Zonula occludens-1 distribution and barrier functions are affected by epithelial proliferation and turnover rates.

Zonula occludens-1 (ZO-1) is a scaffolding protein of tight junctions, which seal adjacent epithelial cells, that is also expressed in adherens junctions. The distribution pattern of ZO-1 differs among stratified squamous epithelia, including that between skin and oral buccal mucosa. However, the causes for this difference, and the mechanisms underlying ZO-1 spatial regulation, have yet to be elucidated. In this study, we showed that epithelial turnover and proliferation are associated with ZO-1 distribution in squamous epithelia. We tried to verify the regulation of ZO-1 by comparing normal skin and psoriasis, known as inflammatory skin disease with rapid turnover. We as well compared buccal mucosa and oral lichen planus, known as an inflammatory oral disease with a longer turnover interval. The imiquimod (IMQ) mouse model, often used as a psoriasis model, can promote cell proliferation. On the contrary, we peritoneally injected mice mitomycin C, which reduces cell proliferation. We examined whether IMQ and mitomycin C cause changes in the distribution and appearance of ZO-1. Human samples and mouse pharmacological models revealed that slower epithelial turnover/proliferation led to the confinement of ZO-1 to the uppermost part of squamous epithelia. In contrast, ZO-1 was widely distributed under conditions of faster cell turnover/proliferation. Cell culture experiments and mathematical modelling corroborated these ZO-1 distribution patterns. These findings demonstrate that ZO-1 distribution is affected by epithelial cell dynamics.

Factors regulating tumor pressure in cases of small hepatocellular carcinoma.

BACKGROUND/AIMS: There is scare information regarding tumor pressure in hepatocellular carcinoma. As the tumor diameter increases, histological manifestations become more diverse. Therefore, studies based on relatively small tumors are needed in order to search for those underlying factors that are directly related to tumor pressure in hepatocellular carcinoma. The purpose of this study was to determine which factors regulate tumor pressure in cases of hepatocellular carcinoma where the diameter of the tumor is 3cm or less. METHODOLOGY: The study included 54 patients with small hepatocellular carcinoma in whom tumor pressure had been determined and in whom the tumor had been confirmed histologically. Tumor pressure was determined percutaneously under ultrasonographic guidance. RESULTS: Hepatic tissue pressure (p = 0.01), tumor size (p < 0.01), number of tumors (p = 0.01), degree of tumor differentiation (p < 0.01), ultrasonographic halo (p < 0.01), angiographic tumor staining (p < 0.01) and angiographic tumor vessel (p = 0.03) all showed significant correlation with tumor pressure. Multivariate analysis revealed that angiographic tumor staining (p = 0.001), hepatic tissue pressure (p = 0.013), and tumor size (p = 0.044) were significant factors associated with tumor pressure. CONCLUSIONS: It was suggested that tumor pressure in small hepatocellular carcinoma was mainly regulated through development of the neovasculature.

Propagermanium: a nonspecific immune modulator for chronic hepatitis B.

Although antiviral agents have been adopted for the management of chronic hepatitis B, they have only limited efficacy because of the underlying impaired immune status. Propagermanium, a hydrophilic polymer of 3-oxygermyl propionate, has been reported to have potent immune modulatory activity associated with antiinflammatory and antineoplastic properties. For example, propagermanium augments lymphocyte functions in CD4 and CD8 cells, and in natural killer (NK) cells, and induces the production of several cytokines. A controlled pilot study of 16-week treatment with propagermanium for chronic hepatitis B (of moderate and mild grades on hepatic histology) revealed a sustained clearance of hepatitis B e (HBe) antigen and a favorable biochemical response at week 16 of treatment and at week 48 post-treatment. An open study also supported the clearance of hepatitis B virus from the blood and the possible improvement of histologic grading in the liver. There were few adverse events. A postmarketing survey, however, revealed the occurrence of moderate to severe liver damage after the treatment in about 4% of patients. Despite the exact nature of the liver damage being unclear, a putative cause is the swift removal of virus-infected hepatocytes by an immune reaction through the treatment. A subtle balance between host and viral conditions is the factor which most determines hepatitis B virus persistence. The rationale for a nonspecific immune modulator for the treatment of chronic hepatitis B will be the restoration of cellular immune responsiveness to viral infection. Although the cellular immunity for hepatitis B virus prior to the treatment should be studied, adequate observation of hepatic functions and viral markers in the recipients is clinically useful to predict liver failure during the treatment. In summary, the propagermanium regimen offers a potent and safe approach that is cost-effective for appropriate chronic hepatitis B patients with reserve hepatic capacity, and will provide new perspectives for immune therapy in chronic hepatitis B.

Usefulness of tumor pressure as a prognostic factor in cases of hepatocellular carcinoma where the diameter of the tumor is 3 cm or less.

BACKGROUND: The current study was designed to determine the usefulness of pretreatment tumor pressure as a new prognostic factor in patients with small hepatocellular carcinoma (HCC; 3 cm or smaller in diameter). METHODS: The study included 39 patients with small HCC in whom tumor pressure was determined. They underwent percutaneous ethanol (with Lipiodol) injection therapy (Lp-PEI) or transcatheter arterial embolization (TAE) of the hepatic artery. Tumor pressure was determined percutaneously under ultrasonographic guidance. The factors analyzed were age, gender, mean blood pressure, the presence/absence of antibody to hepatitis C virus (anti-HCV), alcohol abuse, Child's classification, the presence/absence of esophagogastric varices, serum alpha-fetoprotein (AFP) level, tumor size, number of tumors, degree of tumor differentiation, the presence/absence of tumor capsule, tumor pressure, and the method of treatment. Multivariate analysis using Cox proportional hazards model was conducted on the factors that may have affected prognosis (P < 0.25) according to the univariate analysis using a proportional hazards model. RESULTS: The rates of local and distant recurrence were higher (P < 0.01, P < 0.01, respectively) and the survival rate was lower (P = 0.03) in patients with high tumor pressure than in those with low tumor pressure. Multivariate analysis revealed that tumor pressure (P < 0.01), AFP level (P = 0.01), and age (P = 0.01) were significant predictive factors associated with local recurrence. Tumor pressure (P < 0.01) and AFP level (P < 0.01) were both significantly associated with distant recurrence. The only significant predictive factor associated with survival rate was tumor pressure (P < 0.04). CONCLUSIONS: The current study revealed that tumor pressure was associated significantly with survival rates after Lp-PEI or TAE in patients with small HCC. There were also significant predictive factors associated with local recurrence, these being tumor pressure, AFP level, and age, and with distant recurrence, namely, tumor pressure and AFP level. Tumor pressure measured before the initial treatment of patients with small HCC may be a useful new prognostic factor.