VictorJuiz/thesis huggingface dataset:
Targeted Auger Electron Radiotherapy of HER2-amplified Breast Cancer

Monoclonal antibodies (mAbs) conjugated to nuclear localization sequences (NLS) and labeled with Auger electron-emitters have great potential for targeted radiotherapy of cancer. This approach may be especially appropriate for the 25-30% of patients with breast cancer whose tumors display overexpression of HER2. Trastuzumab (Herceptin) is a humanized anti-HER2 mAb approved for immunotherapy of HER2-amplified breast cancer. The goal of this research was to radiolabel trastuzumab with [111]In, and to modify it with peptides harboring the NLS (CGYGPKKKRKVGG) of the simian virus 40 large-T antigen for targeted radiotherapy of breast cancer. It was hypothesized that the NLS-peptides would mediate the translocation of covalently linked [111]In-trastuzumab molecules into the nuclei of HER2-overexpressing breast cancer cells where subcellular-range Auger electrons are most damaging to DNA and lethal to cells. Trastuzumab was derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate for reaction with NLS-peptides and labeled with [111]In using diethylenetriaminepentaacetic acid. The dissociation constant for binding of [111]In-NLS-trastuzumab to HER2-overexpressing SK-BR-3 human breast cancer cells was reduced < 3-fold compared to [111]In-trastuzumab, demonstrating relatively preserved receptor-binding affinity. The NLS-peptides did not affect the biodistribution of [111]In-trastuzumab, but promoted its nuclear uptake in HER2-overexpressing MDA-MB-361 xenografts. The cytotoxicity of [111]In-NLS-trastuzumab on breast cancer cells correlated with their HER2 expression. Moreover, [111]In-NLS-trastuzumab was 2-fold and 5-fold more potent at killing MDA-MB-361 and SK-BR-3 cells compared to [111]In-trastuzumab, and nearly 3-fold and 6-fold more effective than unlabeled trastuzumab, respectively. Methotrexate is a known radiosensitizer that can amplify the lethal effects of ionizing radiation on tumor cells. Non-cytotoxic, but radiosensitizing doses of methotrexate were therefore combined with [111]In-NLS-trastuzumab; this enhanced the sensitivity of HER2-overexpressing breast cancer cells to [111]In-NLS-trastuzumab. The blood t1/2 of [111]In-NLS-trastuzumab in non-tumor bearing BALB/c mice was 23-34 h when administered intravenously or intraperitoneally. The maximum tolerated dose was 9.2-18.5 MBq; doses >18.5 MBq caused decreased leukocyte and platelet counts. [111]In-NLS-trastuzumab exhibited strong anti-tumor effects against HER2-overexpressing MDA-MB-361 xenografts, reducing their growth rate 2-fold and 3-fold compared to mice administered [111]In-trastuzumab or unlabeled trastuzumab, respectively. These promising results suggest that [111]In-NLS-trastuzumab may be a useful Auger electron radioimmunotherapeutic agent for HER2-positive breast cancer in humans.

Keywords: Breast Cancer
Radioimmunotherapy
Auger electron
Indium-111
HER2
Trastuzumab
Advisor: Reilly, Raymond Matthew
Episodes of Relationship Completion Through Song in Palliative Care

This study utilized a combination of intrinsic and instrumental case studies to describe the experience of four dying persons and their significant relations, as they engaged in music therapy sessions designed with the goal of facilitating relationship completion. The four primary participants were inpatients of the Baycrest palliative care program who were diagnosed with a terminal illness and a life expectancy of less than six months. Two spouses who were involved in music therapy sessions were co-participants. I developed four case studies to represent each of the rich and detailed stories. Through the use of narrative research methods I was able to describe, interpret, and understand the complexity held within the multiple data sources that informed each case study. Data sources included: music created, utilized, recorded, and/or discussed in music therapy sessions; discussions during music therapy sessions; the researcher’s field notes; formal notes placed in the participant’s medical charts; the formal written assessment; transcriptions of audio-taped music therapy sessions; interviews; interview transcriptions; artistic pieces crafted by myself that emerged from the experiences of the participants as reflected in their interviews, and weekly participation in sessions which were verified by the participants; and other artistic material. The rich knowledge that emerged from the individual case studies informed a cross-case analysis where global themes were identified from a thematic analysis of participants’ experiences; and process motifs arising from the progression of participant engagement in music therapy are described. Global themes included: love; loss; gratitude; growth/transformation; courage/strength; and goodbye. The five process motifs that emerged were: (1) music therapy helps and was valued as a means of sharing the participants’ perceptions of their situation. (2) music therapy provides a safe place to become aware of, explore, and express feelings. (3) music enhances communication. (4) music therapy techniques provide creative avenues for self-expression. (5) music therapy provided a vehicle for revisiting and reminiscing. The thesis concludes with a summary of the knowledge revealed and a discussion of implications for music therapists and health care professionals, as well as a presentation of final thoughts and reflections on my role as researcher in this study.

Keywords: Music therapy
palliative care
relationships
narrative
relationship completion
Advisor: Bartel, Lee
Self-assembly and Fibre Formation of Elastin-llke Polypeptides

Elastin is a polymeric protein of the extracellular matrix that imparts the characteristics of extensibility and elastic recoil to tissues. Recombinant polypeptides based on the domain structures and sequences of human elastin self-assemble into organized fibrous structures, with physical properties similar to those of native polymeric elastin. Elastin self-assembly is initiated by a temperature-induced phase separation, called coacervation. Previous to this work, coacervation temperature had been the only parameter available to measure propensity for self-assembly. A variety of techniques were developed using spectrophotometry, microscopy, and rheometry to differentiate the stages of self-assembly, thereby enabling independent observation and quantitation of each stage, and allowing investigations into properties of polypeptides and solution conditions affecting these stages. Kinetic analysis of self-assembly yielded two additional parameters: coacervation velocity and maturation velocity. Examining the effects of agitation, salt concentration, temperature, polypeptide concentration, size of a polypeptide, hydrophobic domain sequence, and cross-linking domain structure on the kinetics demonstrated that coacervation and maturation are independent stages of self-assembly involving distinct mechanisms. Microscopic observations showed that protein-rich droplets of coacervate grew by coalescence to a stable droplet size, which correlated to differences in maturation velocities between polypeptides. Coacervate droplet growth appeared limited by the formation of organized polypeptide at the surface of the droplets, decreasing surface fluidity. Many of the general principles of the physical chemistry of colloids and emulsions appeared to apply to the formation, growth and stabilization of coacervates of the elastin-like polypeptides. Self-assembly in the presence of non-elastin, matrix-associated proteins showed that these proteins maintained the coacervate as small droplets, which sometimes flocculated into fibre-like structures. Rheometry demonstrated a second temperature-induced transition above the coacervation temperature, which resulted in gelation and viscoelastic characteristics similar to microgels. Together, these observations have resulted in a greater level of understanding of the entire self-assembly process, and provided a comprehensive model of elastin-like polypeptide self-assembly that relates to in vivo assembly of elastic fibres.

Keywords: elastin
self-assembly
coacervation
Advisor: Keeley, Fred
Social Cohesion Analysis of Networks: A Novel Method for Identifying Cohesive Subgroups in Social Hypertext

Finding subgroups within social networks is important for understanding and possibly influencing the formation and evolution of online communities. This thesis addresses the problem of finding cohesive subgroups within social networks inferred from online interactions. The dissertation begins with a review of relevant literature and identifies existing methods for finding cohesive subgroups. This is followed by the introduction of the SCAN method for identifying subgroups in online interaction. The SCAN (Social Cohesion Analysis of Networks) methodology involves three steps: selecting the possible members (Select), collecting those members into possible subgroups (Collect) and choosing the cohesive subgroups over time (Choose). Social network analysis, clustering and partitioning, and similarity measurement are then used to implement each of the steps. Two further case studies are presented, one involving the TorCamp Google group and the other involving YouTube vaccination videos, to demonstrate how the methodology works in practice. Behavioural measures of Sense of Community and the Social Network Questionnaire are correlated with the SCAN method to demonstrate that the SCAN approach can find meaningful subgroups. Additional empirical findings are reported. Betweenness centrality appears to be a useful filter for screening potential subgroup members, and members of cohesive subgroups have stronger community membership and influence than others. Subgroups identified using weighted average hierarchical clustering are consistent with the subgroups identified using the more computationally expensive k-plex analysis. The value of similarity measurement in assessing subgroup cohesion over time is demonstrated, and possible problems with the use of Q modularity to identify cohesive subgroups are noted. Applications of this research to marketing, expertise location, and information search are also discussed.

Keywords: cohesive subgroups
social network
social network analysis
hierarchical clustering
centrality
similarity analysis
social hypertext
Advisor: Chignell, Mark
Amplified Photochemistry with Slow Photons

Slow photon, or light with reduced group velocity, is a unique phenomenon found in photonic crystals that theoreticians have long suggested to be invaluable for increasing the efficiency of light-driven processes. This thesis demonstrates experimentally the feasibility of using slow photons to optically amplify photochemistry of both organic and inorganic systems. The effect of photonic properties on organic photochemistry was investigated by tracing out the wavelength-dependent rate of photoisomerization of azobenzene anchored on silica opals. The application of slow photons to inorganic photochemical processes was realized by molding nanocrystalline titania into an inverse opal structure and investigating its photodegradation efficiency in relation to the photonic properties. Changes in the photodegradation efficiency were directly linked to modifications of the electronic band gap absorption as a result of the photonic properties. The highest enhancement of twofold was achieved when the energy of the slow photons overlaps with the electronic band gap absorption, such that the loss of light due to photonic stop-band reflection was significantly reduced. In addition, the strength of slow-photon amplification with respect to the macroscopic structural order was studied by introducing controlled disorder via the incorporation of guest spheres into the opal templates. For the first time, a correlation between structural order, photonic properties and a photochemical process was established. The ability to combine slow-photon optical amplification with chemical enhancement was further achieved by incorporating platinum nanoparticles in inverse titania opals where the platinum nanoparticles increased the lifetimes of the higher population of electron-hole pairs arising from slow photon. Overall, various important factors governing the slow photon enhancement were investigated in detail, including the energy of the photonic stop band, angle dependence, thickness of the film, degree of structural order, filling fraction of the dielectric material and diffusion of a second medium if present. Theoretical calculations based on scalar-wave approximation in support of the experimental findings were provided wherever possible. The findings provide a blueprint for achieving optical amplification using slow photons in the broad range of photochemical or photophysical processes.

Keywords: slow photons
photochemistry
photonic crystal
Advisor: Ozin, Geoffrey Alan
Diffractive Optics Near-field Laser Lithography for Fabrication of 3-dimensional Periodic Nanostructures

The main objective of the present research work is to fabricate three dimensional photonic nanostructures in photo-sensitive polymers using a novel diffractive optical element (DOE) based lithography technique. A diffractive optical element is a promising alternative device for 3D fabrication where one DOE creates multiple laser beams in various diffraction orders that are inherently phase-locked and stable for reproducible creation of 3D near-field diffraction patterns from a single laser beam. These near-field patterns are captured inside a photosensitive material like photoresist to fabricate 3D photonic crystal templates. We have demonstrated fabrication of a wide range of 3D structures having different crystal symmetries and different relative crystal axis ratios. The present work has provided 3D photonic crystal nanostructures with uniform optical and structural properties over large sample area (~3-4 mm diameter) and through large 15-50 micron thickness with large number of layers (> 40) having period 550 nm - 650 nm and feature sizes between 200 nm and 300 nm. The short exposure time and small number of process steps shows promise for scaling to very large volume fabrication, dramatically improving the throughput, quality and structural uniformity of 3D periodic nanostructures, especially over that provided by tedious and costly semiconductor processing technology. The diffractive optics lithography is a parallel processing method that is easily scalable to generate centimeter-scale 3D nanostructures having large number of layers in several seconds. Due to low refractive index contrasts these polymer templates possess partial stopgaps along several crystallographic directions which can be practically used in several device or sensor applications where complete bandgap is not necessary. The potential usefulness of these partial stopbands for refractive index sensing of liquids has been demonstrated. These low refractive index polymer structures have been inverted with amorphous silica to convert a "soft" polymer structure to a robust "hard" structure. Further, few preliminary tests were done in fabricating 3D nanostructures into micro-fluidic channels for potential chromatography applications. The practical merits of this 3D fabrication technique will enable new practical manufacturing methods for optical and MEMS applications of 3D micro and nano structures.

Keywords: Electronics and Electrical
Nano-fabrication
Laser fabrication
Photonic crystal
Laser material processing
Diffractive optical element
Optics
Photonics
Advisor: Herman, Peter R.
School Choice, Competition, and Public School Performance

Reforms that expand school choice have been the focus of considerable policy interest, not least as a possible means of improving public school performance. According to the standard argument, increased choice will intensify competition, forcing public schools to improve quality in order to retain enrolment. Yet in principle, increased choice need not always raise performance, pointing to the need for careful empirical analysis. A key challenge in measuring the effects of greater choice on school performance is that convincing variation in choice is often hard to come by, especially in cross-sectional studies. And while school choice policy experiments have the advantage that choice increases in a clear way, few large-scale school choice policies have been implemented in North America. An important exception is the 2002 Ontario tuition tax credit, which eased access to private schools throughout Canada's most populous province. Analyzing the effects of the tax credit reform provides the focus of this thesis. The thesis begins by presenting the literature and gaps in existing research. The next chapter presents a model to clarify the link between increases in competition and school performance, and to motivate the empirical identification strategy. To set the stage for the main empirical analysis, I also provide some relevant institutional background relating to the Ontario education policy environment and the Ontario tuition tax credit as well as a descriptive analysis on the Ontario private school market. I then present an initial examination of the possible performance effects of the Ontario tuition tax credit using a difference-in-differences setup, before turning to the main empirical analysis, which exploits the differential competitive effects for public schools in districts with relative to those without a significant private school presence. The empirical results indicate that public school performance improved for schools facing the greatest competitive pressures following the introduction of the policy, controlling for a host of other relevant factors. To assess whether the effect is due primarily to increases in productivity, the analysis controls carefully for a series of alternative mechanisms. Overall, the Ontario findings are consistent with increased choice giving rise to productivity improvements in public schools.

Keywords: School choice
Competition
School performance
Productivity
Advisor: McMillan, Robert
Making the Invisible Visible: Public Library Reference Service as Epistemic Practice

Public library services are evolving in response to the changing informational needs and behaviours of the citizens of the knowledge society. Reference statistics are declining and the move to self-service, virtual reference and an increasing use of mediating information and communication technologies calls into question the ongoing role of human, face-to-face information interaction at the public library’s front-line reference “desk”. An ethnographic case study of face-to-face adult reference service was conducted in a large Canadian urban public library. Over 8 months during 2006, a pilot study was conducted, followed by 170 hours of observations at the reference desks in three branch libraries of varying sizes and semi-structured interviews with front-line reference staff, library managers and reference service clients. 480 reference interactions were documented and policy documents were reviewed. An inductive staged process of analytical abstraction, a narrative approach to the interpretations and a critical reflexivity as participant researcher were employed. The main contribution of this study is the articulation of a practice framework for understanding and studying the reference service within the public library as organization. Sharing knowledge, finding meaning and learning are the outcomes of this epistemic practice. A typology of four reference encounters characterized in three dimensions of interpersonal communication; information exchange and mode of practice is detailed. This study challenges previous interpretations of reference services as a transactional, unitized question-answer activity and depicts it in a larger context as an interactional, relational set of activities that altogether characterize an epistemic practice. The three dimensions of structure (library organization), agency (reference staff and clients) and objects (library collections) anchor this conceptual framework – they are interdependent dimensions interacting to illuminate a robust understanding of face-to-face reference service. This study responds to previous research in which the reference process is studied separately from its social practice and its structural-organizational contexts.

Keywords: public libraries
epistemic practice
reference service
ethnographic
knowledge
case study
Advisor: Choo, Chun Wei
Howarth, Lynne C.
Digesting the Third: Reconfiguring Binaries in Shakespeare and Early Modern Thought

My argument assesses and reconfigures binary structures in Shakespeare’s plays and in Shakespeare criticism. I contend that ideas in early modern literature often exhibit three aspects, but that critics, who mostly rely upon a binary philosophical vocabulary, tend to notice only two aspects at a time, thereby “digesting” the third. My opening chapter theorizes the superimposition of triadic structures upon dyads, arguing that this new polyrhythmic strategy helps recapture an early modern philosophical perspective by circumventing the entrenched binary categories we have inherited from the Enlightenment. In Chapter Two, I examine the relationship of tyranny and conscience in Tudor politics, Reformed psychology, and Richard III. Early modern political theorists often employ a binary opposition of kingship and tyranny, and historians typically draw a binary distinction between absolutists and resisters. I argue that there were in fact three ideological positions on offer which these binaries misrepresent. As well, Reformed psychology emphasizes the relationship of the individual subject and an objective God, unmediated by community, and I propose that this opposition of subjectivity and objectivity digests the idea of intersubjectivity. In Richard III, Shakespeare interrogates the implausibility of Tudor political binaries and stages a nostalgia for intersubjective community and conscience. In Chapter Three I read the debates on value in Troilus and Cressida alongside contemporary economic writings by Gerard de Malynes on currency reform and “merchandizing exchange.” Our current models of value – intrinsic and extrinsic, use and exchange, worth and price – are emphatically binary, but the mercantile practices that Malynes describes depend upon a triadic conception of value. My contention is that Troilus and Cressida becomes a less problematic problem play when value is conceived as triadic rather than dyadic. In Chapter Four I explore early modern scepticism in connection with Coriolanus. Reading Montaigne and Wittgenstein in parallel, I distinguish between various conceptions of truth that are regularly grouped together under the blanket term “scepticism.” Then I turn to read Coriolanus as an experiment in competing modes of early modern epistemology, arguing that the play ultimately endorses the same sort of polyphonous Pyrrhonian scepticism that we find in Montaigne and Wittgenstein.

Keywords: Shakespeare
Richard III
Troilus and Cressida
Coriolanus
critical theory
philosophy
Montaigne
Wittgenstein
scepticism
Advisor: Levenson, Jill L.