ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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- All Subjects: Biology
- Creators: Maley, Carlo C
- Creators: Robert, Jason
Description
This study aims to unearth monological and monocultural discourses buried under the power of the dominant biomedical model governing the HIV/AIDS debate. The study responds to an apparent consensus, rooted in Western biomedicine and its "standardizations of knowledge," in the production of the current HIV/AIDS discourse, especially in Sub-Saharan Africa. As a result, biomedicine has become the dominant actor (in) writing and rewriting discourse for the masses while marginalizing other forms of medical knowledge. Specifically, in its development, the Western biomedical model has arguably isolated the disease from its human host and the social experiences that facilitate the disease's transmission, placing it in the realm of laboratories and scientific experts and giving full ownership to Western medical discourse. Coupled with Western assumptions about African culture that reproduce a one-sided discourse informing the social construction of HIV/AIDS in Africa, this Western monopoly thus constrained the extent and efficacy of international prevention efforts. In this context, the goal for this study is not to demonize the West and biomedicine in general. Rather, this study seeks an alternative and less monolithic understanding currently absent in scientific discourses of HIV/AIDS that frequently elevates Western biomedicine over indigenous medicine; the Western expert over the local. The study takes into account the local voices of Sub-Saharan Africa and how the system has affected them, this study utilizes a Foucauldian approach to analyze discourse as a way to explore how certain ways of knowledge are formed in relation to power. This study also examines how certain knowlege is maintaned and reinforced within specific discourses.
ContributorsAbdalla, Mohamed (Author) / Jacobs, Bertram (Thesis advisor) / Robert, Jason (Committee member) / Klimek, Barbara (Committee member) / Arizona State University (Publisher)
Created2014
Description
The immune system plays a dual role during neoplastic progression. It can suppress tumor growth by eliminating cancer cells, and also promote neoplastic expansion by either selecting for tumor cells that are fitter to survive in an immunocompetent host or by establishing the right conditions within the tumor microenvironment. First, I present a model to study the dynamics of subclonal evolution of cancer. I model selection through time as an epistatic process. That is, the fitness change in a given cell is not simply additive, but depends on previous mutations. Simulation studies indicate that tumors are composed of myriads of small subclones at the time of diagnosis. Because some of these rare subclones harbor pre-existing treatment-resistant mutations, they present a major challenge to precision medicine. Second, I study the question of self and non-self discrimination by the immune system, which is fundamental in the field in cancer immunology. By performing a quantitative analysis of the biochemical properties of thousands of MHC class I peptides, I find that hydrophobicity of T cell receptors contact residues is a hallmark of immunogenic epitopes. Based on these findings, I further develop a computational model to predict immunogenic epitopes which facilitate the development of T cell vaccines against pathogen and tumor antigens. Lastly, I study the effect of early detection in the context of Ebola. I develope a simple mathematical model calibrated to the transmission dynamics of Ebola virus in West Africa. My findings suggest that a strategy that focuses on early diagnosis of high-risk individuals, caregivers, and health-care workers at the pre-symptomatic stage, when combined with public health measures to improve the speed and efficacy of isolation of infectious individuals, can lead to rapid reductions in Ebola transmission.
ContributorsChowell-Puente, Diego (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Anderson, Karen S (Thesis advisor) / Maley, Carlo C (Committee member) / Wilson Sayres, Melissa A (Committee member) / Blattman, Joseph N (Committee member) / Arizona State University (Publisher)
Created2016
Description
Resistance to existing anti-cancer drugs poses a key challenge in the field of medical oncology, in that it results in the tumor not responding to treatment using the same medications to which it responded previously, leading to treatment failure. Adaptive therapy utilizes evolutionary principles of competitive suppression, leveraging competition between drug resistant and drug sensitive cells, to keep the population of drug resistant cells under control, thereby extending time to progression (TTP), relative to standard treatment using maximum tolerated dose (MTD). Development of adaptive therapy protocols is challenging, as it involves many parameters, and the number of parameters increase exponentially for each additional drug. Furthermore, the drugs could have a cytotoxic (killing cells directly), or a cytostatic (inhibiting cell division) mechanism of action, which could affect treatment outcome in important ways. I have implemented hybrid agent-based computational models to investigate adaptive therapy, using either a single drug (cytotoxic or cytostatic), or two drugs (cytotoxic or cytostatic), simulating three different adaptive therapy protocols for treatment using a single drug (dose modulation, intermittent, dose-skipping), and seven different treatment protocols for treatment using two drugs: three dose modulation (DM) protocols (DM Cocktail Tandem, DM Ping-Pong Alternate Every Cycle, DM Ping-Pong on Progression), and four fixed-dose (FD) protocols (FD Cocktail Intermittent, FD Ping-Pong Intermittent, FD Cocktail Dose-Skipping, FD Ping-Pong Dose-Skipping). The results indicate a Goldilocks level of drug exposure to be optimum, with both too little and too much drug having adverse effects. Adaptive therapy works best under conditions of strong cellular competition, such as high fitness costs, high replacement rates, or high turnover. Clonal competition is an important determinant of treatment outcome, and as such treatment using two drugs leads to more favorable outcome than treatment using a single drug. Switching drugs every treatment cycle (ping-pong) protocols work particularly well, as well as cocktail dose modulation, particularly when it is feasible to have a highly sensitive measurement of tumor burden. In general, overtreating seems to have adverse survival outcome, and triggering a treatment vacation, or stopping treatment sooner when the tumor is shrinking seems to work well.
ContributorsSaha, Kaushik (Author) / Maley, Carlo C (Thesis advisor) / Forrest, Stephanie (Committee member) / Anderson, Karen S (Committee member) / Cisneros, Luis H (Committee member) / Arizona State University (Publisher)
Created2023
Description
Prior to the first successful allogeneic organ transplantation in 1954, virtually every attempt at transplanting organs in humans had resulted in death, and understanding the role of the immune mechanisms that induced graft rejection served as one of the biggest obstacles impeding its success. While the eventual achievement of organ transplantation is touted as one of the most important success stories in modern medicine, there still remains a physiological need for immunosuppression in order to make organ transplantation work. One such solution in the field of experimental regenerative medicine is interspecies blastocyst complementation, a means of growing patient-specific human organs within animals. To address the progression of immune-related constraints on organ transplantation, the first part of this thesis contains a historical analysis tracing early transplant motivations and the events that led to the discoveries broadly related to tolerance, rejection, and compatibility. Despite the advancement of those concepts over time, this early history shows that immunosuppression was one of the earliest limiting barriers to successful organ transplantation, and remains one of the most significant technical challenges. Then, the second part of this thesis determines the extent at which interspecies blastocyst complementation could satisfy modern technical limitations of organ transplantation. Demonstrated in 2010, this process involves using human progenitor cells derived from induced pluripotent stem cells (iPSCs) to manipulate an animal blastocyst genetically modified to lack one or more functional genes responsible for the development of the intended organ. Instead of directly modulating the immune response, the use of iPSCs with interspecies blastocyst complementation could theoretically eliminate the need for immunosuppression entirely based on the establishment of tolerance and elimination of rejection, while also satisfying the logistical demands imposed by the national organ shortage. Although the technology will require some further refinement, it remains a promising solution to eliminate the requirement of immunosuppression after an organ transplant.
ContributorsDarby, Alexis Renee (Author) / Maienschein, Jane (Thesis advisor) / Robert, Jason (Thesis advisor) / Ellison, Karin (Committee member) / Arizona State University (Publisher)
Created2020
Description
This thesis reviews the initial cases of fetal surgery to correct myelomeningocele, a severe form of spina bifida, and discusses the human and social dimensions of the procedure. Myelomeningocele is a fetal anomaly that forms from improper closure of the spinal cord and the tissues that surround it. Physicians perform fetal surgery on a developing fetus, while it is in the womb, to mitigate its impacts. Fetal surgery to correct this condition was first performed experimentally in the mid-1990and as of 2020, it is commonly performed. The initial cases illuminated important human and social dimensions of the technique, including physical risks, psychological dimensions, physician bias, and religious convictions, which affect decision-making concerning this fetal surgery. Enduring questions remain in 2020. The driving question for this thesis is: given those human and social dimensions that surround fetal surgery to correct myelomeningocele, whether and when is the surgery justified? This thesis shows that more research is needed to answer or clarify this question.
ContributorsEllis, Brianna (Author) / Maienschein, Jane (Thesis advisor) / Ellison, Karin (Thesis advisor) / Robert, Jason (Committee member) / Arizona State University (Publisher)
Created2020
Modeling Spatial Competition and Adaptive Therapy Protocols in Three-Dimensional Vascularized Tumors
Description
In contrast to traditional chemotherapy for cancer which fails to address tumor heterogeneity, raises patients’ levels of toxicity, and selects for drug-resistant cells, adaptive therapy applies ideas from cancer ecology in employing low-dose drugs to encourage competition between cancerous cells, reducing toxicity and potentially prolonging disease progression. Despite promising results in some clinical trials, optimizing adaptive therapy routines involves navigating a vast space of combina- torial possibilities, including the number of drugs, drug holiday duration, and drug dosages. Computational models can serve as precursors to efficiently explore this space, narrowing the scope of possibilities for in-vivo and in-vitro experiments which are time-consuming, expensive, and specific to tumor types. Among the existing modeling techniques, agent-based models are particularly suited for studying the spatial inter- actions critical to successful adaptive therapy. In this thesis, I introduce CancerSim, a three-dimensional agent-based model fully implemented in C++ that is designed to simulate tumorigenesis, angiogenesis, drug resistance, and resource competition within a tissue. Additionally, the model is equipped to assess the effectiveness of various adaptive therapy regimens. The thesis provides detailed insights into the biological motivation and calibration of different model parameters. Lastly, I propose a series of research questions and experiments for adaptive therapy that CancerSim can address in the pursuit of advancing cancer treatment strategies.
ContributorsShah, Sanjana Saurin (Author) / Daymude, Joshua J (Thesis advisor) / Forrest, Stephanie (Committee member) / Maley, Carlo C (Committee member) / Arizona State University (Publisher)
Created2023