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You searched for +publisher:"Vanderbilt University" +contributor:("Jonathan M. Irish, Ph.D."). Showing records 1 – 2 of 2 total matches.

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Vanderbilt University

1. Spurlock III, Charles Floyd. Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints.

Degree: PhD, Microbiology and Immunology, 2014, Vanderbilt University

Rheumatoid arthritis is the most common serious autoimmune disease affecting almost one percent of the human population worldwide. Methotrexate is the most commonly used disease-modifying agent in patients with rheumatoid arthritis. Despite decades-long experience with the use of methotrexate in this disease, the mechanisms responsible for its activity in rheumatoid arthritis are not very well understood. Through a series of biochemical approaches and in vivo studies in patients with rheumatoid arthritis, we have defined two novel pathways contributing to the anti-inflammatory effects of methotrexate in T cells. The first pathway is dependent upon blockade of tetrahydropbiopterin biosynthesis resulting in increased activation of c-Jun-N-terminal kinase, restoration of cell cycle checkpoint deficiencies, and reduced levels of nuclear factor kappa B, a master regulator of inflammation. Finally, we also discovered that methotrexate induces expression of the long, intergenic non-coding RNA, lincRNA-p21. Independent of methotrexate-mediated blockade of tetrahydrobiopterin and increased activity of c-Jun-N-terminal kinase, induction of lincRNA-p21 by methotrexate also reduces indices of inflammation via blockade of nuclear factor kappa B activity. Thus, multiple pathways are responsible for the immunomodulatory effects of methotrexate in the treatment of rheumatoid arthritis. Advisors/Committee Members: Subramaniam Sriram, M.B., B.S. (committee member), Jonathan M. Irish, Ph.D. (committee member), Amy S. Major, Ph.D. (committee member), Andrew J. Link, Ph.D. (chair), Thomas M. Aune, Ph.D. (committee member).

Subjects/Keywords: methotrexate; autoimmune disease; inflammation; rheumatoid arthritis; cell cycle checkpoints; c-Jun-N-terminal kinase; p53; tetrahydrobiopterin; long non-coding RNA

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Spurlock III, C. F. (2014). Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;

Chicago Manual of Style (16th Edition):

Spurlock III, Charles Floyd. “Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 26, 2019. http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;.

MLA Handbook (7th Edition):

Spurlock III, Charles Floyd. “Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints.” 2014. Web. 26 Apr 2019.

Vancouver:

Spurlock III CF. Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2019 Apr 26]. Available from: http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;.

Council of Science Editors:

Spurlock III CF. Methotrexate and Rheumatoid Arthritis: At the Crossroads Between Inflammation and Defects in Cell Cycle Checkpoints. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://etd.library.vanderbilt.edu//available/etd-03212014-091439/ ;

2. Diggins, Kirsten Elizabeth. Quantifying Cellular Heterogeneity in Cancer and the Microenvironment.

Degree: PhD, Cancer Biology, 2016, Vanderbilt University

In spite of recent advances in therapy, cancer remains a leading cause of death worldwide. Therapy response is often unpredictable and relapse frequently occurs. In many cases, this therapy resistance is attributed to subsets of therapy resistant cancer cells and surrounding stromal cells that support a resistant phenotype. A better understanding of cellular heterogeneity in cancer is therefore crucial in order to develop novel therapeutic strategies and improve patient outcomes. Experimental technologies like mass cytometry (CyTOF) allow for high-content, multi-parametric single-cell analysis of human tumor samples. However, analytical tools and workflows are still needed to standardize and automate the process of identifying and quantitatively describing cell populations in the resulting data. This dissertation presents a novel workflow for automated discovery and characterization of novel and rare cell subsets, quantification of cellular heterogeneity, and characterization of cells based on population-specific feature enrichment. First, a modular workflow is described that combines biaxial gating, dimensionality reduction, clustering, and hierarchically clustered heatmaps to maximize rare population discovery and to create an interpretable visualization of cell population characteristics. Next, a novel method is introduced for quantifying cellular heterogeneity based on two-dimensional mapping of cells in phenotypic space using tSNE analysis. Finally, an algorithmic method termed Marker Enrichment Modeling (MEM) is introduced that automatically quantifies population-specific feature enrichment and generates descriptive labels for cell populations based on their feature enrichment scores. MEM analysis is shown to identify features important to cell identity across multiple datasets, and MEM labels are effectively used to compare populations of cells across tissue types, experiments, institutions, and platforms. Going forward, the tools presented here lay the groundwork for novel computational methods for machine learning of cell identity and registering cell populations across studies or clinical endpoints. Automated methods for identifying and describing cell populations will enable rapid discovery of biologically and clinically relevant cells and contribute to the development of novel diagnostic, prognostic, and therapeutic approaches to cancer and other diseases. Advisors/Committee Members: Todd D. Giorgio, Ph.D. (committee member), Vito Quaranta, M.D. (chair), Jonathan M. Irish, Ph.D. (committee member), Melissa Skala, Ph.D. (committee member).

Subjects/Keywords: mass cytometry; computational analysis; cancer; immunology; flow cytometry; single-cell analysis; high-dimensional analysis

…following protocols approved by Vanderbilt University Medical Center (VUMC)… 

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Diggins, K. E. (2016). Quantifying Cellular Heterogeneity in Cancer and the Microenvironment. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-11282016-171056/ ;

Chicago Manual of Style (16th Edition):

Diggins, Kirsten Elizabeth. “Quantifying Cellular Heterogeneity in Cancer and the Microenvironment.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed April 26, 2019. http://etd.library.vanderbilt.edu/available/etd-11282016-171056/ ;.

MLA Handbook (7th Edition):

Diggins, Kirsten Elizabeth. “Quantifying Cellular Heterogeneity in Cancer and the Microenvironment.” 2016. Web. 26 Apr 2019.

Vancouver:

Diggins KE. Quantifying Cellular Heterogeneity in Cancer and the Microenvironment. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2019 Apr 26]. Available from: http://etd.library.vanderbilt.edu/available/etd-11282016-171056/ ;.

Council of Science Editors:

Diggins KE. Quantifying Cellular Heterogeneity in Cancer and the Microenvironment. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://etd.library.vanderbilt.edu/available/etd-11282016-171056/ ;

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