In GERD patients, mucosal repair associated genes are upregulated in non-inflamed oesophageal epithelium.

Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6-12% and SAP > or = 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P-value < 1(E)- 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell-cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function.

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors.

In vitro evaluations of the selectivity of COX inhibitors are based on a great variety of experimental protocols. As a result, data available on cyclooxygenase (COX)-1/COX-2/5- lipoxygenase (LOX) selectivity of COX inhibitors lack consistency. We, therefore, performed a systematic analysis of the COX-1/COX-2/5-LOX selectivity of 14 compounds with selective COX inhibitory activity (Coxibs). The compounds belonged to different structural classes and were analyzed employing the well-recognized whole-blood assay. 5-LOX activity was also tested on isolated human polymorphonuclear leukocytes. Among COX inhibitors, celecoxib and ML-3000 (licofelone) inhibited 5-LOX in human neutrophils at micromolar ranges. Surprisingly, ML-3000 had no effect on 5-LOX product synthesis in whole-blood assay. In addition, we could show that inhibition of COX pathways did not increase the transformation of arachidonic acid by the 5-LOX pathway.

Fibroblast-matrix interactions in wound healing and fibrosis.

The regulation of matrix deposition is a key event in many physiological and pathological situations. It involves the activity of mediators in autocrine and paracrine fashions and the contact of cells with the surrounding extracellular matrix as well. The tightly regulated balance of both mechanisms guarantees rapid and adaptive cellular responses to meet changes in the biological requirements of the environment. Disturbances lead to wound healing defects or the development of fibrosis. The molecular mechanisms for these regulatory events are only partially understood, but involve the activity of integrins and a structural continuum of extracellular matrix-receptor-cytoskeleton-nucleus for transfer of information and the regulation of activated genes.

Charting the NCIC's future: stakeholder support for identified options.

The National Cancer Institute of Canada (NCIC) conducted a survey of representatives of its stakeholder populations (members of the cancer research and control communities, past and present NCIC grantees, senior administrators in academic institutions, NCIC governing committee representatives and major partners) to get input on proposals to restructure the NCIC's research programs. The survey results demonstrate support for changes that are likely to significantly alter how the NCIC operates as well as the programs it sponsors. The results suggest support for increasing the percentage of NCIC funds allocated to the Individual Operating Grants area and for changing the NCIC's programs and operating procedures. While there was widespread support for an NCIC-sponsored regional development initiative, many issues remain unresolved, such as what type of cancer research to develop within the provinces.

Issues for interpreting external stakeholder feedback on restructuring NCIC's research programs.

The National Cancer Institute of Canada surveyed members of its stakeholder groups on a number of issues pertaining to restructuring research programs. While it was hoped that the survey would ensure input from its primary stakeholder groups and thereby facilitate decision-making on critical issues like distribution of funds and research awards, there is reason to believe this may not have occurred. Some of the stakeholder groups seemed to be over-represented in the respondent population and the effect of this on the results was therefore examined. Analysis revealed several important issues: 1) a clear definition of who constitutes a "stakeholder" needs to be developed when stakeholder input-gathering is being contemplated; 2) multi-faceted strategies need to be developed to gain input from stakeholders; 3) potential sources of bias can emerge from the various techniques used to gather feedback from stakeholders; and 4) a clear outline of how the feedback is to be used in the decision-making process needs to be determined.