VictorJuiz/thesis huggingface dataset:
Efficacy of Tamoxifen, Alone or in Combination with Vincristine and Temsirolimus, in in vitro and in vivo Models of Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, with an estimated five-year overall survival of less than 30% in patients with metastatic disease. Despite refinements in risk stratification and multimodality chemotherapy, improvements in RMS survival have been minimal and few molecularly targeted therapies are currently available. Previously, we demonstrated that RMS cells express estrogen receptor (ER) and are sensitive to 4-hydroxytamoxifen (4OHT), an active metabolite of tamoxifen. Here, we investigate the mechanisms by which 4OHT exert these effects. Previously, our group also found that 4OHT-induced apoptosis involves ER-dependent phosphorylation of c-Jun N-terminal kinase (JNK). Here, we found that inhibition of the pro-survival AKT/mTOR pathway is involved in 4OHT-induced apoptosis as well. These mechanisms can be exploited by combining 4OHT with other drugs acting on the JNK and AKT/mTOR pathways: vincristine (a core RMS chemotherapy agent) enhances JNK phosphorylation, while temsirolimus (an emerging RMS drug currently in phase III trials) inhibits mTOR complex 1. Combining tamoxifen with either of these drugs led to increased efficacy against cell proliferation in vitro. In an alveolar RMS (ARMS) xenograft mouse model, tamoxifen causes significantly reduced tumour growth and increased apoptosis. In contrast, long-term tamoxifen treatment led to enhanced tumour growth in an embryonal RMS (ERMS) xenograft model. A tolerable dose and schedule was optimized for tamoxifen in combination with vincristine and temsirolimus in vivo. However, preclinical phase II studies found that vincristine in combination with temsirolimus had similar efficacy with or without tamoxifen, at the given dose and schedule. Taken together, our work provides in vivo confirmation that tamoxifen may be an effective agent for treatment of ARMS, and provides a mechanistic framework that explains the anti-RMS effects of tamoxifen and its ability to potentiate vincristine and temsirolimus.

Advisor: Malkin, David
Cariño in the Borderlands: Pedagogical Relationships in a Community-Based Education Support Program

This dissertation examines the development of pedagogical relationships between tutor mentors and students, parents, and staff in a tutoring and mentoring program dedicated to decreasing the push-out rates among students of Spanish- and/or Portuguese-speaking descent in the Toronto public school system. Using a Transnational Latina Feminist framework, I examine program documents, observation and interview data to understand how these relationships develop, and how tutor mentors navigate issues of cultural and linguistic identity in these relationships. Furthermore, I examine how discourses of identity and community are articulated by the tutor mentors in the development of these relationships. Identity featured prominently in participant narratives, and participation in the program was often positioned as an enactment of cultural identification. I found that discourses of linguistic and ethnic identity were often conflated in participant narratives, constructing a homogenous community of Portuguese-speakers at the exclusion of other lusophones in the city. Latinx tutor mentors identifications as Latinxs featured prominently as motivators to enter the program and engage in these mentoring relationships with their students. Discourses of community critically shaped the program, which utilized its relationships with the Lusophone and Latinx communities to function as a bridge between the communities and an alienating school system. Thereby providing important spaces for the creation of counter-narrative for the parents in the community, building the social capital necessary for Lusophone and Latinx families to effectively engage with the education system. Authentic caring relationships, characterized by cariño and the consejos were a critical part of the program experience. These relationships provided a positive learning environment for students, as well as a place for tutor mentors to heal from their own negative schooling pasts. This dissertation contributes to our understandings of the importance of relationships in pedagogy, and how these relationships can help educators to heal from past experiences. I highlight the benefits of community-based education. My dissertation contributes to the growing fields of Latinx-Canadian and Luso-Canadian studies. I also offer a different reading on Latinidad as it is lived in Canada and how the different reading of the Canadian context can enrich our understandings of mestizxs.

Keywords: community education
equity
ethnicity
immigration
race
relationships
Advisor: Gaztambide-Fernandez, Ruben
Land-use and Transportation Interactions through the Lenses of Two-Worker Households, Rising Commuting Costs and Transit-Oriented Development

Integrated land-use and transportation planning is critical for dealing with the challenges of urbanization and for ensuring the social, economic and environmental sustainability of our cities. Effective planning requires a proper understanding of land-use and transportation interactions. To improve this understanding, the research conducted in this dissertation includes empirical studies to examine interactions in the contexts of two-worker households, rising commuting costs and transit-oriented development. First, econometric models are developed to examine the relationship between factors related to the transportation network and the land-use configuration of two-worker households. Geometrical variables are utilized as descriptors of the land-use configuration and are used to draw relationships with commuting modal accessibility and commuting trade-offs. Second, discrete choice models are developed to examine household choices concerning land-use configuration in the event of significant increases in commuting costs. A discrete choice model is also developed to examine the direction of home location choice relative to the workplace. Framing the model in this manner enables the identification of factors that may contribute to urban sprawl. Third, empirical models are developed to examine travel behaviour in the context of transit-oriented development. Trip generation models for rail trips with walk access/egress are developed to identify the influence of station-level attributes and characteristics of the surrounding environment. The Living Near Transit survey is then designed to collect disaggregate household-level data from households who reside within a walking catchment area of GO Transit rail stations. The collected data is used to develop a behavioural model that identifies specific demographic factors and transit-oriented development characteristics that influence mode choices. The empirical studies in this dissertation contribute to the existing body of literature by revealing new findings of land-use and transportation interactions in the three noted contexts and have corresponding policy implications.

Keywords: Civil Engineering
Econometrics
Transit
Transportation Planning
Urban Planning
Advisor: Nurul Habib, Khandker M
A Conductor's Guide to Tenor/Bass Choral Music by Canadian Composers

This study examines the presence of active tenor/bass choirs in Canada and the growing volume of repertoire for this voicing by Canadian composers. From Vancouver’s Chor Leoni to St. John’s Newman Sound, numerous tenor/bass choirs are thriving in Canada. Canadian tenor/bass choirs have long been actively commissioning some of the country’s finest choral composers to write specifically for tenor/bass voices. The result is a growing library of high-quality choral music by Canadian composers for tenor/bass voices that deserves greater recognition. Unfortunately, the contributions of Canadian composers have been greatly overlooked on recommended lists of tenor/bass choir music, however, and this research seeks to rectify that situation. This conductor’s guide contains analyses of one hundred selected works for tenor/bass ensembles by Canadian composers. All of the works have been written specifically for tenor/bass voices and are readily available to conductors and choirs. Both secular and sacred repertoire is represented. Analysis information includes date of composition, voicing, accompaniment, performance duration, publisher information, text source and complete texts, vocal ranges, general musical characteristics, and technical considerations. In addition, four of the selected works include an expanded analysis to assist conductors while preparing these specific works with tenor/bass choirs. This supplemental conductor’s guide includes background on the composer and composition, exploration of the text and connections with the music, and teaching strategies to help meet the identified challenges in the score. The music examined is appropriate for community and school ensembles comprising tenors and basses ranging in age from youth through adult groups. For the purposes of this study, it does not include barbershop style repertoire. Appendices include a representative list of active tenor/bass choirs in Canada, listings of the one hundred selected works by various parameters (i.e. sacred/secular, voicing, level, etc.), as well as a listing of additional original and re-voiced repertoire for tenor/bass choirs by Canadian composers.

Keywords: bass
Canadian
choral
male
music
tenor
Advisor: Apfelstadt, Hilary
One Hundred Twenty Years of Canadian Academic Medicine: How Michael Porter Became the New Abraham Flexner

One hundred and twenty years after the Flexner report purged for-profit practices from academic medicine in North America, a new era of commercialization, or an era of “de-Flexnerization”, is under way. High cost structures in academic medical centres and limits on funding support seem to have triggered academic medical institutions to engage in a variety of for-profit revenue-generative practices, many targeting the global community. This new commercialization seems in tension with Abraham Flexner’s findings that an over dependence on for-profit practices is linked with poor health care outcomes and poorly trained physicians. Using the Toronto academic health science centre as a case study, this dissertation employs Foucauldian theories of discourse and space to make visible the shifts in the economic and management logics of the leadership of a Canadian academic health science centre over 120 years that have made this new commerciality possible. A new management framework for Canadian academic medicine is identified, “The Discourses of Management”. Specific attention is given to Canadian academic medicine’s journey from the “local” to the “global”. More specifically, this thesis documents a change in the global space from being a space of reputational formation to being a space of wealth creation, or more accurately, a rhetorical space of wealth creation. That is to say, this thesis argues that the global space instead of functioning as an actual space of material resource accumulation is in actuality functioning as an imaginary space where wealth may be created but in actuality is not. The emergence of health care as a policy field, health care as a sector of the economy, and academic health science centres as a new overarching institution are documented in a 120-year history. Evidence is presented that the academic health science centres may be emerging in Toronto as a more tangible overarching governing body for the Toronto’s academic hospitals and its faculty of medicine.

Keywords: Academic Health Science Centres
Academic Medicine
Foucault
Health Policy
History
Management
Advisor: Austin, Zubin
Investigating the Roles of Executive Functioning and Self-Regulation in Gambling

The purpose of this study was to investigate a self-regulation model of gambling in which the mood regulation function of gambling was examined in the context of deficits in executive functioning and mood dysregulation. It was predicted that deficits in executive dysfunction would be associated with increased emotion regulation difficulties, greater use of gambling to regulate emotions and, in turn, more problematic gambling patterns, particularly during states of increased negative affect. To test this hypothesis, two research questions were investigated. The first question used path analysis to evaluate direct and indirect relationships between executive dysfunction, emotion dysregulation, gambling motives (coping and enhancement), and gambling frequency and problems. Difficulties in executive functioning was associated with emotion dysregulation, which in turn was associated with both coping and enhancement motives. In addition, emotion dysregulation mediated the relationship between executive dysfunction and these motives. In terms of gambling motives, enhancement motives mediated the relationship between emotion dysregulation and gambling behaviour and problems, whereas coping motives mediated the relationship between emotion dysregulation and gambling problems only. In addition, the relationship between coping motives and gambling problems was stronger than enhancement motives-gambling relationship. Regarding the second research question, a mood induction was used to prospectively examine whether mood condition (i.e., negative mood versus positive mood state) moderated the indirect relationship between executive dysfunction and mood-related gambling expectancies through emotion dysregulation. Although mood condition was not a moderator, additional exploratory analyses focusing on high versus low negative mood states revealed that the mediating effect of emotion dysregulation on the relationship between executive dysfunction and relief-related gambling expectancies (but not reward-related gambling expectancies) was greater at higher levels of negative mood. Overall, the results support a model of gambling that highlights negative affect as a critical component for understanding how and when deficits in executive functioning and emotion regulation contribute to greater risk of gambling problems. Impairments in the capacity to effectively manage negative emotions may be instrumental for building relief-related gambling cognitions and motivating problematic gambling behaviours. Findings have important implications for gambling theory as well as for prevention and treatment strategies for problematic gambling.

Keywords: Emotion Regulation
Executive Functioning
Gambling
Gambling Problems
Self-Regulation
Advisor: Goldstein, Abby L
The Effect of Natural Variation on Perturbed Phenotypes in Caenorhabditis elegans

A common problem in the study of human disease genetics is that the severity of symptoms can vary greatly between individuals, even when the underlying disease mutations are identical. Natural variation in genetic background is recognized as one of the contributors to variation in phenotype severity, but our understanding of the underlying mechanisms is limited. Here, I endeavour to explore why differences in genetic background lead to phenotypic variations by systematically examining a large set of single-gene perturbations in Caenorhabditis elegans. In the first section of this thesis, I broadly examine the effect of genetic background on these perturbed phenotypes employing RNAi in two C. elegans isolates, the canonical lab strain N2 and a commonly used wild-type CB4856 for comparison. This screen yielded 120 genes that produced a more severe phenotype in N2 and 127 genes that produced a more severe phenotype in CB4856 (p-value ≤0.05), with notable enrichments in specific functional groups. These differences in phenotypic severity are recapitulated in both genetic mutants and animals chemically treated to perturb the same functional networks. In the latter part of my thesis, I explore the genetics of variation in perturbed phenotypes and find that they are complex, affected by both the expression level of the gene itself and that of genes within the same functional group. For instance, a gene that has lower expression in N2 will likely exhibit a more severe phenotype in N2, and experimentally lowering the gene expression of the gene itself or genes within the same functional group will increase the severity of the phenotype. I further explore the genetics underlying the phenotypic variation of a subset of these gene perturbations using quantitative trait loci (QTL) mapping. With this approach, I identified a broad trend of four QTLs that repeatedly underlie the phenotypic variations in a set of functionally unrelated genes and that most perturbation variations between N2 and CB4856 have more than one underlying genetic cause. Together, these data show that genetic backgrounds frequently modify perturbed phenotype severities and that the genetics underlying this variation is complex.

Keywords: Caenorhabditis elegans
Genetic Background
Mendelian Disorders
Natural Variation
RNAi
Advisor: Fraser, Andrew G
EFFECT OF VITAMIN D SUPPLEMENTATION ON ORAL GLUCOSE TOLERANCE IN INDIVIDUALS AT RISK FOR DEVELOPING TYPE 2 DIABETES

Vitamin D status is inversely associated with insulin resistance, β-cell dysfunction, and an increased risk for type 2 diabetes (T2D). Clinical trials examining the effect of vitamin D supplementation on various glycemic outcomes and incident T2D have been equivocal. The objectives of this thesis were to determine the effect of weekly vitamin D3 supplementation on oral glucose tolerance, indices of insulin resistance/sensitivity and β-cell function and inflammatory markers in individuals at an increased risk for T2D. We conducted a 24-week, double-blind, randomized, placebo-controlled trial to examine the effect of 28,000 IU of vitamin D3 once weekly on plasma glucose 2 hours after a 75g oral glucose tolerance test (2hPC glucose) and additional glucose-related outcome measures. Seventy-one participants with serum 25-hydroxyvitamin-D [25(OH)D] ≤65 nmol/L, impaired fasting glucose, and/or elevated glycated haemoglobin (HbA1c) were randomly assigned to receive 28,000 IU of vitamin D3 (vitD, n=35) or placebo (n=36) cheese once weekly. The primary outcome was the change in 2hPC glucose. Additional outcomes of interest included fasting glucose, fasting and postprandial insulin, insulin resistance/sensitivity and β–cell function, HbA1c, fasting lipids and inflammatory biomarkers. Participants underwent an oral glucose tolerance test at baseline and week-24. Mean±SD baseline 25(OH)D was 48.1±14.3 and 47.6±14.3 nmol/L in the vitD and placebo groups, respectively; vitamin D3 supplementation increased 25(OH)D to 98.7±36.8 nmol/L (p

Keywords: Beta-cell function
Insulin resistance
Randomized trial
Type 2 diabetes
Vitamin D
Advisor: Wolever, Thomas MS
Undressed Toronto: The Transformation of Bathing, 1850 to 1935

Bathing transformed between 1850 and 1935 as Toronto moved from a vernacular system, epitomized by the swimming hole, to the heterosocial public beach. I’ve coined the term vernacular bathing to describe a system that was predominantly male, nude, and relied on a shared embodied knowledge of found spaces within the urban environment. I treat the beach as a competing system, rather than merely a space. It emerged in the nineteenth century in North Atlantic cultural circuits and relied on the bathing suit to cloak and contain the body and surveillance to ensure the moral and physical security of male and female bathers. While its implementation seems inevitable today, the rules and expectations of the beach were negotiated and challenged by men and women in the nineteenth century. Importing the beach rewrote the recreational geography of the Toronto; popular vernacular spaces in the Don River could never be made to fit the image and expectations of the beach, while Sunnyside, on the city’s western shoreline, was reimagined by the Toronto Harbour Commission to fit the model of a twentieth century beach and amusement space. This project upends assumptions about class, the urban environment, and the presentation of the naked body. Rather than attempting to drive vernacular bathers out of urban space, the middle class viewed the bathing boy through the lens of anti-modernism and turned them into pre-industrial folk figures. That gloss of nostalgia preserved and romanticized vernacular spaces in the city even as the order and structure of the beach was emerging. Puncturing the nostalgic gloss of the swimming hole allows us to see the city with new eyes. We can over-turn declensionist narratives that imagine the city’s rivers and waterfront as too polluted or too industrial for recreational use. When we follow the bathers we find they often nestled within the most industrialized sections of the waterfront and used that industrialization to cloak their presence. Seen with new eyes the industrial waterfront becomes a hybrid world where recreation and labour, industry and nature, blended and where the undressed male body, rather than being hidden, was part of the urban experience.

Keywords: Culture
Environmental History
Gender and Sexuality
History of Leisure
History of the Body
Social History
Advisor: Penfold, Steve
Resource Boom to Revitalization: The Local Economic Planning and Governance Implications of Fracking in Northern Appalachia

Small cities in Appalachia have been battling an ongoing struggle against economic decline for decades, but now some find themselves amidst a new natural resource boom. The technological innovation of hydraulic fracturing drilling, commonly known as ‘fracking’, has revolutionized global energy markets overnight, leaving a gap of understanding about its local implications in the process. Most early research focused on documenting the environmental risks of fracking, but little work has gone into understanding its local economic and planning impacts. Promises of economic growth and blue-collar jobs give hope to this declining region, but resource extraction municipalities often struggle with inadequate fiscal and administrative capacity to deal with the environmental and infrastructure externalities caused by the industry. As municipalities grapple with these challenges, the ‘boom-bust cycle’ may become reflected on their balance sheets, putting their fiscal health at risk. What are the local economic planning and governance implications of the fracking boom in Northern Appalachia? Additionally, because of the newness of fracking, this specific industry in this specific region offers a rare opportunity to study the impact the introduction of natural resource development impacts local economic resilience. My doctoral dissertation offers a unique theoretical contribution, as tension in literature exists on whether contemporary extractions industries positively or negatively impact diversification. It also offers a practical contribution, considering that little research exists on job estimates and governance issues that arise with fracking. Each chapter of this dissertation, intended to be independent academic works with their own literature reviews and methods, contributes to our understanding through: (Chapter 1) introducing the geography of the region, (Chapter 2) overviewing the economic history of Northern Appalachia; (Chapter 3) testing changes in economic diversity indices; (Chapter 4) investigating migration, housing, and employment patterns; and (Chapter 5) surveying local planners about regulatory responses. Finally, my dissertation concludes with a review of findings and a brief set of policy recommendations. The goal of this research is to provide information that helps small cities best plan and manage the fracking boom; finding that the industry is not dramatically altering patterns of long-term decline in Appalachia.

Keywords: Appalachia
Coal
Economic Development
Fracking
Local Governance
Regional Planning
Advisor: Hackworth, Jason