Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract.

PURPOSE: It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. EXPERIMENTAL DESIGN: Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, beta-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. RESULTS: Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 +/- 2.0%; high-grade dysplasia, 82.9 +/- 1.6%; cancer, 87.5 +/- 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. CONCLUSIONS: Bmi1 overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1 dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.     

Chenodeoxycholic acid stimulates the progression of human esophageal cancer cells: A possible mechanism of angiogenesis in patients with esophageal cancer

Bile acids are known to promote the growth of gastrointestinal cancer. However, the underlying mechanism remains unclear. We examined whether bile acids induce tumor growth via the cyclooxygenase (COX)-2 angiogenic pathway. In vitro, esophageal squamous cell carcinoma (ESCC) cells and esophageal adenocarcinoma cells were studied. Production of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) in response to treatment with chenodeoxycholic acid (CDCA) was assessed by enzyme-linked immunosorbent assay (ELISA). COX-2 protein and VEGF protein were measured by immunoblot analysis, and COX-2 activity was measured by ELISA. In vivo, CDCA was administered to ESCC cell-bearing mice. Tumor tissues were analyzed immunohistochemically, and microvessel density was evaluated. Clinically, 134 patients with ESCC who underwent esophagectomy were studied. In vitro, CDCA induced the production of PGE2 and VEGF in dose- and time-dependent manners, and these effects were attenuated by a selective COX-2 inhibitor, mitogen-activated protein kinases inhibitor, or epidermal growth factor receptor inhibitor. CDCA-induced COX-2 in the cell lysate increased the secretion of VEGF into the culture medium. In vivo, CDCA markedly enhanced tumor growth and increased vascularization. Clinically, patients whose tumors expressed both COX-2 and VEGF had poor outcomes. Our results suggest that bile acids, important constituents of duodenal fluid, stimulate the development of human esophageal cancer by promoting angiogenesis via the COX-2 pathway.     

Treatment of chronic hepatitis C patients complicated with the other disease

Because of relatively low efficacy, considerable side effect and high cost, HCV infected patients complicated with the other disease(patients with hematologic dysorders, chronic renal failure on hemodialysis, HIV co-infection and collagen disease) have been excluded from large trials evaluating the efficacy of IFN or in combination with ribabirin. So, little is known about treatment of these patients. We analyzed the medical literature focusing on treatment of HCV infection in these patients, to suggest conclusion about indication based on tolerance and efficacy. In case the other disease is well controlled and long term sevival is expected, treatment should be required based on the evaluation of liver function test including liver pathology for preventing liver disease from developing terminal stage. Further studies are needed to better define HCV therapies in these patients.     

A study on the clinical features of pulmonary tuberculosis in elderly patients

The clinical findings of pulmonary tuberculosis in elderly patients aged 75 years of age or older (elderly group) were compared with the middle-aged patients aged between 45 and 54 years of age (middle-aged group) and the young patients aged 34 years of age or younger (young group). The elderly patients who died in hospital were also compared with the elderly patients who survived. Study subjects were culture-positive pulmonary tuberculosis patients who were discharged from our hospital from December 1996 to November 1998. There were 79 patients in the elderly group, 95 in the middle-aged group, and 88 in the young group. The results were as follows. 1) The male/female ratio was significantly lower in the elderly group (1.9:1) than the middle-aged group (6.9:1). 2) Complication was noted more frequently in the elderly group. However, diabetes mellitus was noted less frequently in the elderly group (12.7%) than the middle-aged group (28.4%). 3) The frequency of cavitation was lower in the elderly group (59.5%) than the middle-aged group (87.4%). 4) The fever over 38 degrees C was noted less frequently in the elderly group (17.7%) than the other groups, while the frequency of the fever over 37 degrees C showed no significant difference between the elderly group and the other groups. 5) The frequencies of hypoalbuminemia and appetite loss were higher in the elderly group than the other groups. 6) The elderly group showed high mortality rate of 31.6%. The complication with cerebrovascular disease was noted significantly higher in the patients who died in hospital than those who survived. The frequency of widespread infiltrates, fever over 38 degrees C, neutrophilia, hypoalbuminemia and appetite loss were all significantly higher in the patients who died in hospital while their sputa were still positive on culture than those who survived. Our study clearly showed the features of elderly pulmonary tuberculosis patients in comparison with middle-aged patients and young patients. These features are very important to suspect the diagnosis of pulmonary tuberculosis in elderly patients with some atypical manifestation. Our study also suggests that the delay in diagnosing tuberculosis causes more frequently the patients' deterioration and death in elderly patients than in middle-aged patients and young patients.     

Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism in rabbits

OBJECTIVES: Clinical impact of magnesium (Mg) therapy remains controversial in acute myocardial infarction. We investigated the infarct size limiting effects of Mg and its mechanism in rabbits. METHODS: Anesthetized rabbits underwent 30 min coronary occlusion and 3 h reperfusion in ten groups: (1) Control, (2) Low Mg, (3) Mg, (4) High Mg, (5) calcium (Ca), (6) Mg+Ca, (7) 8-phenyltheophylline (8PT), an adenosine receptor blockade, (8) 8PT+Mg, (9) alpha, beta-methylene-adenosine diphosphate (AOPCP), a selective inhibitor of ecto-5'-nucleotidase, and (10) AOPCP+Mg groups. Infract size (IS) to area at risk (AR) was measured by triphenyltetrazorium chloride method. RESULTS: The IS/AR ratio was significantly smaller in Mg, 27+/-3% (P<0.05) and High Mg, 24+/-2% (P<0.05) compared to Control, 50+/-3% and Low Mg, 42+/-4%. The IS limiting effects of Mg were abolished in 8PT+Mg, AOPCP+Mg and Mg+Ca. The IS/AR ratio correlated with neither rate-pressure products nor incidence of arrhythmia. CONCLUSION: Magnesium administration has an infarct size limiting effect independent of its effects on myocardial oxygen consumption and incidence of arrhythmia in rabbits. The infarct size limiting effect of magnesium is attributable, at least in part, to augmentation of adenosine mechanism.     

Clinical characteristics of hepatitis B core antibody-positive hepatocellular carcinoma

The pathology and prognosis of hepatitis B surface antigen (HBsAg)-positive hepatocellular carcinoma (HCC) and hepatitis C virus antibody (HCVAb)-positive HCC is well documented. However, patients with HBsAg-negative/hepatitis B core antibody (HBcAb)-positive HCC are included with non-B non-C disease and have been characterized independently. A series of 125 patients who had undergone hepatectomy for HCC were divided into three groups and compared. The HBsAg group comprised 25 HBsAg-positive patients, the HCV group comprised 70 HCVAb-positive patients, and the HBcAb group comprised 22 HBcAb-positive/HBsAg-negative patients. Eight patients of negative virus markers were excluded in this study. Tumors were larger in the HBcAb group (6.2 cm) than in the HBsAg (4.4 cm) and HCV (3.7 cm) groups. Disease-free 1-, 3-, and 5-year survival rates were, respectively, 75.0%, 57.1%, and 57.1% in the HBcAb group; 60.9%, 41.8%, and 41.8% in the HBsAg group; and 88.0%, 54.0%, and 37.8% in the HCV group. HBcAb-positive HCC patients had larger tumors, but their prognosis was relatively good. Although HBsAg and HCVAb are used for conventional screening of patients with hepatic disorders, we believe that screening is also necessary in patients with positive HBcAb titers for early detection of HCC.     

Adenovirus-mediated wild-type p53 gene expression radiosensitizes non-small cell lung cancer cells but not normal lung fibroblasts

PURPOSE: We compared the ability of adenoviral-mediated wild-type p53 RPR/INGN201(Ad5/CMV/p53) to radiosensitize non-small cell lung carcinoma (NSCLC) and normal lung fibroblast cells. MATERIALS AND METHODS: NSCLC cell lines (A549 and H322) and human lung fibroblast cells (MRC-9 and CCD-16) were used in this study. Radiosensitivity was determined by clonogenic assay and tumor growth delay. Expression of p53, Bax, and p21WAF1 protein were evaluated by immunoblot. A FITC conjugate of annexin V was used for flow cytometric detection of apoptosis. RESULTS: Clonogenic and apoptotic assays indicated that Ad5/CMV/p53 enhanced the radiosensitivity of both NSCLC cell lines. On the other hand, the two normal human fibroblast cell lines appeared to be resistant to the cytotoxic effects of Ad5/CMV/p53 and were not radiosensitized compared to the NSCLC cells. According to immunoblot analysis, Bax expression was increased in the NSCLC cells treated with the combination therapy; Bax expression, however, was unchanged in normal cells. In in vivo studies, tumor growth suppression was enhanced by this combination strategy in xenograft tumors growing in nude mice compared to Ad5/CMV/p53 or radiation therapy when used alone. CONCLUSIONS: Our data indicate that therapy using Ad5/CMV/p53 and irradiation in combination is more effective than either treatment when used alone on NSCLC cells, is not limited to cells with defective endogenous p53, and does not enhance the radiosensitivity of normal cells.     

Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties associated with reduced cardiovascular disease and reduced cancer risk. To evaluate the possibility and potential mechanism(s) of which resveratrol inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis, 96 F344 male rats were divided into 10 groups and resveratrol (1 and 2 mg/kg) was administered orally or intraperitoneally (i.p.). In the groups in which resveratrol was administered at 2 mg/kg (orally, for 16 weeks), 1 and 2 mg/kg (i.p., for 16 weeks) and 1 mg/kg (i.p., for 20 weeks), the number of NMBA-induced esophageal tumors per rat was significantly reduced to 78, 62, 54 and 48, respectively (P < 0.05), and the size of maximum tumors in each group with resveratrol treatment was also significantly smaller than that in NMBA alone group (P < 0.05). Although the pathological examination did not indicate significantly decreased incidence of carcinomas by administering resveratrol, the tendency of carcinogensis suppression was observed (P = 0.177). Semi-quantitative RT-PCR and ELISA analysis demonstrated that following NMBA treatment, the expression of COX-1 mRNA was strongly present in tumor tissues, while weakly present in non-tissues; the expression of COX-2 mRNA was induced in both tumor and non-tumor tissues. The production of prostaglandin E(2) (PGE(2)) increased approximately 6-fold, compared with the normal esophageal mucosa. The higher expression of COX-1, the up-regulated COX-2 expression and the increased levels of PGE(2) synthesis were all significantly decreased by administering resveratrol. Our study suggests that resveratrol suppressed NMBA-induced rat esophageal tumorigenesis by targeting COXs and PGE(2), and therefore may be a promising natural anti-carcinogenesis agent for the prevention and treatment of human esophageal cancer.