Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although both sporadic colorectal cancer (CRC) and colitis-associated CRC arise from dysplastic precursor lesions and share several molecular alterations, the nature of the dysplasia and the frequency and timing of several of the key molecular changes differ enough to consider colitis-associated CRC a rather unique entity. To date, cancer surveillance in both ulcerative colitis and Crohn's colitis rests upon the detection of dysplasia. However, because there are considerable limitations to the detection and interpretation of dysplasia, there is a need for other molecular markers to complement the histologic analysis of dysplasia. Because patients with inflammatory bowel disease (IBD) undergo repeated, periodic surveillance colonoscopies, it affords an opportunity to study marker expression over time. Of the few markers that have been studied chronologically, aneuploidy, p53, and mucin-associated sialyl-Tn antigen expression each hold promise as markers of CRC risk in IBD. It will be important to study whether these markers, or other panels of gene or protein expression, can identify patients at highest risk for developing CRC in future clinical studies.
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PMID:Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice. 1270 69

The gastrointestinal epithelium is known to undergo constant and rapid renewal resulting in millions of cells being shed into the fecal stream every day. The conventional wisdom was that these cells disintegrate upon exfoliation and will not survive the transit through the intestinal tract. In 1990, we (P.N.) made the discovery that a significant number of these cells remain intact and viable and that they can be isolated. The implications of this important discovery became apparent when we demonstrated that these cells are exclusively of colonic origin, are anatomically representative of the entire colon, and can be used for clinical investigations of disease processes. The term coprocytobiology (CCB) was coined to encompass the broad range of applications of this new technology. The somatic cell sampling and recovery (SCSR) process involves the isolation of exfoliated colonocytes from a small sample of stool ( approximately 1 g) collected and transported in a unique medium at ambient temperature, providing cells for the detection of a number of biomarkers of disease propensity. These exfoliated colonocytes express cytokeratins indicating epithelial lineage as well as colon-specific antigen. Over the years, the study of exfoliated colonocytes has provided striking new insights into the biology of colon cancer and inflammatory bowel disease, including detection of p53 gene mutations, reverse transcriptase polymerase chain reaction amplification, and identification of CD44 splice variants, neoplasia-associated specific binding of plant lectins, and expression of COX-2, the inducible form of cyclooxygenase. The functional diversity of cells isolated by SCSR is revealed by the demonstration of cell surface markers such as secretory component, IgA, and IgG on the one hand and the amplification and cloning of the human insulin receptor and the expression of the multidrug resistance gene mdr-1 on the other hand. This review portrays the immense potential of CCB as a powerful tool for investigating the pathophysiology of disease, identifying genetic variants in pharmacogenetics, assessment of mucosal immunity, and several other applications that use somatic cells.
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PMID:Coprocytobiology: on the nature of cellular elements from stools in the pathophysiology of colonic disease. 1270 72

Ulcerative colitis and Crohn's disease (together known as Inflammatory Bowel Disease or IBD) are both associated with increased risk for colorectal cancer. Although it is conventional to emphasise differences between IBD-associated and sporadic colon cancer, such as a lower rate of Adenomatosis Polyposis Coli mutations and earlier p53 mutations, IBD-associated cancer has a similar dysplasia-cancer sequence to sporadic colon cancer, similar frequencies of major chromosomal abnormalities and of microsatellite instability and similar glycosylation changes. This suggests that IBD-associated colon cancer and sporadic colon cancer might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to suggest that both IBD-associated and sporadic colon cancer may be the consequence of bacteria-induced inflammation. We have speculated that the glycosylation changes might result in recruitment to the mucosa of bacterial and dietary lectins that might otherwise pass harmlessly though the gut lumen. These could then lead to increased inflammation and/or proliferation and thence to ulceration or cancer. The glycosylation changes include increased expression of onco-fetal carbohydrates, such as the galactose-terminated Thomsen-Friedenreich antigen (Gal beta1,3GalNAc alpha-), increased sialylation of terminal structures and reduced sulphation. These changes cannot readily be explained by alterations in glycosyltransferase activity but similar changes can be induced in vitro by alkalinisation of the Golgi lumen. Consequences of these changes may be relevant not only for cell-surface glycoconjugates but also for intracellular glycoconjugates.
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PMID:Altered glycosylation in inflammatory bowel disease: a possible role in cancer development. 1282 Jul 18

Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-kappaB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.
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PMID:Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. 1519 58

Increased cancer risk occurs in inflammatory bowel disease (IBD) undergoing long-term chronic inflammation. To evaluate whether inducible nitric oxide synthase (iNOS)-dependent DNA damage plays a role in the carcinogenic process triggered by IBD, we prepared a mouse model of IBD induced by transfer of CD45RBhighCD4+ T cells lacking regulatory T cells to female severe combined immunodeficiency (SCID) mice. CD45RBhighCD4+ T cells were isolated from mouse spleen after staining with fluorescein isothiocyanate (FITC)-conjugated anti-CD45RB monoclonal antibody, followed by anti-FITC-conjugated microbeads. This IBD mouse model showed that the bodyweight increased with aging to a lesser extent than non-treated controls, and that the intestine was shortened. Pathological findings of this mouse model, which showed severe inflammation in colon tissues, were similar to IBD patients. Double immunofluorescence technique revealed that both 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) were formed mainly in epithelial cells of the IBD mouse model. 8-Nitroguanine was formed in most of 8-oxodG-immunoreactive nuclei of epithelial cells. iNOS, proliferating cell nuclear antigen and p53 protein were also expressed in the colon epithelium. These results indicate that nitrative DNA damage, as well as oxidative DNA damage, is induced in colon epithelial cells of the IBD mouse model followed by proliferation of these cells, which may contribute to colon carcinogenesis.
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PMID:Inducible nitric oxide synthase-dependent DNA damage in mouse model of inflammatory bowel disease. 1577 18

Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both epsilondA and epsilondC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only epsilondC was found to be increased in affected colonic mucosa of Crohn's disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean epsilondC-levels in tissues were five- to ninefold higher than those of epsilondA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.
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PMID:Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis. 1677 90

Pathogenic mechanisms responsible for inflammatory bowel disease (IBD) are poorly understood. In an IBD animal model, the oral administration of polysaccharides such as dextran sulfate sodium (DSS) induces colitis, which exhibit several clinical and histological features for IBD. However, pathogenic factors in the development of colitis remain unclear. Therefore, we investigated possible mechanisms for DSS-induced colitis, and mainly focused on biological responses from an intestinal epithelial cell line, Caco-2. Cytotoxicity and cytokine release were measured using MTS assays and ELISA, respectively. The effect of DSS on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers was also evaluated. Cell cycle progression was estimated using antibodies directed against p53 and cdc-2 proteins. The generation of reactive oxygen species (ROS) was measured using a DCFH-DA method. Pyridylamino-DSS (PA-DSS) was used as a fluorometric label in order to investigate fluorescence-microscopically the location of DSS in Caco-2 cells. DSS induced cytotoxicity on Caco-2 cells at 5%. DSS also induced strong TEER decrease at 3%. DSS induced the weak release of IL-8, IL-6, and TGF-beta1. Remarkably DSS arrested Caco-2 cell cycle and reduced the intracellular generation of ROS. Under fluorescence microscopy, PA-DSS entered cells and bound to the nucleus, indicating this binding of DSS may be involved in the cell cycle arrest of Caco-2 cells. The cell cycle arrest and reduced intracellular generation of ROS may be involved during initiation or throughout the early stages of DSS-induced colitis.
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PMID:In vitro effects of dextran sulfate sodium on a Caco-2 cell line and plausible mechanisms for dextran sulfate sodium-induced colitis. 1708 61

A close association between inflammatory bowel disease (IBD) and increased risk of developing adenocarcinoma exists. Moreover, chronic induction of high levels of nitric oxide (NO) produced from inducible nitric oxide synthase (iNOS) is a consistent observation in IBD. In this study we made interleukin-10/inducible nitric oxide synthase double-deficient (IL-10(-/-)/iNOS(-/-)) mice and studied the development of adenocarcinoma. Mice >6 months of age were compared with healthy wild-type (WT) controls. Inflammation was assessed using macroscopic/histological scores and myeloperoxidase activity as an indication of granulocyte infiltration. Mucosal polyps were scored macroscopically and hyperproliferation was quantified by 5-bromo-2-deoxyuridine immunohistochemistry. Dysplastic changes were assessed histologically based on cytologic and architectured atypia as well as the presence of submucosal invasion. The p53 and beta-catenin messenger RNA mRNA and protein expression were assessed using real-time polymerase chain reaction and immunohistochemistry, respectively. Inflammatory indices were significantly elevated in interleukin-10-deficient (IL-10(-/-)) over WT and not significantly different from IL-10(-/-)/iNOS(-/-) mice. The incidence of mucosal polyps was similar between IL-10(-/-) (79%) and IL-10(-/-)/iNOS(-/-) (83%) mice; however, significantly higher numbers of polyps were observed in the absence of iNOS (P < 0.05). Hyperproliferation was noted in both groups. Signs of dysplasia and submucosal invasion were significantly higher in IL-10(-/-)/iNOS(-/-) compared with IL-10(-/-) mice (P < 0.05). No significant increase in p53 and beta-catenin mRNA levels was observed in IL-10(-/-) over WT mice; however, a 2-fold (P = 0.06) and 3-fold (P < 0.05) increase, respectively, was noted in IL-10(-/-)/iNOS(-/-) mice. Our data suggest exposure to chronic NO limits abnormal p53 and beta-catenin expression and reduces incidence of adenocarcinoma in IL-10(-/-) mice.
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PMID:Induction of inducible nitric oxide synthase: a protective mechanism in colitis-induced adenocarcinoma. 1711 28

Anti-TNF-alpha [anti-(tumour necrosis factor-alpha)] therapy is widely considered to be among the most efficient treatments available for rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. In the present study a tetravalent mini-antibody, named 'TNF-TeAb', was constructed by fusing the tetramerization domain of human p53 to the C-terminus of an anti-TNF-scFv [anti-(TNF-alpha-single-chain variable fragment)] via a long and flexible linking peptide derived from human serum albumin. TNF-TeAb was overexpressed as inclusion bodies in the cytoplasm of Escherichia coli, purified to homogeneity by immobilized- metal affinity chromtaography under denaturing conditions and produced in functional form by using an in vitro refolding system. In vitro bioactivity assays suggested that tetramerization of TNF-scFv resulted in an enormous gain in avidity, which endowed TNF-TeAb with a stronger ability to inhibit both receptor binding and cytolytic activity of TNF-alpha. TNF-alpha targeting therapy in rats with collagen-induced arthritis demonstrated that TNF-TeAb provided a much more significant therapeutic effect than did TNF-scFv in suppressing arthritis progression, attenuating inflammation and destruction in joints, and down-regulating pro-inflammatory cytokines and anti-(type II collagen) antibody. The conclusions are therefore (i) that multimerization of the antibody fragment by a self-association peptide is an efficient way to increase its avidity and (ii) that TNF-TeAb has potential applicability for anti-TNF-alpha therapy.
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PMID:Targeting TNF-alpha with a tetravalent mini-antibody TNF-TeAb. 1747 72

Here, we report on a patient with squamous cell carcinoma (SCC) arising from recurrent anal fistula. The patient was a 57-year-old woman who had 32-year history of having a recurrent perianal abscesses that ruptured spontaneously. Six months before her admission to our hospital, anal pain developed. She had no history of inflammatory bowel disease. Physical examination revealed three external fistulous openings at the two o'clock position, 2 cm from the anal verge. One internal opening in the lower rectum was found with proctoscopy. The patient underwent fistulectomy. Microscopic examination showed SCC arising from the anal fistula, which was accompanied by vessel invasion. The tumor was observed to be continuous from the external opening but was not exposed to the internal opening of the rectal mucosa. Because human papillomavirus (HPV) infection was suspected, immunohistochemical analysis was performed, but showed no HPV infection. Two weeks after fistulectomy, abdominoperineal resection with lymph node dissection was performed. Histopathological examination revealed no remnant cancer tissue or lymph node metastasis. She was discharged after surgery without complications. Eight years after the operation, she complained of constant pain during micturition. Urological examination revealed urinary bladder cancer, and transurethral resection of the bladder tumor was performed. Histopathological examination revealed transitional cell carcinoma of the urinary bladder. Two years later, the patient died of metastatic urinary bladder cancer, without recurrence of the fistula cancer. Because the patients mother had died of urinary bladder cancer and she herself had metachronous urinary bladder cancer in addition to fistula cancer, we investigated whether microsatellite instability (MSI) and chromosomal instability correlated with fistula cancer development. Immunohistochemical analysis of formalin-fixed, paraffin-embedded surgical tumor specimens for p53, MLH1, and MSH2 was performed. The tumor specimens showed no MLH1 expression but did show normal MSH2 expression. p53 was not expressed. Five microsatellite loci were examined using the tumor specimens to detect MSI, namely two loci with mononucleotide runs (i.e., BAT25 and BAT26) and three loci with dinucleotide repeats (i.e., APC, Mfd15, and D2S123). The tumor specimens showed alternations in the repeated sequences of two loci (i.e., BAT26 and D2S123). As a result, the tumor was classified as MSI-H (high) according to the Bethesda criteria. Our patient had MSI and one of the smallest reported SCCs arising from recurrent anal fistulae.
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PMID:Squamous cell carcinoma arising from recurrent anal fistula. 1787 4


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