Celecoxib treatment alters the gene expression profile of normal colonic mucosa
ABSTRACT A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-beta signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-beta signaling.
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- "In animal models for IBD, direct inhibition of SMAD7 via application of antisense oligonucleotides in vivo resulted in lower production of inflammatory cytokines and less injury to intestinal tissues (Monteleone et al., 2008). Gene expression studies have observed SMAD7 underexpression in colonic mucosa following treatment with COX2 inhibitors (Glebov et al., 2006), and expression of members of the TGFB superfamily, including NSAID-activated gene 1/growth differentiation factor 15 (NAG1/GDF15), is known to be influenced by COX2 (Iguchi et al., 2009). The molecular mechanisms by which antiinflammatory medications would interact directly with SMAD7, specifically, are not yet apparent, and the ability of COX2 overexpression to alter TGFB functionality may very well take place through SMAD-independent pathways (Enders, 2007). "
ABSTRACT: Common single nucleotide polymorphisms (SNPs) in SMAD7 (18q21) have been linked to colorectal cancer (CRC) risk in genome-wide association studies, but little is known about their effects on survival. SMAD7 regulates gastrointestinal inflammation by inhibiting transforming growth factor-β (TGFB), which can act as both a tumor suppressor and a promoter of metastasis. Regular use of cyclooxygenase-2 (COX2) inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), reduces the risk of developing CRC. Because COX2 overexpression reduces the growth suppressing effects of TGFB, we hypothesized that survival may depend on both SMAD7 genotype and prediagnostic NSAID use. Postmenopausal women, ages 50-74, diagnosed with incident invasive CRC from 1997 to 2002 were identified using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. Information on prediagnostic NSAID use and other risk factors was ascertained by interview, and women were followed-up for survival through December 31, 2009. Seven hundred and twenty-seven cases were genotyped for two GWAS hits in SMAD7 with minor allele frequency > 30%, one with minor allele associated with decreased risk (rs4939827) and one with minor allele associated with increased risk (rs4464148). Two hundred and forty-two deaths occurred, 160 attributable to CRC. Among those without distant disease at diagnosis, CRC-specific survival differed by genotype only for NSAID users: each minor allele of rs4939827 was associated with worse survival [hazard ratio (HR) = 2.67, 95% confidence interval (CI): 1.33-5.37] and each minor allele of rs4464148 was associated with better survival (HR = 0.41, CI 0.18-0.94). SMAD7 variants known to be important for CRC risk were associated with disease-specific survival among prediagnostic NSAID users.Genes Chromosomes and Cancer 11/2011; 50(11):875-86. DOI:10.1002/gcc.20913 · 3.84 Impact Factor
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ABSTRACT: This paper presents a formula-based method for the design of IIR filters having more zeros than (nontrivial) poles. The filters are designed so that their square magnitude frequency responses are maximally-flat at ! = 0 and at ! = and are thereby generalizations of classical digital Butterworth filters. A main result of the paper is that, for a specified half-magnitude frequency and a specified number of zeros, there is only one valid way in which to split the zeros between z = Gamma1 and the passband. IIR filters having more zeros than poles are of interest, because often, to obtain a good trade-off between performance and the expense of implementation, just a few poles are best. 1. INTRODUCTION Probably the best known and most commonly used method for the design of IIR digital filters is the transformation of the classical analog filters (the Butterworth, Chebyshev I and II, and Elliptic filters) . One advantage of this technique is the existence of formulas for these filters...IEEE Transactions on Signal Processing 05/1998; 46(6). DOI:10.1109/78.678493 · 3.20 Impact Factor
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ABSTRACT: Cancer cells treated with the cyclooxygenase-2 inhibitor celecoxib show growth inhibition and induced apoptosis. This study was conducted to determine if the same processes are relevant to celecoxib's effects on human colorectal adenocarcinomas treated in vivo. A cohort of 23 patients with primary colorectal adenocarcinomas was randomised to receive a 7-d course of celecoxib (400mg b.i.d.) or no drug prior to surgical resection. Gene expression profiling was performed on resected adenocarcinomas from the cohort of patients. Using fold change (>1.5) and p-value (<0.05) cut-offs, 190 genes were differentially expressed between adenocarcinomas from patients receiving celecoxib and those that did not. The celecoxib pre-treated samples showed decreased expression levels in multiple genes involved in cellular lipid and glutathione metabolism; changes associated with diminished cellular proliferation. Celecoxib pre-treatment for 7 d in vivo is associated with alterations in colorectal adenocarcinoma gene expression which are suggestive of diminished cellular proliferation.European journal of cancer (Oxford, England: 1990) 08/2008; 44(12):1754-60. DOI:10.1016/j.ejca.2008.05.010 · 4.82 Impact Factor