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- Genre: Masters Thesis
- Member of: Theses and Dissertations
Description
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 have been a major threat to survival throughout human history. Humans have developed a behavioral immune system to prevent infection by causing individuals to avoid people, food, and objects that could be contaminated. This current project investigates how ambient temperature affects the activation of this system. Because temperature is positively correlated with the prevalence of many deadly diseases, I predict that temperature moderates the behavioral immune system, such that a disease prime will have a stronger effect in a hot environment compared to a neutral environment and one's avoidant behaviors will be more extreme. Participants were placed in a hot room (M = 85F) or a neutral room (M = 77F) and shown a disease prime slide show or a neutral slide show. Disgust sensitivity and perceived vulnerability surveys were used to measure an increased perceived risk to disease. A taste test between a disgusting food item (gummy bugs) and a neutral food item (gummy animals) measured food avoidance. There was no significant avoidance of the gummy and no significant difference in ratings of disgust sensitivity or perceived vulnerability as a function of temperature conditions. There were no significant interactions between temperature and disease. The conclusion is that this study did not provide evidence that temperature moderates the effect of disease cues on behavior.
ContributorsOsborne, Elizabeth (Author) / Cohen, Adam B. (Thesis advisor) / Kwan, Sau (Committee member) / Neuberg, Steven (Committee member) / Arizona State University (Publisher)
Created2012
Description
Recombinant protein expression is essential to biotechnology and molecular medicine, but facile methods for obtaining significant quantities of folded and functional protein in mammalian cell culture have been lacking. Here I describe a novel 37-nucleotide in vitro selected sequence that promotes unusually high transgene expression in a vaccinia driven cytoplasmic expression system. Vectors carrying this sequence in a monocistronic reporter plasmid produce >1,000-fold more protein than equivalent vectors with conventional vaccinia promoters. Initial mechanistic studies indicate that high protein expression results from dual activity that impacts both transcription and translation. I suggest that this motif represents a powerful new tool in vaccinia-based protein expression and vaccine development technology.
ContributorsFlores, Julia Anne (Author) / Chaput, John C (Thesis advisor) / Jacobs, Bertram (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2012
Description
A study was conducted to assess the effects of generational status on various measures of stigmatization, acculturative stress, and perceived social and interpersonal threat within the Mexican heritage population in the Southwest. The role of the fear of stigma by association, regardless of actual experiences of stigmatization, was investigated, including its relationships with acculturative stress, perceived threat, and social distancing. Exploratory analyses indicated that first generation Mexican Americans differed significantly from second generation Mexican Americans on the perception of Mexican nationals as ingroup members, the fear of stigma by association by Americans, and levels of acculturative stress. Additional analyses indicated that Mexican Americans with one parent born in Mexico and one in the United States held opinions and attitudes most similar to second generation Mexican Americans. Results from path analyses indicated that first-generation Mexican Americans were more likely than second-generation Mexican Americans to both see Mexican nationals as ingroup members and to be afraid of being stigmatized for their perceived association with them. Further, seeing Mexican nationals as in-group members resulted in less social distancing and lower perceived threat, but fear of stigma by association lead to greater perceived threat and greater acculturative stress. Implications for within- and between-group relations and research on stigma by association are discussed.
ContributorsBoyd, Brenna Margaret (Author) / Knight, George P (Thesis advisor) / Kwan, Sau (Committee member) / Neuberg, Steven (Committee member) / Arizona State University (Publisher)
Created2010
Description
Z-DNA binding protein 1 (ZBP1) is an interferon-inducible protein that plays a crucial role in antiviral defense by recognizing Z-form nucleic acid (Z-NA), a left-handed conformer of double-stranded DNA/RNA. When ZBP1 binds to Z-NA, it can trigger programmed cell death pathways, including apoptosis and necroptosis, in collaboration with receptor interacting protein kinases 1 and 3 (RIPK1 and RIPK3). Z-NA positive viruses including poxviruses and influenza A virus (IAV) activate ZBP1-dependent cell death during replication. Little is known whether ZBP1 plays any role during Z-NA negative virus infection. Doxycycline-inducible A549 ACE2 Tet-On cells were constructed to express ZBP1 and were infected with Z-NA negative viruses. ZBP1-expressing cells infected with Sindbis virus (SINV), La Crosse virus (LACV), Vesicular stomatitis virus (VSV) and human coronavirus OC43 (hCoV-OC43) underwent extensive cell death, which could be rescued by a caspase inhibitor but not by JAK1/2 or RIPK1 kinase inhibitors. However, cell death was not observed upon Zika virus (ZIKV), Encephalomyocarditis virus (EMCV), Chikungunya virus (CHKV) or human coronavirus 229E (hCoV-229E) infection. ZBP1 expression did not impact the replication of all tested viruses. In addition, ZBP1-mediated cell death during infection depends on the Zα2 and RHIM1 domains and partially on the C-terminal domain. These findings suggest that Z-NA can be detected by the Zα2 domain to initiate cell death pathways during infection with some Z-NA negative viruses and that the RHIM1/C-terminal domains are necessary for ZBP1-induced cell death. Further research is needed to determine the Z-NA ligand and the precise mechanism of ZBP1-mediated antiviral responses and how they can be exploited for the development of novel antiviral therapies.
ContributorsLa Rosa, Bruno Andres (Author) / Li, Yize (Thesis advisor) / Jacobs, Bertram (Committee member) / Hogue, Brenda (Committee member) / Arizona State University (Publisher)
Created2023
Description
Access to testing for the human immunodeficiency virus (HIV), as well as other care services related to HIV/AIDS, have greatly improved in Tanzania over the last decade. Despite the country’s efforts to increase the number of individuals who get tested for HIV annually, it is estimated that only 52.2-70.0% of people living with HIV (PLWH) knew their HIV positive status at the end of 2017. In addition, research in Tanzania has shown that HIV-related stigma and discrimination are widespread and contribute to low uptake of HIV testing and non-adherence to antiretroviral treatment (ART). In order to achieve the goals set forth by the Government of Tanzania and the Joint United Nations Programme on HIV/AIDS (UNAIDS), as well as move towards an AIDS-free generation, a deeper understanding of the stigma-related barriers to seeking an HIV test is necessary. This research aims to better understand the relationship between HIV-related stigma and attitudes towards HIV testing among community members in Northern Tanzania. In addition, it looked at the specific barriers that contribute to low uptake of HIV testing, as well as the impact of social networks on an individual’s motivation and willingness to get tested for HIV. In this research, community members in Meru District (N = 108, male = 69.4%, female = 28.7%) were surveyed using various validated instruments that covered a range of topics, including knowledge of HIV/AIDS, testing attitudes, and perceived risk of HIV infection. The mean overall score for correct answers on the knowledge measure was 69.8% (SD = 16.4). There were no significant group differences between individuals who had ever tested and individuals who had not tested in relation to HIV/AIDS knowledge or HIV testing attitudes. The factors that were significantly associated with getting an HIV test were knowing someone who had previously tested (p = 0.003), as well as openly discussing HIV testing within one’s social group (p = 0.017). Participants also provided qualitative responses for barriers to receiving an HIV test, motivations for getting tested, and suggested interventions for improving HIV testing uptake. The goal of this research is to develop recommendations for interventions that are better informed by attitudes and motivations for testing.
ContributorsAllen, Megan (Author) / Jacobs, Bertram (Thesis advisor) / Neuberg, Steven (Committee member) / Ellison, Karin (Committee member) / Arizona State University (Publisher)
Created2019
Description
Previous research on experiences of the endowment effect and buyer's remorse has often failed to compare the two seemingly related phenomena. The current study attempts to provide a framework in which the two can be compared and to offer a possible suggestion as to when it may be beneficial to experience either the endowment effect or buyer's remorse, namely situations of resource scarcity versus abundance. The current study employed an online dating paradigm in which resource scarcity was operationalized as the sex ratio of users on the site. Two hundred and one participants were exposed to a favorable sex ratio, an unfavorable sex ratio, or a no information control condition and asked to bid on potential dates. Once matched with a potential date, participants were asked how willing they would be to give up their date and the minimum amount of points they would request to do so. These dependent variables served as indicators of experiences of the endowment effect or buyer's remorse. Results indicated that the sex ratio of the online dating site did not influence experiences of the endowment effect versus buyer's remorse. Potential mediators and moderators were also investigated although no significant effects were found. Possible reasons for the null results are discussed as well as future directions.
ContributorsMeyer, Kaitlin (Author) / Cohen, Adam B. (Thesis advisor) / Kenrick, Douglas (Committee member) / Neuberg, Steven (Committee member) / Arizona State University (Publisher)
Created2014
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
Novel biological strategies for cancer therapy have recently been able to generate improved anti-tumor effects in the clinic. Of these new advancements, oncolytic virotherapy is a promising strategy through a dual mechanism of oncolysis and stimulation of tumor immunogenicity against the target cancer cells. Myxoma virus (MYXV) is an oncolytic poxvirus that has a natural tropism for Leporids, being nonpathogenic in humans and all other known vertebrates. MYXV is able to infect cancer cells due to mutations and defects in many innate signaling pathways, such as those involved in anti-viral responses. While MYXV alone infects and kills many classes of human cancer cells, recombinant techniques allow for the implementation of therapeutic transgenes, which have the potential of ‘arming’ the virus to enhance its potential as an oncolytic virus. The implementation of certain transgenes allows improved cancer cell killing and/or promotion of more robust anti-tumor immune responses. To investigate the potential of immune-inducing transgenes in MYXV, in vitro screening experiments were performed with several single transgene-armed recombinant MYXVs. As recent studies have shown the ability of MYXV to uniquely target malignant human hematopoietic stem cells, the potential of oncolytic MYXV armed with individual immune-enhancing transgenes was investigated through in vitro killing analysis using human acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines. Additionally, in vitro experiments were performed using primary bone marrow (BM) cells obtained from human patients diagnosed with MM. Furthermore, the action of an engineered bispecific killer engager (huBIKE) was investigated through co-culture studies between the CD138 surface marker of target MM cells and the CD16 surface marker of primary effector peripheral blood mononuclear cells (PBMCs), particularly NK cells and neutrophils. In this study, several of the test armed MYXV-infected human AML and MM cell lines resulted in increased cell death compared to unarmed MYXV-infected cells. Additionally, increased killing of CD138+ MM cells from primary human BM samples was observed following infection with huBIKE-armed MYXV relative to infection with unarmed MYXV. Furthermore, analysis of co-culture studies performed suggests enhanced killing of target MM cells via engagement of NK cells with U266 MM cells by huBIKE.
ContributorsMamola, Joseph (Author) / McFadden, Grant (Thesis advisor) / Jacobs, Bertram (Committee member) / Blattman, Joseph (Committee member) / Arizona State University (Publisher)
Created2020
Description
Resource transfers can confer many adaptive benefits such as specialization, helping genetically related individuals, future compensation, and risk-pooling. Need-based transfers are a risk-pooling mechanism in which partners mitigate unpredictable losses by transferring resources based on need. Need-based transfers are likely to be most useful for resources that are necessary and unpredictable because being unable to reliably obtain essential resources would be devastating. However, need-based transfers make people vulnerable to two types of exploitation: a person can be greedy by asking when not in need and a person with a surplus of resources can be stingy by not giving to someone in need. Previous research suggests that people might have cognitive mechanisms for detecting greediness and stinginess, which would serve to protect against exploitation by cheaters. This study investigated whether resources that are necessary and unpredictable are most likely to trigger greediness and stinginess detection mechanisms. Participants saw four types of rules. One rule could be violated through greedy behavior, another through stingy behavior, another by not paying a debt, and another was a descriptive rule that could be violated by not finding one type of resource near another type of resource. Then, participants saw information about events relating to one of the rules and indicated whether the rule in question could have been violated. Consistent with past research, participants were better at detecting greediness, stinginess, and debts not paid than at detecting violations of a descriptive rule. However, contrary to my predictions, the necessity and unpredictability of resources did not impact people’s ability to detect greediness and stinginess. The lack of support for my hypothesis might be because the benefits of detecting greediness and stinginess might outweigh the costs even for situations in which need-based transfer rules are unlikely to apply, because people might be able to consciously activate their greediness and stinginess mechanisms even for resources that would not naturally trigger them, or because of methodological limitations.
ContributorsMunoz Castro, Andres (Author) / Aktipis, Athena (Thesis advisor) / Hruschka, Daniel (Committee member) / Neuberg, Steven (Committee member) / Arizona State University (Publisher)
Created2019