the High/Low risk group was 0.06 QALYs. The model was sensitive to variations in the cost of edoxaban. For each group, the optimal strategy was cost-effective in 50% or less of the simulations. Discussion and Conclusion: Depending on a patient’s risk for stroke and bleeding, the most effective and cost-effective strategy is dabigatran 150mg, apixaban or edoxaban LD. This thesis serves as the first economic evaluation of antithrombotic treatment in AF to include an original NMA and costing study. We have produced a robust economic evaluation, based on high-quality effectiveness and cost data that can inform future economic evaluations, and provided an example of how to employ best practices when conducting them.

Keywords: Atrial fibrillation
Cost-effectiveness analysis
Decision modeling
Economic analysis
Network meta-analysis
Novel oral anticoagulants
Advisor: Krahn, Murray
"A House of Prayer for All People": Promises of Citizenship in Queer Church

Queer theory’s tradition of subjectless critique, which refuses to limit an understanding of sexuality to LGBTQ identity, dreams not only of more dexterous scholarly analysis, but of nourishing coalitional solidarities among differently marginalized subjects. My dissertation argues that subjectless critique’s capacious ethico-political aspirations make it possible to imagine citizenship differently. Although queer studies often regards citizenship as a hazardous object, exclusively bound up with nation-state violence and Eurocentric universalism, I follow geographers in mapping citizenship as multiscalar and teeming with radical potential, particularly at the urban scale. Advocating a reparative – but not optimistic – approach to the concept, I propose what I call “subjectless queer citizenship” to imagine bundles of solidarity, sympathy, rights and redistribution that take neither the nation-state nor LGBTQ identity as an exclusive referent. I ground this theoretical exploration in analysis of three years of ethnographic study at the Metropolitan Community Church of Toronto, a large, predominantly LGBTQ Toronto congregation that promises “a house of prayer for all people.” While the church has played a key role in a range of citizenship struggles, I focus on four: refugee rights, debates on race and gender in religious leadership, global outreach to LGBTQ Christians, and activism around urban police-minority relations. On the one hand, I point to the church as a space that realizes subjectless queer citizenship. I highlight the church’s refugee program, which has resisted pressure from the Canadian nation-state to weed out “fake” refugee claimants who are not “really” LGBTQ, and insisted on providing support and resources to all refugees on the basis of vulnerability alone. On the other hand, I trace the church’s considerable limits – moments of racialized and gendered exclusion; failure to criticize forms of police and geopolitical violence; and unreflexive, dangerous aspirations to save the world. I take inspiration, however, from the affective, spiritual and political praxis of church leaders, particularly women of color, who integrate the church’s good and bad fragments in order to pursue capacious, “minor” visions of citizenship. The promise of a subjectless queer citizenship, I contend, ultimately depends not on good political analysis alone, but on people’s capacity for affective reparation.

Keywords: affect
citizenship
queer
race
religion
reparation
Advisor: Cowen, Deborah E.
Georgis, Dina S.