To develop an efficient animal model for colitis-related carcinogenesis, male Crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic colonic carcinogen, azoxymethane (AOM), and a 1-week oral exposure (2% in drinking water) to a non-genotoxic carcinogen, dextran sodium sulfate (DSS), under various protocols. At week 20, colonic neoplasms (adenocarcinomas, 100% incidence with 5.60 ± ± ± ±2.42 multiplicity; and adenomas, 38% incidence with 0.20 ± ± ± ±0.40 multiplicity) with dysplastic lesions developed in mice treated with AOM followed by DSS. Protocols in which AOM was given during or after DSS administration induced a few tubular adenomas or no tumors in the colon. Immunohistochemical investigation of such dysplasias and neoplasms revealed that all lesions were positive for β β β β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase, but did not show p53 immunoreactivity. The results indicate that 1-week administration of 2% DSS after initiation with a low dose of AOM exerts a powerful tumor-promoting activity in colon carcinogenesis in male ICR mice, and may provide a novel mouse model for investigating colitis-related colon carcinogenesis and for identifying xenobiotics with modifying effects. (Cancer Sci 2003; 94: 965-973) n the developed world, colorectal cancer (CRC) is one of the commonest non-smoking related cancers. This malignancy is one of the most serious complications of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), 1,2) and the risk of CRC increases with increasing extent and duration of the disease.Animal experiments are assumed to simulate or at least provide plausible pathophysiological mechanisms in various diseases including cancer and inflammatory disorders. For IBD and IBD-related CRC, several animal models have been reported. The most widely used is a mouse model with dextran sodium sulfate (DSS).3) There are a number of reports on modifying effects of xenobiotics on CRC-related colon carcinogenesis in this model 4,5) : folic acid, short chain fatty acid (butyrate), ursodeoxycholic acid, nonsteroidal anti-inflammatory drugs (NSAIDs)/cyclooxygenase (COX)-2 inhibitors, and 5-aminosalicylic acid (5-ASA) were found to inhibit the occurrence of UC-related CRC. However, this colitis model using DSS with or without carcinogen needs a long period or repeated administration of DSS to induce colitis and colitis-related CRC, and the incidence and/or multiplicity of induced tumors are relatively low.6) Many studies have suggested that chronic or repeated mucosal inflammation may result in carcinogenesis through mechanisms such as induction of genetic mutations, increased cryptal cell proliferation, changes in crypt cell metabolism, changes in bile acid enterohepatic circulation, and alterations in bacteria flora. 7,8) These ideas are consistent with the hypothesis that chronic inflammation could be associated with epithelial malignant neoplasia in the large bowel. 8) We recently reported c...

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

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Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fedcontrol mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.

Aim-To investigate the colonisation with Bifidobacterium breve of the bowels of very low birthweight (VLBW) infants. Methods-The adverse eVects of B breve were examined in 66 VLBW infants (preliminary study). A prospective randomised clinical study of 91 VLBW infants was also completed and these infants were followed up for three years. Precise viable bacterial counts of serial stool specimens were examined for the first eight weeks after birth in 10 infants. The colonisation rates of administered bacteria were examined using immunohistochemical staining of stool specimens with a B breve specific monoclonal antibody. Results-In the preliminary study there were no side eVects attributable to the bacteria. Immunohistochemical staining of stool specimens showed that the colonisation rates of the administered bacteria were 73% at 2 weeks of age, but only 12% in the control group. Early administration of B breve significantly decreased aspirated air volume from the stomach and improved weight gain. Conclusions-B breve can colonise the immature bowel very eVectively and is associated with fewer abnormal abdominal signs and better weight gain in VLBW infants, probably as a result of stabilisation of their intestinal flora and accelerated feeding schedules. (Arch Dis Child 1997;76:F101-F107)

Specific age distribution of right-sided colon cancer was observed and the difference between male and female patients was highlighted. Other clinical features also differed between right- and left-sided colon cancer, suggesting that different mechanisms may be at work during right and left colon carcinogenesis.

This is the first report to demonstrate consistent and profound elevation of hs-CRP in cases of NASH compared with in cases of simple nonprogressive steatosis. Our results suggest that hs-CRP may be a clinical feature that not only distinguishes NASH from simple nonprogressive steatosis but also indicates the severity of hepatic fibrosis in cases of NASH.