Matching Items (521)
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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

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
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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

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
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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

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
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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)

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
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Description
Breast microcalcifications are a potential indicator of cancerous tumors. Current visualization methods are either uncomfortable or impractical. Impedance measurement studies have been performed, but not in a clinical setting due to a low sensitivity and specificity. We are hoping to overcome this challenge with the development of a highly accurate

Breast microcalcifications are a potential indicator of cancerous tumors. Current visualization methods are either uncomfortable or impractical. Impedance measurement studies have been performed, but not in a clinical setting due to a low sensitivity and specificity. We are hoping to overcome this challenge with the development of a highly accurate impedance probe on a biopsy needle. With this technique, microcalcifications and the surrounding tissue could be differentiated in an efficient and comfortable manner than current techniques for biopsy procedures. We have developed and tested a functioning prototype for a biopsy needle using bioimpedance sensors to detect microcalcifications in the human body. In the final prototype a waveform generator sends a sin wave at a relatively low frequency(<1KHz) into the pre-amplifier, which both stabilizes and amplifies the signal. A modified howland bridge is then used to achieve a steady AC current through the electrodes. The voltage difference across the electrodes is then used to calculate the impedance being experienced between the electrodes. In our testing, the microcalcifications we are looking for have a noticeably higher impedance than the surrounding breast tissue, this spike in impedance is used to signal the presence of the calcifications, which are then sampled for examination by radiology.
ContributorsWen, Robert Bobby (Co-author) / Grula, Adam (Co-author) / Vergara, Marvin (Co-author) / Ramkumar, Shreya (Co-author) / Kozicki, Michael (Thesis director) / Ranjani, Kumaran (Committee member) / School of Molecular Sciences (Contributor) / Electrical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
Breastfeeding has been shown by a number of studies to have numerous benefits on both the mother and the infant. Major health organizations such as the World Health Organization (WHO), now agree that breastfeeding should be encouraged and supported in all countries. But like many things, the wheels of the

Breastfeeding has been shown by a number of studies to have numerous benefits on both the mother and the infant. Major health organizations such as the World Health Organization (WHO), now agree that breastfeeding should be encouraged and supported in all countries. But like many things, the wheels of the law are slow to catch up with scientific evident. Although breastfeeding is supported, working women do not have the option of breastfeeding without consequences. For example, in 2003, Kirstie Marshall, a then member of parliament in Australia was ejected from the lower house chamber on February 23, for breastfeeding her baby [3]. According to standing order 30 at the time, "Unless by order of the House, no Member of this House shall presume to bring any stranger into any part of the House appropriated to the Members of this House while the House, or a Committee of the whole House, is sitting" [3]. The rules did not specify the age of strangers, so the then 11-day-old baby, Charlotte Louise and her mother were shown the exit door of parliament. She had to choose between being present at times of major discussions or leaving the house to breastfeed her child, she chose to leave. More recent statistics show that developed nations like the US and Australia which also have high rates of women employment had low rates of breastfeeding. This might mean that workplace policies do not favor breastfeeding or expressing milk at work. Fortunately, laws have since been introduced in both the United States and Australia that support breastfeeding at the workplace. The next step would be to access how these laws affect breastfeeding statistics and how variation between these two countries like the paid parental leave in Australia (which is not present in all US states) would affect these numbers.
ContributorsSakala, Lydia (Author) / Alison, Alison (Thesis director) / Reddy, Swapna (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
Ketone bodies are produced in the liver from the acetyl CoA derived from fatty acids that cannot enter the Krebs cycle. This is a sub-analysis of a larger study which had numerous outcome markers. This analysis focuses on the relationship between ketone blood levels and cognition. The study looked at

Ketone bodies are produced in the liver from the acetyl CoA derived from fatty acids that cannot enter the Krebs cycle. This is a sub-analysis of a larger study which had numerous outcome markers. This analysis focuses on the relationship between ketone blood levels and cognition. The study looked at the relationship between Time Restricted Feeding (TRF), a method of intermittent fasting. TRF is something that can be easily adapted into an individual’s lifestyle and has been shown to have multiple advantages. This 8-week study began with 23 enrolled participants, but due to COVID-19 only 11 participants could be tested for cognition and blood ketone levels after week 4. All participants had similar ranges of weight, height, age, BMI, hip, and waist measurements at baseline. Moreover, these demographic variables were not related to ketone levels or cognition. The data indicate that ketone bodies increased in participants practicing TRF and that the increase in ketone bodies in the blood, specifically β-hydroxybutyrate was strongly correlated to increased cognitive function. This is consistent with theories that elevated ketone levels allowed for early hunter-gather communities and other mammals to survive prolonged periods of nutrient deprivation while keeping high cognitive function.
ContributorsTaha, Basel Mahmoud (Author) / Johnston, Carol (Thesis director) / Karen, Sweazea (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
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Description
The purpose of this thesis experiment was to design and create an Acoustically Active Cannula (AAC), which is furnished by a piezoelectric crystal placed at its tip that produces an acoustic navigation signal. I tested the functionality of the cannula in vitro and demonstrated its navigational abilities in vivo in

The purpose of this thesis experiment was to design and create an Acoustically Active Cannula (AAC), which is furnished by a piezoelectric crystal placed at its tip that produces an acoustic navigation signal. I tested the functionality of the cannula in vitro and demonstrated its navigational abilities in vivo in anesthetized pigs. This experiment was based upon ultrasound science and technology, and thus some practical experience with conventional (B-mode) and Doppler ultrasound was achieved as well. The results of bench and experimental animal studies indicated proper functionality of the AAC for identification and spatial navigation of its tip with color Doppler ultrasound imaging.
ContributorsShamsa, Kayvan (Author) / Tyler, William (Thesis director) / Belohlavek, Marek (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
The academic study of eSports, or professional competition through the medium of video games, has tended to focus on players' motivations to play and watch eSports as well as marketing concerns of huge eSports corporations. Instead of utilizing marketing or psychology to analyze this phenomenon, I investigate three areas of

The academic study of eSports, or professional competition through the medium of video games, has tended to focus on players' motivations to play and watch eSports as well as marketing concerns of huge eSports corporations. Instead of utilizing marketing or psychology to analyze this phenomenon, I investigate three areas of focus in accordance with available literature: the fans and their characteristics, the design of the game itself, and the relationship between fans and the game's developer. This investigation was conducted by first examining existing literature surrounding eSports fans, then collecting public domain data such as Reddit posts, forum posts, and YouTube videos, and last by studying interviews with developers and players. With this thesis, I apply a fan studies approach to eSports by creating a series of indicators based in each of the three focus areas which can be utilized as a systematic method of evaluating an eSport's popularity and growth.
ContributorsHilliker, Noah Henry (Author) / Ingram-Waters, Mary (Thesis director) / Schmidt, Peter (Committee member) / Anderson, Sky (Committee member) / School of Molecular Sciences (Contributor) / W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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DescriptionThis project is designed to generate enthusiasm for science among refugee students in hopes of inspiring them to continue learning science as well as to help them with their current understanding of their school science subject matter.
ContributorsSipes, Shannon Paige (Author) / O'Flaherty, Katherine (Thesis director) / Gregg, George (Committee member) / School of Molecular Sciences (Contributor) / Division of Teacher Preparation (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12