Matching Items (4)
Filtering by
- All Subjects: Biomarkers
- All Subjects: African American women--Health and hygiene.
- Creators: Lake, Douglas F
Description
Coccidioidomycosis, or Valley fever, is an endemic pneumonia of the arid and semi-arid regions of North and South America and is responsible for up to 30% of community-acquired pneumonias in endemic and highly populated areas of the United States southwest. The causative agents of Valley fever are the dimorphic fungi Coccidioides immitis and Coccidioides posadasii, which grow as mycelia in the environment and spherules within the lungs of vulnerable hosts. The current diagnostics for Valley fever are severely lacking due to poor sensitivity and invasiveness, strongly contributing to a 23-day median time-to-diagnosis. There is a critical need for sensitive and non-invasive diagnostics for identifying Valley fever lung infections. The long-term goal of my work is to substantially shorten the time-to-diagnosis for Valley fever through the development of sensitive and specific breath-based diagnostics for coccidioidomycosis lung infections. Herein, I characterized the volatile organic compounds (VOCs) produced by C. immitis and C. posadasii in vitro and evaluated the relationship of the volatile metabolomes to lifecycle. I explored the VOC profiles of bronchoalveolar lavage fluid (BALF) samples from mouse model lung infections of Valley fever. Finally, I investigated the VOC profiles of BALF from persons with community-acquired pneumonia. All VOCs were analyzed by headspace solid-phase microextraction and comprehensive two-dimensional gas chromatography–time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS). The volatile metabolomes were compared using a variety of statistical analyses. For the in vitro samples, I detected a total of 353 VOCs that were at least two-fold more abundant in a Coccidioides culture versus medium controls and found the volatile metabolome of Coccidioides is more dependent on lifecycle than species. The mouse BALF samples indicate that lung infection VOCs are correlated to cytokine production and classify mice based on their individual level of infection. From the human BALF samples, I identified VOCs that were able to differentiate between Coccidioides and bacterial pneumonia. Combined, these studies suggest that Coccidioides spp. and the host produce volatile metabolites that may yield biomarkers for a Valley fever breath test.
ContributorsHiggins Keppler, Emily (Author) / Bean, Heather D (Thesis advisor) / Barker, Bridget M (Committee member) / Borges, Chad R (Committee member) / Lake, Douglas F (Committee member) / Arizona State University (Publisher)
Created2023
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
Biomarkers find a wide variety of applications in oncology from risk assessment to diagnosis and predicting and monitoring recurrence and response to therapy. Developing clinically useful biomarkers for cancer is faced with several challenges, including cancer heterogeneity and factors related to assay development and biomarker performance. Circulating biomarkers offer a rapid, cost-effective, and minimally-invasive window to disease and are ideal for population-based screening. Circulating immune biomarkers are stable, measurable, and can betray the underlying antigen when present below detection levels or even no longer present. This dissertation aims to investigate potential circulating immune biomarkers with applications in cancer detection and novel therapies. Over 600,000 cancers each year are attributed to the human papillomavirus (HPV), including cervical, anogenital and oropharyngeal cancers. A key challenge in understanding HPV immunobiology and developing immune biomarkers is the diversity of HPV types and the need for multiplexed display of HPV antigens. In Project 1, nucleic acid programmable protein arrays displaying the proteomes of 12 HPV types were developed and used for serum immunoprofiling of women with cervical lesions or invasive cervical cancer. These arrays provide a valuable high-throughput tool for measuring the breadth, specificity, heterogeneity, and cross-reactivity of the serologic response to HPV. Project 2 investigates potential biomarkers of immunity to the bacterial CRISPR/Cas9 system that is currently in clinical trials for cancer. Pre-existing B cell and T cell immune responses to Cas9 were detected in humans and Cas9 was modified to eliminate immunodominant epitopes while preserving its function and specificity. This dissertation broadens our understanding of the immunobiology of cervical cancer and provides insights into the immune profiles that could serve as biomarkers of various applications in cancer.
ContributorsEwaisha, Radwa Mohamed Emadeldin Mahmoud (Author) / Anderson, Karen S (Thesis advisor) / LaBaer, Joshua (Committee member) / Lake, Douglas F (Committee member) / Stout, Valerie (Committee member) / Arizona State University (Publisher)
Created2018
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