VictorJuiz/thesis huggingface dataset:
Optimizing the Tailored Treatment of Breast Cancer

Background: Breast cancer is a diverse disease. Over the past 3 decades it has been increasingly appreciated that therapy should be targeted to specific patient and tumour characteristics. In recent years the evaluation of tailored therapy has been dominated by the development of new drug therapy which when successful has been marketed at a high price. There have been few successful attempts to optimize currently available therapies. This thesis explores the optimization of currently available therapies in three domains: efficacy, toxicity and supportive care. Methods: Three independent studies were undertaken. First, a prospective cohort study was conducted to assess the impact of re-biopsy of recurrent breast cancer on physician choice of therapy and on patient satisfaction. The second study comprised a systematic review and meta-analysis of randomized trials exploring toxicities associated with different endocrine therapy options for early breast cancer with the aim of identification of patients who may be harmed by certain drugs. Finally, a randomized feasibility study was conducted to evaluate de-escalated intravenous bisphosphonates in women with low-risk metastatic breast cancer to bone. Results: All studies met their objectives in showing that the tailored use of available therapies can be optimized. The prospective study of the impact of re-biopsy showed that treatment decisions were modified in 14% of women. Patient satisfaction with the process of re-biopsy was high. The meta-analysis of toxicities of endocrine therapy identified cardiovascular disease as a statistically significant toxicity of aromatase inhibitors, thereby suggesting that those with established cardiovascular disease or risk factors thereof should reduce their exposure to these drugs. Finally, the randomized feasibility study showed that it is possible to conduct randomized trials of de-escalated bisphosphonates in women with low-risk breast cancer and there was no signal that reducing the frequency of treatment was associated with untoward outcomes. Conclusions: It is possible to optimize the tailored therapy of breast cancer using currently available treatments. This may lead to improved patient outcome while using existing resources. Further studies assessing the optimization of other treatments are warranted.

Keywords: Breast Cancer
Optimized therapy
Advisor: Tannock, Ian
Identifying Susceptibility Genes for Familial Pancreatic Cancer Using Novel High-resolution Genome Interrogation Platforms

Familial Pancreatic Cancer (FPC) is a cancer syndrome characterized by clustering of pancreatic cancer in families, but most FPC cases do not have a known genetic etiology. Understanding genetic predisposition to pancreatic cancer is important for improving screening as well as treatment. The central aim of this thesis is to identify candidate susceptibility genes for FPC, and I used three approaches of increasing resolution. First, based on a candidate-gene approach, I hypothesized that BRCA1 is inactivated by loss-of-heterozygosity in pancreatic adenocarcinoma of germline mutation carriers. I demonstrated that 5/7 pancreatic tumors from BRCA1-mutation carriers show LOH, compared to only 1/9 sporadic tumors, suggesting that BRCA1 inactivation is involved in tumorigenesis in germline mutation carriers. Second, I hypothesized that the germline genomes of FPC subjects differ in copy-number profile from healthy genomes, and that regions affected by rare deletions or duplications in FPC subjects overlap candidate tumor-suppressors or oncogenes. I found no significant difference in the global copy-number profile of FPC and control genomes, but I identified 93 copy-number variable genomic regions unique to FPC subjects, overlapping 88 genes of which several have functional roles in cancer development. I investigated one duplication to sequence the breakpoints, but I found that this duplication did not segregate with disease in the affected family. Third, I hypothesized that in a family with multiple pancreatic cancer patients, genes containing rare variants shared by the affected members constitute susceptibility genes. Using next-generation sequencing to capture most bases in coding regions of the genome, I interrogated the germline exome of three relatives who died of pancreatic cancer and a relative who is healthy at advanced age. I identified a short-list of nine candidate genes with unreported mutations shared by the three affected relatives and absent in the unaffected relative, of which a few had functional relevance to tumorigenesis. I performed Sanger sequencing to screen an unrelated cohort of approximately 70 FPC patients for mutations in the top two candidate genes, but I found no additional rare variants in those genes. In conclusion, I present a list of candidate FPC susceptibility genes for further validation and investigation in future studies.

Keywords: familial pancreatic cancer
tumor suppressor genes
oncogenes
copy number variation
exome sequencing
Advisor: Gallinger, Steven
Formulating Evaluation Measures for Structured Document Retrieval using Extended Structural Relevance

Structured document retrieval (SDR) systems minimize the effort users spend to locate relevant information by retrieving sub-documents (i.e., parts of, as opposed to entire, documents) to focus the user's attention on the relevant parts of a retrieved document. SDR search tasks are differentiated by the multiplicity of ways that users prefer to spend effort and gain relevant information in SDR. The sub-document retrieval paradigm has required researchers to undertake costly user studies to validate whether new IR measures, based on gain and effort, accurately capture IR performance. We propose the Extended Structural Relevance (ESR) framework as a way, akin to classical set-based measures, to formulate SDR measures that share the common basis of our proposed pillars of SDR evaluation: relevance, navigation and redundancy. Our experimental results show how ESR provides a flexible way to formulate measures, and addresses the challenge of testing measures across related search tasks by replacing costly user studies with low-cost simulation.

Keywords: information retrieval
XML
tree retrieval
relevance
redundancy
navigation
Advisor: Consens, Mariano P.
Osteocytes: Sensors of Mechanical Forces and Regulators of Bone Remodeling

Osteocytes make up the largest cell population in bone and are believed to be the main mechanosensory bone cells. During mechanical disuse and overuse, osteocyte viability is compromised and is found to be co-localized with increased osteoclastic bone resorption. Osteoclasts are recruited to remodel sites of apoptosis or bone microdamage; however, it is unclear whether the apoptotic or neighbouring healthy osteocytes are responsible for targeted bone remodeling. I hypothesized that apoptotic osteocytes are: (a) directly responsible for initiating bone remodeling by recruiting osteoclast precursors and directing osteoclast differentiation, and (b) indirectly responsible by signaling to nearby healthy osteocytes that, in turn, regulate osteoclastogenesis. In this in vitro study, apoptotic osteocytes were found to increase osteoclast precursor migration and osteoclast formation. Inhibition of the osteoclastogenic protein, receptor activator of nuclear factor kappa B ligand (RANKL), in conditioned medium abolished the osteoclastogenic effect of apoptotic osteocytes. Healthy osteocytes surrounded by apoptotic regions were modeled by applying apoptotic osteocyte conditioned medium to healthy osteocytes. These cells also promoted osteoclastogenesis, and had increased expression of macrophage colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF). Inhibition of these factors abrogated the pro-osteoclastic effect of healthy osteocytes conditioned by apoptotic osteocytes. These findings support the hypothesis that apoptotic osteocytes directly and indirectly, by signaling to nearby healthy osteocytes, initiate osteoclastogenesis. One limitation of our and other conventional in vitro models is the lack of real-time cell communication and physiologically-relevant mechanical environment. Using a microfluidics approach, a miniature fluid shear delivery system was created for in vitro osteocyte cultures. The purpose of this microsystem was to increase control of the cell microenvironment for subsequent integration into scalable screening platforms or co-culture systems for studying osteocyte mechanobiology under physiological loading conditions. Fluid shear stress was periodically applied without external pumping using a deflecting elastomer membrane, where up to 2 Pa of oscillating shear stress was possible by manipulating membrane dimensions. Osteocyte culture, viability and calcium response were demonstrated in the microdevice. Further studies should attempt to characterize calcium signaling in osteocytes which, using a conventional macro-scale system, was found to dependent on cell-cell communication.

Keywords: osteocyte
bone remodeling
mechanical loading
apoptosis
microfluidics
fluid shear stress
Advisor: You, Lidan
Guenther, Axel
Hybrid Plasmon Waveguides: Theory and Applications

The study and applications of surface plasmon polaritons (SP) – also known as plasmonics – has attracted the interest of a wide range of researchers in various fields such as biology, physics, and engineering. Unfortunately, the large propagation losses of the SP severely limit the usefulness of plasmonics for many practical applications. In this dissertation a new wave guiding mechanism is proposed in order to address the large propagation losses of the plasmonic guides. Possible applications of this guiding scheme are also investigated. The proposed hybrid plasmonic waveguide (HPWG) consists of a metal layer separated from a high index slab by a low index spacer. A detailed analysis is carried out to clarify the wave guiding mechanism and it is established that the mode guided by the HPWG results from the coupling of a SP mode and a dielectric waveguide mode. A two dimensional HPWG is proposed and the effects of various parameters on the HPWG performance are analyzed in detail. This structure offers the possibility of integrating plasmonic devices on a silicon platform. The proposed waveguide supports two different modes: a hybrid TM mode and a conventional TE mode. The hybrid TM mode is concentrated in the low index layer, whereas the conventional TE mode is concentrated in the high index region. This polarization diversity is used to design a TM- and a TE-pass polarizer and a polarization independent coupler on a silicon-on-insulator (SOI) platform. Moreover, the performance of a HPWG bend is investigated and is compared with plasmonic waveguide bends. The proposed devices are very compact and outperform previously reported designs. The application of HPWG for biosensing is also explored. By utilizing the polarization diversity, the HPWG biosensor can overcome some of the limitations of plasmonic sensors. For example, unlike plasmonic sensors, the HPWG biosensor can remove the interfering bulk and surface effects.

Keywords: Surface plasmon
Plasmonics
Integrated optics
Hybrid plasmonic waveguide
Advisor: Mojahedi, Mohammad
Stewart, Aitchison John
Topology and Dynamics of Macromolecular Aggregates Studied by Pressure NMR

The topology and dynamics of biomolecules are intricately linked with their biological function. The focus of this thesis is the NMR-based measurement of topology and dynamics in biomolecular systems, and methods of measuring immersion depth and orientation of membrane-associated molecules. In detergent micelles and lipid bilayers, the local concentrations of hydrophobic and hydrophilic molecules are a function of their bilayer immersion depth. For paramagnetic molecular oxygen or metal cations, the magnitudes of the associated paramagnetic isotropic contact shifts and relaxation rate enhancements (PREs) are therefore depth-dependent. NMR measurements of these effects reveal the immersion depth of bilayer- or detergent-associated molecules. This work first explores transbilayer oxygen solubility and thermodynamics, as measured from contact shifts and PREs of the constituent lipid molecules in the presence of 30 bar oxygen. Contact shifts revealed the transmembrane O2 solubility profile spans a factor of seven across the bilayer, while PREs indicated that oxygen partitioning into bilayers and dodecylphosphocholine (DPC) micelles is entropically driven. Next, this work describes how paramagnetic effects from molecular oxygen and Ni(II) cations may be employed to study the immersion depth and topology of drug and protein molecules in DPC micelles. In one study, the positioning of the amphipathic drug imipramine in micelles was determined from O2- and Ni(II)-induced contact shifts. A second study, relying solely on O2-induced PREs, determined the tilt angles and micelle immersion depths of the two alpha helices in a monomeric mutant of the membrane protein phospholamban. A third study utilized 19F NMR to explore the importance of juxtamembraneous tryptophans on the topology of the membrane protein synaptobrevin, via O2-induced contact shifts and solvent-induced isotope shifts of a juxtamembraneous 19F-phenylalanine. Comparison of synaptobrevin constructs with zero, one, and two juxtamembraneous tryptophans revealed that while one tryptophan is sufficient to ‘anchor’ the protein in micelle, the addition of a second tryptophan dampens local dynamics. These solution state NMR studies demonstrate how paramagnetic effects from dissolved oxygen, complemented with measurements of local water exposure, provide detailed, accurate descriptions of membrane immersion depth and topology. These techniques are readily extended to the study of a wide range of biomolecules.

Keywords: nuclear magnetic resonance spectroscopy
membrane proteins
membrane topology
protein dynamics
paramagnetic NMR
oxygen solubility
Advisor: Prosser, Robert Scott
Molecular Mechanisms of Aryl Hydrocarbon Receptor Transactivation and Crosstalk with Estrogen Receptor alpha

The aryl hydrocarbon receptor (AHR) and estrogen receptor alpha (ERα) are ligand-activated transcription factors. Reciprocal crosstalk between these two receptor systems has been previously established but the exact molecular mechanisms of their interactions remain incompletely understood. Using chromatin immunoprecipitation followed by DNA microarrays (ChIP-chip), I assessed the role of ERα in AHR signalling after dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) treatment in the T-47D human breast cancer cell line. I determined that ERα is recruited to a subset of AHR target genes suggesting that it is a gene-specific modulator of AHR activity. Transcription factor binding site analysis of our data set also revealed that forkhead motifs were over-represented, implying that they may be important in AHR signalling. To address this, I focused on the regulation of cyclin G2 (CCNG2) to determine the importance of FOXA1 (forkhead box A1) in AHR signalling. CCNG2 is a negative regulator of cell cycle and known to be repressed by ERα. Using ChIP, Co-IP, CCNG2 reporter gene constructs and RNA interference targeting FOXA1, I demonstrated that FOXA1 was important for the AHR-mediated and TCDD-dependent induction of CCNG2. Another finding from the ChIP-chip study was that AHR was recruited to estrogen target genes. To determine the importance of this I used zinc-finger nuclease mediated knockout of AHR and studied ERα signalling as well as the role of AHR in the cell cycle using breast cancer cell lines. Focusing on the regulatory regions of trefoil factor 1 (TFF-1) and gene upregulated in breast cancer 1 (GREB1) I determined that AHR had an inhibitory effect. Cell cycle analysis indicated that AHR facilitated cell cycle progression with cells accumulating in both the G¬1 and G2/M phases in the absence of AHR. My novel findings demonstrated the complexity of AHR-ERα crosstalk, its importance in the cell cycle, and the need for further study.

Keywords: breast cancer
AHR
Advisor: Matthews, Jason
Towards Real-time Simulation of Ultrasound Systems

Diagnostic ultrasound is a non-invasive image modality commonly used to diagnose multiple diseases. Sonographers and physicians have to devote a substantial amount of time learning how the combination of the various parameters of the ultrasound system affects the resulting ultrasound information among its different modalities. The primary objective of this thesis is to create a mechanistic ultrasound simulation method that could achieve near real-time performance to teach and train sonographers and physicians. A major bottleneck for achieving real-time performance with available tools was the transducer field simulation method that uses the impulse response technique. To address this problem a new simulation approach was developed. This project was realized in a three-phase approach, specifically to simulate spectral Doppler. In first place, it was shown that is possible to mechanistically simulate the sample volume power distribution using a novel method based on an array of point sources to represent the transducer geometry. Secondly, by comparison with the Field II results, it was demonstrated that the time-domain signal could be closely reproduced using point sources. Finally, by treating the array of point sources as point receivers, the received signal was compared with the results from Field II, and again, good agreement was achieved. Simulation results were compared against the standard simulation method for a number of examples involving steady and pulsatile flow, for which the spectrograms were compared against Field II. Also presented are preliminary results obtained using the point source approach to simulate B-mode images. As well, methods are described for generating Doppler spectrograms from the results of computation fluid dynamics velocity fields obtained in realistic arterial geometrical models. It is pointed out that the successful simulation of the time domain signal opens the possibility for real-time simulation of other ultrasound modes.

Keywords: simulation
ultrasound
real-time
Advisor: Steinman, David
Cobbold, Richard
Measurements of Atmospheric Ozone, NO2, OClO, and BrO at 80°N using UV Visible Spectroscopy

The motivation for this thesis was to study chemical and dynamical processes in the Arctic stratosphere, using data from two ground-based spectrometers (GBSs). The GBSs took atmospheric trace gas measurements at the Polar Environment Atmospheric Research Laboratory (PEARL), which is located at Eureka, Nunavut, Canada (80.05°N, 86.42°W) and operated by the Canadian Network for the Detection of Atmospheric Change. The University of Toronto GBS took measurements at Eureka on a campaign basis from 1999 2011. The PEARL GBS was installed permanently at Eureka in 2006 and has taken measurements during the sunlit part of the year since then. GBS and other ground based ozone and NO2 column measurements were compared with Atmospheric Chemistry Experiment (ACE) and Optical Spectrograph and Infra Red Imaging System (OSIRIS) satellite measurements above Eureka. Ozone from all instruments agreed within 9.2%, while NO2 from most instruments, including the GBS, agreed to within 20%. On 1 August 2008, a solar eclipse of 98% totality passed over Eureka. GBS NO2 increased to 1.84 times normal levels. This agrees with a ratio of 1.91 that was calculated using a photochemical model, adjusted for reduced sunlight during the eclipse. In spring/winter 2011, up to 47% (250 DU) ozone loss was calculated using GBS and modeled passive ozone. This was the largest ozone loss in the 11 year GBS measurement record. GBS OClO was elevated, indicating chlorine activation and NO2 was low, suggesting denitrification. GBS, satellite, and chemical transport model data were used to investigate the 2011 vortex breakup. NOx transport led to middle stratosphere ozone loss within an anticyclone. Furthermore, isolated, or “frozen-in”, vortex and lower-latitude airmasses were observed following the vortex breakup. Stratospheric BrO was retrieved from spring 2008 GBS zenith sky measurements, using an optimal estimation technique. GBS BrO was compared with OSIRIS and Ozone Monitoring Instrument (OMI) satellite data. Discrepancies are partly attributed to bromine explosions in the boundary layer. New off axis GBS measurements taken in spring 2010 are sensitive to boundary layer bromine. The combination of GBS stratospheric and tropospheric BrO measurements will be useful for future estimates of the Arctic bromine budget.

Keywords: Atmospheric composition
UV-visible spectroscopy
Advisor: Strong, Kimberly
Reconsidering Similarity in an Agent-oriented Account of Scientific Modeling

In this thesis, I present a novel account of scientific modeling that achieves the stability and generalizability of static approaches with the flexibility and practical relevance of diachronic approaches. In this account, modeling is characterized by the use of a similarity relation for the purpose of surrogate reasoning. Many criticisms of similarity are based on the fact that there is no way to objectively assess similarity between two things that share some, but not all, features. This account does not rely on the inherently flawed notion of objectively assessing similarity. Instead, the focus is on subjective assessment of similarity, within the specific context of an agent using the similarity for surrogate reasoning. This account captures the diversity of models while providing coherence among common features and functions, as evidenced by application to a series of interrelated examples in a case study from mid-twentieth century cognitive psychology. The similarity/difference account advocated in this thesis is particularly significant because its demonstrated success, evidenced by the case study, dispels several misconceptions about the study of scientific models. Advocates of static approaches claim that a diachronic approach cannot provide the generalizability necessary for a unified account, but the functional and agent-oriented similarity/difference account proves otherwise. Advocates of practice-based approaches often suggest that imilarity is too restrictive to capture the diversity of scientific models, but the similarity/difference account demonstrates that this concern only applies to a radically naturalized concept of similarity. As part of an agent-oriented account, a non-naturalized concept of similarity can be flexible enough to capture the full range of scientific models. Combining a diachronic approach with the similarity relation usually associated with static approaches results in an account that can circumvent the issues usually associated with either diachronic approaches or similarity alone.

Keywords: scientific representation
scientific modeling
Advisor: Brown, James Robert
Baigrie, Brian