Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009324 (ulcerative colitis)
 17,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with ulcerative colitis who undergo proctocolectomy and an ileal anal anastomosis (IPAA) require surveillance; dysplasia and carcinoma occur in both the small intestinal mucosa of the ileal pouch and the retained rectal mucosa as early as 2 yr after ileostomy closure. This study evaluated risk factors for carcinoma (eg, dysplasia, p53 overexpression, labeling index, and aneuploidy) in the small intestinal and rectal mucosa. Thirty patients (age 14-64 yr) with ulcerative colitis and IPAA were studied. The mean duration of ulcerative colitis prior to IPAA was 3 yr (range 6 mo-21 yr). Patients were followed by annual endoscopy and biopsies of the ileal pouch and rectal mucosa. Sections of small intestine and rectal mucosa were evaluated for inflammation and dysplasia, and by immunohistochemical stains Ki-67 (MIB-1) for a labeling index and for p53. Ploidy determination was performed by flow cytometry. Active inflammation of the small intestinal mucosa and the rectal mucosa was frequent and the labeling index of both the pouch and rectal mucosa was abnormal. Two patients had changes indefinite for dysplasia, one involving the small bowel mucosa of the pouch and the other the retained rectal mucosa. Fifteen of the 30 patients had overexpression of p53, 9 from the pouch, and 6 from the rectal mucosa. Overexpression of p53 was seen in both of the patients with indefinite dysplasia. Aneuploidy was noted in 3 patients: two from the pouch and one from the rectal mucosa. All aneuploidic specimens were p53-positive, but negative for dysplasia. In conclusion, most biopsies of the ileal pouch and rectal mucosa were inflamed. The labeling indexes of the small bowel and rectal mucosa were higher than normal. The risk factors for carcinoma (dysplasia, overexpression of p53, and aneuploidy) occurred in the small intestinal and the rectal mucosa. Overexpression of p53 was noted in 16 patients, dysplasia only in 2. Therefore, p53 overexpression and aneuploidy should be considered in the evaluation of surveillance biopsies of patients with ulcerative colitis with IPAA, whereas dysplasia is an insensitive marker.
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PMID:Risk factors for carcinoma of the pelvic ileal pouch/anal canal in ulcerative colitis. 1522 25

In ulcerative colitis (UC)-associated tumours, p53 gene mutations and p53 protein overexpression are frequently found in early stages, but the two types of alteration do not always coincide. To clarify this discrepancy, p53 mutations and expression of p53-associated molecules were analysed in UC-associated dysplasias by a combination of microdissection, polymerase chain reaction-direct sequencing and immunohistochemistry at the single crypt level. Mismatch of p53 protein overexpression (+)/mutation (-) or p53 overexpression (-)/gene mutation (+) was found in nine crypts in regenerative mucosa (19 crypts), in 27 in low-grade dysplasia (41), in one in high-grade dysplasia (5) and in 12 in invasive carcinomas (17). Regarding these mismatched crypts of the first type, significant increase in p16(INK4A) and Bax expression was found. The Ki-67 labelling index was depressed in such p53-diffusely positive lesions with the wild-type p53 gene, compared to their p53-diffusely positive and mutant type counterparts. p16(INK4A) was upregulated indirectly as part of the negative feedback, and increase in Bax, directly controlled by wild-type p53, indicates upregulation of apoptosis. No significant relation with p53-related gene products was detected with the p53 protein overexpression (-)/p53 mutation (+) mismatch. Therefore, a tumorigenesis pathway independent of p53 dysfunction appears to exist in association with ulcerative colitis.
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PMID:Upregulation of p16(INK4A) and Bax in p53 wild/p53-overexpressing crypts in ulcerative colitis-associated tumours. 1529 38

During tumor progression, the accumulation in genetic alterations is a fundamental characteristic of malignant cells. p53 gene is frequently mutated in human tumor. Cellular accumulation of p53 protein can initiate an immune response with generation of circulating anti-p53 antibodies. Patients with ulcerative colitis have an increased risk of developing colorectal neoplasm and, among the different genes involved in carcinogenesis, p53 may play a key role. Sera and tissues from 97 patients (M = 53, F = 44) affected with ulcerative colitis (UC) were collected. Serum anti-p53 antibodies (p53Abs) were detected in duplicate with ELISA method. Serum p53Abs were detectable in 9.3% (9/97) of patients affected with UC. In these patients, the titer of p53Ab ranged between 3.1 and 14.9 U/mL (mean, 6.6 U/mL; SD, 4.64). Serum p53Abs were undetectable in control group. With an immunoluminometric assay for the quantitative determination of p53, we found 9/97 positive samples (> or = 0.69 mg/mg of total proteins). In contrast, the samples of the remaining 89 patients were found negative (< or = 0.30 mg/mg of total proteins). All patients that were positive for anti-p53 antibodies were also positive with p53 protein accumulation in the tissue of colonic biopsies. In UC, follow-up with colonoscopy has several advantages. The colonoscopy is not well accepted by patients, and poor patient observance has the potential to seriously devalue the technique as a screening tool, despite practical considerations of competence within endoscopy service. Serological detection of p53Abs by enzyme-linked immunosorbent assay (ELISA) is easy to perform, does not require tumor specimen, can be performed in a routine diagnostic procedure, may be used in clinical practice, and could facilitate physicians in patient monitoring. We suggest that serum p53Abs assessment, indirect marker for p53 gene mutations, and abnormally high p53 protein levels could be considered to have a potential for use as a complementary test to improve surveillance program performance.
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PMID:Serum p53 antibodies in patients affected with ulcerative colitis. 1547 22

Although a chronic inflammation-carcinoma sequence has been proposed in cases of longstanding ulcerative colitis (UC), the relationship of morphological alteration or remodeling of regenerated mucosa to carcinoma development is yet to be clarified. Therefore, mucosae of 49 resected rectae from individuals with UC were histologically and quantitatively analyzed, with regard to thickness and morphological parameters of crypts, in relation to the disease duration, clinical disease activity and neoplastic development. An immunohistochemical examination of Ki-67, p53, p21(WAF1) and ssDNA labeling was also included. Significant correlations of number, height, angle, fusion and Paneth cell metaplasia of crypts, as well as thickness of the muscularis mucosae, were revealed with disease duration, as confirmed by three-dimensional reconstructed image analysis. p53 and p21(WAF1)-positive cells increased with disease duration and were significantly more frequent in cases with neoplasia, suggesting more DNA damage. However, this was not the case for ssDNA labeling, assessed as an indicator of apoptosis. In general, histological changes and p53, p21(WAF1) and Ki-67 labeling were correlated. In conclusion, histological parameters for mucosal remodeling correlate well with UC duration, indicating accumulation of structural alterations. Accumulated damage to DNA, reflected by increased p53 and p21(WAF1) labeling indices, might be involved in cancer development, as well as longstanding inflammation.
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PMID:Significant correlation of morphological remodeling in ulcerative colitis with disease duration and between elevated p53 and p21 expression in rectal mucosa and neoplastic development. 1574 19

Chronic inflammation predisposes to cancer. We used an inflammation-induced human model of tumorigenesis to explore how populations of mutated cells expand and initiate the earliest stages of cancer. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with an increased risk of colorectal cancer mediated through a process of genomic instability. In order to characterize the process of clonal expansion, arbitrary primed (AR) and inter-simple sequence repeat (ISSR) PCR DNA fingerprint mutation profiles of single crypts were compared with the mutational profiles from clusters of crypts and whole biopsies within the same individual. To provide information at the earliest steps of neoplastic progression, we examined histologically negative crypts, as well as dysplastic crypts. Crypts from UC dysplasia/cancer show alterations in 10-20% of DNA fingerprint sites, regardless of (i) whether the crypts were dysplastic or non-dysplastic and (ii) whether the DNA came from one crypt or thousands of crypts. Of the mutational changes in single crypts, almost half are clonally expanded to adjacent crypts and/or to the thousands of crypts in a single biopsy. Using fluorescent in-situ hybridization to examine p53 alterations in individual crypt cells, we demonstrate that the mechanism of clonal expansion can occur through crypt fission. DNA alterations are initiated in colonic crypts and expand to adjacent crypts through crypt fission. Our data suggest that a continuous process of DNA mutations, clonal expansion through crypt fission and clonal succession initiates the development of inflammatory-associated colon cancer; this mutational process is moderated by crypt cell turn-over and cell death. This paradigm may apply to other inflammatory-induced cancers.
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PMID:The initiation of colon cancer in a chronic inflammatory setting. 1586 May 6

Although several genetic alterations have been identified in patients with ulcerative colitis (UC), it remains unclear whether these changes indicate an increased risk for malignancy. This paper analyzes the involvement of suppressor, mutator, and methylator pathways in malignant transformation associated with UC. A total of 60 colonic samples (47 affected non-neoplastic mucosa, 7 dysplasia, and 6 carcinoma) from 51 UC patients were analyzed for 22 microsatellite markers. p53 gene exons 5-8 were analyzed by single-strand conformational polymorphism, and APC gene by denaturing gradient gel electrophoresis (exons 1-14) and protein truncation test (exon 15). Methylation studies for MLH1 and CSPG2 genes were also performed. Microsatellite instability was absent in all samples whereas allelic imbalance (AI) and loss of heterozygosity (LOH) were detected mainly in samples with neoplastic transformation (P<0.0001). AI and/or LOH at loci located on chromosomes 5, 9, and 18 were significantly more frequent in neoplastic samples (P<0.01), as were TP53 gene mutations (P<0.007). A single mutation was detected for APC gene in a cancer sample. MLH1 gene methylation was absent in all analyzed samples, whereas CSPG2 gene methylation was detected in a single non-neoplastic sample. Our results suggest that the suppressor pathway plays the main role in UC associated tumorigenic progression. LOH at specific loci located on chromosomes 5, 9, and 18 appears to be specifically associated with malignancy risk.
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PMID:Who takes the lead in the development of ulcerative colitis-associated colorectal cancers: mutator, suppressor, or methylator pathway? 1615 3

We investigated the case of a 13-year-old male with juvenile polyposis (JP) to determine the extent of intraepithelial neoplasia and associated genetic changes, as well as cellular proliferation, within these polyps using immunohistochemistry with antibodies against p53, bcl-2, and Ki-67. Examination of the total proctocolectomy specimen revealed 70 polyps. The 18 largest polyps were investigated microscopically and disclosed the typical hamartomas with frequent erosions of the surface epithelium and reparative changes. Only one polyp showed focal low-grade intraepithelial neoplasia. The immunohistochemical studies revealed an expression of p53 and an abnormal Ki-67 pattern of the surface epithelium only within the neoplastic area. These findings may hint at a possible pathogenetic mechanism for the evolution of colorectal cancer in JP. As in ulcerative colitis, carcinomas in JP may develop along a dysplasia-carcinoma sequence resulting from permanent mechanical insults, inflammation, and repair rather than from an adenoma-carcinoma sequence as in familial adenomatous polyposis (FAP).
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PMID:Juvenile polyposis coli: a facultative precancerosis with some similarities to ulcerative colitis? 1616 47

With ulcerative colitis (UC)-associated tumorigenesis, p53 gene alteration is considered to be a key event. To clarify whether the p53-checkpoint is operating in foci of inflammation and that its disruption is a feature of UC-associated neoplasms, the present immunohistochemical study was conducted. Since accumulation of butyric acid with active UC is associated with apoptosis, effects of in vitro exposure of newly established UC-cancer derived cell lines to organic acids were also assessed. The regulatory subunit of ribonucleotide reductase, p53R2, was found to be localized with p53 in situ, and levels of p53, phospho-p53, p53R2 and inducible nitric oxide synthase were significantly intercorrelated. However, p53R2 expression was clearly reduced with progression through UC-associated dysplasia to carcinoma, demonstrating an inverse relation with p53 overexpression. In vitro treatment with butyrate or propionic acid, but not succinic acid, elicited a positive response in the p53-p53R2 system. Moreover, p53-dependent DNA repair, investigated by radioactive nucleotide incorporation, was induced by butyric acid and inhibited by short-interfering p53 and p53R2 RNAs. Therefore, it was concluded that the p53-p53R2-dependent DNA repair system is constitutively stimulated by butyric acid, which accumulates in UC inflammatory lesions. Since failure of the p53-G(1) checkpoint may cause dysfunction of repair under the influence of butyrate, gene alterations may increase and spread through the genome, leading to tumorigenesis.
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PMID:Disruption of the p53-p53r2 DNA repair system in ulcerative colitis contributes to colon tumorigenesis. 1620 88

Activation of the p53 network plays a central role in the inflammatory stress response associated with ulcerative colitis and may modulate cancer risk in patients afflicted with this chronic disease. Here, we describe the gene expression profiles associated with four microenvironmental components of the inflammatory response (NO*, H2O2, DNA replication arrest, and hypoxia) that result in p53 stabilization and activation. Isogenic HCT116 and HCT116 TP53-/- colon cancer cells were exposed to the NO* donor Sper/NO, H2O2, hypoxia, or hydroxyurea, and their mRNA was analyzed using oligonucleotide microarrays. Overall, 1,396 genes changed in a p53-dependent manner (P < 0.001), with the majority representing a "unique" profile for each condition. Only 14 genes were common to all four conditions. Included were eight known p53 target genes. Hierarchical sample clustering distinguished early (1 and 4 hours) from late responses (8, 12, and 24 hours), and each treatment was differentiated from the others. Overall, NO* and hypoxia stimulated similar transcriptional responses. Gene ontology analysis revealed cell cycle as a key feature of stress responses and confirmed the similarity between NO* and hypoxia. Cell cycle profiles analyzed by flow cytometry showed that NO* and hypoxia induced quiescent S-phase and G2-M arrest. Using a novel bioinformatic algorithm, we identified several putative p53-responsive elements among the genes induced in a p53-dependent manner, including four [KIAA0247, FLJ12484, p53CSV (HSPC132), and CNK (PLK3)] common to all exposures. In summary, the inflammatory stress response is a complex, integrated biological network in which p53 is a key molecular node regulating gene expression.
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PMID:The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. 1628 13

The link with chronic inflammation and cancer has been recognized for certain cancers for several decades. However, only recently has the biology of chronic inflammation begun to be understood, to the point that it may play a major role in tumour development. The biology of chronic inflammation has many similarities with that of wound healing. In particular, local cell mediated immunity is attenuated and angiogenesis is increased along with other growth factors. When present long-term, this provides the ideal environment for mutated cells to be nurtured and escape immune surveillance. It is of note that this process still appears to take two or three decades, as witnessed by the close association between chronic ulcerative colitis and colon cancer as well as chronic hepatitis and hepatocellular carcinoma. Closer study of the inflammatory pathways show the close interaction with apoptosis and anti-apoptotic pathways, as well as the main tumour suppressor genes, such as p53, as well as a number of growth factors, such as the insulin-like growth factor. A full study of these processes reveals that there are key molecules in these pathways which may provide therapeutic as well as anti-inflammatory targets.
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PMID:Inflammation and cancer: the role of the immune response and angiogenesis. 1661 Jul 1


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