Global ETD Search

41	Lack of CFTR in CD3+ Lymphocytes Leads to Aberrant Cytokine Secretion and Hyper-Inflammatory Adaptive Immune Responses: A Master's Thesis Mueller, Christian 24 April 2012 (has links) Background: Cystic fibrosis (CF) remains the most common fatal monogenic disease in the US, affecting 1 in 3,300 live births. CF is the result of mutations in CFTR, a chloride channel and regulator of other ion channels. The mechanisms by which CFTR mutations cause chronic lung disease in CF are not fully defined, but may include the combined effects of altered ion and water transport across the airway epithelium and aberrant inflammatory and immune responses to pathogens within the airways. We have shown that Cftr-/- mice mount an exaggerated IgE response towards Aspergillus fumigatus (Af) when compared to Cftr+/+ mice. Along with the increased IgE levels, the Cftr-/- mice had higher levels of IL-13 and IL-4, mimicking both the Th-2 biased immune responses and predilection to mounting Af-specifc IgE seen in CF patients. Herein we hypothesize that these immune aberrations are primarily due to the lack of Cftr expression in lymphocytes rather than with Cftr deficiency in the epithelium. Results: Our results indicate that adoptive transfer experiments with Cf splenocytes confer higher IgE response to Af in host mice as compared to hosts receiving wild-type splenocytes. The predilection of Cftr-deficient lymphocytes to mount Th2 responses was confirmed by in vitro antigen recall experiments, where higher levels of IL-13 and IL-4 where seen only in the presence of Cftr-deficient lymphocytes. Conclusive data on this phenomenon were obtained with conditional Cftr knockout mice, where mice lacking Cftr in T-cell lineages developed the higher IgE titers as compared to their wild-type littermate controls. Further analysis of Cftr-deficient lymphocytes revealed an enhanced intracellular Ca 2+ flux in response to T cell receptor activation as compared to normal lymphocytes. This was accompanied by a significant increase in nuclear localization of the calcium-sensitive transcription factor NFAT, which could contribute to the enhanced secretion of IL-13 and other cytokines. Conclusions: In summary, our data identified that CFTR dysfunction in T cells can lead directly to aberrant immune responses. This is the first instance that a CF related phenotype has been entirely modeled in vivo by selectively knocking out CFTR in the immune system. Specifically, Cftr deficient lymphocytes directed skewed responses to Aspergillus fumigatus , leading to a higher than normal IgE response. These findings implicate the lymphocyte population as a potentially important target for therapeutics directed to the treatment of CF lung disease. Cytokines Lymphocytes Mutation Antigens CD3 Amino Acids, Peptides, and Proteins Biological Factors Cells Digestive System Diseases Hemic and Immune Systems Immunology and Infectious Disease Life Sciences Medicine and Health Sciences Respiratory Tract Diseases
42	Reversing Cancer Cell Fate: Driving Therapeutic Differentiation of Hepatoblastoma to Functional Hepatocyte-Like Cells Smith, Jordan L. 20 March 2020 (has links) Background & Aims: Despite advances in surgical care and chemotherapeutic regimens, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and β-Catenin co-activation occurs in 80% of children’s HB; however, a lack of conditional genetic models precludes exploration of tumor maintenance and therapeutic targets. Thus, the clinical need for a targeted therapy remains unmet. Given the predominance of YAP1 and β-catenin activation in children’s tumors, I sought to evaluate YAP1 as a therapeutic target in HB. Approach & Results: Herein, I engineered the first conditional murine model of HB using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A, constitutive β-CateninDelN90, and a luciferase reporter to murine liver. Tumor regression was evaluated using in vivo bioluminescent imaging, and tumor landscape characterized using RNA sequencing, ATAC sequencing and DNA foot-printing. Here I show that YAP1 withdrawal in mice mediates >90% tumor regression with survival for 230+ days. Mechanistically, YAP1 withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative “hbHep cells.” hbHep cells have hepatocyte-like morphology and partially restored mature hepatocyte gene expression. YAP1 withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and can rescue liver damage in mice. Conclusions: YAP1 withdrawal, without modulation of oncogenic β-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. Modulating YAP1 expression alone is sufficient to drive long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes. Therapeutic Differentiation Targeted Therapy Pediatric Cancer Oncogene Liver cancer Mouse Model Conditional Model Genetic Inducible Hepatoblastoma Oncogene Addiction Tumor Dormancy Drug Discovery YAP B-Catenin Hydrodynamic Injection Sleeping Beauty System Tranposase Lineage Tracing Cancer Biology Cell Biology Digestive System Digestive System Diseases Disease Modeling Gastroenterology Genetic Processes Genetics Hepatology Laboratory and Basic Science Research Medical Molecular Biology Molecular Genetics Neoplasms Oncology Pediatrics Translational Medical Research
43	The Effectiveness Of Interventions And Bundles For Central Line-Associated Bloodstream Infections In The Neonatal Intensive Care Unit Alhamwi, Mohamad 01 January 2018 (has links) Introduction: Central Line-Associated Bloodstream Infections (CLABSIs) are a major cause of increased mortality, morbidity and healthcare costs in neonatal intensive care units (NICUs) patients. Despite CDC's efforts to reduce infection rates, patients often suffer consequences. The objective of this study is to perform a systematic review of strategies utilized in the neonatal population and evaluate them with the current CDC's guidelines to assess the effectiveness of bundles in preventing CLABSI in NICUs. Methods: A systematic literature search was conducted using CINAHL Plus with Text, Cochrane Database of Systematic Reviews and MEDLINE from January 2008 up to 2018. There were multiple search terms used and these included "neonate OR newborn OR infant", "CLABSI OR central line-associated bloodstream infection", "intervention OR prevention" and "bundle". The search solely focused on the outcome of infant patients. Therefore studies were excluded for the following criteria: being non-peer reviewed, being published before 2008, and being a case in which CLABSI was assessed in patients outside the NICU. See Table 4 and 5 for further information. Results: Eight articles were eligible for inclusion all of which CDC's guidelines were implemented in their strategy of intervention. The systematic review showed that adherence to care bundles decreases infection rates drastically. All eight articles reported a significant decrease in CLABSI rates following the implementation of the bundle set by CDC with two studies achieving a CLABSI rate of zero. Author's Conclusion: Implementation of care bundles showed a success in reducing CLABSI rates in the NICUs; however none of the studies endorsed a specific bundle application utilized to achieve its intended goal. Some practices adopted CDC's guidelines more than others and those showed a greater decrease in infection rate. In addition, it is evident that nurses deliver the best care when preventing an infection. Further research is needed to assess the effectiveness of a specific bundle element. CLABSI CLABSI Prevention CABSI Bundle Neonatal CLABSI prevention central venous catheters quality improvement Neonatal CLABSI CLABSI Bundle NICU Cardiovascular Diseases Clinical Epidemiology Community Health and Preventive Medicine Critical Care Emergency Medicine Epidemiology Equipment and Supplies Health and Medical Administration Health Information Technology Health Services Administration Health Services Research Investigative Techniques Maternal and Child Health Patient Safety Pediatrics Preventive Medicine Public Health Education and Promotion

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