VictorJuiz/thesis huggingface dataset:
A Monte Carlo-based Model Of Gold Nanoparticle Radiosensitization
Keywords: Gold nanoparticles
Radiation therapy
Radiosensitization
Monte Carlo simulation
radiotherapy
dose enhancement
radiobiology

The goal of radiotherapy is to operate within the therapeutic window - delivering doses of ionizing radiation to achieve locoregional tumour control, while minimizing normal tissue toxicity. A greater therapeutic ratio can be achieved by utilizing radiosensitizing agents designed to enhance the effects of radiation at the tumour. Gold nanoparticles (AuNP) represent a novel radiosensitizer with unique and attractive properties. AuNPs enhance local photon interactions, thereby converting photons into localized damaging electrons. Experimental reports of AuNP radiosensitization reveal this enhancement effect to be highly sensitive to irradiation source energy, cell line, and AuNP size, concentration and intracellular localization. This thesis explored the physics and some of the underlying mechanisms behind AuNP radiosensitization. A Monte Carlo simulation approach was developed to investigate the enhanced photoelectric absorption within AuNPs, and to characterize the escaping energy and range of the photoelectric products. Simulations revealed a 10^3 fold increase in the rate of photoelectric absorption using low-energy brachytherapy sources compared to megavolt sources. For low-energy sources, AuNPs released electrons with ranges of only a few microns in the surrounding tissue. For higher energy sources, longer ranged photoelectric products travelled orders of magnitude farther. A novel radiobiological model called the AuNP radiosensitization predictive (ARP) model was developed based on the unique nanoscale energy deposition pattern around AuNPs. The ARP model incorporated detailed Monte Carlo simulations with experimentally determined parameters to predict AuNP radiosensitization. This model compared well to in vitro experiments involving two cancer cell lines (PC-3 and SK-BR-3), two AuNP sizes (5 and 30 nm) and two source energies (100 and 300 kVp). The ARP model was then used to explore the effects of AuNP intracellular localization using 1.9 and 100 nm AuNPs, and 100 and 300 kVp source energies. The impact of AuNP localization was most significant for low-energy sources. At equal mass concentrations, AuNP size did not impact radiosensitization unless the AuNPs were localized in the nucleus. This novel predictive model of AuNP radiosensitization could help define the optimal use of AuNPs in potential clinical strategies by determining therapeutic AuNP concentrations, and recommending when active approaches to cellular accumulation are most beneficial.
Discourse Comprehension and Informational Masking: The Effect of Age, Semantic Content, and Acoustic Similarity
Keywords: speech comprehension
informational masking
age-related differences
acoustic similarity

It is often difficult for people to understand speech when there are other ongoing conversations in the background. This dissertation investigates how different background maskers interfere with our ability to comprehend speech and the reasons why older listeners have more difficulties than younger listeners in these tasks. An ecologically valid approach was applied: instead of words or short sentences, participants were presented with two fairly lengthy lectures simultaneously, and their task was to listen to the target lecture, and ignore the competing one. Afterwards, they answered questions regarding the target lecture. Experiment 1 found that both normal-hearing and hearing-impaired older adults performed poorer than younger adults when everyone was tested in identical listening situations. However, when the listening situation was individually adjusted to compensate for age-related differences in the ability to recognize individual words in noise, age-related difference in comprehension disappeared. Experiment 2 compared the masking effects of a single-talker competing lecture to a babble of 12 voices, and the signal-to-noise ratio (SNR) was manipulated so that the masker was either of similar volume as the target, or much louder. The results showed that the competing speech was much more distracting than babble. Moreover, increasing the masker level negatively affected speech comprehension only when the masker was babble; when it was a single-talker lecture, the performance plateaued as the SNR decreased from -2 to -12 dB. Experiment 3 compared the effects of semantic content and acoustic similarity on speech comprehension by comparing a normal speech masker with a time-reversed one (to examine the effect of semantic content) and a normal speech masker with an 8-band vocoded speech (to examine the effect of acoustic similarity). The results showed that both semantic content and acoustic similarity contributed to informational masking, but the latter seemed to play a bigger role than the former. Together, the results indicated that older adults&rsquo; speech comprehension difficulties with maskers were mainly due to declines in their hearing capacities rather than their cognitive functions. The acoustic similarity between the target and competing speech may be the main reason for informational masking, with semantic interference playing a secondary role.
The Control of temporally Urgent Movements
Keywords: Reaction Time
Postural Control
Rehabilitation
Neurophysiology

The ability to respond rapidly with spatial precision is required in a number of facets of everyday life, whether catching a falling object, reacting to other drivers on a busy freeway or recovering one’s balance following an unexpected perturbation. The sophisticated central nervous system (CNS) control of these reactions is often overlooked until the speed of such reactions becomes delayed, either due to ageing or brain injury, wherein the individual becomes at risk of injury. Surprisingly, little is known regarding the control of these ‘temporally urgent’ movements. Therefore, the primary objectives of this dissertation were to develop an understanding of the control of these movements by exploring the factors that may be involved in the generation of temporally urgent movements in the healthy CNS, locating the areas within the CNS that such modulation occurs and identifying the relative weighted importance of those modulators based on the initial conditions of stimulus delivery. Specific characteristics of stimulus properties, such as intensity and modality were particularly influential in the latency of motor reactions and physiological electrodermal skin responses fluctuated in accordance with input stimulus parameters. Importantly, outcomes from this dissertation identified that rapid reactions likely utilize a CNS network that includes higher cortical regions such as somatosensory cortex and primary motor cortex, which may be modulated by physiological arousal, rather than the solitary involvement of subcortical structures. The findings from this dissertation have important implications for individuals with disordered speed of processing and indicate the potential modifiability of factors that influence reaction time.
Investigating Novel Biological Mechanisms of Head and Neck Cancers
Keywords: Head and Neck Cancer
MicroRNAs
miR-193b
NF1
HFE
Iron and Cancer

Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), clinical outcome has remained disappointing, with 5-year overall survival rates hovering around 40-50%, underscoring an urgent need to better understand the biological bases of this disease. We chose to address this challenge by studying the role of micro-RNAs (miRNAs), and iron in HNSCC. We performed global profiling on 51 primary HNSCC compared to 4 normal laryngeal epithelial tissues, and identified 38 differentially expressed miRNAs between cancer vs. normal patient tissues. Functional validation confirmed a tumour promoting phenotype for miR-106b and miR-375. Integrating these findings with global miR profiling of HNSCC revealed two significantly over expressed miRNAs in HNSCC cell lines and patient samples: miR-193b and miR-205. Knockdown of miR-205 and miR-193b in HNSCC cell lines significantly decreased cell proliferation and colony formation. Moreover, NF1 was identified as a target of miR-193b. Downstream targets of NF1 including active-RAS and p-ERK were also suppressed after miR-193b knockdown. Finally, HNSCC patients with high levels of miR-193b experienced a lower disease-free survival than patients with low miR-193b expression. The second approach we took to better understand the biology of HNSCC was to examine the involvement of iron in the disease. In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. Knockdown of HFE in HNSCC cell lines significantly decreased intracellular iron levels, resulting in a significant decrease in HNSCC cell proliferation, DNA synthesis, and Wnt signalling. When iron was re-introduced back into the cell after HFE knockdown, these cellular changes were reversed, indicating that iron was mediating this phenotype. Concordantly, HNSCC cells treated with an iron chelator ciclopirox olamine (CPX) significantly reduced proliferation and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression, corroborating the oncogenic role of HFE in HNSCC. In summary, using two independent methods, we have identified two potential prognostic biomarkers for HNSCC, namely miR-193b and HFE. Characterization of these two molecules, exposed critically dysregulated pathways driving disease progression. Specifically, the miR-193b~NF1 axis uncovered a novel mechanism of RAS and p-ERK activation in HNSCC; similarly, HFE exposed a novel tumour promotion role of iron in this disease.
Gene Expression Profile Changes in Neutrophils - From Sterile Compartments into Sites of Inflammation
Keywords: neutrophils
gene expression

Neutrophils, key cells of the innate immune system, are responsible for preventing bacterial infections. They are rapidly recruited to sites of infection where they eliminate bacteria through killing methods that require reactive oxygen dependent processes. It has recently been established that neutrophils are capable of rapid and complex changes in gene expression during inflammatory responses. The concept that neutrophils only directly kill bacteria has been replaced by the concept that activated neutrophils can influence the immune response through the secretion of a variety of cytokines and by acting as antigen-presenting cell (APC) expressing MHC Class II, allowing for activation of T cells. Recent advances in neutrophil biology demonstrated that neutrophils also have an active regulatory role in angiogenesis and tumoral fate. It has been noted that a number of diseases including arthritis, periodontitis and acute respiratory distress syndrome (ARDS) are associated with neutrophil hyperactivity that results in significant tissue damage. Our group has previously shown that for some periodontal diseases, neutrophil hyperactivity is a key determinant of disease progression and severity. However, it remains unclear what factors are responsible for a patient developing a hyperactive neutrophil mediated disease. I hypothesize that local gene expression changes in neutrophils are responsible for the hyperactive behaviour of these cells during an inflammatory response. In order to assess this, I characterized the neutrophil gene expression profile in various compartments (bone marrow, blood and peritoneum in mice and blood and oral cavity in humans) and then characterized this genetic and phenotypic profile during an inflammatory response. I hypothesize that the neutrophil has a characteristic set of genes that are normally activated when it enters a site of inflammation from the circulation and that neutrophils can be polarized into a different functional subset under certain conditions that result in inflammation mediated diseases. To identify changes in neutrophil gene expression in the circulation and inflamed tissue I used recent advances in neutrophil isolation, RNA amplification, and microarray technologies to characterize the specific transcriptome associated with neutrophil site-specific responses.
Preclinical Evaluation of Oral Metronomic Topotecan and Pazopanib for the Treatment of Aggressive Extracranial Pediatric Solid Tumors
Keywords: Pediatric cancer
Angiogenesis
Metronomic topotecan
Pazopanib

Low Dose Metronomic (LDM) chemotherapy, combined with VEGF pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, in three pediatric extracranial solid tumors mouse models. We also investigated the effect of prolonged combination therapy with the combination on tumor behavior in a neuroblastoma mouse xenograft model. In-vitro dose-response study of topotecan and pazopanib was conducted on several cell lines. In-vivo antitumor efficacies of drugs, as single agents and combination, were tested in immunodeficient mice models. For studying the mechanisms of resistance to our therapy, a time-response study (28, 56 and 80 days) was conducted in SK-N-BE(2) xenografts model, treated in same way as earlier. In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, the combination of topotecan and pazopanib demonstrated significant anti-tumor activity compared to the respective single agents in all models. Reductions in the levels of viable Circulating Endothelial Progenitors and/or Circulating Endothelial Cells and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. However, the combination also caused significantly higher myelotoxicity than single agents. Pharmacokinetic study did not reveal any interaction between the two co-administered drugs. In the time-response study, we found that only combination treated animals survived till 80 days. However, tumors in these animals started growing gradually after 50 days. Unlike single agents, all three durations of combination treatment significantly lowered tumor microvessel densities, compared to the control. However, tumors treated with the combination for 56 and 80 days had higher pericyte coverage. The combination increased the hypoxia, angiogenic expression and proliferative index and caused metabolic reprogramming of tumor cells. We conclude that the combination of LDM topotecan and pazopanib has superior efficacy than either single agents, which is attributed to superior antiangiogenic activity. However, prolonged treatment with the combination can have additive myelotoxicity and may encounter adaptive resistance associated with metabolic reprogramming and increased proliferation of the tumor cells.
3D Geometric Morphometric Analysis of Hylobatid Cranial Ontogeny: Implications for Interpreting the Evolutionary Hstory of Hominoid Cranial Growth
Keywords: Hominoid
Growth and Development

Research in hominoid cranial ontogeny has provided significant insight into the similarities and differences between apes and humans. Additionally, questions about within-species variability, allometry, and levels of sexual dimorphism in fossil hominoids are commonly addressed using the extant great apes as a comparative framework. However, this model is incomplete without the addition of the lesser apes, gibbons and siamangs. This analysis completes the hominoid record of cranial ontogeny with the addition of the Hylobatidae, and provides a full description of their cranial ontogeny and adult variation. Three-dimensional coordinates of 145 landmarks and 313 semilandmarks were measured on CT and surface scans from an ontogenetic sample of hominoid crania, comprising Pan, Gorilla, Pongo, Hylobates, and Symphalangus, with a cercopithecoid out-group, Colobus. After Procrustes superimposition, principal component analyses were computed in shape space. Regressions of shape coordinates on centroid size were used to assess within-group ontogenetic and static allometric trajectories. Results indicate that the shape changes during ontogeny in gibbons are similar to the shape changes previously reported for great apes. Genus-specific differences are already observable early in ontogeny, and the subsequent ontogenetic trajectories are almost parallel. Sexual dimorphism for both shape and size is found in Symphalangus adults, which was previously unobserved. Analysis of all taxa in the sample shows nearly parallel ontogenetic trajectories within the Hominoidea, which is consistent with previous studies. With the addition of hylobatids and Colobus, this analysis demonstrates that cranial ontogeny is highly conserved in the Catarrhini. Given the existence of this basic catarrhine growth trajectory, it should be possible in the future to predict fossil taxa morphologies at any stage of growth.
China and the United States in Civil-commercial Air and Space: Specialist Cultures and International Relations in High-technology Sectors
Keywords: International Relations
China
United States
outer space
aeronautic policy
space policy

Why are some high-technology sectors trans-nationally integrated while others are sites of interstate competition? This dissertation explores this question through a comparison of China-U.S. relations in two strategic, high-technology sectors: civil-commercial aircraft manufacture and civil-commercial spacecraft manufacture. Between 1989 and 2009, China-U.S. relations took strikingly different trajectories in these two sectors. In the aircraft sector, the two countries&rsquo; industries traded and integrated their activities and their civil agencies cooperated. By contrast, in the space sector, their industries did not trade or integrate, their civil agencies did not cooperate, and the two countries engaged in a form of technological competition. The divergent trajectories taken by China-United States relations in these two sectors are puzzling because both sectors present similar incentives and disincentives for both transnational integration and interstate competition. Theories of international relations do not fully explain this sectoral variation. This research indicates that this variation is traceable to underlying differences in how specialists in each sector, including technical and policy experts, implicitly reason about and represent technologies in general. In both countries, the air and space specialist communities each hold distinct understandings of the relationship between humans and technology. Performing representational practices that reflect these distinct assumptions, aeronautic and space specialists discursively constitute each sector and its technologies as distinct objects of policy, requiring different forms of state action. In air, these include policies adopted by both countries to enhance bilateral trade, industrial partnership, and technical cooperation. In space, these include measures to inhibit bilateral trade and cooperation while preparing for a coming bilateral confrontation.
Diet Projects: A Study of Cardiac Rehabilitation Participants Engaged in Changing Dietary Practices
Keywords: Cardiac Rehabilitation
Diet adherence

Studies have indicated that weight gain, and being overweight, are risk factors for the development of cardiovascular disease. Weight management is particularly intense in cardiac rehabilitation (CR) settings where the majority of participants are medically defined as overweight or obese and often have co-morbid risk factors. CR programs in Canada focus primarily on cardiovascular fitness, but have extended their program interventions to address cardiac risk factor modification, including diet management and weight loss. Health-related research has indicated that on average, CR participants show weight neutrality (no change from baseline weight) upon CR program completion. Prior to this study there was no substantive qualitative data exploring why this occurs. This doctoral study was a concurrent analysis of a larger funded qualitative study that explored the everyday practices of people with heart disease and type 2 diabetes who were participating in one of three large urban CR programs. A total of 33 participants were enrolled in the study (17 men and 16 women). Data was collected through the use of in-depth interviews, an activity journal, and field notes. Data analysis used sociologist Chris Shillings’ work related to body projects and corporeal realism in order to explore themes related to body size, diet management, and weight loss. Study results pointed to the importance of recognizing the role of social practice in health behaviour change, and the role of social discourses in determining how healthy bodies should look and act. Participants described how their social worlds shaped their eating practices, and relayed accounts of attempting to integrate their CR prescription into their daily routines. These findings suggest that a more nuanced approach to CR programming that takes into account the medical and social influences at work on CR participants while they attempt to modify health behaviours, may further inform the development of future CR weight loss and diet programming.
Dana and Dhyana in Jaina Yoga: A Case Study of Preksadhyana and the Terapanth
Keywords: Yoga
Jainism
Jain
Meditation
gift giving
dana
dhyana
Terapanth
Preksha
ecology
social justice
environment

This dissertation examines the role one aspect of the Jaina tradition plays in a globalized world in the 21st century vis-a-vis an economically viable, socially just, and ecologically sustainable society. I address this by means of an in-depth study of dana (giving, gifting, charity) and dhyana (meditation) conducting a case study of preksadhyana, a form of meditation developed by the Terapanth, a Svetambara Jaina sect, in 1975 and their stance on dana. These practices, the Terapanth claim, are transformative on an individual and societal level. I argue that while preksadhyana’s spiritually transformative influence remains narrowly circumscribed to the individual level, nevertheless it allows the Terapanth to participate in the booming economy of the transnational yoga market. Yet, as my analyses of their historically controversial position on dana vis-a-vis the Jaina position on dana and the recent change in this position within the Terapanth reveal, their ability to transform the world is limited to their own community. I explore, through participation/observation, how preksadhyana as a performative ritual brings an individual closer to spiritual liberation, and attempt to demonstrate how the Terapanth construct this practice as a form of modern yoga by using authoritative discourses of science and scripture. I conclude by offering some final iii thoughts on how successful the Terapanth are in their dissemination of preksadhyana to a global audience and what role the authoritative discourses of science and scripture play in the evaluation and/or erosion of Jaina theology.