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Common Meanings and Shared Practices of Phase 1 Clinical Trial Enrollment in Patients with Advanced Cancer: A Hermeneutical Phenomenological Study
No full textD.N.S.This dissertation is comprised of three manuscripts, providing the basis for phase 1 clinical trials as a component of care for advanced cancer patients. The first manuscript provides an updated review of the literature regarding phase 1 clinical trial enrollment. The second manuscript describes the concept of decisional conflict as it applies to clinical trial enrollment. The third manuscript provides the dissertation study examining patients with advanced cancer common meaning and shared practices with phase 1 clinical trial enrollment. Interviews with advanced cancer patients were conducted utilizing Heidegger's interpretive phenomenological methods, to obtain an understanding of the meaning of phase 1 clinical trials in the context of their cancer care. Three themes were identified: (1) approaching phase 1 trials as the next step in cancer treatment, (2) accessing phase 1 trials through advocacy, and (3) preserving hope. One linking constitutive pattern, a hopeful maybe: preserving hope through advocacy and positive thinking was identified. Together these describe the experiences of advanced cancer patients. Manuscript three is currently being prepared for submission to an oncology nursing journal.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Investigating the Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates, T Cells and Bispecific Antibodies
No full textPh.D.Antibody-based therapeutics have been in development for treating cancer by increasing specificity and decreasing off-target toxicity. Many therapies, such as antibody-drug conjugates (ADCs), immune cells redirecting bispecific antibodies, and engineered T cells, take advantage of the targeting properties of antibodies to deliver cytotoxic drugs or to harness the power of immune system against cancer. This dissertation focuses on understanding the pharmacokinetics and pharmacodynamics of such therapies. ADCs have small molecule drugs attached to an antibody via chemical or peptide linkers. The idea behind the development of ADCs is that antibodies can be used to target fast internalizing surface receptors in cancer cells and deliver DNA damaging or anti-mitotic agents that lead to cell death. Pharmacokinetics of ADCs is complicated due to the generation of multiple pharmacologically active species in a biological system such as antibody with a different number of payloads attached, shed payload, and naked antibody. All of these species can have different pharmacokinetic behavior due to their size and physicochemical properties.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Data-Driven Railway Track Deterioration Modeling for Predictive Maintenance
No full textPh.D.Railroad track is a very complex system that involves many interactions, and thus, generates many potential areas where a defect can occur. According to the existing literature, defects appearing on the rail track could be either of a geometry or structural type. Track structural defects (which is referred to as rail defects) indicate ill-conditioned structural parameters. Rail defects can grow in size through the regular rail operations and might lead to complete rail breakage when unnoticed. These events are known as service failures. As a practice of responsive track maintenance, when railroads notice a defect with size over the threshold value, they will take the rail segment out of service. However, due to the intrinsic features of a rail segment, as well the complex interactions between the factors related to the environment, traffic, infrastructure, etc. it is still probable for defects to appear later in the same location. Moreover, despite the effective inspection strategies developed by the railroad, service failures occur in rail track network because of the growth of an undetected defect or the defect that is initiated after an inspection...The main objective of this dissertation is to build and evaluate data-driven risk prediction models for occurrences of rail defects and service failures. The developed models will enlighten the effect of different factors affecting track failures. At the same time the provided analytical models can help railroads on predictive maintenance and capital planning decisions. The dissertation consists of five major components.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Towards Better Interpretability of Machine Learning-Based Decision Support Systems
No full textPh.D.Decision support systems are systems designed to support decision making processes. In recent years, researchers have applied machine learning for the purpose of supporting decision making in a wide range of domains. Yet, how to communicate the system recommendations to human decision makers, and how human decision makers would use and trust the machine learning recommendations remained understudied. To solve this problem, we first conducted work analysis to understand how machine learning could be incorporated into a real world decision making task. Then, we developed machine learning models, and integrated the machine learning recommendations to an experimental test bed to support a human-in-the-loop study of how human make decisions with machine learning recommendations. Finally, we did experiment with the test bed to understand how decision makers would use a decision support system with embedded machine learning recommendations, and how that impacts their decision making strategies.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Translational Control Promotes Oxidative Stress Resistance in the Human Fungal Pathogen Cryptococcus neoformans
No full textPh.D.Cryptococcus neoformans is one of the few environmental fungi that can adapt to a mammalian host and cause disease. As free a living organism, C. neoformans is challenged with a variety of environmental insults that threaten its cellular processes. In some cases, these challenges mimic conditions present within mammals resulting in the accidental selection of virulence factors over evolutionary time. Be it within a host or the soil; fungi must contend with environmental challenges through the production of stress effector proteins while maintaining factors that are required for viability in any condition. Although many of the factors responsible for establishing virulence have been recognized, how they are actually expressed in response to certain host-derived cellular stresses is rarely addressed. Earlier work found that many mRNAs encoding ribosomal proteins (RP) are rapidly repressed during cellular stress and that the bulk of this repression is mediated by deadenylation-dependent mRNA decay. We discovered that many of these RP transcripts possessed a motif in their 3’UTRs, GGAUG...The interplay between mRNA translation and decay and its role in pathogenesis in C. neoformans will be outlined in this manuscript.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Implications of Chronic Infection on Skeletal Muscle Immunity, Regeneration, and Function
No full textPh.D.Skeletal muscle function is indispensable for activities critical to an organism's long-term survival such as voluntary movement, posture, and respiration. Given its importance, several mechanisms exist to ensure the maintenance of proper skeletal muscle function despite exposure to a variety of insults from pathogens to mechanical injury. Among these mechanisms include the robust regenerative potential of the tissue and skeletal muscle immunity. Notably, tissue regeneration and immunity are intricately intertwined. The cellular events that coordinate skeletal muscle repair to acute sterile injuries have been well-studied. However, how chronic inflammatory settings – a hallmark of persistent infection and progressive myopathies – interfere with tissue immunity and the regenerative process remains an outstanding question in the field. To address this gap in knowledge, I use the obligate intracellular protozoan parasite, Toxoplasma gondii, to establish a chronic infection in the skeletal muscle. In these studies, I (1) investigate how chronic T.gondii infection remodels the immunologic landscape of skeletal muscle, (2) determine whether changes to skeletal muscle immunity and function due to chronic infection could be therapeutically alleviated and (3) test how chronic infection-induced inflammation affects the regenerative capacity of skeletal muscle. In the first part of these studies, I show that T. gondii infection leads to loss of muscle function accompanied by ongoing muscle damage and persistent Th1 inflammation. Surprisingly, we demonstrate that Tregs – in contrast to their well-established tissue protective role in other inflammatory settings – become pathogenic during chronic infection and facilitate the injurious accumulation of inflammatory macrophages. In the second part of this study, I show that therapeutic administration of IL-10 and amphiregulin during chronic infection can augment the proportion restorative macrophages in the skeletal muscle and improve overall skeletal muscle fitness. Finally, in the third part of these studies, I show the regenerative capacity of skeletal muscle is disrupted during chronic T. gondii infection. Compared to the current paradigm of skeletal muscle repair, my results reveal macrophages responding to injury exhibit vast heterogeneity defined by unique transcriptional states, not confined to traditional "inflammatory" and "restorative" nomenclature. Furthermore, dysfunctions in skeletal muscle repair during chronic infection are associated with the inability of macrophages to progress toward reparative transcriptional states. Collectively, I demonstrate long-term remodeling of skeletal muscle immunity during chronic T.gondii infection leads to reductions in the function and reparative capacity of skeletal muscle. Tissue-immunity must balance the ability to fight infections, heal injuries, and ultimately maintain tissue homeostasis. My findings highlight how chronic inflammation due to infection can continually tip this balance and destabilize the preservation of tissue homeostasis. A greater understanding of the mechanisms underlying how chronic inflammatory conditions, such as persistent infection or progressive myopathies, alter tissue immunity will embolden the development of targeted therapeutics for these diseases.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
"Finding My Own Way": Exploring the Academic Experiences of First-Generation College Students through Stories of Success
No full textPh.D.The purpose of this qualitative interview study is to explore the experiences of first-generation college students (FGCS) through a unique perspective, specifically, through stories of success. While the majority of research surrounding first-generation college students frames their experiences from a deficit perspective, this study highlights the experiences of FGCS who are successful completers of postsecondary education and are now pursuing graduate education in a variety of disciplines. The in-depth interviews of eighteen "successful" FGCS were analyzed to reveal the challenges, opportunities, motivations and successes these students experienced during their time as undergraduates at a very competitive, R1, university. Student narratives reveal their perceptions of how identifying as a FGCS has impacted their academic experience, the factors that helped facilitate their success, and the advice they would give to incoming FGCS. Additionally, tensions emerged as students negotiated their evolving identities as college students, which reveal gender, class and race implications. Findings are framed through three theoretical frameworks: Social Construction, Social Capital and Cultural Capital. Following the discussion of findings, practical implications and advice for first-generation college students, faculty and the University are offered.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Effects of Experimentally Manipulated and Self-Reported Parental Dietary Restriction on Child Intake and Weight Status
No full textM.S.Restricting a child's access to certain foods might increase their consumption of calories and macronutrients, which in turn, might precede the development of overweight (OW) and obesity (OB) during adolescence and adulthood. Understanding possible mechanisms behind dietary restriction, both self-reported parental and experimentally manipulated, could decrease excessive dietary intake and the risk of OW/OB later in life. Purpose: This study aimed to determine the effect of experimentally manipulated dietary restriction on the intake of total calories and macronutrients, as well as the intake of a specific high energy dense (HED) snack food through the use of restriction and non-restriction paradigms. Additionally, this study also aimed to examine the relationship between dietary restriction, child weight status, and parent-reported use of restriction. Methods: 23 children (8-11 y) completed three study visits. During visit one, parents completed online questionnaires designed to determine feeding practices, and children completed relative reinforcing value (RRV) tasks designed to assess their motivation to earn food and activity rewards. During visits two and three, loss of control (LOC) eating was assessed through test meals and subjective surveys. Restriction and non-restriction paradigms were included to experimentally manipulate dietary restriction. Data Analysis: Paired sample t-tests were used to compare the differences between test meal intakes between restriction and non-restriction periods. An independent sample t-test was used to determine the difference between dietary intake in children with overweight compared to children without overweight. An independent sample t-test with a median split was used to determine intakes of children with parents who reported high instances of dietary restriction compared to children with parents who reported low instances of dietary restriction. Results: There were no differences in calorie, percent carbohydrate, percent protein, or percent fat intakes between restriction and non-restriction paradigms. There were also no differences associated with the intake of a child's preferred food between restriction and non-restriction paradigms. Overweight and healthy weight groups showed a trend toward differences in total calorie consumption during the restriction period. High and low restriction group differences were noted for total calorie consumption during the restriction period. Conclusion: This pilot study protocol will be used to inform a future longitudinal study of the effects of dietary restriction on child eating behavior. Therefore, more research needs to be conducted to examine the true relationship between dietary restriction and intake.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Multiscale Modeling of Charge Dynamics in Photoelectrocatalytic Systems
No full textPh.D.The Holy Grail in efficient and cost-effective conversion of solar energy into electrical and chemical energy is solar energy-driven water splitting using semi-conductor-based photo-catalysts. Overall conversion efficiencies of the best systems so far are however far from the level needed for practical applications. Viable materials must exhibit good visible light absorption and carrier generation, good carrier transport, and good redox reactivity. A fundamental understanding of the charge carrier dynamics will inform the extent to which the photocatalytic performance of the material can be improved. While the charge properties in the form of diffusion length, mobility and lifetime can be determined using a wide variety of spectroscopic, time- and frequency-resolved measurements, an atomistic perspective of the fundamental carrier dynamics can unlock a new avenue for performance enhancement that is only possible through computational modeling. This dissertation work focuses on investigating collective behavior of charge carrier transport in photoelectrocatalytic systems intended towards enhancing carrier transport and separation features. We employed multiscale modeling, combining DFT+U calculations of polaron hopping by Marcus/Holstein theory and kinetic Monte Carlo (KMC) modeling of mesoscale transport. We developed a KMC based computational model called PyCD (Python-based Charge Dynamics) to characterize the collective charge dynamics in crystalline systems by modeling the multiscale physics of interaction and carrier dynamics. Employing this modeling framework, we investigated the charge carrier dynamics in stoichiometric bulk BiVO4 (BVO), the most promising anode material to date for solar water splitting: simulations reveal that hole transport is bi-modal and confirm that charge carrier transport in BVO is gated by e- transport. We also conducted mesoscale characterization of charge transport physics in sulfur anion incorporated BVO. We found sulfur atoms substitutes in pairs, and arrange to result in a uniquely anisotropic doping distribution. Electronic scale calculations using DFT revealed a transformation in the nature of hole transport with sulfur incorporation. Mesoscale hole transport calculations showed the hole mobility is increased with sulfur incorporation, which is validated by experimental observations. Anisotropic analysis of charge transport has allowed us to derive synthesis guidelines for facet selectivity in BVO-based photoelectrode designs. We also performed a mesoscale characterization of electron transport in W/Mo-doped BVO. A comprehensive set of electronic scale calculations indicated the existence of shallow interaction regions around W/Mo dopant atoms acting as 'soft-traps' for electron carriers. Yet, the material conductivity is found to be improved with doping contributed by the motile excess electron carriers from dopants. Current efforts are focused towards characterizing charge transport in complex systems such as W/Mo gradient-doped BVO homojunctions towards enhanced charge separation, finite-sized nanocrystals towards facet selectivity.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Hardware for Stress Detection from ECG Signals using Machine Learning
No full textM.S.A Hardware Implementation of feature extraction and a Machine Learning (ML) system to detect stress from an ECG signal is demonstrated in this work. Only time-domain features have been used instead of frequency or time+frequency domain in order to save the on-chip area and power consumption. Several ML classifiers were used to detect stress from the time-domain features, and out of them, Random Forests (RF) algorithm proved to be the best with 96% accuracy. These time-domain features were also demonstrated on an on-chip Reservoir Computer circuit which resulted in an accuracy of 93%. The software simulations involved training and testing on MATLAB and the hardware implementations for feature extractors were done in Verilog. For testing the on-chip RC, MATLAB was used to inject inputs via a DAQ and the outputs of the chip were probed by a logic analyzer.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*