VictorJuiz/thesis huggingface dataset:
The Effect of Hyperthermia on Nanomedicine Efficacy
Keywords: drug characterization
drug delivery
drug formulation
hyperthermia
nanomedicine
oncology

Chemotherapy remains a cornerstone of oncology and is used to treat the majority of cancer patients. Hyperthermia is a powerful cancer treatment modality, capable of altering tumor physiology and molecular biology, thereby modifying the distribution and efficacy of chemotherapy drugs. In the last 25 years, nanomedicine chemotherapies have become entrenched within the medical oncology field due to decreased side effects compared to the standard of care. The integration of hyperthermia and nanomedicine chemotherapy has the potential to significantly impact patient outcomes. The goal of this thesis is to combine in vitro cytotoxicity and molecular biology assays with nanomedicine drug development and characterization and in vivo medical imaging in order to optimize the therapeutic efficacy of strategies combining hyperthermia with various nanomedicine chemotherapies. Specifically, the ability of hyperthermia to modulate interstitial fluid pressure and nanomedicine accumulation and distribution is demonstrated using computed tomography imaging and correlated with increased efficacy of Doxil®, the most common clinically administered nanomedicine chemotherapy. Currently undergoing Phase III clinical trials, ThermoDox® is a doxorubicin-containing nanomedicine formulation similar to Doxil, but which undergoes heat-triggered release when exposed to hyperthermic temperatures. Research presented within this thesis builds on the successful development of the ThermoDox technology by substituting the drug encapsulated within. The ability of heat-triggered release to increase the tumor accumulation and efficacy of cisplatin is exhibited in multiple preclinical animal models. The ability of hyperthermia to impair a fundamental DNA damage repair pathway of cancer cells is demonstrated to be a contributing factor. A companion therapeutic to ThermoDox that contains a cytotoxic heat shock protein inhibitor was designed and characterized in vitro and in vivo. The heat shock protein inhibitor was selected due to cytotoxic synergy with doxorubicin and physicochemical similarities that allow for comparable formulation strategies. Both formulations were demonstrated to have similar stability and drug release profiles and deliver drug to the tumor with similar efficiency. The results of these studies demonstrate the positive, multifactorial impact that hyperthermia can exert on nanomedicine chemotherapies.
Imaging Immune Functions Induced by Focused Ultrasound and Microbubble Treatments to Increase Blood-brain Barrier Permeability
Keywords: Alzheimer's disease
blood-brain barrier
neuroimmunology
two-photon imaging
ultrasound

Treatment of neurological diseases is limited by the blood-brain barrier (BBB). The BBB controls the exchange of compounds between the brain parenchyma and systemic circulation. One method to bypass the BBB is to use focused ultrasound (FUS). FUS, used in conjunction with preformed microbubbles (MBs), can transiently enhance BBB permeability by increasing transcellular and paracellular transport across the brain endothelium. While FUS+MB BBB treatments have been shown to be an effective method to deliver agents to the brain, the use FUS+MB BBB alone, without additional therapeutics, have also been observed to result in various downstream effects, including the reduction of β-amyloid (Aβ) plaque load in animal models of Alzheimer’s disease. The characteristics of this induced clearance response have yet to be fully elucidated. In this thesis, the time course of the effects of FUS+MB BBB and induced recruitment of peripheral immune cells are investigated using two-photon fluorescence microscopy. Thermal effects of two-photon fluorescence microscopy were assessed to evaluate whether experimental parameters affected the brain milieu. Brain temperatures were moderately hypothermic following cranial window implantation and increased linearly with laser power during imaging. Temporal characteristics of induced Aβ plaque load clearance were investigated by monitoring the size of Aβ plaques following one FUS+MB BBB treatment in the TgCRND8 mouse model of Alzheimer’s disease. Aβ plaque reduction was observed between 2 to 14 days following treatment, and repeated biweekly treatments significantly reduced plaque load. The efficiency of plaque clearance suggested the involvement of peripheral phagocytic immune cells. Blood flow perturbations were observed immediately before and after the onset of sonication, and motile cells were recruited intravascularly within seconds following increase in BBB permeability. Neutrophils were identified to be one of the participating cell types. FUS+MB treated brain hemispheres harboured significantly more neutrophils compared to the contralateral hemispheres, and to control animals. However, the participation of neutrophils in clearing Aβ plaques may be transient, as neutrophil counts in treated brain tissue were not significantly different from control animals following biweekly FUS+MB treatments. The characteristics of immune functions provided in this thesis further inform understanding of biological responses induced by FUS+MB BBB treatments.
The Costs and Clinical Consequences of Rheumatoid Arthritis: Applying Novel Causal Attribution Methods to a Complex Chronic Disease
Keywords: chronic diseases
computational methods
data driven analysis
mahalanobis distance
rheumatoid arthritis
statistical methods

Rheumatoid arthritis (RA) is a lifelong chronic disease affecting about 300,000 Canadians (1% of the population). The complicated treatment pathways and patterns of care for rheumatoid arthritis combined with a high burden of disease make RA a fascinating candidate for testing new methodological approaches to measure the clinical and economic impact of chronic diseases. The treatment pathway for RA involves patients presenting with potentially non-specific symptoms (fatigue, unspecified joint pain etc.), receiving a diagnosis, then being treated with 1 of 4 conventional synthetic disease modifying anti rheumatic drugs (csDMARDS) or 1 of 10 biologics (bDMARDs). Treatment changes in drug regimens are common when medications fail to control disease activity, or initially control disease activity but eventually fail to control disease activity. The treatment structure is unique because csDMARDS (500-900 CAD/yr), can be prescribed in combination with each other or biologics (15,000-30,000 CAD/yr) which can only be prescribed 1 biologic at a time, resulting in thousands of potentially unique treatment pathways. Furthermore, the clinical paradigm of RA has shifted to target inflammation reduction to reduce the direct effects of RA and the systemic inflammatory effects of the disease through adequate control with medications. This unique clinical pathway has led to several important questions. These questions centre around what the true costs and comorbidities attributable to RA are, what proportion of costs and comorbidities are attributable to RA related inflammation, and how have the introduction of biologic medications affected costs and comorbidities over time. This thesis applies causal attribution methods that have not been used in the field of RA, while also utilizing best-practice methods in longitudinal study1-4 design by carefully considering the selection of matched case-control cohorts over time. We used all available follow-up and disease history and available covariates to implement a data-driven approach to case-control matching. Using the population of Ontario RA cases, we applied these methods to determine the associated attribution RA to the acquisition of health care costs and comorbid conditions over a 22-year time horizon.
Modeling, Designing and Evaluating Fully Dilutable Self Microemulsifying Delivery System for Hydrophobic Pharmaceuticals and Nutraceuticals
Keywords: Drug Delivery system
Microemulsion
Nanoencapsulation
Nutraceuticals
SMEDDS

Many newly discovered drugs and nutraceuticals are hydrophobic in nature. When these drugs and nutraceuticals are ingested, their low aqueous solubility limits their ability to dissolve in intestinal fluid and eventually permeate the intestinal membrane to become bioavailable. To overcome this limitation, various delivery systems have been developed to enhance the solubility and absorption of active ingredients. Lipid-based delivery systems (LBDS) such as microemulsions (μE) and self-microemulsifying delivery systems (SMEDS) are among the most advanced systems. However, there are multiple technological challenges in the design and applications of SMEDS. Using lecithin as the main surfactant and hydrophilic and lipophilic linkers as co-surfactants, a platform was developed to produce food-grade, fully dilutable microemulsions containing hydrophobic solutes. The in vitro and in vivo experiments showed a high solubilization capacity for hydrophobic solutes. For ibuprofen, used as a model solute a significant improvement in absorption and bioavailability was observed. The results also showed a shorter absorption time and a longer drug circulation time when ibuprofen was formulated in fully dilutable system. The main tool used to design the fully dilutable SMEDS was the hydrophilic-Lipophilic –Difference (HLD) framework. HLS was used to predict the phase inversion point of surfactant-oil-water (SOW) systems as a function of formulation composition. The HLS was further coupled with Net-Average0Curveture (NAC) model to predict the minimum surfactant required to produce fully dilutable systems. The same tool was also used to characterize the effect of the solute on the formulation and design reformulation strategies to maintain the fully dilutable path. To explore the potential for controlled release with SMEDS, the idea of integrating the concepts of SMEDS and organogels was explored. This novel self-dispersing organogel provides 1-4 days release, which is a substantial improvement over the improved release obtained with SMEDS alone.
The Threat of Small Things: Patterns of Repression and Mobilization against Micro-sized Groups in Indonesia
Keywords: Ethnic Conflict
Indonesia
Qualitative Methods
Religious Conflict
Southeast Asia
Symbolic Politics

Why do very small groups become targets of mobilization and repression? Given their economic and political insignificance, most theories of ethnic and religious conflict expect groups that are less than 1 percent of the population—what I call micro-sized groups—to be ignored. Yet, micro-sized groups like the Jehovah’s Witnesses in Eastern Europe and the Baha’i in Iran have been targets of high levels of state repression and collective mobilization. I argue that the threat of micro-sized groups is linked to fears about group boundaries in flux. When micro-sized groups challenge the institutions, routines, and practices that form the foundations of group belonging through the marking of public space (“visible constitutive threat”), it is seen as a danger to the larger group’s continued existence. Micro-sized groups thus become seen as a perceived threat to the larger ethnic, religious, or national group when: 1) they present a visible constitutive threat; and 2) political entrepreneurs are incentivized to amplify these visible constitutive threats for their own interests. Using archival data, a geo-coded events dataset, and over 135 interviews collected over 17 months of fieldwork, I develop my argument through a study of the Ahmadiyah sect in Indonesia. I show that Ahmadis were a constitutive threat to Muslims in Indonesia because their practices challenged those that allowed a diverse people to belong to a single category. However, Ahmadis were only seen as threatening when these constitutive challenges were publicly visible. When electoral reforms increased the relevance of local clientelist networks, political entrepreneurs were incentivized to exploit and amplify the Ahmadiyah threat. Rates of anti-Ahmadiyah activity consequently multiplied. By identifying why and how micro-sized groups come to be seen as threats, my work challenges longstanding assumptions about the necessary material dimensions of threat. It instead suggests that threat construction and perception is not just driven by concerns around access to resources, but is shaped by a group’s public visibility. Broadly, understanding how visible constitutive threats operate can shed light on political phenomena that appear to be costly, inefficient, and irrational. Finally, my work speaks to the burgeoning literature linking clientelism to conflict.
Performing Invisible Labour: The Globalization of Care in Aesthetic and Everyday Practice
Keywords: affective labour
gender
migration
performance studies
social reproduction
transnational domestic workers

This thesis examines how labour associated with the reproductive sphere—labour historically consigned to women and continually undervalued yet needed to sustain and reproduce daily life—is politicized or made visible through aesthetic and social practices. Tracing the transformation of reproductive work from an unpaid and unrecognized duty shouldered by housewives to a feminized, racialized, and globalized form of waged labour performed by migrant women, I explore the entanglements between labour, gender, migration, and performance in the context of post-Fordist, neoliberal, advanced capitalism. Through close analysis of artistic production, political struggles, commercial interests, market forces, and urban practices that reveal distinct ways of rendering the private public, I show how domestic labour has changed in site, character, and value, and argue that current efforts to theorize, analyze, and valorize such work must respond to shifting divisions of labour and changing social relations of value production. This project begins with social feminist and artistic efforts to visibilize and politicize women’s hidden labour at key moments in the development of global capitalism. It is followed by close readings of gendered labour and durational performance in narrative films that query cinema’s capacity to render visible the otherwise invisible labour of women through its explorations in extended duration and everyday spaces. Next, I explore the affective performances of transnational domestic workers captured in audition videos by online employment agencies. I argue that mobility for these migrant women is dependent on their performances of servility, and that the circulation of these videos on YouTube reproduces the ‘foreign maid’ as a global commodity. I then turn to Filipina domestic workers occupying public spaces in Hong Kong. Considering their increased visibility, their community-building efforts, and their growing awareness of the social and economic value of their labour, I explore the possibilities of transnational domestic labour as a site from which political subjectivities might be constituted. These various case studies, while operating along different aesthetic categories, social registers, and geopolitical contexts, are key sources of analysis for understanding social reproduction and provide distinct perspectives from which to theorize care work, its value and meaning, in the twenty-first century.
Rights to Settle? —Comparing Migrant Care Worker Policies in Taiwan and South Korea
Keywords: Care Migration
East Asia
Eldercare
Migrant Care Workers
Migration Policy
Welfare State

Industrialized countries around the world are facing rapid demographic changes, including declining fertility rates, greater longevity, and an aging population, and these are creating unprecedented challenges in care provision. Many East Asian countries have used migrant care workers to solve the challenges of labour shortages in the social welfare sector. The purpose of this dissertation is to understand why East Asian countries have adopted different policy approaches to recruit migrant care workers. Specifically, it investigates why Taiwan’s policies are designed to recruit “household care workers with a temporary contract” while South Korea’s policies focus on “institutional care workers with access to long-term settlement”? The dissertation explores this question by probing the politics of eldercare and care migration and tracing the development of migrant care worker policies. By employing a framework that intersects care, employment and migration regimes, it highlights the institutional contexts that shape how a country designs its migrant care worker policies. It argues that migrant care worker policies manifest how care work, citizenship, and gender equality are defined and contested by the receiving society. It also demonstrates how the development of migrant care worker policies reflects the legacies of earlier policy decisions, by illuminating the political actors with access to the policymaking process. Based on archival research and 53 personal interviews with government bureaucrats, policymakers and migrant worker activists, the dissertation maps out the political mechanisms that determine the levels of rights, labour mobility, and access to membership rights for migrant care workers in Taiwan and South Korea. It challenges conventional understandings of policy as formal and static and posits the formation of migrant care worker policy as an organic process which is modified and contested as part of a political process.
Homelessness and the Commons: A Theory of Expressively Egalitarian Regulation
Keywords: Homelessness
Law
Legal theory
Poverty law
Public property

This doctoral thesis examines homelessness and the regulation of public property from the perspective of the republican theory of freedom (or republicanism). Republicanism construes freedom as non-domination, meaning the absence of others’ power to interfere with an individual’s actions and purposes. Expressive egalitarianism is a political ideal whereby the state expresses equal respect for individuals. This doctoral thesis advances A Theory of Expressively Egalitarian Regulation. Its central claim is that republicanism provides new insight into the reality of homelessness and how the regulation of public property undermines homeless people’s liberty in ways that existing theories ignore. Republicanism also serves as the foundation for a theory of how laws that govern public property in Canada and the U.S. can operate in a more expressively egalitarian manner, by mitigating domination and treating homeless people with greater respect. This project culminates with concrete proposals that aim to eliminate the most egregious forms of domination that homeless people experience from those laws. A Theory of Expressively Egalitarian Regulation elucidates why laws that govern public property subject homeless people to two distinct forms of domination. First, others can exert control over homeless people’s opportunities to obey laws that regulate public property. Second, homeless people must make non-egalitarian sacrifices to their basic interests to obey laws that manage public property. A core tenet of A Theory of Expressively Egalitarian Regulation is that the justifications for regulating public property result in two fundamental problems for homeless people that are elucidated by the republican theory of freedom: the non-egalitarianism and entrenchment problems. The non-egalitarianism problem implies that the state has a greater capacity to regulate and police homeless people’s basic human acts (e.g.: urinating, defecating, sitting, sleeping, etc.), whereas people with access to housing are meaningfully protected against such regulation and its enforcement. The entrenchment problem implies that the state possesses the power to entrench people in the condition of homelessness, where individuals will continue to be subject to domination that stems from the non-egalitarianism problem. Certain practical limitations (both constitutional and political), however, currently stand in the way of eliminating the domination to which homeless people are subject exclusively through the allocation of resources and entitlements by the state. For that reason, it is necessary to consider how laws that govern public property can subject homeless people to less domination and express greater respect for homeless people. This thesis concludes by offering concrete proposals for how the state can strive to achieve those aims.
Impacts of Perinatal High Fat Diet and Prenatal Stress Exposure on the Programming of the Hypothalamic-Pituitary-Adrenal Axis and Anxiety-like Behaviour in Rats
Keywords: Behaviour
Epigenetics
HPA Axis
Maternal Programming
Obesity
Stress

The maternal environment has a profound effect on the development of offspring, including responses to stress mediated by the hypothalamic-pituitary-adrenal (HPA) axis. Maternal diet and stress are two environmental factors that program the HPA axis in a manner that persists throughout adulthood, however there are no reports of their joint effect on the development of the HPA axis and anxiety-like behaviour. The objective of this thesis was to examine the effects of maternal obesity in the form of high fat diet (HFD) consumption and maternal stress in the form of exposure to chronic variable stress (CVS) on stress-related behavioural, endocrine, and molecular measures in neonatal and adult offspring in rats. I hypothesized that combined effects perinatal HFD and prenatal CVS would have synergistic effects on programming of stress-related phenotypes. I observed strong main effects of perinatal HFD on offspring anxiety-like behaviours and HPA axis physiological responses. Interestingly, CVS normalized the effects of perinatal HFD on anxiety-like behaviour in adult female offspring and physiological stress response in neonate offspring. I also characterized maternal physiological and behavioural responses to HFD consumption and CVS exposure and found increased sensitivity to CVS in HFD dams. Further, examining the interaction between the dam and neonatal offspring using maternal behaviour and pup ultrasonic vocalization (USVs) characteristics, I found impaired pup retrieval in HFD dams and altered USV characteristics in HFD neonates. Finally, due to the main effects of perinatal HFD on behavioural and physiological phenotype, I examined differential effects of maternal HFD consumption on offspring gene expression and the epigenome in brain regions that regulate the HPA axis. I observed increased Crh expression in the PVN and decreased Nr3c1 expression in the ventral hippocampus in neonates along with differential methylation of genes involved in neuronal development in the amygdala. In adulthood, HFD induced differential DNA methylation in genes involved in protein phosphorylation, specifically GTPase related genes. Findings in this thesis provides several avenues for future studies in both mother and offspring, including possible intervention studies targeting dam-pup interaction and molecular mechanism underlying the programming effects of perinatal HFD in offspring.