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Description
Cancer is the second leading cause of death in the United States and novel methods of treating advanced malignancies are of high importance. Of these deaths, prostate cancer and breast cancer are the second most fatal carcinomas in men and women respectively, while pancreatic cancer is the fourth most fatal in both men and women. Developing new drugs for the treatment of cancer is both a slow and expensive process. It is estimated that it takes an average of 15 years and an expense of $800 million to bring a single new drug to the market. However, it is also estimated that nearly 40% of that cost could be avoided by finding alternative uses for drugs that have already been approved by the Food and Drug Administration (FDA). The research presented in this document describes the testing, identification, and mechanistic evaluation of novel methods for treating many human carcinomas using drugs previously approved by the FDA. A tissue culture plate-based screening of FDA approved drugs will identify compounds that can be used in combination with the protein TRAIL to induce apoptosis selectively in cancer cells. Identified leads will next be optimized using high-throughput microfluidic devices to determine the most effective treatment conditions. Finally, a rigorous mechanistic analysis will be conducted to understand how the FDA-approved drug mitoxantrone, sensitizes cancer cells to TRAIL-mediated apoptosis.
ContributorsTaylor, David (Author) / Rege, Kaushal (Thesis advisor) / Jayaraman, Arul (Committee member) / Nielsen, David (Committee member) / Kodibagkar, Vikram (Committee member) / Dai, Lenore (Committee member) / Arizona State University (Publisher)
Created2013
Description
Bully victimization has been associated with blunted cardiovascular responses to stress as well as elevated responses to stress. The difference between these altered physiological responses to stress is largely unknown. This study explored several possible moderators to the relationship between chronic stress and future cardiac output (an indicator of increased stress) in response to future stressors. These moderators include the difference between social and physical stressors and individual levels of loneliness. Participants were administered measures of loneliness and victimization history, and led to anticipate either a "social" (recorded speech) or "non-social" (pain tolerance test ) stressor, neither of which occurred. EKG and impedance cardiography were measured throughout the session. When anticipating both stressors, loneliness and victimization were associated with increased CO. A regression revealed a three-way interaction, with change in cardiac output depending on victimization history, loneliness, and condition in the physical stressor condition. Loneliness magnified the CO output levels of non-bullied individuals when facing a physical stressor. These results suggest that non- bullied participants high in loneliness are more stressed out when facing stressors, particularly stressors that are physically threatening in nature.
ContributorsHaneline, Magen (Author) / Newman, Matt (Thesis advisor) / Salerno, Jessica (Committee member) / Miller, Paul (Committee member) / Arizona State University (Publisher)
Created2013
Description
Purpose: This study examines the role of social support on adjustment to widowhood. Past research has indicated that the role of social support on adjustment to widowhood remains inconclusive, and needs further examination. This study examines the varying coping trajectories of middle-aged and retired bereaved spouses. Additionally, this study examines how bereavement stage may also influence one's adaptation to widowhood. Methods: This study used in-depth and semi-structured interviews as a means of understanding the role of social support on adjustment to widowhood. Participants were recruited through two hospice services available in a major metropolitan area in the United States. Convenient and purposive samplings are used in this study; this study will execute a grounded theory approach in order to determine the inconclusive role of social support on adjustment to widowhood. This study is contrasting between two stages- life course stages (middle aged versus retirement aged people) and bereavement stages (a year or less time following the death of a spouse versus three or more years following the death of a spouse). As a means of reducing bias and subjectivity, all data collected during the interview will be transcribed immediately. Results: Middle-aged bereaved spouses reported higher levels of motivation for adjusting positively and quickly towards widowhood due to their concern for protecting the well-being of their surviving young children compared to retired bereaved spouses. Differences between middle-aged widows and widowers have been found in this study; middle-aged widowers have a higher linkage to negative health behaviors. Retired bereaved spouses may fare better depending upon their housing location. Living in a retirement center may lower negative effects of bereavement on retired spouses' health. Conclusions: Types of social support received and expected varied between middle-aged widows and widowers. Gender norms may influence the type of social support widows and widowers receive. Middle-aged widowers are less likely to receive emotional support which may explain their higher linkage to negative health behaviors. Bereavement stage and housing location may be the key factors that influence widowhood trajectories of retired bereaved spouses. Living in a retirement center may lower the negative effects of bereavement on overall health.
ContributorsRafieei, Noshin (Author) / Kronenfeld, Jennie (Thesis advisor) / Haas, Steven (Committee member) / Damgaard, Anni (Committee member) / Arizona State University (Publisher)
Created2013
Description
Research has demonstrated that temperature and relative humidity substantially influence overall perceptions of indoor air quality (Fang, Clausen, & Fanger, 1998). This finding places temperature quality as a high priority, especially for vulnerable adults over 60. Temperature extremes and fluctuation, as well as the perception of those conditions, affect physical performance, thermal comfort and health of older adults (Chatonnet & Cabanac, 1965, pp. 185-6; Fumiharu, Watanabe, Park, Shephard, & Aoyagi, 2005; Heijs & Stringer, 1988). The American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) and the International Organization for Standardization (ISO) have developed thermal-comfort standards for working-age, healthy individuals. None of these standards address the physiological and psychological needs of older adults (ASHRAE Standard 55, 2010; ISO-7730, 2005). This dissertation investigates the impacts of thermal conditions on self-reported health and perceived comfort for older adults, hypothesizing that warmer and more-table indoor thermal conditions will increase the health and perceived comfort of these adults. To this end, a new set of thermal comfort metrics was designed and tested to address the thermal preferences of older adults. The SENIOR COMFORT Metrics 2013 outlined new thresholds for optimal indoor high and low temperatures and set limits on thermal variability over time based on the ASHRAE-55 2010 model. This study was conducted at Sunnyslope Manor, a multi-unit, public-housing complex in the North Phoenix. Nearly 60% (76 of 118) of the residents (aged 62-82) were interviewed using a 110-question, self-reporting survey in 73 apartment units. A total of 40 questions and 20 sub-questions addressing perceptions of comfort, pain, sleep patterns, injuries, and mood were extracted from this larger health condition survey to assess health and thermal comfort. Indoor environmental thermal measurements included temperature in three locations: kitchen, living area, and bedroom and data were recorded every 15 minutes over 5 full days and 448 points. Study results start to indicate that older adults for Sunnyslope Manor preferred temperatures between 76 and 82.5 degrees Fahrenheit and that lower temperatures as outlined by ASHRAE-55 2010 increases the rate of injuries and mood changes in older adults among other findings.
ContributorsFonseca, Ernesto (Author) / Bryan, Harvey (Thesis advisor) / Ahrentzen, Sherry (Committee member) / Shea, Kimberly (Committee member) / Arizona State University (Publisher)
Created2013
Description
In 1890, the State of Nevada built the Stewart Indian School on a parcel of land three miles south of Carson City, Nevada, and then sold the campus to the federal government. The Stewart Indian School operated as the only non-reservation Indian boarding school in Nevada until 1980 when the federal government closed the campus. Faced with the challenge of assimilating Native peoples into Anglo society after the conclusion of the Indian wars and the confinement of Indian nations on reservations, the federal government created boarding schools. Policymakers believed that in one generation they could completely eliminate Indian culture by removing children from their homes and educating them in boarding schools. The history of the Stewart Indian School from 1890 to 1940 is the story of a dynamic and changing institution. Only Washoe, Northern Paiute, and Western Shoshone students attended Stewart for the first decade, but over the next forty years, children from over sixty tribal groups enrolled at the school. They arrived from three dozen reservations and 335 different hometowns across the West. During this period, Stewart evolved from a repressive and exploitive institution, into a school that embodied the reform agenda of the Indian New Deal in the 1930s. This dissertation uses archival and ethnographic material to explain how the federal government's agenda failed. Rather than destroying Native culture, Stewart students and Nevada's Indian communities used the skills taught at the school to their advantage and became tribal leaders during the 1930s. This dissertation explores the individual and collective bodies of Stewart students. The body is a social construction constantly being fashioned by the intersectional forces of race, class, and gender. Each chapter explores the different ways the Stewart Indian School and the federal government tried to transform the students' bodies through their physical appearance, the built environment, health education, vocational training, and extracurricular activities such as band and sports.
ContributorsThompson, Bonnie (Author) / Iverson, Peter (Thesis advisor) / Gray, Susan (Thesis advisor) / Green, Monica (Committee member) / Arizona State University (Publisher)
Created2013
Description
The bleomycins are a family of glycopeptide-derived antibiotics isolated from various Streptomyces species and have been the subject of much attention from the scientific community as a consequence of their antitumor activity. Bleomycin clinically and is an integral part of a number of combination chemotherapy regimens. It has previously been shown that bleomycin has the ability to selectively target tumor cells over their non-malignant counterparts. Pyrimidoblamic acid, the N-terminal metal ion binding domain of bleomycin is known to be the moiety that is responsible for O2 activation and the subsequent chemistry leading to DNA strand scission and overall antitumor activity. Chapter 1 describes bleomycin and related DNA targeting antitumor agents as well as the specific structural domains of bleomycin. Various structural analogues of pyrimidoblamic acid were synthesized and subsequently incorporated into their corresponding full deglycoBLM A6 derivatives by utilizing a solid support. Their activity was measured using a pSP64 DNA plasmid relaxation assay and is summarized in Chapter 2. The specifics of bleomycin—DNA interaction and kinetics were studied via surface plasmon resonance and are presented in Chapter 3. By utilizing carefully selected 64-nucleotide DNA hairpins with variable 16-mer regions whose sequences showed strong binding in past selection studies, a kinetic profile was obtained for several BLMs for the first time since bleomycin was discovered in 1966. The disaccharide moiety of bleomycin has been previously shown to be a specific tumor cell targeting element comprised of L-gulose-D-mannose, especially between MCF-7 (breast cancer cells) and MCF-10A ("normal" breast cells). This phenomenon was further investigated via fluorescence microscopy using multiple cancerous cell lines with matched "normal" counterparts and is fully described in Chapter 4.
ContributorsBozeman, Trevor C (Author) / Hecht, Sidney M. (Thesis advisor) / Chaput, John (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2013
Description
Genomic structural variation (SV) is defined as gross alterations in the genome broadly classified as insertions/duplications, deletions inversions and translocations. DNA sequencing ushered structural variant discovery beyond laboratory detection techniques to high resolution informatics approaches. Bioinformatics tools for computational discovery of SVs however are still missing variants in the complex cancer genome. This study aimed to define genomic context leading to tool failure and design novel algorithm addressing this context. Methods: The study tested the widely held but unproven hypothesis that tools fail to detect variants which lie in repeat regions. Publicly available 1000-Genomes dataset with experimentally validated variants was tested with SVDetect-tool for presence of true positives (TP) SVs versus false negative (FN) SVs, expecting that FNs would be overrepresented in repeat regions. Further, the novel algorithm designed to informatically capture the biological etiology of translocations (non-allelic homologous recombination and 3&ndashD; placement of chromosomes in cells –context) was tested using simulated dataset. Translocations were created in known translocation hotspots and the novel&ndashalgorithm; tool compared with SVDetect and BreakDancer. Results: 53% of false negative (FN) deletions were within repeat structure compared to 81% true positive (TP) deletions. Similarly, 33% FN insertions versus 42% TP, 26% FN duplication versus 57% TP and 54% FN novel sequences versus 62% TP were within repeats. Repeat structure was not driving the tool's inability to detect variants and could not be used as context. The novel algorithm with a redefined context, when tested against SVDetect and BreakDancer was able to detect 10/10 simulated translocations with 30X coverage dataset and 100% allele frequency, while SVDetect captured 4/10 and BreakDancer detected 6/10. For 15X coverage dataset with 100% allele frequency, novel algorithm was able to detect all ten translocations albeit with fewer reads supporting the same. BreakDancer detected 4/10 and SVDetect detected 2/10 Conclusion: This study showed that presence of repetitive elements in general within a structural variant did not influence the tool's ability to capture it. This context-based algorithm proved better than current tools even with half the genome coverage than accepted protocol and provides an important first step for novel translocation discovery in cancer genome.
ContributorsShetty, Sheetal (Author) / Dinu, Valentin (Thesis advisor) / Bussey, Kimberly (Committee member) / Scotch, Matthew (Committee member) / Wallstrom, Garrick (Committee member) / Arizona State University (Publisher)
Created2014
Description
This study was designed to investigate whether workplace positivity of full-time workers was related to health ratings. Positivity was conceptualized by a high rating of perceived work-performance, and work-engagement as defined by the Utrecht Work-Engagement Scale, including vigor, dedication, and absorption (Schaufeli, & Bakker, 2004). Health was measured utilizing the RAND SF-36 health survey including the eight subscales: overall, general health, physical and social functioning, emotional well-being, role limitations due to physical health or emotional problems, energy or fatigue, and bodily pain. All measures were collected simultaneously. It was predicted that perceived work-performance and all measures of work-engagement are positively associated with the aforementioned health ratings. Multiple regression analyses revealed that higher (positive) perception of work-performance and vigor were positively related to health ratings. Absorption was negatively related to health ratings. Dedication was only negatively related to physical functioning. These findings suggest that not all measures of positivity in the workplace are related to better health. Implications and future directions are discussed.
ContributorsFlores, Melissa Ann (Author) / Vargas, Perla A (Thesis advisor) / Burleson, Mary H (Committee member) / Hall, Deborah (Committee member) / Arizona State University (Publisher)
Created2014
Description
In a 2004 paper, John Nagy raised the possibility of the existence of a hypertumor \emph{i.e.}, a focus of aggressively reproducing parenchyma cells that invade part or all of a tumor. His model used a system of nonlinear ordinary differential equations to find a suitable set of conditions for which these hypertumors exist. Here that model is expanded by transforming it into a system of nonlinear partial differential equations with diffusion, advection, and a free boundary condition to represent a radially symmetric tumor growth. Two strains of parenchymal cells are incorporated; one forming almost the entirety of the tumor while the much more aggressive strain
appears in a smaller region inside of the tumor. Simulations show that if the aggressive strain focuses its efforts on proliferating and does not contribute to angiogenesis signaling when in a hypoxic state, a hypertumor will form. More importantly, this resultant aggressive tumor is paradoxically prone to extinction and hypothesize is the cause of necrosis in many vascularized tumors.
appears in a smaller region inside of the tumor. Simulations show that if the aggressive strain focuses its efforts on proliferating and does not contribute to angiogenesis signaling when in a hypoxic state, a hypertumor will form. More importantly, this resultant aggressive tumor is paradoxically prone to extinction and hypothesize is the cause of necrosis in many vascularized tumors.
ContributorsAlvarez, Roberto L (Author) / Milner, Fabio A (Thesis advisor) / Nagy, John D. (Committee member) / Kuang, Yang (Committee member) / Thieme, Horst (Committee member) / Mahalov, Alex (Committee member) / Smith, Hal (Committee member) / Arizona State University (Publisher)
Created2014
Description
The processes of a human somatic cell are very complex with various genetic mechanisms governing its fate. Such cells undergo various genetic mutations, which translate to the genetic aberrations that we see in cancer. There are more than 100 types of cancer, each having many more subtypes with aberrations being unique to each. In the past two decades, the widespread application of high-throughput genomic technologies, such as micro-arrays and next-generation sequencing, has led to the revelation of many such aberrations. Known types and subtypes can be readily identified using gene-expression profiling and more importantly, high-throughput genomic datasets have helped identify novel sub-types with distinct signatures. Recent studies showing usage of gene-expression profiling in clinical decision making in breast cancer patients underscore the utility of high-throughput datasets. Beyond prognosis, understanding the underlying cellular processes is essential for effective cancer treatment. Various high-throughput techniques are now available to look at a particular aspect of a genetic mechanism in cancer tissue. To look at these mechanisms individually is akin to looking at a broken watch; taking apart each of its parts, looking at them individually and finally making a list of all the faulty ones. Integrative approaches are needed to transform one-dimensional cancer signatures into multi-dimensional interaction and regulatory networks, consequently bettering our understanding of cellular processes in cancer. Here, I attempt to (i) address ways to effectively identify high quality variants when multiple assays on the same sample samples are available through two novel tools, snpSniffer and NGSPE; (ii) glean new biological insight into multiple myeloma through two novel integrative analysis approaches making use of disparate high-throughput datasets. While these methods focus on multiple myeloma datasets, the informatics approaches are applicable to all cancer datasets and will thus help advance cancer genomics.
ContributorsYellapantula, Venkata (Author) / Dinu, Valentin (Thesis advisor) / Scotch, Matthew (Committee member) / Wallstrom, Garrick (Committee member) / Keats, Jonathan (Committee member) / Arizona State University (Publisher)
Created2014