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- Creators: Barrett, The Honors College
- Creators: Arizona State University
- Member of: Theses and Dissertations
- Status: Published
Description
In recent years, the field of nanomedicine has progressed at an astonishing rate, particularly with respect to applications in cancer treatment and molecular imaging. Although organic systems have been the frontrunners, inorganic systems have also begun to show promise, especially those based upon silica and magnetic nanoparticles (NPs). Many of these systems are being designed for simultaneous therapeutic and diagnostic capabilities, thus coining the term, theranostics. A unique class of inorganic systems that shows great promise as theranostics is that of layered double hydroxides (LDH). By synthesis of a core/shell structures, e.g. a gold nanoparticle (NP) core and LDH shell, the multifunctional theranostic may be developed without a drastic increase in the structural complexity. To demonstrate initial proof-of-concept of a potential (inorganic) theranostic platform, a Au-core/LDH-shell nanovector has been synthesized and characterized. The LDH shell was heterogeneously nucleated and grown on the surface of silica coated gold NPs via a coprecipitation method. Polyethylene glycol (PEG) was introduced in the initial synthesis steps to improve crystallinity and colloidal stability. Additionally, during synthesis, fluorescein isothiocyanate (FITC) was intercalated into the interlayer spacing of the LDH. In contrast to the PEG stabilization, a post synthesis citric acid treatment was used as a method to control the size and short-term stability. The heterogeneous core-shell system was characterized with scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy (EDX), dynamic light scattering (DLS), and powder x-ray diffraction (PXRD). A preliminary in vitro study carried out with the assistance of Dr. Kaushal Rege's group at Arizona State University was to demonstrate the endocytosis capability of homogeneously-grown LDH NPs. The DLS measurements of the core-shell NPs indicated an average particle size of 212nm. The PXRD analysis showed that PEG greatly improved the crystallinity of the system while simultaneously preventing aggregation of the NPs. The preliminary in vitro fluorescence microscopy revealed a moderate uptake of homogeneous LDH NPs into the cells.
ContributorsRearick, Colton (Author) / Dey, Sandwip K (Thesis advisor) / Krause, Stephen (Committee member) / Ramakrishna, B (Committee member) / Arizona State University (Publisher)
Created2011
Description
In complex consumer-resource type systems, where diverse individuals are interconnected and interdependent, one can often anticipate what has become known as the tragedy of the commons, i.e., a situation, when overly efficient consumers exhaust the common resource, causing collapse of the entire population. In this dissertation I use mathematical modeling to explore different variations on the consumer-resource type systems, identifying some possible transitional regimes that can precede the tragedy of the commons. I then reformulate it as a game of a multi-player prisoner's dilemma and study two possible approaches for preventing it, namely direct modification of players' payoffs through punishment/reward and modification of the environment in which the interactions occur. I also investigate the questions of whether the strategy of resource allocation for reproduction or competition would yield higher fitness in an evolving consumer-resource type system and demonstrate that the direction in which the system will evolve will depend not only on the state of the environment but largely on the initial composition of the population. I then apply the developed framework to modeling cancer as an evolving ecological system and draw conclusions about some alternative approaches to cancer treatment.
ContributorsKareva, Irina (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Collins, James (Committee member) / Nagy, John (Committee member) / Smith, Hal (Committee member) / Arizona State University (Publisher)
Created2012
Description
Cancer claims hundreds of thousands of lives every year in US alone. Finding ways for early detection of cancer onset is crucial for better management and treatment of cancer. Thus, biomarkers especially protein biomarkers, being the functional units which reflect dynamic physiological changes, need to be discovered. Though important, there are only a few approved protein cancer biomarkers till date. To accelerate this process, fast, comprehensive and affordable assays are required which can be applied to large population studies. For this, these assays should be able to comprehensively characterize and explore the molecular diversity of nominally "single" proteins across populations. This information is usually unavailable with commonly used immunoassays such as ELISA (enzyme linked immunosorbent assay) which either ignore protein microheterogeneity, or are confounded by it. To this end, mass spectrometric immuno assays (MSIA) for three different human plasma proteins have been developed. These proteins viz. IGF-1, hemopexin and tetranectin have been found in reported literature to show correlations with many diseases along with several carcinomas. Developed assays were used to extract entire proteins from plasma samples and subsequently analyzed on mass spectrometric platforms. Matrix assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) mass spectrometric techniques where used due to their availability and suitability for the analysis. This resulted in visibility of different structural forms of these proteins showing their structural micro-heterogeneity which is invisible to commonly used immunoassays. These assays are fast, comprehensive and can be applied in large sample studies to analyze proteins for biomarker discovery.
ContributorsRai, Samita (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Borges, Chad (Committee member) / Ros, Alexandra (Committee member) / Arizona State University (Publisher)
Created2012
Description
Emotional support messages can benefit recipients; however, verbal and nonverbal aspects of these messages can vary in effectiveness, and the process of communicating support can be stressful to some supporters. One potential behavior that may yield more effective support messages for recipients while reducing anxiety and stress for supporters is message planning. Thus, planning theory is used to test whether planning influences message effectiveness, nonverbal delivery of messages, self-reported anxiety, and physiological stress markers. Additionally, an individual’s trait-level reticence and prior support experiences are predicted to moderate the effects of message planning. One hundred laboratory participants were assigned to either a planning condition or writing distraction task and completed a series of self-report and physiological measures before, during, and after recording an emotional support message to a friend who had hypothetically been diagnosed with a serious form of cancer. Subsequently, a sample of one hundred cancer patients viewed the laboratory participants’ videos to provide message effectiveness ratings and four trained coders provided data on nonverbal behaviors from these recorded messages. Findings showed planning leads to more effective messages; however, it also leads to supporters engaging in success bias and inflation bias. Planning also increased vocal fluency, but not other nonverbal behaviors. Likewise, planning attenuated heart rate reactivity, but not other physiological markers. In general, experience and reticence did not moderate these main effects. Theoretical, practical, clinical, pedagogical, and methodological implications are discussed.
ContributorsRay, Colter D (Author) / Floyd, Kory W (Thesis advisor) / Mongeau, Paul A. (Thesis advisor) / Randall, Ashley K. (Committee member) / Arizona State University (Publisher)
Created2018
Description
Patients who attend genetic counseling appointments report high anxiety and varied satisfaction levels following their appointments. It has been suggested in previous literature that some of the increase in anxiety and reduction in satisfaction is caused by lack of prior information. Here, I investigated whether providing patients with a glossary of genetic terms prior to their counseling appointment improves patient satisfaction and reduces anxiety in an oncology genetic counseling appointment. I surveyed 96 patients attending their first genetic counseling appointment at Banner MD Anderson Cancer Center and analyzed 92 patients for which I had complete data. Patients were randomly selected to receive one of two folders, containing either an educational document or an educational document and a glossary comprised of ten genetic terms. Each patient was given a post-counseling survey at the end of the counseling appointment to assess their anxiety and satisfaction levels. I did not observe a statistically significant difference in levels of anxiety or satisfaction, but the data are consistent with increased satisfaction for patients who received a glossary. Interesting, the data are also consistent with decreased anxiety levels for patients who did not receive a glossary. Furthermore, I did observe differences in reported satisfaction with patients who had college experience and patients that did not have any college experience.
ContributorsPeon, Lidia Maria (Author) / Wilson Sayres, Melissa A (Thesis advisor) / Buetow, Kenneth H (Committee member) / Luiten, Rebecca C (Committee member) / Siettmann, Jennifer M (Committee member) / Arizona State University (Publisher)
Created2018
Description
Cancer is a heterogeneous disease with discrete oncogenic mechanisms. P53 mutation is the most common oncogenic mutation in many cancers including breast cancer. This dissertation focuses on fundamental genetic alterations enforced by p53 mutation as an indirect target. p53 mutation upregulates the mevalonate pathway genes altering cholesterol biosynthesis and prenylation. Prenylation, a lipid modification, is required for small GTPases signaling cascades. Project 1 demonstrates that prenylation inhibition can specifically target cells harboring p53 mutation resulting in reduced tumor proliferation and migration. Mutating p53 is associated with Ras and RhoA activation and statin prevents this activity by inhibiting prenylation. Ras-related pathway genes were selected from the transcriptomic analysis for evaluating correlation to statin sensitivity. A gene signature of seventeen genes and TP53 genotype (referred to as MPR signature) is generated to predict response to statins. MPR signature is validated through two datasets of drug screening in cell lines. As advancements in targeted gene modification are rising, the CRISPR-Cas9 technology has emerged as a new cancer therapeutic strategy. One of the important risk factors in gene therapy is the immune recognition of the exogenous therapeutic tool, resulting in obstruction of treatment and possibly serious health consequences. Project 2 describes a method development that can potentially improve the safety and efficacy of gene-targeting proteins. A cohort of 155 healthy individuals was screened for pre-existing B cell and T cell immune response to the S. pyogenes Cas9 protein. We detected antibodies against Cas9 in more than 10% of the healthy population and identified two immunodominant T cell epitopes of this protein. A de-immunized Cas9 that maintains the wild-type functionality was engineered by mutating the identified T cell epitopes. The gene signature and method described here have the potential to improve strategies for genome-driven tumor targeting.
ContributorsRoshdi Ferdosi, Shayesteh (Author) / Anderson, Karen S (Thesis advisor) / LaBaer, Joshua (Thesis advisor) / Woodbury, Neel (Committee member) / Borges, Chad (Committee member) / Arizona State University (Publisher)
Created2017
Description
Prophylactic bilateral mastectomy (PBM) is the current recommended course of action for women with increased genetic risk for breast and ovarian cancer. Nevertheless, many receive negative feedback from family and friends surrounding the decision to undergo this surgery because they do not have cancer when the decision is made; this results in a limited support network for coping with their PBM. Low social support is associated with depression, negativity, and anxiety. Women who had a PBM, were currently undergoing or had completed reconstruction, and were in a committed romantic relationship at the time of the surgery were surveyed (N = 53). The hypotheses that women who received negative feedback about their decision to have a PBM would have poorer individual well-being, and that the use of a couples-based team approach would moderate these adverse effects were tested. Data analyses support the hypotheses that women in couples taking a team approach to PBM have better individual well-being. The effects of negative feedback from others about the decision to undergo a PBM on personal mental health were moderated by use of a couples-based team approach. Women who received negative feedback from multiple sources had better outcomes if they used a couples-based team approach. Many women have a preventative oophorectomy around the same time as their PBM. Menopause is associated with side effects such as increased vasomotor symptoms and decreased sexual functioning. The hypothesis that surgical menopause is related to declines in sexual satisfaction following PBM was also tested. Regression analysis revealed no relationship. This study indicates that women who experience social disapproval and lack collaborative support from their significant other may be at increased risk for poor individual well-being following PBM.
ContributorsGaytán, Jenelle A (Author) / Burleson, Mary H (Thesis advisor) / Roberts, Nicole A. (Committee member) / Mickelson, Krisitin D (Committee member) / Arizona State University (Publisher)
Created2018
Description
Glycans are monosaccharide-based heteropolymers that are found covalently attached to many different proteins and lipids and are ubiquitously displayed on the exterior surfaces of cells. Serum glycan composition and structure are well known to be altered in many different types of cancer. In fact, glycans represent a promising but only marginally accessed source of cancer markers. The approach used in this dissertation, which is referred to as “glycan node analysis”, is a molecularly bottom-up approach to plasma/serum (P/S) glycomics based on glycan linkage analysis that captures features such as α2-6 sialylation, β1-6 branching, and core fucosylation as single analytical signals.
The diagnostic utility of this approach as applied to lung cancer patients across all stages as well as prostate, serous ovarian, and pancreatic cancer patients compared to certifiably healthy individuals, nominally healthy individuals and/or risk-matched controls is reported. Markers for terminal fucosylation, α2-6 sialylation, β1-4 branching, β1-6 branching and outer-arm fucosylation were most able to differentiate cases from controls. These markers behaved in a stage-dependent manner in lung cancer as well as other types of cancer. Using a Cox proportional hazards regression model, the ability of these markers to predict progression and survival in lung cancer patients was assessed. In addition, the potential mechanistic role of aberrant P/S glycans in cancer progression is discussed.
Plasma samples from former bladder cancer patients with currently no evidence of disease (NED), non-muscle invasive bladder cancer (NMIBC), and muscle invasive bladder cancer (MIBC) along with certifiably healthy controls were analyzed. Markers for α2-6 sialylation, β1-4 branching, β1-6 branching, and outer-arm fucosylation were able to separate current and former (NED) cases from controls; but NED, NMIBC, and MIBC were not distinguished from one another. Markers for α2-6 sialylation and β1-6 branching were able to predict recurrence from the NED state using a Cox proportional hazards regression model adjusted for age, gender, and time from cancer. These two glycan features were found to be correlated to the concentration of C-reactive protein, a known prognostic marker for bladder cancer, further strengthening the link between inflammation and abnormal plasma protein glycosylation.
The diagnostic utility of this approach as applied to lung cancer patients across all stages as well as prostate, serous ovarian, and pancreatic cancer patients compared to certifiably healthy individuals, nominally healthy individuals and/or risk-matched controls is reported. Markers for terminal fucosylation, α2-6 sialylation, β1-4 branching, β1-6 branching and outer-arm fucosylation were most able to differentiate cases from controls. These markers behaved in a stage-dependent manner in lung cancer as well as other types of cancer. Using a Cox proportional hazards regression model, the ability of these markers to predict progression and survival in lung cancer patients was assessed. In addition, the potential mechanistic role of aberrant P/S glycans in cancer progression is discussed.
Plasma samples from former bladder cancer patients with currently no evidence of disease (NED), non-muscle invasive bladder cancer (NMIBC), and muscle invasive bladder cancer (MIBC) along with certifiably healthy controls were analyzed. Markers for α2-6 sialylation, β1-4 branching, β1-6 branching, and outer-arm fucosylation were able to separate current and former (NED) cases from controls; but NED, NMIBC, and MIBC were not distinguished from one another. Markers for α2-6 sialylation and β1-6 branching were able to predict recurrence from the NED state using a Cox proportional hazards regression model adjusted for age, gender, and time from cancer. These two glycan features were found to be correlated to the concentration of C-reactive protein, a known prognostic marker for bladder cancer, further strengthening the link between inflammation and abnormal plasma protein glycosylation.
ContributorsRoshdiferdosi, Shadi (Author) / Borges, Chad R (Thesis advisor) / Woodbury, Neal (Committee member) / Hayes, Mark (Committee member) / Arizona State University (Publisher)
Created2018
Description
Due to artificial selection, dogs have high levels of phenotypic diversity, yet, there appears to be low genetic diversity within individual breeds. Through their domestication from wolves, dogs have gone through a series of population bottlenecks, which has resulted in a reduction in genetic diversity, with a large amount of linkage disequilibrium and the persistence of deleterious mutations. This has led to an increased susceptibility to a multitude of diseases, including cancer. To study the effects of artificial selection and life history characteristics on the risk of cancer mortality, we collected cancer mortality data from four studies as well as the percent of heterozygosity, body size, lifespan and breed group for 201 dog breeds. We also collected specific types of cancer breeds were susceptible to and compared the dog cancer mortality patterns to the patterns observed in other mammals. We found a relationship between cancer mortality rate and heterozygosity, body size, lifespan as well as breed group. Higher levels of heterozygosity were also associated with longer lifespan. These results indicate larger breeds, such as Irish Water Spaniels, Flat-coated Retrievers and Bernese Mountain Dogs, are more susceptible to cancer, with lower heterozygosity and lifespan. These breeds are also more susceptible to sarcomas, as opposed to carcinomas in smaller breeds, such as Miniature Pinschers, Chihuahuas, and Pekingese. Other mammals show that larger and long-lived animals have decreased cancer mortality, however, within dog breeds, the opposite relationship is observed. These relationships could be due to the trade-off between cellular maintenance and growing fast and large, with higher expression of growth factors, such as IGF-1. This study further demonstrates the relationships between cancer mortality, heterozygosity, and life history traits and exhibits dogs as an important model organism for understanding the relationship between genetics and health.
ContributorsBalsley, Cassandra Sierra (Author) / Maley, Carlo (Thesis director) / Wynne, Clive (Committee member) / Tollis, Marc (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Breast cancer is the leading cause of cancer-related deaths of women in the united states. Traditionally, Breast cancer is predominantly treated by a combination of surgery, chemotherapy, and radiation therapy. However, due to the significant negative side effects associated with these traditional treatments, there has been substantial efforts to develop alternative therapies to treat cancer. One such alternative therapy is a peptide-based therapeutic cancer vaccine. Therapeutic cancer vaccines enhance an individual's immune response to a specific tumor. They are capable of doing this through artificial activation of tumor specific CTLs (Cytotoxic T Lymphocytes). However, in order to artificially activate tumor specific CTLs, a patient must be treated with immunogenic epitopes derived from their specific cancer type. We have identified that the tumor associated antigen, TPD52, is an ideal target for a therapeutic cancer vaccine. This designation was due to the overexpression of TPD52 in a variety of different cancer types. In order to start the development of a therapeutic cancer vaccine for TPD52-related cancers, we have devised a two-step strategy. First, we plan to create a list of potential TPD52 epitopes by using epitope binding and processing prediction tools. Second, we plan to attempt to experimentally identify MHC class I TPD52 epitopes in vitro. We identified 942 potential 9 and 10 amino acid epitopes for the HLAs A1, A2, A3, A11, A24, B07, B27, B35, B44. These epitopes were predicted by using a combination of 3 binding prediction tools and 2 processing prediction tools. From these 942 potential epitopes, we selected the top 50 epitopes ranked by a combination of binding and processing scores. Due to the promiscuity of some predicted epitopes for multiple HLAs, we ordered 38 synthetic epitopes from the list of the top 50 epitope. We also performed a frequency analysis of the TPD52 protein sequence and identified 3 high volume regions of high epitope production. After the epitope predictions were completed, we proceeded to attempt to experimentally detected presented TPD52 epitopes. First, we successful transduced parental K562 cells with TPD52. After transduction, we started the optimization process for the immunoprecipitation protocol. The optimization of the immunoprecipitation protocol proved to be more difficult than originally believed and was the main reason that we were unable to progress past the transduction of the parental cells. However, we believe that we have identified the issues and will be able to complete the experiment in the coming months.
ContributorsWilson, Eric Andrew (Author) / Anderson, Karen (Thesis director) / Borges, Chad (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05