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The majority of chronic myeloid leukemia (CML) and some of acute lymphocytic leukemia (ALL) cases are associated with possessing the BCR-Abl fusion protein from an oncogenic translocation, resulting in a constantly active form of Abl and rapid proliferation. CML and ALL cells that possess the BCR-Abl fusion protein are known as Philadelphia chromosome positive (Ph+). Currently, Imatinib (selective Abl inhibitor) is used as therapy against CML and ALL. However, some patients may have malignancies which show resistance to Imatinib. Previous work displays that the transformation of progenitor B cells with the v-Abl oncogene of Abelson murine leukemia virus results in cell cycle progression, rapid proliferation, and potentially malignant transformation while preventing any further differentiation. Progenitor B cells transformed with the temperature-sensitive form of the v-Abl oncogene have served as a model to study cellular response to Imatinib treatment. After some manipulation, very few cells were forced to progress to malignancy, forming tumor in vivo. These cells were no long sensitive to v-Abl inactivation, resembling the Imatinib resistant ALL. Autophagy is the process by which proteins and organelles are broken-down and recycled within the eukaryotic cell and has been hypothesized to play a part in cancer cell survival and drug-resistance. LC3 processing is a widely accepted marker of autophagy induction and progression. It has also been shown that Imatinib treatment of Ph+ leukemia can induce autophagy. In this study, we examined the autophagy induction in response to v-Abl inactivation in a Ph+-B-ALL cell model that shows resistance to Imatinib. In particular, we wonder whether the tumor cell line resistant to v-Abl inactivation may acquire a high level of autophagy to become resistant to apoptosis induced by v-Abl inactivation, and thus become addicted to autophagy. Indeed, this tumor cell line displays a high basal levels of LC3 I and II expression, regardless of v-Abl activity. We further demonstrated that inhibition of the autophagy pathway enhances the tumor line's sensitivity to Imatinib, resulting in cell cycle arrest and massive apoptosis. The combination of autophagy and Abl inhibitions may serve as an effective therapy for BCR-Abl positive CML.
ContributorsArkus, Nohea (Author) / Chang, Yung (Thesis advisor) / Kusumi, Kenro (Committee member) / Lake, Douglas (Committee member) / Jacobs, Bertram (Committee member) / Arizona State University (Publisher)
Created2011
Description
Infectious diseases are a leading cause of death worldwide. With the development of drugs, vaccines and antibiotics, it was believed that for the first time in human history diseases would no longer be a major cause of mortality. Newly emerging diseases, re-emerging diseases and the emergence of microorganisms resistant to existing treatment have forced us to re-evaluate our optimistic perspective. In this study, a simple mathematical framework for super-infection is considered in order to explore the transmission dynamics of drug-resistance. Through its theoretical analysis, we identify the conditions necessary for the coexistence between sensitive strains and drug-resistant strains. Farther, in order to investigate the effectiveness of control measures, the model is extended so as to include vaccination and treatment. The impact that these preventive and control measures may have on its disease dynamics is evaluated. Theoretical results being confirmed via numerical simulations. Our theoretical results on two-strain drug-resistance models are applied in the context of Malaria, antimalarial drugs, and the administration of a possible partially effective vaccine. The objective is to develop a monitoring epidemiological framework that help evaluate the impact of antimalarial drugs and partially-effective vaccine in reducing the disease burden at the population level. Optimal control theory is applied in the context of this framework in order to assess the impact of time dependent cost-effective treatment efforts. It is shown that cost-effective combinations of treatment efforts depend on the population size, cost of implementing treatment controls, and the parameters of the model. We use these results to identify optimal control strategies for several scenarios.
ContributorsUrdapilleta, Alicia (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Wang, Xiaohong (Thesis advisor) / Wirkus, Stephen (Committee member) / Camacho, Erika (Committee member) / Arizona State University (Publisher)
Created2011
Description
The concept of vaccination dates back further than Edward Jenner's first vaccine using cowpox pustules to confer immunity against smallpox in 1796. Nevertheless, it was Jenner's success that gave vaccines their name and made vaccinia virus (VACV) of particular interest. More than 200 years later there is still the need to understand vaccination from vaccine design to prediction of vaccine efficacy using mathematical models. Post-exposure vaccination with VACV has been suggested to be effective if administered within four days of smallpox exposure although this has not been definitively studied in humans. The first and second chapters analyze post-exposure prophylaxis of VACV in an animal model using v50ΔB13RMγ, a recombinant VACV expressing murine interferon gamma (IFN-γ) also known as type II IFN. While untreated animals infected with wild type VACV die by 10 days post-infection (dpi), animals treated with v50ΔB13RMγ 1 dpi had decreased morbidity and 100% survival. Despite these differences, the viral load was similar in both groups suggesting that v50ΔB13RMγ acts as an immunoregulator rather than as an antiviral. One of the main characteristics of VACV is its resistance to type I IFN, an effect primarily mediated by the E3L protein, which has a Z-DNA binding domain and a double-stranded RNA (dsRNA) binding domain. In the third chapter a VACV that independently expresses both domains of E3L was engineered and compared to wild type in cells in culture. The dual expression virus was unable to replicate in the JC murine cell line where both domains are needed together for replication. Moreover, phosphorylation of the dsRNA dependent protein kinase (PKR) was observed at late times post-infection which indicates that both domains need to be linked together in order to block the IFN response. Because smallpox has already been eradicated, the utility of mathematical modeling as a tool for predicting disease spread and vaccine efficacy was explored in the last chapter using dengue as a disease model. Current modeling approaches were reviewed and the 2000-2001 dengue outbreak in a Peruvian region was analyzed. This last section highlights the importance of interdisciplinary collaboration and how it benefits research on infectious diseases.
ContributorsHolechek, Susan A (Author) / Jacobs, Bertram L (Thesis advisor) / Castillo-Chavez, Carlos (Committee member) / Frasch, Wayne (Committee member) / Hogue, Brenda (Committee member) / Stout, Valerie (Committee member) / Arizona State University (Publisher)
Created2011
Description
Diseases have been part of human life for generations and evolve within the population, sometimes dying out while other times becoming endemic or the cause of recurrent outbreaks. The long term influence of a disease stems from different dynamics within or between pathogen-host, that have been analyzed and studied by many researchers using mathematical models. Co-infection with different pathogens is common, yet little is known about how infection with one pathogen affects the host's immunological response to another. Moreover, no work has been found in the literature that considers the variability of the host immune health or that examines a disease at the population level and its corresponding interconnectedness with the host immune system. Knowing that the spread of the disease in the population starts at the individual level, this thesis explores how variability in immune system response within an endemic environment affects an individual's vulnerability, and how prone it is to co-infections. Immunology-based models of Malaria and Tuberculosis (TB) are constructed by extending and modifying existing mathematical models in the literature. The two are then combined to give a single nine-variable model of co-infection with Malaria and TB. Because these models are difficult to gain any insight analytically due to the large number of parameters, a phenomenological model of co-infection is proposed with subsystems corresponding to the individual immunology-based model of a single infection. Within this phenomenological model, the variability of the host immune health is also incorporated through three different pathogen response curves using nonlinear bounded Michaelis-Menten functions that describe the level or state of immune system (healthy, moderate and severely compromised). The immunology-based models of Malaria and TB give numerical results that agree with the biological observations. The Malaria--TB co-infection model gives reasonable results and these suggest that the order in which the two diseases are introduced have an impact on the behavior of both. The subsystems of the phenomenological models that correspond to a single infection (either of Malaria or TB) mimic much of the observed behavior of the immunology-based counterpart and can demonstrate different behavior depending on the chosen pathogen response curve. In addition, varying some of the parameters and initial conditions in the phenomenological model yields a range of topologically different mathematical behaviors, which suggests that this behavior may be able to be observed in the immunology-based models as well. The phenomenological models clearly replicate the qualitative behavior of primary and secondary infection as well as co-infection. The mathematical solutions of the models correspond to the fundamental states described by immunologists: virgin state, immune state and tolerance state. The phenomenological model of co-infection also demonstrates a range of parameter values and initial conditions in which the introduction of a second disease causes both diseases to grow without bound even though those same parameters and initial conditions did not yield unbounded growth in the corresponding subsystems. This results applies to all three states of the host immune system. In terms of the immunology-based system, this would suggest the following: there may be parameter values and initial conditions in which a person can clear Malaria or TB (separately) from their system but in which the presence of both can result in the person dying of one of the diseases. Finally, this thesis studies links between epidemiology (population level) and immunology in an effort to assess the impact of pathogen's spread within the population on the immune response of individuals. Models of Malaria and TB are proposed that incorporate the immune system of the host into a mathematical model of an epidemic at the population level.
ContributorsSoho, Edmé L (Author) / Wirkus, Stephen (Thesis advisor) / Castillo-Chavez, Carlos (Thesis advisor) / Chowell-Puente, Gerardo (Committee member) / Arizona State University (Publisher)
Created2011
Analysis of COVID-19 Incident Rate Throughout the U.S. Southwest With Respect to Stay-At-Home Orders
Description
Analyzing Incident Rates of COVID-19 Before and After Stay-At-Home Orders Throughout the Southwestern U.S. with Respect to Limited Mobility Models
ContributorsTilleman, Karl Benson (Author) / Albuquerque, Fabio Suzart de (Thesis director) / Powers, Brian (Committee member) / College of Integrative Sciences and Arts (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Mathematical and analytical approach at the floor and diffuser of a Formula 1 vehicle and how they produce downforce. Reaches a conclusion about how engineers and aerodynamicists creates the desired effects underneath the vehicle to produce substantial downforce.
ContributorsMarcantonio, Nicholas Joseph (Author) / Rajadas, John (Thesis director) / Hillery, Scott (Committee member) / College of Integrative Sciences and Arts (Contributor) / Engineering Programs (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Preeclampsia is a disease that occurs during pregnancy and affects upwards of 10% of pregnancies around the world (Osungbade & Ige, 2011). African American pregnant women are particularly vulnerable and die at a disproportionate rate compared to other races. In this literature review, three research studies were analyzed to determine if African American pregnant women were included in preeclampsia Studies. Only one of the studies included in this review met all criteria by including African American pregnant women. One research study met half of the criteria; however, the authors noted that there was not enough evidence for Black Americans. The third research article also only met half of the criteria. We conclude that further studies are needed that include African American women in studies on preeclampsia.
ContributorsCheeks, Maiya (Author) / Lateef, Dalya (Thesis director) / Briggs, Georgette (Committee member) / College of Integrative Sciences and Arts (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
A research project turned creative project focusing on the narrative of the student's perspective in the Next Generation Service Corps scholarship program. Using survey results from the program members, narratives of their experiences were compiled to offer insight and direction for the growth of the program.<br/><br/>A video of the defense can be found at this link: https://youtu.be/O63NRz0z1Ys
ContributorsJanezic, John Henry (Author) / Hunt, Brett (Thesis director) / Smith, Jacqueline (Committee member) / College of Integrative Sciences and Arts (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
An X class solar flare has the potential to remove our satellites from orbit, permanently deactivate our main forms of communication and bring humanity into a technology-free age. By using Geant4, it is possible to simulate several layers of the Earth's atmosphere and send a simulated solar flare and coronal mass ejection. This thesis will show the interaction of photons and protons of various energies with several kilometers of atmosphere.
ContributorsDolghier, Kristian Adrian (Author) / Shovkovy, Igor (Thesis director) / Steinkamp, Brian (Committee member) / Economics Program in CLAS (Contributor) / College of Integrative Sciences and Arts (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
The Founders lab is a year-long program that gives its students an opportunity to participate in a unique team-based, experiential Barrett honors thesis project to design and apply marketing and sales strategies, as well as business and financial models to start up and launch a new business. This honors thesis project focuses on increasing the rate of vaccination outcomes in a country where people are increasingly busy (less time) and unwilling to get a needle through a new business venture that provides a service that brings vaccinations straight to businesses, making them available for their employees. Through our work with the Founders Lab, our team was able to create this pitch deck.
ContributorsGomez, Isaias Abraham (Co-author) / Hanzlick, Emily (Co-author) / Zatonskiy, Albert (Co-author) / Byrne, Jared (Thesis director) / Hall, Rick (Committee member) / Silverstein, Taylor (Committee member) / College of Integrative Sciences and Arts (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05