VictorJuiz/thesis huggingface dataset:
The GAB2/SHP2 Pathway in BCR-ABL1-Induced Hematopoietic Neoplasia

BCR-ABL1 is a gene product of the t(9, 22) chromosomal translocation. It encodes a fusion protein with constitutively activated tyrosine kinase activity and is the direct cause of chronic myeloid leukemia (CML) and a subset of B-lymphoid acute lymphoblastic leukemia (B-ALL). ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of BCR- ABL1+ hematopoietic neoplasia, but CML patients suffer from persistence of leukemic stem cells (LSCs), and B-ALL patients exhibit poorer response at diagnosis compared with CML patients. Over time, such patients succumb to TKI-resistant leukemic clones. Therefore, additional therapeutic targets are needed to cure these malignancies. I assessed the role of the protein-tyrosine phosphatase (PTP) SHP2 in the initiation and/or maintenance of CML and BCR- ABL1+ B-ALL. I found that SHP2 is required for initiation and maintenance of CML, consistent with its essentiality in normal hematopoietic stem cells (HSCs). In BCR-ABL1+ B-ALL, SHP2 is specifically required for the proliferation of BCR-ABL1+, but not WT, B lymphoid progenitors. The SFK and MEK-ERK pathways downstream of SHP2 independently contribute to this differential requirement. I also assessed the role of GAB2 in downstream signaling from BCR- ABL1, and found that its interaction with SHP2 or PI3K activates different signaling pathways, potentially underlying the differential requirement of these interactions for BCR-ABL1-evoked myeloid and lymphoid malignancies. Furthermore, in a parallel set of studies, I developed a mathematical model to simulate the clinical course of high-grade serous ovarian carcinoma, with potential implications for treatment and screening of this disease. This work is described in the Appendix.

Keywords: B-ALL
BCR-ABL1
CML
GAB2
SHP2
Advisor: Neel, Benjamin G
Functional and Molecular Characterization of Hedgehog Signalling Regulation

Hedgehog (Hh) signalling plays a key role in controlling cell fate and patterning of tissues during development and also throughout adulthood for tissue homeostasis. The physiological importance of this pathway is further highlighted when mutations in Hh pathway components lead to developmental disorders and diseases: defects of the limbs, cranial structure or nervous system, and cancer in adults. Although the pathway is highly conserved between flies and humans, important divergences exist between them, including the necessity for Sufu to negatively regulate the Gli transcription factors, thought to mediate all Hedgehog transcriptional outputs. The first study presented in this thesis describes Zfp629, a new transcription factor first identified as a novel interactor of Sufu through a proteomics study. ChIP-seq analysis and validation confirmed that Zfp629 controlled the expression of Foxp2. Also a member of this pathway is Smoothened (Smo), a class F G-protein coupled receptor (GPCR). Several inhibitors have already been introduced to treat Hh-driven cancers such as medulloblastoma and basal cell carcinoma. However, resistance to these inhibitors rapidly develops thereby limiting their efficacy. The determination of SMO crystal structures enables structure-based discovery of new ligands with new chemotypes that will be critical to combat resistance. In the second study of this thesis, we docked 3.2 million available, lead-like molecules against SMO, looking for those with high physical complementarity to its structure; this represents the first such campaign against a class F GPCR. Twenty-one high-ranking compounds were selected for experimental testing, and four, representing three different chemotypes, were identified to antagonize SMO with IC50 values better than 50 μM. A second screen for analogs revealed another six molecules, with IC50 values in the 2.3 μM-22.4 μM range. Importantly, one of the most active of the new Smo antagonists continued to be efficacious against the D473H mutant of SMO, which confers clinical resistance to the antagonist vismodegib in cancer treatment.

Keywords: Hedgehog
Smoothened
Sufu
Advisor: Angers, Stephane
Science and Secularization: English Drama, the Moon, and Theological Cosmologies, 1592-1614

The theological challenges of the cosmological distortions introduced by the “new philosophy” are well-attested in the work of 17th-century poets like John Donne and John Milton. Yet despite a recent religious turn in the study of early modern drama, comparatively little attention has been paid to its theological registering of the Scientific Revolution. “Science and Secularization” examines dramatic articulations of the relationship between theological and cosmological systems at the turn of the 17th-century, a period in which both were developing under the influence of English church politics and new astronomical observations. Prefaced by a brief treatment of Marlowe’s Doctor Faustus (c. 1592), my study focuses on three plays, Shakespeare’s A Midsummer Night’s Dream (c. 1596) and The Tempest (c. 1611), and Webster’s The Duchess of Malfi (c. 1614). These plays are linked by a mutual concern not only with spiritual agents – devils, fairies, and airy spirits – but also with the moon’s traditional role as a cosmological linchpin, the boundary between the Aristotelian spheres of mutability and change, and the most obvious source of astrological influence over the tides and the humours of the body. Yet two of the plays closely follow the publication of Galileo’s Starry Messenger (1610), whose telescopic observations fueled Copernican speculations and presented a vivid new picture of the moon. The sequence of plays provides a historicized view of theological accommodations to this striking scientific development. “Science and Secularization” engages theories of secularization to read the plays. I read the plays’ different understandings of spiritual agents as reflecting processes of “desacralization” and “resacralization,” the shifting locii of supernatural activity in nature and the human body, including the senses and feelings. Yet the plays consider these immanent understanding of supernatural activity within quite distinct providential frameworks that ground their own social and political theories. In both immanent and providential terms, I suggest ways gender works in the plays to resist certain claims of secularization theory. I also suggest that in dramatizing both immanent and providential effects, the plays imagine and enact the theatre’s own shifting role in the theological cosmologies they articulate.

Keywords: Cosmology
Fertility
Galileo
Moon
Secularization
Spirits
Advisor: Harvey, Elizabeth D
Framing the Holy: Revetments on Late Byzantine Icons

This study examines icon revetments produced during the late Byzantine period (1261–1453), situating them within the diversity of mixed-media, multisensory, and multivalent devotional images that combined personal piety with conspicuous consumption and the public spectacle of lavish patronage. These works are evidence of the “ornamental turn”—a paradigm shift marked by the increase of ornament on visual works that mediated wealth, spiritual devotion, and social power. Revetted icons do not make arguments about the faithful representation of prototypes; they make arguments about faithful veneration. Beginning with a historiographic study of ornament, the thesis examines how the ornamental vocabulary on revetments manifests relationships between specific decorated icons. Indices of ornament motifs and a catalogue of surviving icon revetments and frames from the eleventh through fifteenth centuries constitute the appendices. In chapter 2, I argue that the previously unstudied decorated strips added to the icon of the Mother of God Hodegetria in Ohrid were part of a larger project aimed at legitimizing Serbian emperor Stefan Uroš IV Dušan (r. 1331–55) and his archbishop Nicholas in Ohrid. They structured their leadership in the Balkans on their contemporaries in Constantinople. In chapter 3, I present a new reading of the dedicatory prayers inscribed on the icon of the Mother of God in Freising. These texts manifest the icon veneration of wealthy individuals whose gifts of enamel, silver, and gold mediated their desire for divine aid and broadcasted their piety to viewers. Inscriptions on other revetments complement the central holy figures whose gestures direct viewers to names and key sentiments of the inscribed prayer. In chapter 4, I argue that the hitherto unexamined facture of the revetted icon of the Virgin in Fermo was an invention born of the desire for Byzantine imagery in thirteenth-century Italy. It was designed to emulate the materiality and ornamental vocabulary of Byzantine revetted icons. By drawing conclusions about how elite individuals conceptualized the efficacy and materiality of revetments, this dissertation augments the burgeoning discourse on late Byzantine icons. Examining the ornamental turn reveals new insights into how these objects functioned in late Byzantine political, social, and devotional matrices.

Keywords: Byzantium
Decoration and ornament
Holy icons
Late Byzantine
Revetment
Silver
Advisor: Safran, Linda
Caskey, Jill
Queering the Classics: Gender, Genre, and Reception in the Works of Hrotsvit of Gandersheim

This thesis examines how the worldâ s first female dramatist, the tenth-century canoness Hrotsvit of Gandersheim, challenged pedagogical interpretations of gender in her imitations of Roman literature. The dissertation finds that while Hrotsvit imitated the content and form of Ovid, Terence, and Virgil, she denaturalized the binary conceptions of gender promulgated in their works by inverting the specific markers of gender identified in pedagogical texts associated with them and by linking those behavioural markers to imbalances of social power rather than to biology. Studies of the sex/gender system in the early medieval period have tended to focus on medical discourses which attribute gendered behaviour to biology. My doctoral research uses untapped primary sources to prove that gender was not invariably thought to be tied to biology in the medieval cultural imaginary. The commentaries, glosses, and other pedagogical texts on classical literature used in medieval classrooms presented readers with a concrete set of ideas about gender, including highly specific linguistic and behavioural expectations. While scholars have increasingly begun to analyze commentaries on classical literature for insights into medieval gender norms, the majority of this work has focused on the dissemination of ideas about masculinity in male homosocial schools during the twelfth century and beyond. My research contributes to this conversation by asking how early medieval female readers responded to the educational discourses on gender which they encountered in the female-led classrooms of women's religious institutions. The thesis is also innovative in its proposal that Hrotsvitâ s book of saintsâ legends was written in imitation of Ovid. Overall, the dissertation revises current understandings of the sex/gender system in the Ottonian period, demonstrating that ideas which resemble the social construction of gender were circulating centuries earlier than previously thought.

Keywords: classical reception
early Middle Ages
gender in the Middle Ages
Hrotsvit of Gandersheim
medieval genre
sexuality in the Middle Ages
Advisor: Townsend, David
Modeling, estimation, and control of partially observable failing systems using phase method

Recently, due to the advances in data measurement and computer technology, it has become possible to implement effective condition monitoring (CM) systems for critical equipment which increase plant productivity. The objective is to utilize the information obtained from CM for the assessment of the actual condition of the operating equipment without any unwanted interruption. In most applications, the collected CM data involves uncertainty and relates probabilistically to the exact state of the system. Most previous maintenance and reliability models in the literature do not incorporate CM information for decision making or assume that the CM system provide full information about the system true state, which often results in poor failure prediction. This research presents a new framework for predicting failures of a partially observable deteriorating system using Bayesian control techniques. The system can be in one of three-state: healthy state, an unhealthy or deteriorated state, and a failure state. Only the failure state is assumed to be observable. A vector autoregressive model is fitted to the observation process and residuals are then calculated using the fitted model, which are indicative of system deterioration. The state deterioration evolution is modeled using three-state hidden Markov model and hidden semi-Markov model. We develop optimal maintenance policy using multivariate Bayesian control approach for developed models. The posterior probability that the process operates in an unhealthy condition is updated using Bayes' rule at each sampling epoch and used for decision making. When the posterior probability exceeds a control limit, the system is stopped and full inspection is performed which reveals the true system condition. Preventive maintenance is then carried out if the system is in the unhealthy state. The objective is to find the optimal maintenance policy minimizing the long-run expected average cost. We solve the problem in the semi-Markov decision process framework. The model parameters are estimated and explicit formulas for several important quantities for the system residual life estimation are derived as functions of a posterior probability statistic. The methodologies are illustrated using simulated and the real data.

Keywords: Condition Based Maintenance
Expected-Maximization Algorithm
Hidden Markov Model
Hidden Semi-Markov Model
Partially Observable System
Reliability
Advisor: Makis, Viliam
Determinants of Nanomedicine Performance for the Treatment of Solid Tumors: Whole Tumor and Intratumoral Assessment of Liposome Distribution

The treatment and diagnosis of cancer have advanced with the use of novel formulation strategies for the delivery of chemotherapy and contrast agents for imaging applications. Nanoparticles, in particular, have emerged as a viable modality in the management of cancer, enabling a reduction in chemotherapy-associated toxicities. The ability to label and image nanoparticles further enables a longitudinal assessment of their performance in vivo and at the tumor site. Owing to the unique pathophysiology of tumors, an enhanced tumor accumulation of nanoparticles relative to conventional chemotherapeutic agents has long been a hallmark of nanoparticle-based therapy. However, significant challenges hamper the potential of existing nanomedicines and, in particular, the clinical translation of emerging candidates. Namely, poor tumor penetration and bioavailability of drug at the tumor site may limit the potency of nanomedicines. Furthermore, heterogeneity in the intratumoral distribution of nanomedicines, as well as that of tumor characteristics, challenge conventional paradigms and practices in the development of nanoparticle-based technologies. In this work, a stable liposomal contrast agent was developed by virtue of co-encapsulation of contrast agents iohexol (IOX) and Genhanceâ ˘ 680 (GH680) for dual-modality CT imaging and near-infrared fluorescence microscopy, respectively. The demonstrated systemic and tumor-borne stability of the liposomal construct enabled a reliable measure of the fate of the nanoparticles in vivo and at the target tumor site. Further, an image-based methodology was developed for whole-tumor and intratumoral assessment, enabling a multi-scalar assessment of liposome transport in the same animal. Quantification of liposome and microvascular distribution within defined sub-regions of an orthotopic tumor model revealed spatio-temporal heterogeneities, distinct from corresponding measurements at the whole-tumor level. In particular, the rim of the tumor uniquely exhibited maximum and sustained levels of liposome uptake and microvascular structures. Finally, the impact of modulating properties of both nanoparticle and tumor was investigated, revealing the influence of active targeting and mild hyperthermia on the overall tumor deposition of liposomes.

Advisor: Allen, Christine
Jaffray, David A
Investigating Monoamine Regulation: The Transport Of The Dopamine Transporter To Striatal Terminals And The Effects Of Tyrosine Hydroxylase Overexpression On Dopaminergic and Noradrenergic-Related Phenotypes

Monoamines are a class of neurotransmitter responsible for a variety of functions, from the orchestration of movement to the feeling of reward. The maintenance of homeostatic levels of monoamines in the central nervous system is largely regulated by enzymes responsible for their synthesis, by transporters that package transmitters into vesicles and by transporters clear neurotransmitters from the synaptic cleft, terminating neurotransmission. This thesis focuses on two aspects of monoaminergic regulation. The first project centres around the dopamine transporter protein, describing the biochemical features of a transgenic mouse expressing a dopamine transporter with a hemagglutinin tag at its amino terminus. The mouse was developed with the intention of using proteomic techniques to identify proteins that form a complex with the transporter and aid in its expression and functioning. However, we observed that amino-terminal tagged transporters demonstrated a disproportionally weak expression in the striatum as compared to the midbrain, where cell bodies reside, indicating an interruption of the translocation of HA-tagged transporter from the cell bodies to the terminals. The second project involved the development of a novel mouse line overexpressing tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine and noradrenaline. The aim of this study was to determine whether increased production of catecholamines could create conditions of oxidative stress, particularly in those regions most susceptible to neurodegeneration in Parkinson's disease. The transgenic mice were extensively characterized to demonstrate that functional TH was successfully overexpressed. These mice demonstrated behavioural phenotypes consistent with deleterious dopaminergic and noradrenergic abnormalities. Moreover, they possess biochemical features indicative of oxidative stress, suggesting proof-of-principle that poorly regulated production of monoamines - particularly dopamine - could contribute to neurotoxicity in these cells. Together, the aim of these studies was to better understand aspects of monoaminergic systems that maintain proper functioning, and factors that might contribute to a disordered condition.

Keywords: catecholamines
dopamine
dopamine transporter
Parkinson's disease
transgenic mice
tyrosine hydroxylase
Advisor: Salahpour, Ali
Perspectives on Modal Metaphysics

Contemporary modal metaphysics proceeds against an increasingly complex technical and conceptual backdrop. Intuitive hypotheses of modal metaphysics have become controversial, and have been replaced with complicated and contentious theories in many areas of modal-metaphysical theorizing. That is the case, for example, when it comes to recent thinking concerning the structure and logic of essence, and of metaphysical necessity; the nature of lawhood and the modal status of the laws of nature; the metaphysics of transworld identity and of modal representation de re; and the relation between existence, quantification, and modality. I argue in this dissertation that much of the recent methodological trajectory towards complexity in modal metaphysics has its source in a failure, on the part of contemporary theorists, to properly distinguish between contingency and context dependence. Contingency is a matter of how things go relative to worlds of evaluation that are ‘counterfactual’, from the view of our own actual world. By contrast, the context dependence of modal metaphysics involves the sensitivity of modal-metaphysical questions, and their correct answers, to our capacity as theorists to imaginatively shift the possible world of the context. Such imaginative shifting of the world of context involves the consideration ‘as actual’ of possible worlds other than our own, and the hypothetical supposition of perspectives from which modal metaphysics takes on a different character than it actually has. Failure to appreciate the philosophical significance of context dependence is what explains the increasing technical and conceptual intricacy of contemporary modal metaphysics. Conceiving of the analytical tools of modal metaphysics as contextually-relativized, I show how systematic modal theorizing may be brought more evenly in line with the underlying simplicity of its subject-matter.

Advisor: Wilson, Jessica M.
Hellie, Benj
Showing and Telling the Story of Nikis (My Little House): An Arts-Based Autoethnographic Journey of a Cree Adult Educator

As I look back at my childhood, I search for what was there, in order to explore and understand how I experienced the residential school policy of Canada. I use arts based methods as my approach to Cree autoethnography. My memory map, drawings and poems of Nikis (my little house) reveal the life of a Cree family as I revisit the 1960's of the Flats, Churchill, Manitoba, Canada. Lines are drawn and connections illustrate my spiritual journey as Cree adult educator. As I take the story of Nikis to many communities, I find a space for this truth, people are ready to hear these stories. Ultimately, this journey has brought me to my own reconciliation with the past and the residential school policy. What emerges is ethnography of the Flats, which goes beyond my loss of siblings to residential schools. I searched for Skwessis, the girl left behind, but found my wholeness, my history and my understanding of key issues: removal, sexual abuse, and lateral violence, cycles of violence and how these affected my life as a Cree woman. By allowing others to look into my house of the Flats, they can get an inside look into the experiences of a Cree family. My journey as educator is a spiritual journey as I find self-healing and strength in showing and telling the story of Nikis. I offer my life and my lived experience as the context from which to explore the reality of being Cree and to encourage others to speak about their own culture as well.

Keywords: Aboriginal
Arts-based
Colonization
Cree Autoethnograhy
Indigenous
Residential School
Advisor: Restoule, Jean-Paul