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Personalized Molecular Therapies for Advanced Non-Small Cell Lung Cancer: Overcoming Heterogeneity to Optimize Treatment Response and Clinical Outcomes
Get PDFLung cancer remains one of the deadliest cancers. Novel, paradigm shifting treatments including immunotherapy and targeted therapies have recently been developed to cull the deadly effects of lung cancer, but many challenges remain. There remains a significant unmet need to accurately predict and optimally select for patients who will respond to immune checkpoint inhibitors (ICI) treatment. In Chapter 2 of this dissertation, we investigated a novel live single cell cytokine profiling lab-on-chip platform, IsoLight, using peripheral CD4+ and CD8+ T-cells for ICI biomarker development. A total of 55,175 single T-lymphocytes were analyzed in this proof-of-concept study. We found that an increase in overall polyfunctionality (PolyFx) and polyfunctional strength index (PSI) in single CD8+ T-cells, but not CD4+ T-cells, after 2 cycles of ICI correlated significantly with treatment response, with better performance than PD-L1 TPS (p=0.082) alone. When combined with PD-L1 TPS, the combined index correlated with ICI treatment response with kappa coefficient of 1.0 (p=0.003). Moreover, induction of CD4+ T-cells PSI (ΔPSI\u3e5) correlated with a strong trend of long-term treatment survival outcomes benefits (PFS; 3.9-fold; OS; 3-fold). Chapter 3 focuses on oncogene-addictive ALK-fusion NSCLC as our model for precision therapy drug resistance. We investigated the molecular genesis and evolution of rapid-onset precision therapy drug-tolerant persistence, using both genomics-matching cell lines, and patient-derived (Ma-ALK001.S) cell line and xenograft models. Together, we identified the tumoral autocrine TGFb2-PRC-2-EZH2/UTX-HOXB3 mediated signaling cascade as the key non-genetic epigenetic mechanism of the rapid-onset of ALK-TKI drug-tolerant persister cells, as early as between 8 hr to 14 days. Importantly, we found that EZH2/UTX could be leveraged as therapeutic vulnerabilities of the drug-tolerant persisters. Bulk RNA-sequencing and scRNA-seq bioinformatics analysis on the Ma-ALK001.S PDC under ALK-TKI alectinib identified 3 stages of transcriptomic reprogramming: Genesis (0, 3, 8 hr), Early (3, 6, 9 days), and Late stage (30, 60, 120 days). Pathway analysis nominated a crucial role of cAMP-PKA upregulated signaling in the persister cell states genesis, especially during the 8 hr - 3 days post-alectinib of plasticity reprogramming, associating with dominance of G2/M and G0/G1 cell cycle checkpoint arrest states. Importantly, pharmacologic inhibition with adenylyl cyclase activator forskolin, and inhibitor KH7 provides a promising preemptive treatment approach for drug-tolerant persistence for clinical outcomes improvement in oncogene-addictive NSCLC precision therapy. In summary, we developed strategies to optimize treatment response and clinical outcomes in both ICI- and precision therapy-treated NSCLCs
Power Safety Plan Checklist as an Intervention in the Operating Room
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Power Safety Plan Checklist as an Intervention in the Operating Room
Scott J. Fankhauser
Background: Intraoperative power failures (IOPF) force anesthesia providers to quickly make decisions to prevent patient harm when equipment does not operate as designed. Familiarity with alternative methods is critical during this decision process to deliver high-quality care during IOPF events. Purpose: The purpose of this project was to assess the impact of a checklist on anesthesia providers’ perceptions regarding continuation of care during an IOPF. Interventions: Pre- and post-intervention surveys were conducted during a simulation and education setting for annual competencies. Methods: The study describes a checklist intervention for IOPF in a level 1 academic medical center in the mid-Atlantic United States. The population of interest included anesthesia providers. The project promoted a streamlined approach to efficiently demonstrating patient care safety using the checklist. Results: The project entailed 45 participants during an annual competency day with 27 complete data points. The project found a normal distribution for 70% of Likert-scale questions and a statistical significance in the 80% for paired samples test. Conclusion: The post-intervention group demonstrated a positive relationship between the simulation and using a cognitive aid. All groups revealed an effective intervention for IOPF
Retrospective Feature Exhibits Section
Get PDFThis section of the WVU Art in the Libraries Retrospective (2015-2024) includes a summary of the large feature exhibitions
Retrospective: The Beginning, Section 1
Get PDFThis section of the WVU Art in the Libraries Retrospective (2015-2024) exhibition includes the history of the Art in the Libraries Program, including the first exhibitions and the forming of the committee
Taking It to the Street: Designing Archival Walking Tours for Cultural Heritage Months
Get PDFThis chapter discusses an archives-based walking tour piloted by a mid-size academic library as part of a campus-wide Hispanic Heritage Month celebration. Drawing on materials from university archives, the event served to highlight Latin@/x historical points of interest across campus. The chapter examines the significance of identity-specific programming for distinct BIPOC groups, details aspects of program planning and implementation, and offers practical suggestions and considerations for librarians seeking to offer similar culturally affirming programming. While the following case study discusses a walking tour event primarily designed to support the needs of Latin@/x students, strategies shared can be applied to walking tours targeting other minoritized ethnic groups or contexts outside Heritage Month celebrations
