Investigations into the Influence of Chronic Colitis on Colonic Adenocarcinoma Cell Growth A Progress Report

Graduate Basi

Colitis Induced Microvascular Leak Triggers Colonic Dysmotility

Graduate Basi

Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis in human microvascular endothelial cells through altered intracellular signaling

The immunosuppressive agent cyclosporin A (CsA), a calcineurin inhibitor which blocks T cell activation has provided the pharmacologic foundation for organ transplantation. CsA exerts additional effects on non-immune cell populations and may adversely effect microvascular endothelial cells, contributing to chronic rejection, a long-term clinical complication and significant cause of mortality in solid-organ transplants, including patients with small bowel allografts. Growth of new blood vessels, or angiogenesis, is a critical homeostatic mechanism in organs and tissues, and regulates vascular populations in response to physiologic requirements. We hypothesized that CsA would inhibit the angiogenic capacity of human gut microvessels. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were used to evaluate CsA's effect on four in vitro measures of angiogenesis, including endothelial stress fiber assembly, migration, proliferation and tube formation, in response to the endothelial growth factor VEGF. We characterized the effect of CsA on intracellular signaling mechanisms following VEGF stimulation. CsA affected all VEGF induced angiogenic events assessed in HIMEC. CsA differentially inhibited signaling pathways which mediated distinct steps of the angiogenic process. CsA blocked VEGF induced nuclear translocation of the transcription factor NFAT, activation of p44/42 MAPK, and partially inhibited JNK and p38 MAPK. CsA differentially affected signaling cascades in a dose dependent fashion and completely blocked expression of COX-2, which was integrally linked to HIMEC angiogenesis. These data suggest that CsA inhibits the ability of microvascular endothelial cells to undergo angiogenesis, impairing vascular homeostatic mechanisms and contributing to the vasculopathy associated with chronic rejection

Oral Citrobacter-Secreting Shiga Toxin as a Model of Murine Shigellosis

Undergraduate Basi

The Tissue Microlocalisation and Cellular Expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 Is Correlated to Clinical Outcome in NSCLC

BACKGROUND: We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM) expression of proteins associated with M1 and M2 macrophages in NSCLC. METHODS: Using immunohistochemistry, CD68(+) macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14), or a non-cytotoxic M2 phenotype (CD163 and VEGF) were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES) (median 92.7 months) and 20 patients with poor survival (PS) (median 7.7 months). RESULTS: The NM expression of NM-HLA-DR (p<0.001), NM-iNOS (p = 0.02) and NM-MRP 8/14 (p = 0.02) was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (p<0.001). There was more NM-CD163 expression (p = 0.04) but less NM-iNOS (p = 0.002) and MRP 8/14 (p = 0.01) expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR p<0.001), 65.0% versus 14.6% (NM-iNOS p = 0.003), and 54.3% versus 22.2% (NM-MRP 8/14 p = 0.04), as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41) and 19.4% versus 59.0% (NM-VEGF p = 0.001). CONCLUSIONS: Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome

Sensor fusion for intelligent process control.

An integrated system for the fusion of product and process sensors and controls for production of flat glass was envisioned, having as its objective the maximization of throughput and product quality subject to emission limits, furnace refractory wear, and other constraints. Although the project was prematurely terminated, stopping the work short of its goal, the tasks that were completed show the value of the approach and objectives. Though the demonstration was to have been done on a flat glass production line, the approach is applicable to control of production in the other sectors of the glass industry. Furthermore, the system architecture is also applicable in other industries utilizing processes in which product uniformity is determined by ability to control feed composition, mixing, heating and cooling, chemical reactions, and physical processes such as distillation, crystallization, drying, etc. The first phase of the project, with Visteon Automotive Systems as industrial partner, was focused on simulation and control of the glass annealing lehr. That work produced the analysis and computer code that provide the foundation for model-based control of annealing lehrs during steady state operation and through color and thickness changes. In the second phase of the work, with PPG Industries as the industrial partner, the emphasis was on control of temperature and combustion stoichiometry in the melting furnace, to provide a wider operating window, improve product yield, and increase energy efficiency. A program of experiments with the furnace, CFD modeling and simulation, flow measurements, and sensor fusion was undertaken to provide the experimental and theoretical basis for an integrated, model-based control system utilizing the new infrastructure installed at the demonstration site for the purpose. In spite of the fact that the project was terminated during the first year of the second phase of the work, the results of these first steps toward implementation of model-based control were sufficient to demonstrate the value of the approach to improving the productivity of glass manufacture