Cyclins D1, D2 and D3 play important roles in cell proliferation and differentiation. Although their abnormal expression has been linked to cancer development and progression in a number of tissues, the expression of cyclin D2 and D3 proteins in colon cancer has not yet been characterised. In this study, we examined cyclin D1, D2 and D3 protein expression by Western blot analysis in tumour and adjacent normal colon tissues of 57 patients. In addition, we examined D-type cyclins protein expression in HT29 and LoVo39 cell lines from colon carcinomas, as a function of induced proliferation and differentiation. In both cell lines, the expression of the three D-type cyclins increased as a result of induced proliferation, whereas the expression of cyclin D3 increased as a result of induced differentiation. In colon tumours, cyclin D1 was overexpressed in 44%, cyclin D2 was overexpressed in 53% and cyclin D3 was overexpressed in 35% of the cases. We also found that in 16% of the cases, cyclin D3 protein expression was reduced in the tumour, as compared to the adjacent normal tissue. Examination of D-type cyclin protein overexpression in relation to the TNM stage of the tumours revealed that overexpression of cyclins D1 and/or D2, but not cyclin D3, is linked to colon carcinogenesis and that overexpression of cyclin D2 may be related to a higher TNM stage of the tumour.

The prevalence of AIH in Israel is quite similar to that of other European Caucasian populations, with a relatively long-term good prognosis, despite a low rate of response to immunosuppressive therapy.

Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined. Experimental Design: A/J × C57BL6/J mice with wild-type Egfr (Egfr wt ) or loss-offunction waved-2 Egfr (Egfr wa2 ) received azoxymethane followed by standard (5% fat) or western-style (20% fat) diet. As F 1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and realtime PCR. Results: Egfr wt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfr wa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2% versus 36.7%; P < 0.05) and cancer incidence (43.9% versus 16.7%; P < 0.05) only in Egfr wt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfr wt mice. In tumors, dietary fat and Egfr wt upregulated transforming growth factor-α, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfr wt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor-α in normal colon. Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):6780-9)

Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased h-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-h, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal^regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.Colonic carcinogenesis is characterized by the accumulation of activating mutations in proto-oncogenes and inhibiting mutations in tumor suppressor genes. These mutations dysregulate pathways, including epidermal growth factor receptor (EGFR) signals that control cell growth, maturation, and cell death. Up-regulations of EGFRs and ligands have been described in many tumors, including colon cancers (1). Recently, we reported that EGFR signals were up-regulated in human aberrant crypt foci (ACF) identified in situ using image magnification chromoendoscopy (2). ACF are the earliest identifiable lesions in experimental colonic carcinogenesis and dysplastic ACF are believed to be precursors of colon cancer (3).EGFR (ErbB1) is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2, ErbB3, and ErbB4 (4). Ligand binding induces a conformational change, causing receptors to dimerize and activating the receptor's intrinsic tyrosine kinase. ErbB2 is unique in that it has no identified ligand, but is the preferred heterodimeric partner for other members. EGFR signals activate multiple pathways i...

Autoimmune skin diseases are characterized by dysregulation of the immune system resulting in a loss of tolerance to skin self-antigen(s). The prolonged interaction between the bacterium and host immune mechanisms makes Helicobacter pylori (H. pylori) a plausible infectious agent for triggering autoimmunity. Epidemiological and experimental data now point to a strong relation of H. pylori infection on the development of many extragastric diseases, including several allergic and autoimmune diseases. H. pylori antigens activate cross-reactive T cells and induce autoantibodies production. Microbial heat shock proteins (HSP) play an important role of in the pathogenesis of autoimmune diseases because of the high level of sequence homology with human HSP. Eradication of H. pylori infection has been shown to be effective in some patients with chronic autoimmune urticaria, psoriasis, alopecia areata and Schoenlein-Henoch purpura. There is conflicting and controversial data regarding the association of H. pylori infection with Behçet's disease, scleroderma and autoimmune bullous diseases. No data are available evaluating the association of H. pylori infection with other skin autoimmune diseases, such as vitiligo, cutaneous lupus erythematosus and dermatomyositis. The epidemiological and experimental evidence for a possible role of H. pylori infection in skin autoimmune diseases are the subject of this review.

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The optimal methodology for the identification of colonization by potential respiratory pathogens (PRP) in adults is not well established. The objectives of the present study were to compare the sensitivities of sampling the nasopharynx and the oropharynx for identification of PRP colonization and to compare the sensitivities of samples from the nasopharynx by swab and by washing for the same purpose. The study included 500 participants with a mean age of 65.1 ؎ 17.8 years. Of these, 300 patients were hospitalized for acute febrile lower respiratory tract infection and 200 were controls. Each participant was sampled by oropharyngeal swab (OPS), nasopharyngeal swab (NPS), and nasopharyngeal washing (NPW). The samples were tested by conventional bacteriological methods to identify Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. OPS detected colonization by S. pneumoniae in 30% of the subjects compared with 89% by NPS and NPW (P < 0.000001). The corresponding rates for H. influenzae were 49% and 64%, respectively (no significant difference [NS]), and for M. catarrhalis were 72% and 46%, respectively (P < 0.0004). NPS identified 61% of the cases of colonization with S. pneumoniae, compared with 76% by NPW (NS). The corresponding rates for H. influenzae were 31% and 56%, respectively (P < 0.04), and for M. catarrhalis were 39% and 33%, respectively (NS). We conclude that the sensitivities of nasopharyngeal and oropharyngeal sampling for identification of PRP colonization in adults are different for each of the three bacteria in this category. The combined results of sampling from both sites are necessary to obtain a true picture of the rate of colonization. NPW is superior to NPS.Colonization of the mucosal membrane of the nasopharynx and the oropharynx by the potential respiratory pathogens (PRP), Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, has several clinical manifestations. In most cases colonization causes only a carrier state without producing clinical symptoms, but, if a change occurs in the host's condition, the PRP can cause disease (3). In addition, the bacteria that are carried in the upper respiratory tract can spread from person to person (6, 7, 10), which is why their presence can provide useful and important information on the emergence of resistance in clinical isolates (8,11).Age is the most influential factor in the rate of colonization by PRP in healthy individuals. The maximal rates seen in preschool children decline during the school years and decline sharply in adults (5, 6). The high colonization rates in the pediatric age group are the reason that the vast majority of studies on this issue were conducted on this age group, while the number of studies that evaluated PRP colonization in adults is small (3). In these circumstances, it is not surprising that even the basic methodology to test for colonization in adults is not well established. The present study was designed to deal with one of the aspects of this issue.The two technique...

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