VictorJuiz/thesis huggingface dataset:
Discovery of Novel Circulating Biomarkers in Metastatic Castration Resistant Prostate Cancer to Guide Optimal Treatment Decisions

Circulating cell free DNA (cfDNA) is emerging as a key tool to identify treatment resistance in metastatic castration resistant prostate cancer (mCRPC). Numerous studies have reported specific genomic aberrations, including androgen receptor mutations and splice variants, associated with resistance to current androgen targeting agents, enzalutamide and abiraterone acetate. While promising, genomic alterations alone do not account for the disease heterogeneity among mCRPC patients. Indeed, global changes in tumor DNA methylation patterns are a major hallmark of prostate cancer. In this study, cfDNA methylation changes in mCRPC patients receiving androgen targeting agents were explored. Firstly, genome-wide methylome alterations were characterized through sequential collection of blood samples from prior to initiating treatment until clinical progression. Patients that sustained methylation changes throughout therapy tended to exhibit a longer time to clinical progression (TTCP). Upon disease progression, alterations in key oncogenic genes involved in proliferation, development and neuronal pathways were demonstrated. In addition, increased detection of cfDNA methylation markers associated with a highly treatment-resistant form of the disease, neuroendocrine prostate cancer, was associated with a faster TTCP. A targeted panel consisting of these methylated regions was developed using droplet digital PCR and independently confirmed correlation with TTCP. This novel cfDNA biomarker panel could potentially serve as a monitoring tool to track the emergence of aggressive disease and could aid with the clinical management of mCRPC. The functional implications of these methylation changes in neuroendocrine disease were also explored using an established pre-clinical cell-line model of mCRPC. Progressive methylation alterations from the castration-sensitive state to castration resistant and neuroendocrine disease were tracked. These epigenetic modifications were integrated with mRNA expression changes and several key genes associated with oncogenic and developmental/lineage reprogramming pathways were identified. Neuroendocrine-related methylation changes from this model were also found in cfDNA from mCRPC patients and correlated with clinical response. Overall, this study highlighted the potential of monitoring the cfDNA methylome during therapy in mCRPC and further revealed novel therapeutic targets for metastatic prostate cancer.

Keywords: Biomarker
Circulating cell-free DNA
DNA methylation
Epigenetics
Liquid biopsy
Prostate Cancer
Advisor: Bapat, Bharati
Obesity-driven Immunometabolic Activation of Myeloid Cells

Background/Rationale: Obesity is a chronic inflammatory disorder and a strong predictor of tissue insulin resistance and Type 2 Diabetes. Accumulation of pro-inflammatory adipose tissue macrophages (ATM) are culprits to tissue insulin resistance. Tissue infiltration and the subsequent differentiation of Ly6Chigh monocytes largely contribute to ATM accumulation during obesity. Interestingly, Ly6Chigh monocytes are elevated in the circulation and in the bone marrow (BM) during obesity. However, the temporal relation of the obesity-driven increase in ATM and BM Ly6Chigh monocytes are unknown. Furthermore, it is also unknown what obesity-induced changes drive the increased production of Ly6Chigh monocytes in the BM. Moreover, it is unknown how monocytes are affected with obesity and whether the metabolic skewing, as observed in ATM, are also induced in BM monocytes. Hypotheses: I hypothesized, that increased BM Ly6Chigh monocytosis occur prior to ATM accumulation with high fat diet (HFD). Additionally, I hypothesized, that local BM adipocyte (BMA) expansion favour increased Ly6Chigh monocyte development. Lastly, I hypothesized, that a glycolytic shift would be induced in BM monocytes with HFD. Methods: A murine HFD feeding model with the durations of 3, 8 and 18 weeks were adopted. Using flow cytometry analysis, the accumulated ATM and BM monocytes were quantified. Furthermore, in vivo correlative analysis between BMA and monocytes were assessed. In vitro models were adopted to assess the direct influence of adipocytes on monocyte development. Lastly, the metabolic status of monocytes were studied using the Seahorse assay, MitoTrackerTM staining and expression analysis of mitochondrial genes via RT qPCR. Results/conclusion: An earlier elevation of the BM monocytes compared to the ATM were detected with HFD. Furthermore, BMA whitening temporally correlated with Ly6Chigh monocyte expansion in the BM during HFD. White adipocytes and HFD-derived BMA directly favoured Ly6Chigh monocytes, in vitro. Interestingly, white adipocytes induced conversion of Ly6Clow to Ly6Chigh monocytes. We further discovered that Ly6Chigh monocytes prefer glycolytic and Ly6Clow monocytes prefer oxidative metabolism. During HFD, the metabolism of Ly6Clow monocytes are skewed to resemble that of Ly6Chigh monocytes. The findings reported here place the BM as a key site for the origin of cellular and metabolic disruptions with obesity.

Keywords: Bone Marrow Adipocytes
Glycolytic Shift
Immunometabolism
Ly6Chigh Monocytes
Obesity
Tissue Invasive Monocytes
Advisor: Klip, Amira
Girardin, Stephen
In the Image of Industry: Indigeneity and Migrant Labor in the Making of Filipino America

This dissertation presents a cultural and labor history of race in 20th century Filipino America through the political-economic conditions that displaced lowlands peasants and indigenous groups from Northern Luzon in the 19th century. It argues that the constellation of contradictory identities that constitute the “Filipino”—the indigenous “savage” and the industrious migrant worker—across the early 20th century Pacific emerge out of archival productions that decontextualized political economic upheavals, as the island of Luzon became repurposed into a commodity producing colony. Industrial empires, nationalist political elites, rural intellectuals, migrant peasants, and indigenous Cordillerans alike competed over the terms of what the modern “Filipino” would look like as northern resource frontiers produced a global labor force, bringing with it a vibrant transpacific political culture. This dissertation investigates the racial economy of the colonial archive, or the phenomenon of archival production and circulation through which race manifested as ways for empires to manage human resources.

Keywords: Archival Theory
Critical Race Studies
Filipino America
Indigeneity
Labor History
Visual Culture
Advisor: Fujitani, Takashi
Bender, Daniel
What Does it Mean to be a Solution?: Teachers of Colour Doing Social Justice in the Multicultural School in Canada

This project conceptualizes the racialized teacher subject in the multicultural Canadian school in Toronto, Ontario, by examining what it means for the Black, Indigenous and teacher of colour to be positioned to solve inequity and racial injustice in schools. It asks: What does it mean for the racialized teacher to be a solution? To address this overarching question, the project examines the following issues: how racialized teacher subjectivity becomes constituted prior to and while working in the multicultural school; what kinds of expectations the racialized teacher subject navigates; and the systems that function to produce and constrain the racialized teacher’s social justice goals. Because the project is interested in the complexity of the racialized teacher in a white settler state such as Canada, the space of the racially diverse or “multicultural” Toronto area high school was the site of investigation. The core argument presented is that the racialized teacher subject is restricted through liberal and neoliberal discourses, contending with the position of what I term the multicultural helper – an idealized figure who is expected to facilitate the inclusion of the racialized student into the multicultural school. The types of solutions racialized teachers are typically invited to take up are those that model and facilitate depoliticized and culturally acceptable subjectivities for their students. I argue that racialized teachers do not and cannot actually embody social justice; rather they struggle against and negotiate the position of the multicultural helper. Crucially, they unlearn dominant notions of Canadian multiculturalism in the production of a politically conscious subjectivity. I further argue that the liberal expectations inscribed in multicultural helping require racialized teachers to navigate the contradictions between the benefits and harms of the ways they are positioned in schools. I illustrate that spaces and systems within schooling, in particular those outside the direct influence of the racialized teacher, are governed by discourses of control (Nolan, 2011) and discipline (Foucault, 1995), reproducing injustice and limiting the transformative potential of the racialized teacher’s work.

Keywords: Black
Indigenous and teachers of colour
Equity and social justice
Race
Racialized teachers
Teacher Education
Teacher subjectivity
Advisor: Bakan, Abigail
A Compositional History of Ben Sira in the Context of the Transmission of Instruction Literature in the Ancient Mediterranean

The prevailing scholarly opinion is that the Hebrew original of Ben Sira is an irretrievable holy grail or at best very difficult to retrieve. Scholars of Ben Sira are particularly discouraged by the great variation in the extant manuscript traditions in Greek, Hebrew, Syriac, and Latin. Many despair at getting close to a reliable base text in the original Hebrew. The great variability of the manuscript tradition is often given as the implicit and sometimes explicit reason for not doing any redaction-critical studies of Ben Sira. In this dissertation I offer a blueprint for how, in spite of these difficulties, a compositional history of Ben Sira may be approached, and why this is desirable. I will begin by pinpointing the textual categories to which Ben Sira belongs. I shall focus on late biblical literature and the gnomic literature of the ancient Mediterranean in the Hellenistic and Roman periods, and show how the preponderance of evidence suggests and often demonstrates that these works are for the most part the product of multiple authors. In this section I will broadly describe the types of evolutions these texts undergo, focusing on the nature of the material later authors added to earlier versions of the text. Basing my analysis on the likelihood that Ben Sira was the work of multiple authors and on these patterns of textual accretion, I will focus on Ben Sira and show how the manuscript evidence has likely captured different moments in its textual evolution. Next, with the aid of redaction-critical tools and the patterns I have observed, I will extrapolate regarding passages for which there is no manuscript evidence. Finally, on the basis of these findings, I will offer preliminary analyses of the earlier versions of the book, some thoughts on the dates of composition of the versions of this book, and the relevance of this dissertation to the diachronic study of religious texts in general.

Keywords: Ben Sira
Redaction
Wisdom
Advisor: Kloppenborg, John
Newman, Judith
Biowire II Platform: High Fidelity Heart-on-a-chip for Drug Screening and Disease Modeling

Cardiotoxicity is a major cause of drug failure at the late stages of clinical trials and it is linked to unqualified candidates as early as possible is key for reducing the costs of drug discovery and preventing the patient fatality. Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to tissue maturation, cardiac chamber specification and platform versatility can be overcome. The plastic-based platform developed in this thesis, Biowire II, facilitates the scalable, miniaturized 3D tissue cultivation with multiple cell sources in a low absorption environment. The platform deploys two fluorescent, elastic polymer wires to serve as tissue anchors and force sensors, and enables on-line, non-invasive, recording of passive tension, active force, contractile dynamics, Ca2+ transients, endpoint assessments of action potentials and conduction velocity. The conditions of cardiac tissue formation, including cell seeding density, non-myocyte populations and hydrogels, were characterized in detail to ensure the consistent production of functional tissues with hallmarks of adult myocardium. The temporary electrical pacing and long-term electrical conditioning were incorporated and optimized for the platform to facilitate standardized drug testing and chamber-specific cardiac tissue maturation. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. This study is the first to report the engineering of the heteropolar cardiac tissues, which contain well-separated atrial and ventricular ends, and demonstrate their spatially confined responses to serotonin and ranolazine. More importantly, Biowire II platform enabled modeling of polygenic left ventricular hypertrophy with induced pluripotent stem cell derived cardiomyocytes from six different patients, using uniquely designed 8-months-long electrical conditioning protocol. The platform was scaled up into a 96 well-plate format with all the key features, such as plastic culture environment, elastic force sensors and embedded carbon electrodes. An innovative fabrication method was developed to rapidly cast suspended force sensors on top of a patterned surface. This advanced version of platform eliminates adhesives, standardizes and further increases the throughput of tissue production and drug testing.

Keywords: drug testing
heart
maturation
microenvironment
organ-on-a-chip
Tissue engineering
Advisor: Radisic, Milica
“Freeing” the Chinese Migrant: Diasporic Entanglements of Qing and British Universal Empire

This dissertation critically reconstructs the historical emergence of the “free migrant” in China through the encounter of the Qing and British empires across the 18th and 19th centuries. It challenges dominant narratives of the Qing state’s British-guided transition from disdaining Chinese migrants to embracing them as free subjects. Instead, this project traces complex entanglements between the all-encompassing ideologies or “universalisms” of these two imperial powers as they attempted to govern Chinese mobilities in Asia and around the world. While Qing elites did not originally conceive of Chinese circulating overseas as free subjects, I argue that over a long 18th century, the imperial state ultimately chose to enable certain freedoms for migrants within the expanding framework of a centering emperor-focused universalism. In the 19th century, British agents guided by a liberal imperial universalism aggressively sought to “free” Chinese migrants, but chronically subordinated the freedoms of racialized Chinese in the production of freedoms for white liberal subjects. A crisis in human trafficking triggered by British interventions provided an opportunity for British liberal advisors to incorporate and subordinate the Qing within a global order of capitalist nation-states, but also for Qing elites to mobilize liberalism’s terms to contest this subordination. In parallel, jurisdictional contests over the colonial “Anglo-Chinese” in China highlighted the conceptual gap between British legal and liberal subjects, and opened the door for both powers to develop syncretic strategies that appealed to international law. Finally, as Qing thinkers followed diaspora into liberalism’s worlds of racially stratified colonial capitalism, their strategies drew deeper and deeper from its principles, reimagining migrants as political, economic, racial, and ultimately “free” subjects beholden to these regimes. Collectively, this dissertation tells a global history of China, following human and capital flows across a transformative age of mass migration. In doing so it helps us understand not only the emergence of the modern relationship between China and its diaspora, but the broader global order of states and subjects, and the racial inequities built into it.

Keywords: British
China
Diaspora
Empire
Free
Qing
Advisor: Lam, Tong
The Measure of Emotion During an Attention Demanding Task and Mindfulness Biofeedback for Improved Selective Attention

Teenage scholar-athletes are at risk of mental health concerns, including high levels of stress due to the constant demands across academic and athletic domains (Lavallee Wylleman, 2000; Watt Moore, 2001). One must be able to self-regulate to reach optimal levels of attention (Gross, 1998a). Additionally, one must have the ability to deliberately shift into a state of attention for optimal performance in sports and academics (Wilson et al., 2018). Research indicates that practicing mindfulness is beneficial in improved executive functioning, and in well-being (Zanesco et al., 2018, Farb et al. 2015; Kabat‐Zinn, 2003). Biofeedback training is a method of self-regulation of autonomic responses (Moss, 2016). Mindfulness biofeedback (MB) has recently gained attention regarding its benefits (Khazan Moss, 2020). MB improves athletic performance (Perry, 2018); however, the effect of MB on selective attention has yet to be investigated. This study details the effects of MB induction on selective attention scores and psychophysiological changes in electrodermal activity (EDA). Method: 71 high-school scholar- athletes were randomly assigned to play a multiple object (MOT) game with MB (experimental) and without MB (control). EDA recordings of alerting and orienting phases provided an active measure of emotional arousal throughout the MOT phases and a selective attention test was conducted pre and post (Cambridge Brain Science [CBS]). Results: Significant effects of MB were evident through higher selective attention scores. As predicted, EDA decreased during the orienting phase; however, a decrease in EDA variability in the orienting phase of the MOT (Coefficient-of -Variability) had a mediating effect on MB and the CBS test. A 1-month-follow-up survey showed MB was applied by participants to regulate preperformance in sport and academic domains. Conclusion: The experience of (a) conscious awareness (mindfulness) of psychophysiological feedback regulation (Biofeedback-EDA changes) and (b) MB significantly impacted selective attention scores (CBS). The effect of MB on selective attention is mediated by a decrease in the variability of emotional arousal. The study design and results capture the dynamic relationship between cognition and emotion as explained by theory and Gross’ Process Model of Emotion Regulation. Follow-up-questionnaires revealed that students applied MB beyond the experiment in everyday life.

Keywords: Appraisal Theory
Emotion Regulation
Mindfulness Biofeedback
Psychophysiology
Scholar Athletes
Teens
Advisor: Woodruff, Earl
Bayesian causal inference with longitudinal data

Bayesian statistical methods are becoming increasingly in demand in clinical and public health research. In the context of causal inference, Bayesian methods propagate estimation uncertainty, allow direct probability summaries of the causal parameters of interest, and afford us the ability to incorporate prior clinical/expert beliefs. Despite their unique estimation features and wide applicability, Bayesian causal inference methods for handling longitudinal data under observational designs have received little attention in the statistical literature. Under the observational setting, treatment assignment at each clinical visit follows a patient-adaptive decision strategy, where the clinician tailors treatment to the individual patient based on the current and past clinical measurements, as well as the treatment histories. Given the inherent time-dependent structure with longitudinal data, any additional data complexity, such as a repeatedly measured outcome, censoring, and high dimensional time-dependent covariates, brings substantial analytical challenges. In this thesis, two novel Bayesian causal methods to account for time-dependent confounding and time-dependent treatment in longitudinal observational studies are proposed. The first method extends Bayesian propensity score analysis and Bayesian marginal structural models to estimate visit-specific treatment effects with a repeatedly measured outcome. The second method introduces a Bayesian latent class approach to achieve causal inference from a joint model of time-dependent covariates, treatment and an end of study outcome. These proposed methods are compared to existing frequentist causal methods in simulation studies and their use is illustrated using real-world pediatric clinical data.

Keywords: Bayesian estimation
Causal inference
Latent class
Longitudinal data
Marginal structural models
Repeated measurements
Advisor: Pullenayegum, Eleanor M
Characterizing Star Formation Processes in Clumpy Turbulent Disk Galaxies with DYNAMO

The redshift range 1 < z < 3 (referred to as “cosmic noon”) defines a characteristic epoch for the formation of stars and heavy elements in galaxies. Understanding the processes that drive and regulate star formation at this period is essential for linking the earliest phases of galaxy evolution with those observed in the local Universe and remains a key missing component of a comprehensive evolution model for galaxies. The population of systems dominating this era of massive galaxy assembly and disk growth are particularly important in that they are responsible for the majority of stellar mass density in the Universe. However, efforts to directly resolve star formation in z > 1 galaxies are substantially challenged by redshift and resolution effects. This doctoral thesis aims to investigate the mechanisms driving clumpy star formation in turbulent, high-z disks using a subset of galaxies from the DYnamics of Newly-Assembled Massive Objects (DYNAMO) sample. DYNAMO comprises a sample of extremely rare, nearby (z ∼ 0.07 & 0.12) galaxies whose system properties closely resemble those observed in z ∼ 1 − 2 main-sequence galaxies. Using a combination of CO[1-0] NOEMA-PdBI observations and blackbody modeling of infrared Herschel data we assess the molecular gas content and explore the state of the ISM in DYNAMO. Coupling these measurements with resolved kinematics, we test predictions from Toomre instability theory and find the first direct observational evidence indicating the role the internal gas velocity dispersion plays in the formation of massive star forming clumps within galaxies. Using high-resolution imaging from Keck Telescope we discover 32 stellar clumps in 5 DYNAMO targets via KP -band maps of star light and perform robust stellar mass estimates for these clump-like structures. For one galaxy in DYNAMO, G04-1, we present a detailed case study of stellar clumps using multi-filter follow-up observations from Hubble Space Telescope and find evidence of radial gradients in clump mass and color. These findings provide new, crucial insight into the global and resolved star formation properties of z ∼ 1 − 2 galaxies and underscore how advantageous high-z analogue samples are for obtaining the high-resolution imaging and kinematics necessary for a comprehensive study of star formation at cosmic noon.

Keywords: Extragalactic astronomy
Galaxy evolution
Galaxy kinematics
High-z Universe
Interstellar medium
Star formation
Advisor: Abraham, Roberto G