VictorJuiz/thesis huggingface dataset:
Mechanisms of Reversible Sorafenib Resistance in Hepatocellular Carcinoma

Conventional wisdom in oncology is that drug resistance is a stable and heritable phenotype due largely to cancer cell acquisition of genetic alterations. Thus, most cancer agents are given as sequential lines of therapy since continued use of the same agent is considered futile after disease progression. The anti-angiogenic tyrosine kinase inhibitor sorafenib is the only approved treatment for advanced hepatocellular carcinoma (HCC) patients. Its efficacy is further hindered by intrinsic (upfront) and acquired drug resistance (initial response and subsequent relapse) and a lack of alternative therapies. Our laboratory previously demonstrated using a human xenograft model of locally advanced HCC that acquired resistance to sorafenib is reversible due to re-sensitization of the tumour following transfer of resistant cancer cells to new hosts. An implication is that continued or rechallenge treatment with sorafenib could be effective strategies in HCC. The mechanistic basis of reversible sorafenib resistance was investigated and was observed to be multifactorial. First, prompted by similar findings in HCC patients, tissue and plasma sorafenib levels of sorafenib were found to gradually decline over time in drug-resistant relative to sensitive tumour-bearing mice. These changes were partially attributed to tumoural induction of the sorafenib-metabolizing enzyme CYP3A4. Escalating the dose to restore drug levels resulted in excessive toxicity and did not completely reverse drug resistance. Second, sorafenib treatment was found to effectively inhibit angiogenesis to the same extent in responding as well as resistant tumours. Rather, tumours hijacked or â co-optedâ the host liver vasculature by becoming increasingly invasive and incorporating the adjacent parenchyma. Many of the changes associated with resistance were reversed by stopping treatment. Altogether, sorafenib treatment of HCC could be improved by 1) individualizing the dosage of drug; 2) prolonging anti-angiogenic treatment after disease progression; and 3) targeting co-opted vessels in conjunction with angiogenesis. From a survey of the literature, unstable forms of drug resistance may be applicable to other classes of anti-cancer therapy, including agents that directly target cancer cells. This phenomenon appears to be highly under-appreciated as a characteristic of cancers but offers important opportunities to extend the utility of many existing cancer drugs.

Keywords: angiogenesis
hepatocellular carcinoma
liver cancer
resistance
vessel co-option
xenograft
Advisor: Kerbel, Robert S
Exploring the Role of Community in Online Learning

Distance education is growing rapidly at the post-secondary level in Canada. Despite the growing popularity of online learning in higher education, distance education often suffers from high dropout rates, which have been attributed to the physical separation of students. Such separation tends to give rise to feelings of isolation and disconnection. According to the literature, these feelings can be overcome by fostering a sense of community, that is a sense of belonging and interactivity among online learners. While a growing body of literature emphasizes the importance of fostering a community in online course communities, it is not clear how this is best accomplished. There is neither an accepted set of rules or strategies nor clearly defined steps in the development of a community in online course communities. In addition, the research on the effects of a community on learning is mixed. A few scholars criticize existing research for failing to demonstrate the role of community in learning through rigorous empirical studies. My research is concerned with this gap in the literature. So far, current research has made little progress in providing answers concerning the role of community. Findings from this study revealed that strong community levels were associated with instructor-facilitated online course communities, whereas weak community levels were associated with peer-facilitated online course communities. Students in the online course communities with stronger community levels, posted more notes, replied to more notes, and reread notes more often. They also spent more time revising the notes that they posted. Most interestingly, students in the online course communities with stronger community levels were more likely to link to and ‘Like’ their classmates’ notes. Furthermore, unlike their peers from online course communities with weaker community levels, students from online course communities with stronger community levels believed that they learned more because they had access to their professor and their peers’ ideas, and also expressed their enjoyment of the online course community discussions. It was also found that instructors from online course communities with stronger community levels were more hands-on than those from online course communities with weaker community levels. Considering these findings, I argue that fostering a sense of community in online course communities enhances social capital through the creation of relationships. This produces better student outcomes, deeper learning and more positive online learning experiences for students.

Keywords: Community
Facilitation methods
Online behaviours
Online learning
Advisor: Hewitt, Jim
The Direct and Interactive Effects of Life Stressors and Dispositional Traits in the Prediction of Youth Psychopathology

Dispositional differences are likely to influence youth's adjustment to stressors; however, the potential for interactions among stressors and dispositional traits is uncertain. Prior efforts to examine these interactions have yielded mixed results: whereas some results have shown that presence of both exposure to stressors and trait vulnerabilities are needed to trigger psychopathological responses (i.e., the diathesis-stress model), other results have shown that trait vulnerabilities trigger psychopathological responses regardless of exposure to stressors (i.e., the direct vulnerability model). Moreover, variability in operationalizations of stressors and dispositional traits has made it difficult to draw conclusions across studies. The current research aims to elucidate the potential interactive effects of stressors and dispositional traits while overcoming these limitations. To enhance consistency with results from prior investigations, the direct and interactive effects of stressors and dispositional traits were examined (1) across family-level versus youth-specific stressors (i.e., to allow the evaluation of specific effects across different types of stressors) and (2) using comprehensive models of dispositional trait (i.e., five-factor model of child personality; higher- and lower-order temperament traits). To this end, two investigations using nonclinical youth samples were conducted. In the first study, the hypothesis that child personality traits moderate stress-psychopathology associations during the transition into early adolescence was examined. No systematic evidence for moderation emerged; rather, results supported an additive hypothesis. In the second study, the hypothesis that dispositional traits influence the appraisal of stressors by examining their associations with discrepancies among parent- and youth-reports of stressors was examined. Informant discrepancies for stressors were positively correlated with negative affectivity, supporting the hypothesis that negative affectivity influences appraisal of stressors. Overall, this research elucidates idiographic responses to stressors in youth, and therefore has implications for assessment, prevention, and intervention efforts in clinical child and adolescent psychology.

Keywords: dispositional traits
personality
psychopathology
stressors
temperament
youth
Advisor: Bagby, R. Michael
Tackett, Jennifer L
The Impact of Herpes Therapy on Genital and Systemic immunology

HIV infects more than 34 million people globally. Herpes simplex virus type 2 (HSV-2) has been associated with a 3-fold increase in the rate of HIV acquisition, which may be due to physical breaks in the mucosal barrier during symptomatic episodes and/or an increased number of HIV target cells being exposed in the genital tract. Although clinical trials have demonstrated that herpes suppression in HIV uninfected individuals had no impact on HIV incidence, acyclovir was associated with a decrease in plasma HIV viral load and delayed disease progression in HSV-2 co-infected individuals. In addition, many HIV infected individuals display persistent systemic immune activation, which correlates with disease progression, despite successful antiretroviral therapy (ART). It is hypothesized that HSV could be one of the drivers of this activation. To further assess these relationships, my thesis focused on examining the impact of herpes therapy on genital tract immunology and systemic immune activation in HIV uninfected women and a comparison of systemic immune activation in individuals co-infected with HIV and HSV-2 on ART randomized to valacyclovir or placebo. A randomized, placebo-controlled, double-blinded, cross-over trial was conducted in HSV-2 infected, HIV uninfected, women using valacyclovir. No differences were observed in the number of various HIV target cells in the endocervix between valacyclovir and placebo phases. Further, valacyclovir had no impact on systemic immune activation in the same cohort. In a second clinical trial, the role of herpes therapy on systemic immune activation and inflammation in HIV and HSV-2 co-infected individuals on ART was evaluated. It was concluded that valacyclovir therapy had no impact on these parameters in this population. In summary, we were unable to demonstrate that herpes therapy was able to reduce the number of HIV target cells in the endocervix of HSV-2 infected, HIV uninfected women or systemic immune activation in either HIV uninfected or HIV infected individuals. These findings demonstrate that currently available herpes therapy in standard doses does not appear to reverse the immunological changes associated with HSV-2 infection.

Keywords: HIV
HSV
Advisor: Kaul, Rupert
Modulation of p53 Family Proteins in the Treatment of Neuroblastoma

Neuroblastoma is the most common type of extra-cranial solid tumour in children. Additional investigation is required to fully understand the genetics and tumour biology of neuroblastoma for improvements in patient care. We explored the importance of p53 family proteins in neuroblastoma tumorigenesis and response to therapy. Despite aggressive multi-modality treatments, more than half of patients with high-risk neuroblastoma relapse, and cure after recurrence is rare. Repurposing medications already in use for other indications is a safe and expedient way to discover novel therapies for neuroblastoma. Using a high-throughput screen of FDA-approved drugs we identified the beta-adrenergic receptor antagonist propranolol and cardiac glycosides as candidate compounds to investigate for the treatment of neuroblastoma. Studies have demonstrated that propranolol and cardiac glycosides have anti-cancer effects in range of malignancies in both in vitro and epidiomologic studies. Propranolol has a well-documented safety profile in children and more recently is used to treat infants with large hemangiomas. Cardiac glycosides have a narrower therapeutic window therefore analogues were designed in an attempt to develop a more effective anti-proliferative cardiac glycoside without cardiotoxic side effects. While these drugs have disparate anti-cancer mechanisms in neuroblastoma, both classes of compounds are able to induce neuroblastoma cell death and may reveal new targets to further improve patient care.

Keywords: Neuroblastoma
Advisor: Irwin, Meredith
Malkin, David
From the Chapel to the Gallery: The Aestheticization of Altarpieces in Early Modern Italy

This dissertation examines the aesthetic response to altarpieces in early modern Italy, which culminated in the reconstitution of altarpieces as gallery paintings, when, beginning in the seventeenth century, wealthy collectors began removing them from churches and displaying them in their private collections. Such a transformation not only entailed a complete rupture in the function of these paintings – from object of public veneration to private delectation – but also frequently met with resistance and censure from local authorities. It is precisely because it was a very difficult thing to do that the documents concerning the removal of altarpieces are frequently revealing about contemporary attitudes toward art among collectors as well as ecclesiastics. In order to understand the mechanisms – both theoretical and practical –that had to be in place for such a transformation to occur, I explore the history of the altarpiece from the rise of ius patronatus as an economically motivated form of piety in late-medieval Italy, through the encroachment of artistic criteria such as invention and difficulty in the making and viewing of religious art in the sixteenth century, and, finally, to the post-Tridentine discourse on sacred images. Because the purpose of this study is to establish the church as a venue for a nascent connoisseurial discourse, I also consider the development of art collecting in Italy, which was circumscribed in extent through most of the sixteenth century. Lastly, I provide a comprehensive overview of the removal of altarpieces in seventeenth-century Italy, a phenomenon that has previously received only scant attention in art historical literature.

Keywords: Altarpieces
Art collecting
Painting, 16th century
Renaissance Italy
Art collectors
Painting, 17th century
Advisor: Sohm, Philip
International Higher Education Agents in Canada: Protecting a Socially and Commercially Valuable Service

Foreign universities looking to increase their Canadian student enrolment typically contract with non-exclusive agents or representatives to reach that objective. The global higher education sector pays nearly a billion dollars in commissions to agents annually. Although largely unknown to the public, Canadian students pursuing an international education â some sources indicating as high as 80% - choose to work with and rely on agents throughout the information gathering, assessment, selection, and application process. Unfortunately, the question of industry regulation in Canada has failed to appreciate the impact agents representing foreign institutions have on the education decisions of Canadians. Despite this oversight, the absence of statutory protection does not preclude the application of fiduciary law where the nature of the relationship gives rise to such obligations. Without such a relationship a socially and commercially valuable industry may become overrun with self-interested agents, to the detriment of Canadian students.

Keywords: Agents
Disclosure
Education
Fiduciary
Incentives
Recruitment
Advisor: Green, Andrew
Extending the Social Model of Migration and Incorporation to Include Migrant Occupational Communities: The Case of Ghanaian Nurses

The flow of skilled migrants to Canada has increased significantly over recent decades. Considerable research has focused on explaining skilled migration and economic incorporation outcomes, with a focus on economic factors. This qualitative dissertation examines how skilled workers come to the decision to migrate to Canada, and how they navigate the skilled economic incorporation process and challenges that emerged along the way, with a focus on the social forces influencing these processes. To do so, the dissertation drew on the early social migration model advanced by Massey and his colleagues (Massey et al.1987; Massey et al. 1993), but extended this model by analyzing the influence of the migrant occupational community among skilled migrants. The project primarily draws on 18 interviews with Ghanaian nurses of varying ages, seniority levels and types of nursing training who migrated to Canada. The analysis revealed key social processes, within both the migrant residential community and what this dissertation has termed the â migrant occupational communityâ , which influenced skilled migration and incorporation. The migrant residential community had a generally positive influence on skilled migration perceptions and aspirations through a local culture of migration, as well as on migration decision-making via general information on better living conditions transmitted via migrant residential networks, similar to that predicted in the early social model. The migrant occupational community also had an importance influence on skilled migration. The migrant occupational culture influenced skilled migration perceptions and aspirations in positive and negative ways, while migrant occupational networks influenced migration decision-making by providing information and encouragement related to occupational conditions and opportunities abroad. The migrant occupational community played an even more significant role in shaping the skilled incorporation process, primarily via migrant occupational networks and to some extent migrant occupational associations, which helped navigate the numerous steps to skilled incorporation to resume the nursing profession. This dissertation makes two contributions. First, and primarily, it extends the early social migration model to include the migrant occupational community found among skilled migrants. Second, this project moves beyond an analysis of skilled migration and incorporation outcomes, to an in-depth analysis of the processes of skilled migration and incorporation, in line with Masseyâ s holistic social migration model focused on low-skilled migration, as well as a growing number of skilled migration studies.

Keywords: Incorporation
Migrant networks
Migration
Advisor: Cranford, Cynthia
A Legal Analysis of the Access to Court Record Policies of the Provincial and Territorial Courts of the Common Law Jurisdiction of Canada and Public Accessibility

The Supreme Court of Canada has recognized the importance of court openness to public confidence in the transparency and integrity of the administration of justice. These principles are promoted when the public and media have access to court proceedings, which also includes access to court records. Canadaâ s highest court has also recognized the importance of the Charter right of expression and the mediaâ s essential role in disseminating information about the courts to the public, which means accessibility to the courts and records. However, there is inconsistency within the access to court record policies of the provincial and territorial courts of the common law jurisdiction of Canada. While some policies may recognize the importance of court openness and public accessibility, they may not contain provisions that meaningfully adopt these principles. Moreover, there is much debate and hesitation when it comes to digitization of court records and public accessibility.

Keywords: Court records
freedom of expression
media
public accessibility
Advisor: Weinrib, Lorraine
The Customer Isn't Always Right: Exploring the Protective Ambit of the Employment Protection in the Ontario Human Rights Code through Customer-on-Worker Harassment

This thesis argues that the "right to equal treatment with respect to employment" under section 5(1) of the Ontario Human Rights Code extends to protect workers from customer harassment. In so doing, this thesis aims to provide an account of section 5(1) and the way in which it imposes duties on parties who do not fit the traditional definition of an employer. This project argues that the statutory language of section 5(1) demonstrates a legislative intent to cover relationships outside of the paradigmatic employer-employee relationship and that it is broad enough to cover customer-worker interactions. This thesis will further argue that there is sufficient proximity between customers and employees to justify extending a duty onto customers to refrain from harassment. Finally, this project demonstrates that broader policy considerations justify extending section 5(1) coverage to address customer-worker harassment.

Keywords: discrimination
employment
harassment
human rights
Ontario Human Rights Code
Advisor: Réaume, Denise G
Fair Dealing in Music - A Case for Mash-ups

Abstract: Fair dealing in Canada is liberalizing itself. However, it is time to test whether the wa- ter is deep enough to incorporate newer changes in the field of music which changes in technolo- gy bring in. The endeavor is to take the case of mash-ups and a hypothetical 20-part mash-up artist and examine whether the doctrine of fair dealing is potent enough to apply in his case. I compare and contrast the Feist approach on ‘creativity’ with the Canadian ‘skill and judgment’ approach in CCH and infer that the Canadian approach is not too far removed from doing justice to the efforts of a mash-up artist in selecting and arranging pieces of music to bring a coherent whole into existence, by treating borrowed pieces of music as fair dealing.

Keywords: copyright
mash-ups
music
sampling
Advisor: Stern, Simon
Applicability of the Charter in the Healthcare Context Through the Lens of Vaccination-or-mask Policies

Despite numerous Supreme Court of Canada decisions on Charter applicability, there has been limited discussion on how the Charter applies to entities operating in the healthcare sector. This paper uses vaccination-or-mask policies as a test case to illustrate the difficulties in applying the current law to determine if the Charter applies to various actors, including hospitals, regional health authorities, physiciansâ offices and other for-profit healthcare companies, and the professional regulatory bodies. The analysis demonstrates that the current test remains confusing and unclear, does not significantly reduce the possibility of government shirking its Charter obligations, and may lead to a differential protection of rights across the provinces. A solution is proposed that requests the court to consider a more holistic approach to characterizing an entity as governmental or not. Also, it may be useful to recognize that healthcare as a public monopoly is a unique case for Charter applicability.

Keywords: Canadian Charter of Rights and Freedoms
constitutional law
healthcare workers
influenza
vaccination-or-mask policy
Advisor: Rogerson, Carol