VictorJuiz/thesis huggingface dataset:
Biologic and Therapeutic Studies to Improve the Anti-tumor Efficacy of Antiangiogenic Tyrosine Kinase Inhibitors
Keywords: antiangiogenic drugs
bone marrow-derived cells
immune checkpoint inhibitor
metastasis
preclinical models
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.
Identity Formation at the Keffer Iroquoian Village: A Relational Network Approach to Communities of Practice
Keywords: Communities of Practice
Iroquoian Archaeology
Social Network Analysis

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.
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
Keywords: ATLAS
Boson
Higgs
LHC
Quark
Top

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.
Controlled Synthesis of Polytellurophenes
Keywords: Conjugated Polymers
Controlled Polymerization
Kumada Catalyst Transfer Polycondensation
Polytellurophenes

Polytellurophenes are an emerging class of conjugated polymers. This thesis presents studies on the controlled synthesis of polytellurophenes, charge carrier mobilities in polytellurophenes transistors as well as sulfur and selenium analogues, and the role of halogens in Kumada catalyst transfer polycondensation (KCTP). Chapter 2 describes the first controlled synthesis of well-defined, high molecular weight poly(3-alkyltellurophene)s using KCTP through a systematic investigation of polymerization conditions, computation, and molecular design. This enables the preparation of a series of regioregular, high molecular weight, low dispersity poly(3-alkylchalcogenophene)s (S, Se, Te) (Chapter 3). Due to the improved intrachain carrier transport conferred by heavier heteroatoms, polytellurophene exhibits the highest hole mobility in field-effect transistors even though polytellurophene appears to be the least crystalline compared to its lighter analogues. In Chapter 4, the nickel-catalyzed polymerization mechanisms of a series of thiophene monomers bearing different halogen functionalities (Cl, Br, I) were investigated. The significant role that halogens and magnesium salts play in this polymerization was discovered. These findings were used to guide the design of a new monomer, 2-bromo-3-(2-ethylhexyl)-5-iodotellurophene, which enables the first controlled polymerization of a tellurophene monomer containing a sterically encumbered 2-ethylhexyl side chain. Chapter 5 presents preliminary results on the thiophene-tellurophene block copolymerization as well as the isolation of living polymer chains in KCTP.
After Reading Recovery: Collective Case Studies of the Writing Development of Former Reading Recovery Students in Grade Two
Keywords: Classroom
Development
Literacy
Literacy Processing
Reading Recovery
Writing

This qualitative collective case study explored the written language development of four grade two students who made accelerated progress in Reading Recovery. The focus was children writing in classrooms — the ways in which their literacy behaviours continued to develop, and the ways in which the classroom context influenced development. The study was positioned within a sociocultural framework, acknowledging the importance of social interaction as a context for learning and development (Vygotsky, 1978). Literacy behaviours observed during the act of writing were interpreted from a literacy processing view of progress (Clay, 2001). What emerged from the data were a number of observable behaviours which showed how each student went about communicating in written language. Analyses of the type and frequency of each behaviour revealed a menu of actions that the students drew on in individual ways. These actions were interpreted as composing, constructing and monitoring actions, which were further described as internal resources within the child’s control and external resources coming from the social context of the classroom. Students also had unique profiles for applying directional and spatial rules, letter, word and sentence knowledge, and punctuation, with movement toward conventional forms of meaningful communication in written language. Students also drew on external resources within the classroom environment — classroom materials, classmates, classroom volunteers or assistants, and their teacher. Teachers influenced writing development through personalized learning experiences. Interactions facilitated a next step, focused attention, and provided the student with feedback. Knowledge of case study students as developing writers and the specific expectations of the curriculum for grade two students influenced the content of teacher and student interactions. Although not meeting all of the specific expectations for writing, the case study students were making progress in the classroom, and interviews revealed their sense of themselves as writers intertwined with their identity as learners.
Investigating Fine Structures of the Earth’s Interior Based on Spectral-element Seismic-wave Simulations
Keywords: Computational Seismology
Deep Earth structures
Seismic wave modeling
Spectral-element method

One of the ultimate goals in the studies of seismic waves is to utilize the entire records of seismograms and exploit these waveforms to map the heterogeneity and anisotropy in the Earth's interior. An important technique towards this goal is full waveform inversion (FWI), which often combines accurate numerical solvers of wave equations with gradient-based iterative model updates. Meanwhile, the model resolved by seismic tomography using the relatively low-frequency component of seismograms is only an equivalent smooth one (i.e., homogenized model) of the complex geological structures (i.e., the Earth). In this thesis, we first present the application of homogenization theory to transversely isotropic models and demonstrate the computational efficiency gained from using effective media in forward seismic wave simulations. An efficient wave-equation solver is vital to FWI as forward modeling is repeatedly used to compute accurate synthetics for the updated model to match the observations. Full numerical solvers based on spectral-element method (SEM) are desirable in this task of resolving fine-scale structures, but the associated computational cost can be prohibitive when the simulation frequency becomes high. Hybrid method can be used to reduce the computational cost by restricting the 2D/3D numerical solver to the target region where complex structures reside. We present the framework of an SEM-based two-way hybrid method where the target region can be anywhere inside the Earth. This two-way hybrid method can help map detailed heterogeneities in the lowermost mantle with the unprecedented resolution of FWI. As part of the work in this thesis to investigate fine-scale structures, we have also systematically measured the apparent splitting of vertically and horizontally polarized diffracted S waves along the core-mantle boundary (CMB) based on cross-correlation traveltimes, choosing Aleutian and west Africa as the study regions. Waveform simulations based upon SEM demonstrate that the SHdiff/SVdiff apparent splitting times from isotropic effects are comparable in magnitude to those from actual observations. These apparent splittings should be attributed to the different SHdiff and SVdiff sensitivities even in isotropic Earth models. Therefore, 1D and 3D isotropic effects, rather than intrinsic anisotropy, need to be first incorporated in the interpretation of SHdiff/SVdiff apparent splitting.
A Critical Ethnography of Disability in Committed Relationships
Keywords: disability
intimacy
relationships
sexuality

Finding loving, committed relationships can be a difficult journey for many people, but the quest poses additional challenges for disabled people (Rintala et al., 1997; Wade, 2002). Disability rights has advanced in many areas—for example, physical accessibility of the built environment—but harmful social stigma regarding attractiveness, sexual function, and abilities related to fulfilling a partnership role continues to enact barriers for disabled people when seeking and enjoying romantic relationships (Bahner, 2012; Esmail, Darry, Walter, Knupp, 2010; Gill, 1996; Rintala et al., 1997; Shakespeare, Gillespie-Sells, Davies, 1996). Although discrimination in the area of dating, partnership and relationships can often be the most distressing and painful aspects of social exclusion for disabled people, there is a lack of comprehensive research and advocacy surrounding these issues (Finger, 1992; Shakespeare, 2000). Using a critical ethnographic approach (Madison, 2011; Thomas, 1993) in this research, I explore whether the experiences of disabled people and their partners reflect, reject, and/or reimagine dominant cultural assumptions about the experience of disability within relationships. Eight couples, where one or both people identify as having a disability, were interviewed about their experiences as a couple and the role that disability had in their relationships. Interview transcripts were analyzed using Charmaz's (2014) constructivist grounded theory, and the analysis is presented within two broad categories: disability-related experiences in the foreground and background of committed relationships; and the productive and positive value of disability-related experiences in committed relationships. I conclude that disability is experienced in a wide variety of ways both between and among individuals and couples; disability is not necessarily the most important or the most pressing consideration in the day-to-day lives of couples, and disability-related experiences have the potential to be positive and productive within committed relationships.
Increasing Chemosensitivity in Colorectal Cancer
Keywords: aggregation
antioxidant
cancer
colorectal
Nrf2
p53

Despite being one of the most genetically understood cancers, colorectal cancer is still one of the leading causes of death due to cancer. Here we focus on two mechanisms of chemoresistance in colorectal cancer; the increased antioxidant response of colorectal cancer-initiating cells (CC-ICs) and the aggregation of p53. Most CRCs contain a subset of self-renewing CC-ICs responsible for tumor initiation and maintenance that are chemoresistant compared to the bulk tumor cell population. The overexpression of Nrf2, the master regulator of the antioxidant response system, allows for the detoxification of chemotherapy and increased CC-IC survival. We show that CRC cells upregulate their antioxidant activity in response to chemotherapy and that CC-IC self-renewal is dependent on Nrf2 function where genetic knockdown of Nrf2 results in decreased CC-IC frequency in vitro. Since transcription factors like Nrf2 are difficult to target, we instead targeted mechanisms that regulate Nrf2 activity. Nrf2 is significantly correlated with the epigenetic regulator histone acetyl transferase (HAT1) and studies show that acetylation of Nrf2 promotes enhanced Nrf2 activity. Treating CC-IC enriched Nrf2 knockdown cells with chemotherapy results in HAT1 upregulation. Furthermore, treating CC-IC enriched HAT1 knockdown cells with chemotherapy caused increased cell death and a decrease in CC-IC frequency in vitro. Another mechanism of CRC chemoresistance is the aggregation of p53, causing the loss of its pro-apoptotic function. It has previously been established that CBP/p300 bromodomain inhibition decreases protein amyloid-like aggregation. CBP/p300 regulates p53 through its acetylation, ubiquination, and bromodomain activity, however it has never been shown that CBP/p300 bromodomain inhibition results in a decrease in p53 disaggregation. We show that treatment of mutant p53 CRC cells with 5FU increases p53 aggregation and acetylation of p53 lysine K382, a binding site for the CBP/p300 bromodomain. By treating cells with the CBP/p300 bromodomain inhibitor, SGC CBP30 (CBP30), we decreased 5FU-induced p53 aggregation and restored the pro-apoptotic function of p53. p53 mutant cells treated with CBP30 became more sensitive to 5FU, while CBP30 had no significant effect on CRC viability in p53 knockdown cell lines. Therapeutically targeting mechanisms that drive chemoresistance in CRC will improve chemotherapeutic response and decrease relapse in CRC patients.
Resolve - For Symphony Orchestra
Keywords: Classical
Composition
Contemporary
Orchestra

Written as the thesis composition for the DMA in Composition degree, Resolve is simple in concept: it would be a musical composition that unravels at a glacial pace in one movement over the span of 16 minutes. By setting this conceptual limitation upon myself, I hoped to create a composition with a focus on melody, harmony, and counterpoint. The inspiration behind writing a very slow work for orchestra in part came from the music of John Luther Adams and Olivier Messiaen. Both composers are known for works which stretch over long periods of time and challenge the listeners’ ability to perceive the larger scale form. I especially admire the way these composers create extremely long lines that are suspended in beautiful harmony. In this work, harmony is created through the complex overlapping of individual melodic lines, which in turn create a harmonic field which slowly shifts as lines merge and disperse. The title Resolve reflects two important elements in the piece - first, the sense of slow determination that pervades the piece through its slow build up and secondly, the idea of long-term harmonic and musical resolution that comes in the form of two major climaxes. The work is ultimately a musical reflection on the crises of our time and attempts to capture the immensity of time through deliberately slow motion, allowing space for meditation and thought.
To the 21st Century, and Beyond! Investigating the Practical Ways that Secondary School Teachers can Develop the “21st Century Competencies” in their Students
Keywords: 21st century competencies
case study
constructivism
global competencies
secondary school
technology

In this study, I aimed to investigate the practical ways that secondary school teachers in different subject areas could better develop the 21st century competencies – critical thinking and problem solving; innovation, creativity, and entrepreneurship; self-directed learning; collaboration; communication; and citizenship – in their students, as outlined by the Ontario Ministry of Education (2016; 2017), as well as the challenges they faced in their pursuit of developing the competencies. While many of the competencies have been encouraged over the past century in education and promoted in policy documents, teachers still struggle with how to most effectively develop the competencies in their students, and I was interested in observing the day-to-day experiences and approaches of my participants. To collect the data used in this qualitative case study, I conducted interviews with eight participants, followed by over sixty hours of in-class observations and ongoing document analysis. To wrap up the data collection, I concluded with another round of interviews before narrowing my final data analysis to five of the eight participants. Data collection took place over the 2017 and 2018 school year at my workplace, an independent school called Gates Tech in the Greater Toronto Area. From my data collection, the research participants felt that there were a few keys to success when it came to developing the competencies in their students. These characteristics included the importance of a supportive school culture and administration, the importance of establishing trust in the classroom, the necessity of co-constructing knowledge with students, viewing the curriculum as flexible, focusing on bringing the outside world into the classroom, having access to (and the confidence to use) multiple technologies and flexible spaces, rethinking assessment practices, and continuing to learn and reflect as a teacher. Challenges faced by the teachers in this study included overload, a fear of failure, a fear of pushback from students and parents, the pressure to be “all-knowing,” and the ongoing pressures to produce high test scores. Ongoing research and support are recommended to better support teachers and students as they pursue the development of the competencies in an ever-changing world.