VictorJuiz/thesis huggingface dataset:
Molecular Characterization of the Spectrum of Peripheral Nerve Sheath Tumors
Keywords: genetics
malignant peripheral nerve tumors
molecular characterization
peripheral nerve tumors
sarcoma

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and the most lethal form of cancer in the context of neurofibromatosis type 1. The current standard of care includes surgery plus radiation, with no effective chemo or targeted therapeutic options. Here we examined the genomic and epigenomic drivers of MPNSTs, analyzing 108 tumors spanning the full spectrum of peripheral nerve sheath tumors, using a multiplatform integrated approach to identify drivers of MPNST. We established through multiple unsupervised analyses of methylome and transcriptome profiles that there exist two distinct pathways of malignant transformation leading to MPNSTs, one through SHH pathway activation (MPNST-G1) and the other through WNT pathway activation (MPNST-G2). We discovered distinct copy number aberration, mutational profiles, and targetable oncogenic programs that define each sub-group. Further, single nuclear RNA sequencing characterizes the complex cellular architecture that defines each subgroup, with MPNST-G1 and MPNST-G2 resembling neural crest-like and Schwann cell precursor-like cells, respectively. Additionally, in-vitro and in-vivo models confirm that inhibition of the SHH pathway can prevent growth and malignant progression of MPNSTs, proving sonidegib to be novel therapeutic option in these lethal cancers.
“Thinking Outside the Box”: A Snapshot of Child and Adolescent Therapists’ Early Experiences Adapting Services to the COVID-19 Context
Keywords: children
COVID
technology
telehealth
therapy
youth

COVID-19 has had numerous impacts on the general population, including increased physical health risks, social isolation, and prolonged uncertainty (Gruber et al., 2020). Some have argued these impacts disproportionately affect younger populations (Powell et al., 2020). Within Canada, there has been a sharp uprise in children/youth accessing the Kids Help Phone over the past 18 months (Watson, 2020), underscoring the importance of continued access to mental health supports for this population. Child/youth practitioners have faced the arduous task of transitioning their services online, which may be uniquely challenging to accomplish with younger clients. This study employed a mixed-methods concurrent embedded design to explore the experiences of 36 child/youth therapists in Ontario as they have navigated this new professional landscape. An interpretative phenomenological analysis revealed both negative and positive impacts of COVID-19. Therapists reported feelings of reduced self-efficacy, difficulties engaging with and interpreting nonverbal communication using virtual mediums, technological challenges, and personal challenges relative to balancing work/home commitments as primary challenges. Younger clients appeared most significantly impacted due to developmental challenges inherent in online engagement. In response, therapists described creatively adapting their services, relying on team members or others for support and/or consultation, and various self-care strategies. Positively, many therapists felt youth were benefitting from the increased accessibility of virtual services. Despite the challenges identified, a repeated-measures MANOVA revealed no significant changes to therapist self-reported state empathy levels when reflecting on challenging clinical interactions prior to and since the onset of COVID-19. Implications for future research and clinical practice are discussed.
Homeostatic Control of Nuclear-encoded Mitochondrial Gene Expression by the Histone Variant H2A.Z is Essential for Neuronal Survival
Keywords: Cerebellum
Epigenetics
Histone
Mitochondria
Neurodegeneration

Histone variants are crucial regulators of chromatin structure and gene transcription, yet their functions within the brain remain largely unexplored. Here we show that the H2A histone variant H2A.Z is essential for neuronal survival. Mice lacking H2A.Z in GABAergic neurons or Purkinje cells (PCs) present with a progressive cerebellar ataxia accompanied by widespread degeneration of PCs. Ablation of H2A.Z in other neuronal subtypes also triggers cell death. H2A.Z binds to the promoters of key nuclear-encoded mitochondrial genes to regulate their expression and promote organelle function. Bolstering mitochondrial activity genetically or by organelle transplant enhances the survival of H2A.Z-ablated neurons. Changes in bioenergetic status alter H2A.Z occupancy at the promoters of nuclear-encoded mitochondrial genes, an adaptive response essential for cell survival. Our results highlight that H2A.Z fulfills a key, conserved role in neuronal survival by acting as a transcriptional rheostat to regulate the expression of genes critical to mitochondrial function.
The Molecular Determinants of Response to Immune Checkpoint Therapy in Solid Tumors
Keywords: Biomarkers
Cancer Genomics
Cancer Immunology
Immunotherapy
Precision Medicine
Tumor microenvironment

Immune checkpoint therapy (ICT) has demonstrated lasting clinical benefit unparalleled by other cancer treatments in a small percentage of patients. Thus, optimizing patient selection, monitoring emerging resistance, and understanding resistance pathways remain significant challenges for improving ICT efficacy and personalization. In the absence of appropriate preclinical models of cancer immunity, clinical trials supported by next generation sequencing and data-driven experimental designs have enabled simultaneous characterization of cancer cells, their immune contexts, and microenvironment to support biomarker evaluation and discovery. This dissertation describes the design and implementation of a centralized biospecimens processing and immunogenomic data workflow for the phase II basket trial of pembrolizumab ICT in metastatic solid tumors (INSPIRE; NCT02644369), followed by the in-depth integrated analysis of the sequencing and clinical data to identify molecular features associated with therapeutic efficacy. In chapter 2, we reported the technical feasibility of conducting DNA and RNA sequencing and immune monitoring assays on serial blood and tumor samples for biomarker evaluation. In chapter 3, we used personalized mutation panels designed from matched patient normal-tumor exomes to quantify changes in circulating tumor DNA (ctDNA) burden during treatment. We showed that ctDNA increases within 6 weeks of treatment initiation were associated with disease progression across all tumor types. ctDNA dynamics also paralleled target lesion changes suggesting its potential as a sensitive and minimally invasive method to detect therapeutic resistance in patients undergoing ICT. Building on this new molecular response framework, in chapter 4, we integrated ctDNA and target lesion dynamics to stratify patients into distinct prognostic groups for correlative analysis of tumor exomes and transcriptomes. This tumor-agnostic approach enabled us to elucidate pharmacodynamic effects of pembrolizumab by comparing matched baseline and on-treatment tumor tissues and to identify biomarker candidates and correlates of therapeutic response.
Queering and Trans-gressing Care: Towards a Queer Ethic of Care in QTBIPOC Education
Keywords: care work
colonialism
gender and sexuality education
race
teacher education

This research details the findings from three interviews with QTBIPOC educators in Ontario. Using qualitative interviews and art-based responses, teachers in this study theorized about a queer ethic of care while offering their best practices to illustrate how they move from theory to pedagogy when working with QTBIPOC youth. This research asked the following questions: How do QTBIPOC educators understand and practice a queer ethic of care? Two findings emerged from this study: (1) a queer ethic of care is nuanced and expansive, disruptive and transgressive and an individualized practice that takes place within a care web and (2) care as it exists in schools right now, is inherently white, colonial and violent and has forced QTBIPOC educators to imagine new forms of care practices. These disruptive practices include creating (1) authentic, fluid, mutually vulnerable relationships with students (2) explicitly anticolonial, antiracist moments in their teaching and interactions with students and (3) affirmation and recognition as moments of healing. Collectively, these disruptive and transgressive practices create space for mutual healing for both queer and trans racialized students and teachers and paves the way for queer futurity and thriving. The findings from this study indicate a few things: educators must continually reimagine and disrupt their knowledge of care and care practices that are built upon white, colonial, cisheteronormative assumptions; educators must engage in anticolonial and antiracist care practices that are trans-gressive to the understandings of care in schools; teachers must learn how to create care webs in community with their students in ways that are vulnerable, authentic and fluid; a queer ethic of care is possible to implement at the grassroots, individual level first, but must move towards systemic practices in order to be sustainable and effective for QTBIPOC students in the long term; and a queer ethic of care offers a way for QTBIPOC teachers and students to feel recognition, affirmation and mutually heal by imagining new futures through thriving, joyful care.
Identifying Vulnerabilities for Diversion of Controlled Substances to Inform The Safeguards Needed in Canadian Hospitals to Protect Patients and Healthcare Workers
Keywords: Controlled Substances
Diversion
Health system safety
Hospitals

Introduction: Diversion or theft of controlled substances (CS) is a recognized problem affecting healthcare systems globally. Diversion from hospitals can occur through falsifying orders, tampering with medications, and pilfering stock. The impacts of diversion are serious, causing severe harm to patients, healthcare workers, hospitals, and the public. Selecting effective interventions for safeguarding against diversion cannot occur without first having a thorough understanding of how the hospital system is susceptible to diversion. Aims: To establish a detailed understanding of how hospital medication-use processes are vulnerable to CS diversion, characterize the vulnerabilities, and develop a framework to conceptualize how system factors set the stage or shape processes for diversion to take place. Study Design/Approach: Guided by the System’s Engineering Initiative for Patient Safety (SEIPS) Human Factors model, I used a multimethod study design comprised of observations that informed a Healthcare Failure Mode and Effect Analysis (HFMEA) to identify critical failure modes (CFMs) in two Ontario hospitals in the inpatient pharmacy (Study 1), emergency department (ED) (Study 2), and intensive care unit (ICU) (Study 3). The prospective analysis was followed by a framework analysis to build a conceptual framework for diversion. Results: Study 1 demonstrated that CFMs provide detailed descriptions of vulnerabilities which exist in every medication-use process involving CS. Studies 2 and 3 built on these finding and showed that all CFMs stemmed in part from person-related factors (e.g., intentional actions to falsify documentation), but were always also precipitated by technology-, organization-, environment-, or task-related deficits in how healthcare systems are designed and organized. I developed a novel framework based on findings from Studies 1-3 to conceptualize the relationship between system factors and how they interact and coalesce to enable pilfering and/or forgery which leads to diversion-related harms. Conclusion: My thesis findings further our understanding of diversion as a systems issue, whereby vulnerabilities stem from failures not only by individual actions, but in the interaction between processes, technologies, environments, and organization factors. My framework can be used to inform broader efforts to develop guidelines and technological solutions for Canadian hospitals.
U-Pb Dating of Fossils and Hydrogenic Minerals: Toward Practical Paleontological Chronometry
Keywords: Geochronology
LA-ICPMS
U-Pb Dating

This thesis studied the feasibility of using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) for U-Pb dating of fossil and pedogenic carbonates. New LA-ICPMS data using improved processing methods provide early diagenetic U-Pb ages of fossils and constrain the mechanisms of trace element mobility during late-diagenesis. The first accurate U-Pb age on fossilized soft tissue, yields an age of 3.16 ± 0.08 Ma consistent with its late Pliocene stratigraphy while coexisting shark teeth are variably reset by late-diagenesis. A study of late diagenetic overprinting in dentine versus enamel of another shark tooth within a phosphorite allows both early and late-diagenetic ages to be extracted and challenges the current syn-sedimentary model of phosphorite formation. Apatite fossils such as conodonts and brachiopods show high Th/U ratios combined with evidence of significant excess 206Pb. This requires large (>104) Th enrichment factors during diagenesis. In a study of calcite invertebrate fossils, the apical line of belemnites was found to be enriched in U, allowing dating of belemnites for the first time while dating of rugose corals agreed with previous isotope dilution results. This shows that LA-ICPMS U-Pb dating can be effective on samples with <1 ppm U. Pedogenic carbonate nodules from an early-Triassic conglomerate unit in the Karoo Basin, South Africa have been successfully dated to precisions of (±1-2 Ma). The maximum depositional age determined from the nodules is consistent with the early-Triassic stratigraphic age. Carbon isotopes in nodules can be used as proxies for atmospheric CO2 content so more precise dating by ID-TIMS combined with C isotope analysis may reveal a detailed record of CO2 increase associated with mass extinction. The possibility of dating early hominid cave settlements using vertebrate fossils was explored. Fossil tortoise shells show high U contents and are thus free from biases that could affect currently used speleothem ages. However, they show restricted ranges of U/Pb and are less radiogenic than speleothem data, limiting age precision to about ±1 Ma by LA-ICPMS. Age errors could be improved by measuring more precise data using ID-TIMS and by application to a wider variety of fossils within caves.
Hybrid Nonlinear Control Systems: Stability, Optimality, Dissipativity, and Spacecraft Applications
Keywords: Galerkin/Collocation-based Approximation
Hybrid Dynamical Systems
Hybrid Nonlinear Optimal Control
Hybrid Nonlinear Passivity-based Control
Spacecraft Attitude Regulation utilizing Magnetic and Impulsive Actuation
Spacecraft Formation Flying using Lorentz Force and Impulsive Thrusting

Hybrid dynamical systems, as an emerging discipline within dynamical systems theory and control, can be defined an interacting collection of dynamical systems involving a mixture of continuous-time and discrete-time dynamics. Exhibiting continuous evolution and instantaneous changes on appropriate manifolds, hybrid dynamical systems consist mainly of three elements: a continuous-time set of differential equations, which characterizes the motion of the dynamical system between discrete-time events; a discrete-time set of difference equations, which governs discontinuous changes in the system state; and a criterion to determine when discrete-time dynamics are to be applied.Stability, optimality, and dissipativity of hybrid nonlinear time-dependent dynamical systems are considered in this thesis. Control design frameworks of optimal and passivity-based characters are accordingly developed for hybrid nonlinear dynamical systems involving an interacting amalgam of continuous-time and discrete-time dynamics whose dynamical properties evolve periodically over time. The overall framework, in fact, provides a solid foundation for extending hybrid linear control to nonlinear control synthesis. To this end, a hybrid version of the underlying mathematical formulation characterizing optimality and dissipativity for hybrid nonlinear time-dependent dynamical systems is first presented. A hybrid computational framework, which alternates between continuous-time and discrete-time subsystems at an appropriate sequence of time instants, is subsequently developed to solve the resultant set of equations in an interacting manner. The outcome is therefore a hybrid nonlinear time-varying control law which combines a continuous-time control input with impulsive control inputs in accordance with a resetting criterion. Practical considerations for implementing the proposed control design frameworks are subsequently discussed in detail. The proposed control design schemes are ultimately utilized to synthesize hybrid controllers of a nonlinear nature for two real-world spacecraft applications: spacecraft attitude regulation with a hybrid source of magnetic and impulsive actuation, and spacecraft formation flying under the actions of the Lorentz force and impulsive thrusting.
An Adjoint Approach to Aerodynamic Shape Optimization for Unsteady Flows with Application to Laminar and Transonic Turbulent Flows
Keywords: Adjoint
Aerodynamics
Flows
Laminar
Optimization
Unsteady

An adjoint approach to aerodynamic shape optimization has been developed, implemented, applied, and investigated for several deterministic unsteady flow problems. The optimization framework integrates a robust geometry parameterization and geometry control strategy, a mesh-movement technique based on linear elasticity theory, and a high-fidelity parallel Newton-Krylov flow algorithm to evaluate the forward problem needed to compute the optimization objective function. A gradient-based algorithm is used to solve the optimization problems, and the objective gradients are computed using the discrete adjoint methodology. The aerodynamic shape optimization framework is applied to a range of unsteady flow problems. For the two-dimensional optimization problems, three objectives based on the mean aerodynamic quantities were considered: a lift-constrained drag minimization, lift-to-drag ratio maximization, and lift maximization. For the drag minimization and lift-to-drag ratio maximization problems, the optimizer improved the performance of the baseline airfoil primarily by keeping the flow on the upper surface attached as long as possible and introduced an aft-camber to maintain or increase the lift coefficient. This novel aft-camber feature is consistent with results seen in the literature for ultra-low Reynolds number flows. A first attempt at studying the multi-modality of optimization problems driven by unsteady flows indicated that the lift-maximization problem is likely to be multimodal, while the other design objectives are likely to be unimodal. For the three-dimensional laminar flow studies, a mean drag minimization at a fixed mean coefficient of lift was considered. The optimizer exploited the section shape, chord length, and twist geometric freedoms given to improve the design objective, and introduced a significant aft-camber throughout the sections similar to the two-dimensional studies. Finally, a first attempt at optimizing aerodynamic shapes in the presence of transonic buffet was undertaken using the unsteady Reynolds-averaged Navier-Stokes equations. The mean coefficient of drag was minimized at a fixed mean lift coefficient using the NASA Common Research Model wing-only geometry. These preliminary optimization results showed that the optimization framework is capable of solving such a design problem, thus enabling such an optimization framework to include buffet conditions considered in a multi-point optimization of wings and aircraft under transonic flow conditions.
Rhodium-catalyzed Asymmetric Addition/Aldol Cascades and Studies towards the Synthesis of Aconitine
Keywords: Aconitine
Asymmetric Catalysis
Epoxides
Total Synthesis

Asymmetric synthesis is a powerful tool often used in the synthesis of natural products and pharmaceutical compounds. The rhodium-catalyzed asymmetric conjugate addition is one of the most robust reactions widely employed for this purpose. We sought to harness the reactivity of the rhodium enolate intermediate generated through this process for the synthesis of stereochemically complex (hetero)cyclic scaffolds. Chapter 1 of this thesis details a rhodium-catalyzed asymmetric conjugate alkynylation/aldol cascade to generate densely functionalized chiral cyclic α-propargyl-β-hydroxyketones bearing three new contiguous stereocenters. The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations. Chapter 2 expands upon our previous findings and describes a rhodium-catalyzed asymmetric conjugate addition/aldol/spirocyclization cascade to generate enantioenriched spiro-oxiranes. Starting from a linear substrate, the cascade enabled the formation of a spirocyclic framework in a single step. Chapter 3 reviewed reported total syntheses of C19-diterpenoid alkaloids. Chapter 4 describes the preliminary studies towards the synthesis of the C19-diterpenoid alkaloid aconitine, proposing the use of a pinacol reaction, a Mannich reaction, and aldol reactions as key steps. Routes to access the A-, C- and D-ring fragments were developed, and the fragments were successfully coupled. The next steps require the formation of the C-ring via an intramolecular aldol reaction.
Development of a Generic Emergency Department Discrete Event Simulation Model
Keywords: discrete event simulation
generic simulation
industrial engineering
operations research
simulation modelling

Emergency Departments’ (EDs') critical role in patient care and their complex process flow contribute to them being one of the most frequently modelled systems in healthcare Operations Research (OR). The goal of this research was to develop a simulation model flexible enough to be applicable to any ED, that could be easily applied to diagnose bottlenecks and evaluate performance improvement approaches. We used Discrete Event Simulation (DES) to create a single input-driven generic model and validated it against limited de-identified datasets belonging to nine sites in Canada, U.S.A, and U.K. in such metrics as length of stay and key wait times (e.g., time to initial assessment). The validation results indicate performance on par with existing site-specific DES designs. We gain additional insights into the effects of resource and process duration changes on model performance and conclude that the model is slightly more sensitive to resource amounts than to granular process durations. The key benefit of the model is its flexibility and the speed with which it can be implemented at any hospital in need of a DES study. The model can be used to evaluate performance and preview the effects of staffing and flow changes before committing to the improvement measures.