VictorJuiz/thesis huggingface dataset:
Small Molecule Inhibitors of Stat3 Protein as Cancer Therapeutic Agents

Advances in anti-cancer drug development have vastly improved cancer treatment strategies over the past few decades. Chemotherapeutic agents are now being replaced with targeted therapies that have much greater potency and far fewer unpleasant side effects. At the center of this, cell signaling pathways have been targeted as they moderate gene expression, control proliferation and are often dysregulated in cancer. The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes in response to extracellular signals. Of the seven mammalian members described to date, Stat3 has received particular attention, as it regulates the expression of genes involved in a variety of malignant processes including proliferation, survival, migration and drug resistance. Aberrant Stat3 activation has been observed in a number of human cancers, and its inhibition has shown promising anti-tumour activity in cancer cells with elevated Stat3 activity. Thus, Stat3 has emerged as a promising target for the development of cancer therapeutics. While Stat3 signaling can be inhibited by targeting upstream regulators of Stat3 activation (such as Janus kinase 2), direct inhibition of Stat3 protein may offer improved response, larger therapeutic windows for treatment and fewer side effects. The work presented within this thesis is focused on optimizing known Stat3 inhibitor S3I-201, a small molecule Stat3 SH2 domain binder that was discovered in 2007. We have performed an extensive structure activity relationship study that has produced some of the most potent Stat3 inhibitors in the scientific literature. These compounds showed high-affinity binding to Stat3’s SH2 domain, inhibited intracellular Stat3 phosphorylation and selectively induced apoptosis in a number of cancer cell lines. Lead agents further inhibited tumour growth in xenograft models of human malignancies and had favourable pharmacokinetic and toxicity profiles.

Keywords: Anti-cancer
Medicinal Chemistry
Stat3
Apoptosis
Drug Resistance
Drug Design
Advisor: Gunning, Patrick
Cultural Transition in the Northern Levant during the Early Iron Age as Reflected in the Aegean-style Pottery at Tell Tayinat

Did an invasion of the Sea Peoples cause the collapse of the Late Bronze Age palace-based economies of the Levant, as well as of the Hittite Empire? Renewed excavations at Tell Tayinat in southeast Turkey promise to shed new light on the critical transitional phase of the Late Bronze/Early Iron Age (c. 1200-1000 B.C.), a period which in the Northern Levant has until recently been considered a Dark Age, due in large part to the few extant textual sources relating to its history (Hawkins 2002: 143). Specifically, this thesis is based upon a stylistic analysis of a distinctive painted pottery known as Late Helladic IIIC (LH IIIC) excavated at the site. Its core is comprised of a diachronic study of the Tayinat ceramics tied into a synchronic comparison with sites across the region—the Amuq Valley, the Levantine coast, Anatolia, Cyprus, and the Aegean Sea basin. Two key objectives of the pottery analysis are to discern Aegean stylistic characteristics from those that are local, and to chronologically situate the assemblage on the basis of regional parallels. What precisely was the nature of Iron I occupation at the site? Renewed excavations suggest that a rudimentary village settlement may have been constructed. Were the inhabitants that founded the Iron Age settlement immigrants that originated in areas to the west—Cyprus, Western Asia Minor, or the Greek Mainland—who were in iii search of more hospitable environs to settle? Or were they elements of the indigenous population forced to start anew after the socio-economic disruptions at the end of the Late Bronze Age? Perhaps they comprised a mixed population of both groups? Stylistic analysis of the painted ware would seem to support the third alternative, resulting in a hybrid style that fused Aegean shapes and motifs with local traditions. Did they simply relocate from the ruins of neighboring Tell Atchana (ancient Alalakh) or from other settlements in the Amuq Valley? Perhaps the movements were not en masse, but rather consisted of small elite groups or tradesmen that assimilated into the local economy, the result of a prolonged process of acculturation. The nature and relative amount of LH IIIC pottery in the Tayinat assemblage favors a traditional migration model. This research begins to fill a longstanding lacuna in the Amuq Valley and attempts to correlate with major historical and cultural trends in the Northern Levant and beyond.

Keywords: Aegean
Pottery
Tell Tayinat
Early Iron Age
Advisor: Harrison, Tim
The Solubility and Metal-silicate Partitioning of Some Highly Siderophile Elements: Implications for Core-formation and Planetary Accretion

Understanding Earth&rsquo;s accretion and primary differentiation is a long-standing goal of geology. The segregation of FeNi metal from molten silicate to form Earth&rsquo;s core is expected to deplete and fractionate the highly siderophile elements (HSEs). Estimates of the primitive upper mantle (PUM) composition however, reveal only modest HSE depletions and chondritic element ratios. Past experiments to determine if the mantle composition is set by high-temperature metal-silicate equilibrium have involved measuring the solubility of HSEs in silicate melt at conditions more reducing than the iron-wustite (IW) buffer. Accurate determination of solubilities at such conditions has been hindered by the formation of dispersed metal inclusions; this work describes methods to circumvent the problem. Results of three separate studies are presented which document the solubility of Re, Pt and Au in molten silicate which is demonstrably nugget-free. Data obtained from experiments done at 0.1 MPa&ndash;2 GPa, 1573&ndash;2573 K and ~ IW -1.5 to +3 reveal: 1) Re, Pt and Au solubility increases with increasing temperature, 2) Re solubility increases with increasing oxygen fugacity (fO2), consistent with dissolution as oxide species, 3) Below ~ IW +3, Pt and Au solubility increases with decreasing fO2, consistent with dissolution as neutral or silicide species, and 4) that Au is amongst the most soluble HSE in molten silicate, with values increasing with temperature, but insensitive to changes in P, fO2 and melt composition, making it well suited as a geothermometer for core formation. Partition coefficients calculated from these and previous solubility measurements indicate that metal-silicate equilibrium is unable to reproduce the Re/Os and Pt/Os ratios required by PUM Os isotope systematics if simultaneously accounting for the observed absolute element abundances. Instead, results support late accretion of material following core formation, elevating element abundances and endowing chondritic inter-element ratios. Experimental results are incorporated into a terrestrial accretion model, which differs from the standard approach by explicitly accounting for the distribution of oxygen. Model results show siderophile element abundances in PUM are best reproduced if the mantle undergoes oxidation during accretion and metal-silicate equilibrium occurs near the peridotite solidus.

Keywords: Accretion
Core
Rhenium
Platinum
Gold
Partitioning
Silicate Melt
Metal
Temperature
Pressure
Fugacity
Solubility
Advisor: Brenan, James
Randomized Trial of the Effects of Vitamin D on Tissue Vitamin D Metabolites and on Prostate Cancer Pathology

Epidemiologic, laboratory and clinical data suggest that vitamin D plays a favourable role in the prevention and prognosis of prostate cancer (PCa) and other malignancies. However, the metabolism and function of vitamin D in tissues beyond those involved in bone metabolism are poorly understood. The objective of this thesis was to investigate whether higher levels of vitamin D consumed orally or achieved in the circulation result in increased concentrations of vitamin D metabolites in human tissue, and how this affects cellular biology. The hallmark of this work is a randomized clinical trial of oral vitamin D3 (400-, 10,000-, or 40,000 IU/d) in PCa patients to evaluate the effects of supplementation on prostatic vitamin D metabolism and on PCa pathology. Various methods to measure vitamin D metabolites in serum were evaluated and modified to allow for measurement of these metabolites in tissue. Ultimately, I developed a robust tissue extraction method coupled to enzyme immunoassay and liquid chromatography-tandem mass spectrometry for measurement of calcitriol hormone, as well as 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D), respectively. Human colon tissue was analyzed first and found to contain calcitriol at physiologically relevant concentrations partly determined by serum calcitriol, with some evidence of local colonic synthesis. In the clinical trial, prostate tissue and serum levels of calcitriol, 25(OH)D and 24,25(OH)2D increased dose-dependently (p<0.02) without adverse side effects. The level of calcitriol attained in prostate tissue was inversely associated with the expression of Ki67 protein, a proliferation marker (p<0.05). Serum parathyroid hormone (PTH) and prostate specific antigen (PSA) declined from baseline in the combined higher-dose groups (10,000-40,000 IU/d) (p<0.02). We provide clinical trial evidence that prostatic vitamin D metabolism can be modulated in vivo by oral consumption of vitamin D3. Higher prostate calcitriol and vitamin D doses also showed suggestion of clinical benefit, including lowered Ki67 expression and modest reductions in serum PSA and PTH. Further studies are needed to validate the potential utility of dietary vitamin D3 supplementation in cancer prevention and therapy.

Keywords: vitamin D
cancer
Advisor: Vieth, Reinhold
Negotiating Activism: Women of Colour Crafting Antiracist Feminist Organizational Change

Starting from the standpoint of antiracist feminists in Southern Ontario, Canada, I examine the everyday social organization of antiracist feminist activism. Using key concepts from institutional ethnography and other critical research methods, I explore how women of colour activists engage, contest and modify existing social relations within women’s organizations to craft antiracist feminist organizational change. I describe how women of colour negotiate their antiracist, feminist and social justice commitments in ways which both respond to, and are constitutive of, contradictory social relations within women’s organizations. An analysis of in-depth interviews with women of colour activists reveals dialectic processes of accountability in their everyday antiracist feminist practice. Activists are accountable, on the one hand, to hierarchical relations within the daily practices of women’s organizations, and, on the other hand, to other feminist, antiracist and social justice activists. I describe how relations of accountability, named respectively, organizational accountability and activist responsibility, socially organize women of colour’s everyday experience of antiracist feminist activism. In particular, I argue that organizational accountability must be understood as relations of hierarchical answerability within the organization that extend outside the organization, while activist responsibility needs to be seen as the relations by which activists become accountable to other activists in the enactment of an explicitly antiracist feminist praxis. I describe further how women of colour creatively and consciously do antiracist feminist activism by mobilizing and negotiating both sets of relations of accountability to develop antiracist feminist social and organizational change. I highlight the importance of everyday activist work by revealing the ways women of colour seize the potential for crafting antiracist feminist change through relations of accountability. Significantly, this study offers a conceptualization of everyday antiracist feminist activist practice as a negotiation of relations of accountability.

Keywords: women's organizations
antiracism
feminism
activism
social movements
intersectionality
institutional ethnography
political activist ethnography
organizational change
organizational behaviour
critical research
organizational accountability
activist responsibility
non-profit organizations
NGOs
accountability
Advisor: Ng, Roxana
Dehli, Kari
Some Black Male Teachers' Perspectives on Underachievement Problems for Black Male Students

This dissertation examines some structural and cultural problems that can contribute to the problem of underachievement facing Black, male students in the educational system. A phenomenological approach was used to gain the perspectives of six Black, male educators on this problem. Underachievement problems for these students have garnered much interest in the research literature and in pedagogical debates. It is a problem with a long history from the Royal Commission on Learning (1993) to TDSB Urban Diversity Strategy (2008) the problem continues to baffle educators. Data also presents a dismal picture, with 40% from this group underachieving. Black, male teachers‟ perspectives are significant because presently their voices are limited in the literature. Their perspectives are also influenced by race, ethnicity and gender, and these are issues that impact on the problem being investigated. The main questions of the study are: - What are some Black male educators' perspectives of the role of structural and cultural factors that contribute to the problem of underachievement and school failure for Black, male students? Were these the same barriers they faced and how did they overcome these barriers as students? - How might the narratives of these Black male educators both challenge and support multicultural approach to curriculum that purports to particularly address the problems facing Black, male students? The result of the research indicates that there are structural and cultural factors that can cause underachievement problems for Black, male students. It suggests that an iii integrated approach which acknowledges the influence of both structure and culture could be used as a means for improving learning outcomes for this group of earners.

Keywords: Black Male students
Underachievement Problems
Black male teachers' perspectives
Advisor: McCready, Lance
Metformin and Prostate Cancer among Diabetic Men

Background: This thesis is composed of three studies. In the first paper, we tested the association of metformin use with prostate cancer incidence. In the second paper, we examined the association of metformin use with all-cause and prostate cancer specific mortality. The final paper explored the benefit of detailed pathology review to predict mortality among diabetic men with prostate cancer. Methods: A total of 5306 incident diabetic men older than 66 who subsequently developed prostate cancer were identified using the Ontario Diabetes Database and the Ontario Cancer Registry between 1994-2008. The association of metformin use and risk of prostate cancer and its grade was tested with a nested case-control design using a conditional logistic regression model. We used a cohort design with a time dependent Cox-proportional hazard model to examine the association of metformin use and mortality. Finally, we employed a c-statistic and Net Reclassification Improvement analysis to study the impact of pathology abstraction on predicting mortality. Results: The data suggest metformin use was not associated with the risk of prostate cancer or its grade at presentation. However, each additional 6 month of metformin use was associated with a 24% decrease in prostate-cancer-specific and 8% decrease in all-cause mortality. Pathology abstraction improved the accuracy in predicting all-cause and prostate-cancer specific mortality. Conclusions: In our study metformin use was not associated with a decreased risk of prostate cancer, but had a significant impact on all-cause and prostate cancer specific mortality. These results may serve as proof of concept in designing an interventional study of metformin to delay progression in prostate cancer.

Keywords: Prostate Cancer
Metformin
Population based research
prevention
Advisor: Urbach, David
Reliability of Disclosed Internal Control Weakness and Changes in Disclosure Regulation

This paper investigates whether changes in internal control weakness (ICW) disclosure regulation affect the reliability of a firm’s disclosed ICW in a unique Canadian setting. In Canada, public firms have been required to provide internal control weakness disclosures since 2006. However, the credibility enhancement mechanisms (i.e., the implementation of effectiveness evaluation and CEO/CFO certification) were not adopted until 2008. Taking advantage of such an evolutionary process of regulations and inferring the reliability of the disclosed ICW from the magnitude of the negative association between disclosed ICW and investment efficiency, I first document that in the pre-adoption period, the association between Canadian firms’ disclosed ICW and their investment efficiency is insignificant; however, in the post-adoption period, the disclosed ICW negatively affects firms’ investment efficiency. This finding suggests that the credibility enhancement mechanisms improve the reliability of disclosed ICW in Canada. In addition, using the U.S. sample as a benchmark, I find that in the post-adoption period, the association is weaker between Canadian firms’ disclosed ICW and their investment efficiency, which is consistent with my prediction that the external audit requirement increases the reliability of the disclosed ICW. Overall, the study implies that changes in disclosure regulation lead to efficient resource allocation by improving the reliability of the information disclosed.

Keywords: Internal Control
Regulation
Advisor: Callen, Jeffrey
Wong, Franco
Environmental Chemistry of Commercial Fluorinated Surfactants: Transport, Fate, and Source of Perfluoroalkyl Acid Contamination in the Environment

Perfluoroalkyl carboxylates (PFCAs) and perfluoroalkane sulfonates (PFSAs)are anthropogenic fluorinated surfactants that have been detected in almost every environmental compartment studied, yet their production and applications are far outweighed by those of other higher molecular weight fluorinated surfactants used in commerce. These fluorinated surfactants are widely incorporated in commercial products, yet their post-application fate has not been extensively studied. This thesis examines various biological and environmental processes involved in the fate of these surfactants upon consumer disposal. Specific focus was directed towards the environmental chemistry of polyfluoroalkyl phosphate esters (PAPs), perfluoroalkyl phosphonates (PFPAs), and perfluoroalkyl phosphinates (PFPiAs), and their potential roles as sources of perfluoroalkyl acids (PFAAs) in the environment. PAPs are established biological precursors of PFCAs, while PFPAs and PFPiAs are newly discovered PFAAs in the environment. Incubation with wastewater treatment plant (WWTP) microbes demonstrated the ability of PAPs to yield both fluorotelomer alcohols (FTOHs), which are established precursors of PFCAs, and the corresponding PFCAs themselves. WWTP biosolids-applied soil-plant microcosms revealed that PAPs can significantly accumulate in plants along with their degradation metabolites. This has implications for potential wildlife and human exposure through the consumption of plants grown and/or livestock raised on farmlands that have been amended with contaminated biosolids. A number of compound-and environmental-specific factors were observed to significantly influence the partitioning of PFPAs and PFPiAs between aqueous media and soil, as well as, aquatic biota during sorption and bioaccumulation experiments respectively. In both processes, PFPAs were primarily observed in the aqueous phase, while PFPiAs predominated in soil and biological tissues, consistent with the few environmental observations of these chemicals made to date. Detection of the PAP diesters (diPAPs), PFPiAs, and fluorotelomer sulfonates (FTSAs),all of which are used commercially, in human sera is evidence of human exposure to commercial fluorinated products, but the pathways by which this exposure occurs remain widely debated. Overall, this work presents novel findings on the environmental fate of commercial fluorinated surfactants and each of the process studied shows a clear link between the use of commercial products and the fluorochemical burden currently observed in the environment.

Keywords: fluorinated surfactants
perfluoroalkyl acid
polyfluoroalkyl phosphate esters
perfluoroalkyl phosphonates
perfluoroalkyl phosphinates
biodegradation
plant uptake
sorption
bioaccumulation
biomonitoring
Advisor: Mabury, Scott A.
Constructing School Science: Physics, Biology, and Chemistry Education in Ontario High Schools, 1880 -1940

This thesis is a history of science education reform in Ontario, from 1880 to 1940. It examines successive eras of science education reform in secondary (pre-university) schools, including the rise of laboratory science; the spread of general science programs; and efforts to teach science “humanistically.” This research considers the rhetorical strategies employed by scientists and educators to persuade educational policymakers and the public about the value and purpose of science education. Their efforts hinged in large part on building a moral framework for school science, which they promoted an essential stimulus to students’ mental development and a check on the emotive influence of literature and the arts. These developments are placed in international context by examining how educational movements conceived in other places, especially the United States and Britain, were filtered and transformed in the distinct educational context of Ontario. Finally, the sometimes-blurry boundaries between “academic” science education and technical education are explored, most notably in Ontario in the late nineteenth century, when science education was undergoing a rapid, driven expansion in the province’s high schools. This research contributes to a relatively recent body of literature that promotes a greater appreciation of pre-college science education – an area that has often been overlooked in favour of higher education and the training of specialists – as an important window onto the public perception of science.

Keywords: science education
chemistry education
physics education
biology education
nature study
high schools
Advisor: Yeang, Chen-Pang
Gingras, Yves