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Description
Metabolomics focuses on the study of metabolic changes occurring in varioussystems and utilizes quantitative and semi-quantitative measurements of multiple metabolites in parallel. Mass spectrometry (MS) is the most ubiquitous platform in this field, as it provides superior sensitivity regarding measurements of complex metabolic profiles in biological systems. When combined with MS, multivariate statistics and advanced machine learning algorithms provide myriad opportunities for bioinformatics insights beyond simple univariate data comparisons. In this dissertation, the application of MS-based metabolomics is introduced with an emphasis on biomarker discovery for human disease detection. To advance disease diagnosis using MS-based metabolomics, numerous statistical techniques have been implemented in this research including principal component analysis, factor analysis, partial least squares-discriminant analysis (PLS-DA), orthogonal PLS-DA, random forest, receiver operating characteristic analysis, as well as functional pathway/enzyme enrichment analyses. These approaches are highly useful for improving classification sensitivity and specificity related to disease-induced biological variation and can help identify useful biomarkers and potential therapeutic targets. It is also shown that MS-based metabolomics can distinguish between clinical and prodromal disease as well as similar diseases with related symptoms, which may assist in clinical staging and differential diagnosis, respectively. Additionally, MS-based metabolomics is shown to be promising for the early and accurate detection of diseases, thereby improving patient outcomes, and advancing clinical care. Herein, the application of MS methods and chemometric statistics to the diagnosis of breast cancer, coccidioidomycosis (Valley fever), and senile dementia (Alzheimer's disease) are presented and discussed. In addition to presenting original research, previous efforts in biomarker discovery will be synthesized and appraised. A Comment will be offered regarding the state of the science, specifically addressing the inefficient model of repetitive biomarker discovery and the need for increased translational efforts necessary to consolidate metabolomics findings and formalize purported metabolic markers as laboratory developed tests. Various factors impeding the translational throughput of metabolomics findings will be carefully considered with respect to study design, statistical analysis, and regulation of biomedical diagnostics. Importantly, this dissertation will offer critical insights to advance metabolomics from a scientific field to a practical one including targeted detection, enhanced quantitation, and direct-to-consumer considerations.
ContributorsJasbi, Paniz (Author) / Johnston, Carol S (Thesis advisor) / Gu, Haiwei (Thesis advisor) / Lake, Douglas F (Committee member) / Sweazea, Karen (Committee member) / Tasevska, Natasha (Committee member) / Arizona State University (Publisher)
Created2022
Description
Valley Fever (VF), is a potentially lethal fungal pneumonia caused by Coccidioides spp., which is estimated to cause ~15-30% of all community-acquired pneumonias in the highly endemic Greater Phoenix and Tucson areas of Arizona. However, an accurate antigen-based diagnostic is still lacking. In order to identify protein and glycan antigen biomarkers of infection, I used a combination of genomics, proteomics and glycomics analyses to provide evidence of genus-specific proteins and glycosylations. The next goal was to determine if Coccidioides-specific glycans were present in biological samples from VF patients. Urine collected from 77 humans and 63 dogs were enriched for glycans and evaluated by mass spectrometry for Coccidioides-specific glycans and evaluated against a panel of normal donor urines, urines from patients infected with other fungi, and fungal cultures from closely related pneumonia-causing fungi. A combination of 6 glycan biomarkers was 100% sensitive and 100% specific in the diagnosis of human VF subjects, while only 3 glycan biomarkers were needed for 100% sensitivity and 100 specificity in the diagnosis of dog VF subject. Additionally, a blinded trial of 23 human urine samples was correctly able to classify urine samples with 93.3% sensitivity and 100% specificity. The results of this research provides evidence that Coccidioides genus-specific glycosylations have potential as antigens in diagnostic assays.
ContributorsMitchell, Natalie M (Author) / Lake, Douglas F (Thesis advisor) / Bean, Heather D (Committee member) / Grys, Thomas E (Committee member) / Magee, Dewey M (Committee member) / Arizona State University (Publisher)
Created2019
Description
In the U.S., breast cancer (BC) incidences among African American (AA) and CA (CA) women are similar, yet AA women have a significantly higher mortality rate. In addition, AA women often present with tumors at a younger age, with a higher tumor grade/stage and are more likely to be diagnosed with the highly aggressive triple-negative breast cancer (TNBC) subtype. Even within the TNBC subtype, AA women have a worse clinical outcome compared to CA. Although multiple socio-economic and lifestyle factors may contribute to these observed health disparities, it is essential that the underlying biological differences between CA and AA TNBC are identified. In this study, gene expression profiling was performed on archived FFPE samples, obtained from CA and AA women diagnosed with early stage TNBC. Initial analysis revealed a pattern of differential expression in the AA cohort compared to CA. Further molecular characterization results showed that the AA cohort segregated into 3-TNBC molecular subtypes; Basal-like (BL2), Immunomodulatory (IM) and Mesenchymal (M). Gene expression analyses resulted in 190 differentially expressed genes between the AA and CA cohorts. Pathway enrichment analysis demonstrated that differentially expressed genes were over-represented in cytoskeletal remodeling, cell adhesion, tight junctions, and immune response in the AA TNBC -cohort. Furthermore, genes in the Wnt/β-catenin pathway were over-expressed. These results were validated using RT-qPCR on an independent cohort of FFPE samples from AA and CA women with early stage TNBC, and identified Caveolin-1 (CAV1) as being significantly expressed in the AA-TNBC cohort. Furthermore, CAV1 was shown to be highly expressed in a cell line panel of TNBC, in particular, those of the mesenchymal and basal-like molecular subtype. Finally, silencing of CAV1 expression by siRNA resulted in a significant decrease in proliferation in each of the TNBC cell lines. These observations suggest that CAV1 expression may contribute to the more aggressive phenotype observed in AA women diagnosed with TNBC.
ContributorsGetz, Julie (Author) / Baumbach-Reardon, Lisa L (Thesis advisor) / Lake, Douglas F (Thesis advisor) / Bussey, Kimberly (Committee member) / Kusumi, Kenro (Committee member) / Arizona State University (Publisher)
Created2015
Description
Thrombus (blood clot) formation is at the roots of hemostasis and pathological thrombosis. Although many studies have successfully elucidated the cellular and molecular mechanisms underlying thrombus formation, there is still a void in understanding the processes limiting thrombus growth beyond that needed for stabilization. As a hemostatic thrombus grows, its surface consisting primarily of platelets changes to that composed of fibrin, which mechanically stabilizes the thrombus. Formation of fibrin ceases after some time; however, it is unclear why this fibrin is non-thrombogenic. This is puzzling since fibrin is known to support strong integrin-mediated adhesion of both platelets and leukocytes in vitro. Therefore, it would be expected that the fibrin surface of hemostatic thrombi in the circulation also support accumulation of these cells and thus continuous thrombus growth or degradation. Nevertheless, many in vivo studies did not detect any accumulation of blood cells including platelets at the fibrin surfaces of thrombi. This finding suggests the existence of natural processes that modulate the adhesive properties of fibrin to ensure proper regulation of thrombus growth, stability and degradation. In this dissertation, I document and discuss the findings supporting the existence of anti-adhesive mechanisms and their physiological relevance in surface-mediated control of thrombus growth and stability. The studies discussed in my dissertation have the potential to establish a novel aspect of hemostasis. Furthermore, it may provide new insights into the intricate and dynamic interplay between the mechanisms underlying hemostatic balance, which is essential to understanding the dysfunction of this process during pathological conditions.
ContributorsOwaynat, Hadil (Author) / Chandler, Douglas E. (Thesis advisor) / Wilson-Rawls, Norma J (Committee member) / Lake, Douglas F (Committee member) / Baluch, Debra P (Committee member) / Arizona State University (Publisher)
Created2016