Sex, Race, and Age Disparities in the Improvement of Survival for Gastrointestinal Cancer over Time.

There have been notable improvements in survival over the past 2 decades for gastrointestinal (GI) cancer. However, the degree of improvement by age, race, and sex remains unclear. We analyzed data from 9 population-based cancer registries included in the SEER program of the National Cancer Institute (SEER 9) in 1990 to 2009 (n = 288,337). The degree of survival improvement over time by age, race, and sex was longitudinally measured. From 1990 to 2009, improvements in survival were greater for younger age groups. For patients aged 20 to 49 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.74 (95% CI, 0.66-0.83), 0.49 (95% CI, 0.37-0.64), 0.69 (95% CI, 0.65-0.76), 0.62 (95% CI, 0.54-0.69), and 0.56 (95% CI, 0.42-0.76), for cancer of the stomach, small intestine, colon, rectum and anus, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. Compared with African Americans, whites experienced greater improvement in small intestinal and anal cancer survival. Female anal cancer and regional anal cancer patients experienced no improvement. Our data suggest that different improvement in survival in age, sex and race exists.

[CpG methyltransferase induced down-regulation of claudin-7, -8 and its effects on proliferation and apoptosis of human colorectal cancer HT-29 cells].

OBJECTIVE: To explore the regulatory effect of CpG methyltransferase (M.SssI) on expression of claudin-7 and claudin-8, promoting apoptosis and inhibiting proliferation of human colorectal cancer HT-29 cells. METHODS: HT-29 cells were treated with M.SssI (50 U/ml) for 24 hours. The methylation status of claudin-7 and claudin-8 gene promoters was assayed by bisulfite sequencing PCR (BSP). Real-time PCR with SYBR green I technique was used to detect the relative expression of claudin-7 and -8 mRNA, and claudin-7 and claudin-8 proteins were tested by cell immunofluorescence and Western blotting, while the effect on cell apoptosis was assessed by Hoechst 33342 fluorescence and flow cytometry. Inhibition of cell proliferation was measured by MTT assay. RESULTS: The amounts of methylated claudin-7 and claudin-8 gene CpGs were 25, 10 in the M.SssI group, 9 and 5 in the PBS group, 0 and 3 in the 5-azacytidine group, respectively. Compared with the PBS group, Claudin-7 and -8 were significantly reduced by M.SssI (P < 0.05), but increased by 5-azacytidine (P < 0.05) at both mRNA and protein levels. Hoechst 33342 staining revealed that HT-29 cells treated with PBS and 5-azacytidine were not significantly different, showing even blue fluorescence, round shape and same cell volume. But the M.SssI group presented more apoptotic cells with intensive white fluorescence intensity. Cytometry indicated that early apoptotic index of the M.SssI group was increased by 84.7%, compared with that of the PBS group (P = 0.002). Measurement of MTT optical density demonstrated that cell growth of the M.SssI group was significantly lower than that of the PBS group (P = 0.002), with an inhibition rate of 32.1%, whereas the proliferation of 5-azacytidine group was similar to that of the PBS group (P = 0.084). CONCLUSIONS: Our findings suggest that M.SssI can down-regulate claudin-7, -8 mRNA and proteins in the human colon cancer HT-29 cells by up-regulating methylation status of claudin-7 and -8 gene promoters, and finally induce apoptosis and inhibit proliferation of the tumor cells.

CXCR4 antagonist AMD3100 attenuates colonic damage in mice with experimental colitis.

AIM: To investigate the effects of the chemokine stromal cell-derived factor-1 (CXCL12) receptor (CXCR4) antagonist AMD3100 on colonic inflammation and epithelial barrier in dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Experimental colitis was induced by administration of 5% DSS for 7 d, and assays performed on intestinal segments from the ileocecal valve to the anus. Colonic morphology was examined by hematoxylin and eosin staining. Colonic cytokines were determined by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity (indicator of inflammatory infiltration) was observed spectrophotometrically. Gut permeability was assessed by mucosal-to-serosal clearance of fluorescein isothiocyanate-conjugated dextran 4000 (FD4) in everted gut sacs. The apoptosis of colonic epithelium was assessed by Hoechst-33342 staining. To further elucidate the role of CXCR4 in colonic inflammation, we also investigated the effect of AMD3100 on migration and cytokine production of isolated peripheral blood mononuclear cells (PBMCs). RESULTS: DSS-induced colitis was characterized by morphologic changes, as well as increased colonic cytokines, inflammatory infiltration, epithelial apoptosis, and intestinal permeability in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced; colonic tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) levels, as well as MPO activity were significantly decreased. Increased intestinal permeability in DSS-treated mice was significantly reduced by AMD3100. The number of apoptotic cells in colitis mice was markedly increased after DSS administration, and decreased when treated with the CXCR4 antagonist AMD3100. In pre-activated PBMCs, CXCL12 stimulation significantly increased the migration of PBMCs, and was inhibited by AMD3100. Moderately increased TNF-alpha, IL-6, and IFN-gamma from CXCL12-treated PBMCs were also reduced by AMD3100. CONCLUSION: The CXCR4 antagonist AMD3100 exerts therapeutic effects on experimental colitis by inhibiting colonic inflammation and enhancing epithelial barrier integrity.