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Description
Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) is a rare and highly aggressive ovarian cancer that affects children and young women at a mean age of 24 years. Most SCCOHT patients are diagnosed at an advanced stage and do not respond to chemotherapy. As a result, more than 75% of patients succumb to their disease within 1-2 years. To provide insights into the biological, diagnostic, and therapeutic vulnerabilities of this deadly cancer, a comprehensive characterization of 22 SCCOHT cases and 2 SCCOHT cell lines using microarray and next-generation sequencing technologies was performed. Following histological examination, tumor DNA and RNA were extracted and used for array comparative genomic hybridization and gene expression microarray analyses. In agreement with previous reports, SCCOHT presented consistently diploid profiles with few copy number aberrations. Gene expression analysis showed SCCOHT tumors have a unique gene expression profile unlike that of most common epithelial ovarian carcinomas. Dysregulated cell cycle control, DNA repair, DNA damage-response, nucleosome assembly, neurogenesis and nervous system development were all characteristic of SCCOHT tumors. Sequencing of DNA from SCCOHT patients and cell lines revealed germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 79% (19/24) of SCCOHT patients in addition to SMARCA4 protein loss in 84% (16/19) of SCCOHT tumors, but in only 0.4% (2/485) of other primary ovarian tumors. Ongoing studies are now focusing on identifying treatments for SCCOHT based on therapeutic vulnerabilities conferred by ubiquitous inactivating mutations in SMARCA4 in addition to gene and protein expression data. Our characterization of the molecular landscape of SCCOHT and the breakthrough identification of inactivating SMARCA4 mutations in almost all cases of SCCOHT offers the first significant insight into the molecular pathogenesis of this disease. The loss of SMARCA4 protein is a highly sensitive and specific marker of the disease, highlighting its potential role as a diagnostic marker, and offers the opportunity for genetic testing of family members at risk. Outstanding questions remain about the role of SMARCA4 loss in the biology, histogenesis, diagnosis, and treatment of SCCOHT.
ContributorsRamos, Pilar (Author) / Anderson, Karen (Thesis advisor) / Trent, Jeffrey (Committee member) / Kusumi, Kenro (Committee member) / Lake, Douglas (Committee member) / Arizona State University (Publisher)
Created2014
Description
Vaccination remains one of the most effective means for preventing infectious diseases. During viral infection, activated CD8 T cells differentiate into cytotoxic effector cells that directly kill infected cells and produce anti-viral cytokines. Further T cell differentiation results in a population of memory CD8 T cells that have the ability to self-renew and rapidly proliferate into effector cells during secondary infections. However during persistent viral infection, T cell differentiation is disrupted due to sustained antigen stimulation resulting in a loss of T cell effector function. Despite the development of vaccines for a wide range of viral diseases, efficacious vaccines for persistent viral infections have been challenging to design. Immunization against virus T cell epitopes has been proposed as an alternative vaccination strategy for persistent viral infections, such as HIV. However, vaccines that selectively engage T cell responses can result in inappropriate immune responses that increase, rather than prevent, disease. Quantitative models of virus infection and immune response were used to investigate how virus and immune system variables influence pathogenic versus protective T cell responses generated during persistent viral infection. It was determined that an intermediate precursor frequency of virus-specific memory CD8 T cells prior to LCMV infection resulted in maximum T cell mediated pathology. Increased pathology was independent of antigen sensitivity or the diversity of TCR in the CD8 T cell response, but was dependent on CD8 T cell production of TNF and the magnitude of initial virus exposure. The threshold for exhaustion of responding CD8 T cells ultimately influences the precursor frequency that causes enhanced disease.In addition, viral infection can occur in the context of co-infection by heterologous pathogens that modulate immune responses and/or disease. Co-infection of two unrelated viruses in their natural host, Ectromelia virus (ECTV) and Lymphocytic Choriomeningitis virus (LCMV) infection in mice, were studied. ECTV infection can be a lethal infection in mice due in part to the blockade of antiviral cytokines, including Type I Interferons (IFN-I). It was determined that ECTV/LCMV co-infection results in decreased ECTV viral load and amelioration of ECTV-induced disease, presumably due to IFN-I induction by LCMV. However, immune responses to LCMV in ECTV co-infected mice were also lower compared to mice infected with LCMV alone and biased toward effector-memory cell generation. Thus, providing evidence for bi-directional effects of viral co-infection that modulate disease and immunity. Together the results suggest heterogeneity in T cell responses during vaccination with viral vectors may be in part due to heterologous virus infection or vaccine usage and that TNF-blockade may be useful for minimizing pathology while maintaining protection during virus infection. Lastly, quantitative mathematical models of virus and T cell immunity can be useful to generate predictions regarding which molecular and cellular pathways mediate T cell protection versus pathology.
ContributorsMcAfee, Megan (Author) / Blattman, Joseph N (Thesis advisor) / Anderson, Karen (Committee member) / Jacobs, Bertram (Committee member) / Hogue, Brenda (Committee member) / Arizona State University (Publisher)
Created2015
Description
Osteosarcoma is the most common bone cancer in children and adolescents. Patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T-lymphocytes (CTL) limit the development of metastatic osteosarcoma. I have investigated the role of Programmed Death Receptor-1 (PD-1) in limiting the efficacy of immune mediated control of metastatic osteosarcoma. I show that human metastatic, but not primary, osteosarcoma tumors express the ligand for PD-1 (PD-L1) and that tumor infiltrating CTL express PD-1, suggesting this pathway may limit CTL control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor infiltrating CTL during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTL in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. My results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy. However, PD-1/PD-L1 blockade treated mice still succumb to disease due to selection of PD-L1 mAb resistant tumor cells via up-regulation of other co-inhibitory T cell receptors. Combinational α-CTLA-4 and α-PD-L1 blockade treated mice were able to completely eradicate metastatic osteosarcoma, and generate immunity to disease. These results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma, although improves survival, may lead to tumor resistance, requiring combinational immunotherapies to combat and eradicate disease.
ContributorsLussier, Danielle (Author) / Blattman, Joseph N. (Thesis advisor) / Anderson, Karen (Committee member) / Goldstein, Elliott (Committee member) / Lake, Douglas (Committee member) / Arizona State University (Publisher)
Created2015
Description
V(D)J recombination is responsible for generating an enormous repertoire of immunoglobulins and T cell receptors, therefore it is a centerpiece to the formation of the adaptive immune system. The V(D)J recombination process proceeds through two steps, site-specific cleavage at RSS (Recombination Signal Sequence) site mediated by the RAG recombinase (RAG1/2) and the subsequent imprecise resolution of the DNA ends, which is carried out by the ubiquitous non-homologous end joining pathway (NHEJ). The V(D)J recombination reaction is obliged to be tightly controlled under all circumstances, as it involves generations of DNA double strand breaks, which are considered the most dangerous lesion to a cell. Multifaceted regulatory mechanisms have been evolved to create great diversity of the antigen receptor repertoire while ensuring genome stability. The RAG-mediated cleavage reaction is stringently regulated at both the pre-cleavage stage and the post-cleavage stage. Specifically, RAG1/2 first forms a pre-cleavage complex assembled at the boarder of RSS and coding flank, which ensures the appropriate DNA targeting. Subsequently, this complex initiates site-specific cleavage, generating two types of double stranded DNA breaks, hairpin-ended coding ends (HP-CEs) and blunt signal ends (SEs). After the cleavage, RAG1/2 proteins bind and retain the recombination ends to form post-cleavage complexes (PCC), which collaborates with the NHEJ machinery for appropriate transfer of recombination ends to NHEJ for proper end resolution. However, little is known about the molecular basis of this collaboration, partly attributed to the lack of sensitive assays to reveal the interaction of PCC with HP-CEs. Here, for the first time, by using two complementary fluorescence-based techniques, fluorescence anisotropy and fluorescence resonance energy transfer (FRET), I managed to monitor the RAG1/2-catalyzed cleavage reaction in real time, from the pre-cleavage to the post-cleavage stages. By examining the dynamic fluorescence changes during the RAG-mediated cleavage reactions, and by manipulating the reaction conditions, I was able to characterize some fundamental properties of RAG-DNA interactions before and after cleavage. Firstly, Mg2+, known as a physiological cofactor at the excision step, also promotes the HP-CEs retention in the RAG complex after cleavage. Secondly, the structure of pre-cleavage complex may affect the subsequent collaborations with NHEJ for end resolution. Thirdly, the non-core region of RAG2 may have differential influences on the PCC retention of HP-CEs and SEs. Furthermore, I also provide the first evidence of RAG1-mediated regulation of RAG2. Our study provides important insights into the multilayered regulatory mechanisms, in modulating recombination events in developing lymphocytes and paves the way for possible development of detection and diagnotic markers for defective recombination events that are often associated immunodeficiency and/or lymphoid malignancy.
ContributorsWang, Guannan (Author) / Chang, Yung (Thesis advisor) / Levitus, Marcia (Committee member) / Misra, Rajeev (Committee member) / Anderson, Karen (Committee member) / Arizona State University (Publisher)
Created2012
Description
Aside from uplifting and tearing down the mood of a young LGBTQ+ kid, journalistic media has the potential to alter the way audiences understand and react to individuals of the LGBTQ+ community. Looking at the rhetorical approaches, frameworks, and expanded narratives of news sources, this project engages with the concepts of same-sex marriage, lifestyles, bans, and children in education in order to attain an understanding of what media messages are being shared, how they are being communicated, and what the implications of such rhetoric are. Summary of the findings:
• Same-sex marriage as the win that cannot be repeated.
Infamously known as the central legal battle for the LGBTQ+ community, same-sex marriage finds itself in many political speeches, campaigns, and social commentaries. Interestingly, after being legalized through a Supreme Court decision in the United States, Same-Sex Marriage finds itself framed as the social inevitability that should not be repeated in politics or any legal shift. In other words, “the gays have won this battle, but not the war.”
• There are risks around the “LGBTQ+ lifestyle” and its careful catering to an elite minority and the mediation through bans.
The risks of the LGBTQ+ “lifestyle” date back far, with many connotations being attached to being LGBTQ+ (AIDS epidemics, etc.). In modern journalism, many media outlets portray LGBTQ+ individuals to be a tiny minority (.001% according to some) that demands the whole society to adhere to their requests. This framework portrays the LGBTQ+ community as oppressors and obsessed advocates that can never “seem to get enough” (ex: more than just marriage). The bans are framed as the neutralizing factor to the catering.
• LGBTQ+ children and topics in academic and social spaces are the extreme degree.
When it comes to LGBTQ+ issues and conversations as they revolve around children, media outlets have some of the most passionate opinions about them. Often portrayed as “the line that shouldn’t be crossed,” LGBTQ+ issues, as they find themselves in schools and other spaces, are thus portrayed as bearable to a certain degree, never completely. Claims of indoctrination are also presented prominently even when institutional efforts are to protect LGBTQ+ kids.
• Same-sex marriage as the win that cannot be repeated.
Infamously known as the central legal battle for the LGBTQ+ community, same-sex marriage finds itself in many political speeches, campaigns, and social commentaries. Interestingly, after being legalized through a Supreme Court decision in the United States, Same-Sex Marriage finds itself framed as the social inevitability that should not be repeated in politics or any legal shift. In other words, “the gays have won this battle, but not the war.”
• There are risks around the “LGBTQ+ lifestyle” and its careful catering to an elite minority and the mediation through bans.
The risks of the LGBTQ+ “lifestyle” date back far, with many connotations being attached to being LGBTQ+ (AIDS epidemics, etc.). In modern journalism, many media outlets portray LGBTQ+ individuals to be a tiny minority (.001% according to some) that demands the whole society to adhere to their requests. This framework portrays the LGBTQ+ community as oppressors and obsessed advocates that can never “seem to get enough” (ex: more than just marriage). The bans are framed as the neutralizing factor to the catering.
• LGBTQ+ children and topics in academic and social spaces are the extreme degree.
When it comes to LGBTQ+ issues and conversations as they revolve around children, media outlets have some of the most passionate opinions about them. Often portrayed as “the line that shouldn’t be crossed,” LGBTQ+ issues, as they find themselves in schools and other spaces, are thus portrayed as bearable to a certain degree, never completely. Claims of indoctrination are also presented prominently even when institutional efforts are to protect LGBTQ+ kids.
ContributorsNieto Calderon, Ramon Antonio (Author) / Himberg, Julia (Thesis director) / Sturges, Robert (Committee member) / Department of English (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Waltz, is a collection of poems written to play along the boundaries between sound, language, and meaning. As a vehicle for exploration, the poems in Waltz, commandeer themes of nostalgia, love, loss, and abstraction, all of which build up and break each other down to create something of a nonlinear narrative, and concomitant sketch of the poet.
ContributorsAieta, Joseph (Author) / Ball, Sally (Thesis director) / Liston, Chelsea (Committee member) / Department of English (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The primary purpose of this thesis is two-fold: (1) to understand the resources presently available for Native American college student leaders at Predominantly White institutions (PWIs), and; (2) to consider ways to develop their leadership abilities and knowledge of how experience with college leadership contributes to becoming successful leaders with/in their Indigenous communities. The secondary purpose of this thesis is to propose additional resources for PWIs that can inform Native American leadership practices across academic disciplines and fields through the creation of the Indigenous & Innovative Leadership course syllabus and conference. This Honor's Thesis Project begins by exploring leadership development opportunities for Native American undergraduate students at Arizona State University, a predominantly White institution. Also explored are conceptions of Indigenous leadership as it applies to engagement in or with on-campus student organizations, tribal governments, and within surrounding Indigenous communities. This project has implications for thinking about American Indian student success beyond graduation and the role leadership and organization development has for the success of tribal communities.
ContributorsTom, Megan Joyce (Author) / Brayboy, Bryan (Thesis director) / Solyom, Jessica (Committee member) / Department of English (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Genocide studies have traditionally focused on the perpetrator’s intent to eradicate a particular identity-based group, using the Holocaust as their model and point of comparison. Although some aspects of the Holocaust were undoubtedly unique, recent scholars have sought to challenge the notion that it was a singular phenomenon. Instead, they draw attention to a recurring pattern of genocidal events throughout history by shifting the focus from intent to structure. One particular branch of scholars seeks to connect the ideology and tactics of imperialism with certain genocidal events. These anti-imperialist genocide scholars concede that their model cannot account for all genocides, but still claim that it creates meaningful connections between genocides committed by Western colonialist powers and those that have occurred in a neoimperialist world order shaped according to Western interests. The latter includes genocides in postcolonial states, which these scholars believe were shaped by the scars of their colonial past, as well as genocides in which imperial hegemons assisted local perpetrators. Imperialist and former colonial powers have contributed meaningfully to all of these kinds of genocides, yet their contributions have largely been ignored due to their own influence on the creation of the current international order. Incorporating the anti-imperialist perspective into the core doctrine of genocide studies may lead to breakthroughs in areas of related policy and practice, such as prevention and accountability.
ContributorsParker, Ashleigh Mae (Author) / Thies, Cameron (Thesis director) / Sivak, Henry (Committee member) / School of Politics and Global Studies (Contributor) / School of Social Transformation (Contributor) / Department of English (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
There has been a recent push for queer fiction, especially in the young adult genre, whose focus is gay and lesbian relationships. This growth is much needed in terms of visibility and the furthering of acceptance, but there are still subjects within the LGBTQ+ community that need to be addressed, including bisexual, asexual, and non-binary erasure. There are many people who claim that these identities do not exist, are labels used as a stepping stone on one's journey to discovering that they are homosexual, or are invented excuses for overtly promiscuous or prudish behavior. The existence of negative stereotypes, particularly those of non-binary individuals, is largely due to a lack of visibility and respectful representation within media and popular culture. However, there is still a dearth of non-binary content in popular literature outside of young adult fiction. Can You See Me? aims to fill the gap in bisexual, asexual, and non-binary representation in adult literature. Each of the four stories that make up this collection deals with an aspect of gender and/or sexuality that has been erased, ignored, or denied visibility in American popular culture. The first story, "We'll Grow Lemon Trees," examines bisexual erasure through the lens of sociolinguistics. A bisexual Romanian woman emigrates to Los Angeles in 1989 and must navigate a new culture, learn new languages, and try to move on from her past life under a dictatorship where speaking up could mean imprisonment or death. The second story "Up, Down, All Around," is about a young genderqueer child and their parents dealing with microaggressions, examining gender norms, and exploring personal identity through imaginary scenarios, each involving an encounter with an unknown entity and a colander. The third story, "Aces High," follows two asexual characters from the day they're born to when they are 28 years old, as they find themselves in pop culture. The two endure identity crises, gender discrimination, erasure, individual obsessions, and prejudice as they learn to accept themselves and embrace who they are. In the fourth and final story, "Mile Marker 72," a gay Mexican man must hide in plain sight as he deals with the death of his partner and coming out to his best friend, whose brother is his partner's murderer.
ContributorsOchser, Jordyn M. (Author) / Bell, Matt (Thesis director) / Free, Melissa (Committee member) / Department of English (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The purpose of this essay is to explain how celebrities manage their brand, as an image and commodity, using social media. Merriam-Webster defines "celebrity" as the "state of being celebrated." This essay will continue to explain how this state of celebration is a manufactured idea by the individual and the media's portrayal. Celebrities are "well-known for their well-knowness" (Boorstin, 1961, p. 58). Boorstin (1961) explains celebrities achieve fame not for their achievements, but by creating a unique personality (as cited in Turner, 2004). Crowd culture, networks, and audience knowledge are tools celebrities must use to navigate digital nuances. They must manage performance of self, adhere to internet social norms, and the obsessive fame culture. Celebrities are often referred to have "star power" and have a certain "charisma." This cultural identity is "negotiated and formed" contrived by a team through promotion, publicity, and advertising (Turner, 2004). Celebrities market themselves through branded content, media used to promote a product, on their social media pages while targeting crowd cultures. Networks truly define how celebrities must brand themselves on social media. This person-to-person contact establishes fan and consumer connections that build the celebrity's base and following. Despite campaigning in a digital world, it goes back to people connecting with people, not accounts linking to accounts. Celebrities manufacture all of these strategies and tactics as they market themselves as a commodity to target crowd culture audiences. This is why targeting crowd cultures is vitally important for celebrities. This essay explores the techniques of select celebrities as they succeed and fail navigating digital nuances.
ContributorsPierce, Ellen (Author) / Jacoby, Jim (Thesis director) / Himberg, Julia (Committee member) / Department of English (Contributor) / Walter Cronkite School of Journalism and Mass Communication (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12