VictorJuiz/thesis huggingface dataset:
Development of PET Imaging Probes for Predicting Response of Breast Cancer to Trastuzumab Emtansine (T-DM1)

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-20% of breast cancers (BC) and represents an aggressive tumour phenotype conferring a poor prognosis in patients. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for treatment of advanced and metastatic HER2-positive BC. Despite the efficacy of T-DM1 and lower side effects compared to conventional chemotherapy, many eligible patients do not respond. The thesis hypothesis is PET imaging that probes T-DM1 delivery to tumours and its ability to mediate HER2 downregulation would be useful in predicting the response to T-DM1 treatment. An in vivo comparison revealed that 89Zr-DFO-T-DM1 exhibited significantly higher uptake than 89Zr-DFO-trastuzumab in mice with HER2-positive BC xenografts suggesting that 89Zr-DFO-T-DM1 may be more effective to study the delivery of T-DM1 to tumours. The correlation between tumour HER2 density, uptake of 89Zr-DFO-T-DM1, response to T-DM1, and in vitro cytotoxicity to T-DM1 was studied. There was a non-linear but direct correlation between the tumour to blood (T/B) ratios for 89Zr-DFO-T-DM1 and HER2 expression (r2=1.00). There was a direct linear correlation between the T/B ratio for 89Zr-DFO-T-DM1 and tumour doubling ratio (r2=0.97). In addition, in vitro cytotoxicity of T-DM1 demonstrated an inverse correlation with tumour doubling ratio and T/B ratio in mice treated with T-DM1 (r2=1.00). The ability of microPET/CT using 64Cu-NOTA-pertuzumab Fab fragments to detect decreased HER2 expression on tumours in vivo in NOD/SCID mice after T-DM1 treatment was also studied. However, instead of reduced tumour uptake of the imaging probe after T-DM1 treatment, an increase was observed. Further ex vivo analysis of the tumour vasculature showed reduced blood vessel density suggesting that T-DM1 caused normalization of vessels in the tumour microenvironment which increased the uptake of the imaging probe. I conclude that PET is a promising tool for imaging response of HER2-positive BC to treatment with T-DM1.

Keywords: Breast Cancer
Molecular imaging
Trastuzumab Emtansine
Advisor: Reilly, Raymond
Localized Corrosion of Friction Stir Welded Magnesium AZ Alloys

Magnesium alloys, being the lightest engineering alloys, have the potential to replace ferrous and aluminum alloys in structural applications in the transportation sector. Thus far, their use has been limited largely due to challenges associated with their inherently poor corrosion resistance properties, a problem that is accentuated when the alloys are welded. The work in this dissertation elucidated the mechanisms governing the corrosion behaviour of friction stir welded magnesium AZ alloys. The investigation utilized an integrated approach consisting of several corrosion measurement techniques (both bulk and localized measurements) to examine the effect of individual microstructural features on the overall corrosion behaviour of the joint. Dissolution of second phase precipitates was determined to govern the corrosion behaviour of the joint by enhancing the corrosion resistance of the weld nugget. Based on the findings, a mixed potential theory model correlating changes in second phase particle size and distribution to the corrosion behaviour of friction stir spot welded AZ31 was constructed. The mechanism governing the corrosion resistance of similar friction stir welded AZ31B joints did not apply to dissimilar AZ31/AZ80 welds. Instead, the corrosion of dissimilar joints was governed by the galvanic coupling between the dissimilar magnesium alloys. Based on the corrosion studies, plasma electrolytic oxidation (PEO) coatings were identified as a promising corrosion mitigating strategy for welded magnesium structures. The application of this coating to friction stir welded specimens improved the corrosion resistance of both similar and dissimilar types of joints. The corrosion mechanism was also altered, as the corrosion of coated specimens was principally governed by the imperfections of the PEO coating, and not by the microstructural changes caused by the welding operation. The findings of this study provide theoretical knowledge that will enable the optimization FSW processing to permit the use of magnesium alloys in the automotive industry.

Keywords: Corrosion
Friction Stir Welding
Magnesium
Microcapillary Polarization
Microstructural Characterization
Plasma Electrolytic Oxidation Coatings
Advisor: Thorpe, Steven J.
North, Tom H.
Alternative Splice Site Prediction with Deep Learning

Alternative splicing of mRNA is tightly regulated in different tissues and developmental stages and its disruption is one of the leading mechanisms that cause genetic disease in humans. Gene splicing depends on the precise interaction of hundreds of cis-motifs that control the action of trans-acting splicing factors. These regulatory factors have been investigated in great detail, but it remains challenging to predict the splicing pattern of a transcript from its sequence, which led to the development of computational “splicing codes” using machine learning methods. I present multiple models that learn regulatory sequence features ab initio using convolutional neural networks instead of requiring a hand-engineered feature library. The first model is trained to distinguish true splice sites from decoys and improves on the performance of a previous support vector machine model. Another model is trained to predict the splicing pattern of pairs of alternative 3′ splice sites, achieving 95% auROC on this task. When this model was applied to the DBASS3 database of genomic variants that activate cryptic splice sites, it was able to identify 63% of cryptic splice sites correctly. Next, I developed the competitive splice site model (COSSMO), which, for the first time, can predict complex, non-binary splicing patterns. COSSMO can analyze a variable number of alternative acceptor or donor splice sites, uses convolutional and recurrent neural networks to learn from directly from sequence, and was trained on over 15M sites. COSSMO achieves 77% accuracy on the task of identifying the dominant splice sites from, on average, 90 candidate sites and matches the true splicing pattern with an R² of 71.3%. On a dataset of deep intronic variants, COSSMO can identify cryptic splice sites that are located hundreds of kilobases within the intron. An ensemble model of MaxEntScan and COSSMO achieves an auROC of 92.6% at discriminating between cryptic splice site-activating variants and common variants nearby. Applying COSSMO to the HGMD dataset of disease-causing variants showed that thousands of missense or nonsense variants also disrupt splicing and that intronic variants up to a distance of 1000 nt affect splicing.

Keywords: alternative splicing
deep learning
genetic variants
genomics
lstm
rna
Advisor: Frey, Brendan J
Hidden among the Under-represented: Foster Youth Access and Persistence in Ontario Post-secondary Education

The pathway to and through post-secondary education begins in early life. Individuals require academic preparation, to be made aware of post-secondary options, become engaged in the processes and procedures necessary for enrollment, transition to their studies, and persist to graduation. This exploratory study investigated the experiences of Ontario’s foster youth (FY as they navigate this pathway. Viewing the issue of FY post-secondary under-representation, and their overall access and persistence, through theories of social reproduction, The Capabilities Framework, cooling-out, and resilience, it posed the question of whether or not FY experience equitable opportunity to attend and succeed in higher education. Semi-structured interviews asked what barriers and supports foster youth experience throughout their post-secondary educational journeys in Ontario. Four foster youth in addition to three child welfare workers, three child welfare experts, and one child welfare advocate shared insights reflective of findings in the literature. Though this study’s findings are introductory, they align with previous research and point to the need for additional, consistent, and efficacious educational and child welfare supports to encourage, prepare, and help FY access and persist within post-secondary education. This study also asked what the Ontario Colleges of Applied Arts and Technology (CAATs) do to address FY under-representation and support greater rates of access and persistence by the demographic. Programs, services, and supports offered by Ontario’s 22 English-speaking CAATs were reviewed to determine how the system directly and indirectly supports FY, and make recommendations for improvement. Once FY are enrolled in post-secondary education, this research points to the need for greater, more tailored and responsive programming, services, and supports in Ontario’s colleges. Overall, this study highlights gaps in data collection on foster youth outcomes after they age-out of child welfare, the need for more research into the post-secondary experiences of youth in the province, and the importance of informed policies and practices in child welfare and post-secondary education in order to advance foster youth post-secondary opportunities and attainment.

Keywords: access
child welfare
foster youth
higher education
marginalization
post-secondary education
Advisor: Janzen, Katharine
Development of High Performance and Solid-state Electrochemical Capacitors for Future Electronics

The development of high energy and power densities, solid-state and flexible energy storage devices is critical for future electronics. In this thesis, a study was performed to address the pressing issue in energy and power density, design and validating flexibility of solid-state electrochemical capacitors (ECs) or supercapacitors. In the first part of this thesis, a novel asymmetrical supercapacitor (ASC) cell was investigated, leveraging a CNT-Zn battery-capacitor hybrid configuration. The device showed capacitive performance and a high voltage of 1.6 V. A further improvement using a dual-pH electrolyte on the same CNT-Zn ASC increased the voltage to 2.4 V, contributing to a 476% improvement in energy and power densities compared to a typical 1 V CNT-CNT symmetrical device. The device voltage significantly overcomes the thermodynamic limit of water decomposition, leading to aqueous ECs with both high energy and power densities. In the second part of this thesis, a systematic fundamental study on the performance of porous carbon electrodes in liquid and polymer electrolytes at high loadings was conducted. This study explored the effects of electrode properties, material loading and electrolyte properties to understand the key factors in the liquid to solid transition. It was found that the infiltration of the polymer electrolytes played a critical role in determining the electrode performance. Carbons with a pore-in-pore hierarchical structure and mesopores are favored in both solid and liquid electrolytes. The results provide a guideline for the transition from liquid to solid-state ECs. In the third part of this thesis, a pilot-process was developed to produce solid-state and flexible ECs with good electrochemical performance and high cell-to-cell consistency. These ECs allowed a systematic study of their bending properties and identifying the key parameters such as radius and cycles as well as the failure mechanisms after bending. In addition, a novel chemical deposition method was also developed to deposit Ni on PET as highly conductive and flexible current collector to further improve the flexibility of solid-state ECs.

Keywords: Bending properties
Flexible
High voltage
Solid-state
Supercapacitor
Advisor: Lian, Keryn
Implementation, Scale, and Spread of Telemonitoring for the Management of Heart Failure

Despite evidence of positive impact, telemonitoring (TM) interventions for the management of heart failure (HF) have seen limited adoption in Canada. Following a literature review that explains evidence inconsistencies on contextual differences between trials, a single case study of the Medly TM program sought to understand the factors that influence the successful implementation, scale, and spread of HF TM. First, an implementation evaluation found that the Medly program was successfully implemented due to facilitators related to characteristics of the clinic and of the adopting clinicians. Barriers that could limit the program’s sustainability, scale, and spread included complexity of the intervention, costs, and the lack of implementation plan. Because successful spread is only possible if interventions are used as intended, the second study explored patient adherence to taking daily TM readings. Results showed an overall average adherence rate of 73.6% (SD 25.0) with a significant decline over time; the decline was significantly steeper in patients of younger compared to older age groups (P=0.04). Adherence rates were further explained by patients’ perceptions of the program’s benefits, ease of use, presence of supporting services, and patients’ ability to form a habit around taking daily TM readings. Finally, because successful implementations generally require the adaptation of interventions to local contexts, a qualitative study identified components of the TM program that could be safely adapted without negatively influencing the program’s ability to yield desired outcomes. The spread of HF TM has been slowed by intervention and contextual complexities. This thesis describes key insights that have led to the development of an implementation strategy for TM programs to mitigate these barriers in the future. As such, this research has contributed to clarifying a path toward the wider adoption of HF TM such that it is available across Canada for HF management.

Keywords: Diffusion of innovation
Heart failure
Implementation
Telemonitoring
Advisor: Seto, Emily
Reinventing Impartiality: Norm and Practice Change in United Nations Peace Operations

This thesis investigates changes in how the norm of impartiality is interpreted on a day-to-day basis in United Nations peacekeeping operations. Historically, peacekeepers remained impartial by serving as passive observers, distancing themselves from ideological disputes, and minimizing involvement in the domestic affairs of host states. Yet practices on the ground have changed dramatically in the last two decades. Today, UN personnel routinely take sides, use force, and engage in practices that are ideologically prescriptive. In the Democratic Republic of the Congo (DRC), for example, UN troops conduct ‘targeted offensive operations’ against non-state armed groups. Critics argue that these activities violate the norm of impartiality. This criticism elicits a puzzling response from many UN officials: they downplay the novelty of new practices, insisting that are still perfectly impartial. I study this disjuncture between a longstanding norm and practices on the ground by asking how new ways of being ‘impartial’ emerge, spread, and become institutionalized in UN peace operations. To answer this question, I combine insights from the literature on international norms – especially theories of norm contestation – with newer scholarship from the ‘practice turn’ in international relations. Drawing on evidence from Sierra Leone, the DRC, Côte d’Ivoire, and UN headquarters in New York, I argue that new practices emerge through two distinct processes: innovation and improvisation. The former involves conscious reflection, while the latter occurs when practitioners make a series of unconscious, incremental adjustments to existing practices. New practices then spread through vertical, horizontal, and what I call ‘managed’ learning as communities of peacekeepers embrace new standards for judging competence. Finally, I show that the institutionalization of new practices remains very uneven. This variation largely depends on the wider social environment and the degree to which new practices resonate with existing norms and overarching ‘webs’ of practices.

Keywords: Impartiality
Norms
Peacebuilding
Peacekeeping
Practices
United Nations
Advisor: Bertoldi, Nancy
Bernstein, Steven
Biologic and Therapeutic Studies to Improve the Anti-tumor Efficacy of Antiangiogenic Tyrosine Kinase Inhibitors

Antiangiogenic tyrosine kinase inhibitors (TKIs), unlike VEGF pathway-targeting antibodies, have failed to show meaningful antitumor efficacy in most solid cancer types, even when combined with standard chemotherapy. The overall goal of the studies undertaken for this thesis was to study various strategies to improve the anti-tumor efficacy of antiangiogenic TKIs that may include mechanisms other than antiangiogenesis, eg. direct tumor cell killing or immunological effects. The conventional daily protocol for the antiangiogenic TKI pazopanib was modified by increasing doses administered intermittently as a possible strategy to overcome intrinsic resistance of VHL-wildtype renal cell carcinoma or advanced metastatic breast cancer. Administering high dose pazopanib intermittently improved efficacy only in the advanced metastatic breast cancer model, suggesting that any benefit may depend on prior sensitivity of the primary tumor to pazopanib. Most of antiangiogenic TKIs have failed to reach primary efficacy endpoints in phase III trials when combined with chemotherapy, in contrast to antiangiogenic antibodies. In a head-to-head comparative study involving two antiangiogenic TKIs (nintedanib, sunitinib), the VEGFR2 antibody DC101, and one chemotherapeutic drug (paclitaxel), I evaluated whether such failures may be related in part to the inability of TKIs to inhibit chemotherapy-induced pro-tumorigenic, host responses, which antiangiogenic antibodies are known to prevent. The difference between antibodies and TKIs in enhancing chemotherapy efficacy seems to be related to their specificity/targets, which impacts the intratumoral immune microenvironment. Based on the results concerning the effects of TKIs on the intratumoral microenvironment, and the local immunosuppressive effect of VEGF, I also tested whether combining nintedanib, and/or paclitaxel with a PD-L1 immune checkpoint antibody, can improve the efficacy of the immunotherapy, using a triple negative breast cancer model. Either nintedanib or paclitaxel can improve the activity of PD-L1 antibody in the primary tumor treatment setting, whereas only the triple combination appears to be more effective when treating metastatic disease. Considering the outcomes of the two strategies tested, and the effect of TKIs on the intratumoral bone marrow-derived immune cells, it appears that the combination of a TKI such as nintedanib with a PD-L1 therapy is a more promising therapeutic option than administering high dose intermittent TKI.

Keywords: antiangiogenic drugs
bone marrow-derived cells
immune checkpoint inhibitor
metastasis
preclinical models
tyrosine kinase inhibitors
Advisor: Kerbel, Robert S
Identity Formation at the Keffer Iroquoian Village: A Relational Network Approach to Communities of Practice

This thesis employs settlement pattern studies and social network analysis of ceramics to present a history of the Keffer village and its multiple ceramic practice communities. Keffer is a fifteenth-century Iroquoian site on the north shore of Lake Ontario. Temporally and spatially patterned variability in the diverse local tradition and nonlocal ceramics materialized the fluid, multivalent, and contingent identity of the Keffer potters at the household level. Nonlocal ceramics, particularly locally produced “emergent” ceramics, expressed unique yet shared identities with others within the village. These same analyses produce a nuanced series of development plans that trace the initial settlement, the growth, and the initial steps in the abandonment of the village. Distinct ceramic practices indicate that, contrary to what has been argued in some of the literature, the longhouse clusters that form the initial village occupation may not reflect kin-based social groups. However, longhouses added independently after this first settlement may reflect the arrival of small, related, kin-based groups. Village growth appears to have occurred at the level of the individual household and was likely unplanned. Village abandonment occurred on the same scale, at the individual household level. This study also shows that social network analysis of ceramic types is an appropriate mechanism for the exploration of multiscalar group identity. Analysis at the pan-Iroquoian, regional, and village levels demonstrates Keffer’s central position in the highly connected north shore interaction network and its distant relations with St. Lawrence and Eastern Iroquoian groups. Social relations and the identities they sustained, from the most intimate level of the household to the pan-cultural interaction sphere, can be successfully revealed and explored through the application of combined social network, community of practice, and agency approaches.

Keywords: Communities of Practice
Iroquoian Archaeology
Social Network Analysis
Advisor: Smith, David G
Searching for the Higgs Boson Produced in Association with a Pair of Top Quarks in Multilepton Final States Using the ATLAS Detector at the LHC

This thesis details a search for the associated production of a Higgs boson with a pair of top quarks using final states with multiple leptonic objects. An integrated luminosity of 36.1 fb−1 of proton-proton collision data was used, collected during 2015 and 2016 at a centre-of-mass energy of √s = 13 TeV with the ATLAS detector at the LHC. The specific final state studied in this thesis is the 3l+1τ channel which includes three light leptons (electrons or muons) and one hadronically-decaying τ-lepton. The 3l+1τ channel is primarily sensitive to the Higgs boson decaying to two τ-leptons, with additional sensitivity to the H → W+W− and H → ZZ decays. The 3l+1τ channel measured a ttH signal strength of μ = 1.6 (+1.8, -1.3) with an observed (expected) significance of 1.3 (0.9) standard deviations relative to the Standard Model background-only hypothesis. The combined ttH multilepton analysis also found an excess of events above the background-only expectation corresponding to an observed (expected) significance of 4.1 (2.8) standard deviations. The combined observed ttH signal strength of μ = 1.6 (+0.5, -0.4) is compatible with the Standard Model expectation to within approximately one standard deviation. This result shows evidence for ttH production.

Keywords: ATLAS
Boson
Higgs
LHC
Quark
Top
Advisor: Orr, Robert S