Analysis of the beta-catenin/T cell factor signaling pathway in 36 gastrointestinal and liver cancer cells.

We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the beta-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or beta-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear beta-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and beta-catenin suggests the involvement of other mechanisms than mutations of APC or beta-catenin.     

Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinoma in Haimen, China.

A case-control study was carried out to investigate the impact of factors including virus infection, aflatoxin B1, microcystins, smoking/drinking and dietary habits as well as genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1), on susceptibility to hepatocellular carcinoma (HCC) in Haimen, China. A total of 248 patients with HCC and 248 sex-, age- and residence-matched population-based controls were recruited into the study. Virus infection, and ALDH2 and CYP2E1 gene polymorphisms were assessed in 134 paired cases and controls. By univariate analysis, hepatitis B virus (HBV) infection (odds ratio [OR]=9.75; 95% confidence interval [CI]=4.71-20.2), history of intravenous injection (OR=1.50; 95%CI=1.02-2.22), average income (OR=0.63; 95%CI=0.43-0.92), frequent intake of foods rich in protein, e.g., egg (OR=0.6; 95%CI=0.42-0.87), chicken (OR=0.53; 95%CI=0.35-0.79), pork (OR=0.67; 95%CI=0.46-0.98) and fresh fish (OR=0.58; 95%CI=0.39-0.87) significantly differed between cases and controls. However, peanut intake (OR=0.66; 95%CI=0.43-1.01), source of drinking water, including tap (OR=1.33; 95%CI=0.81-2.20), deep well (OR=0.94; 95%CI=0.56-1.55), shallow well (OR=0.85; 95%CI=0.55=1.30), river (OR=0.95; 95%CI=0.65-1.38), ditch (OR=1.09; 95%CI=0.76-1.55) and pond water (OR=1.0; 95%CI=0.14-7.10) were not significantly associated with risk. Univariate analysis also indicated that the 1-1 genotype of ALDH2 (OR=1.38; 95%CI=0.86-2.23) as well as the Pst1- and Rsa1-digested c1/c1 genotype of CYP2E1 (OR=1.36; 95%CI=0.81-2.28), was slightly more frequent in the case group. On multivariate analysis, HBV infection (OR=13.9; 95%CI=5.78-33.6) and history of intravenous injection (OR=2.72; 95%CI=1.24-6.00) were still associated with significantly increased risk of HCC, while frequent intake of fresh fish (OR=0.32; 95%CI=0.12-0.86) decreased this risk. These findings suggest that whereas peanut intake, water sources as well as genetic polymorphisms in ALDH2 and CYP2E1 do not significantly correlate with the risk of HCC, HBV infection is a main risk factor, and dietary items rich in protein, especially fresh fish, might protect against the risk of HCC in Haimen, China.     

Analysis of the β-Catenin/T Cell Factor Signaling Pathway in 36 Gastrointestinal and Liver Cancer Cells

We investigated the frequency and mechanism of |bT-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the β-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or β-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear β-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and β-catenin suggests the involvement of other mechanisms than mutations of APC or β-catenin.     

Anti-murine Antibody Response to Mouse Monoclonal Antibodies in Cancer Patients

Although development of human anti-murine inununoglobulin antibody (HAMA) is often seen in patients receiving murine antibodies, the variety of methods used for detecting HAMA makes it difficult to compare directly the HAMA responses measured by different assays. In the present study, several parameters of the HAMA response to two murine monoclonal antibodies were evaluated. The anti-sialosyl Tn antibody MLS102 and anti-CA125 antibody 145-9, which were labeled with ¹¹¹ln, were injected intravenously into 17 colorectal cancer patients and 11 ovarian cancer patients for immnnoscintigraphy, respectively. HAMA was measured by enzyme-linked immunosorbent assay. There was no difference in baseline HAMA levels before antibody injection between the two groups. HAMA developed more frequently in ovarian cancer patients receiving the 145-9 antibody than in colorectal cancer patients receiving the MLS102 antibody (9/11 vs. 6/17, P <0.05). No significant difference was observed in maximal HAMA levels between the two groups of patients. However, time to reach the maximal levels was delayed and the duration of the response seemed longer in ovarian cancer patients. Among 11 patients receiving the 145-9 antibody three patients became positive for HAMA more than 2 months after antibody injection and the other two had HAMA activity in their sera for more than 17 months. HAMA response was different between the two antibodies, and late onset or long duration of HAMA response against the 145-9 antibody suggests the importance of HAMA measurement in patients who receive a second injection of murine antibodies even after a long interval.     

Serum and immunohistochemical studies of NCC-ST-439 in breast cancer

It has been thought that NCC-ST-439 antigen (ST-439) is a tumor-related carbohydrate antigen. The authors conducted serum and immunohistochemical studies to investigate the clinical significance of ST-439 in breast cancer. The level of serum ST-439 was elevated in advanced and recurrent breast cancers. In comparison with CEA and CA15–3, ST-439 was superior in sensitivity but inferior in specificity to these markers. The level of serum ST-439 showed no correlation with the levels of CEA or CA15–3. In the combination assay of these three markers, 80.6% of recurrent cases and 33.8% of primary cases were positive. Immunohistochemically, the expression of ST-439 was observed in 28.1% of noncancerous mammary duct epithelium and in 38.1% of the cancerous portion. From the above, we concluded that ST-439 was a tumor-related antigen and could be a tumor marker with high sensitivity in breast cancer. © 1993 Wiley-Liss, Inc.     

Ethanol-induced state-dependent learning is mediated by 5-hydroxytryptamine3 receptors but not byN-methyl-d-aspartate receptor complex

Involvement ofN-methyl-d-aspartate (NMDA) receptor complex and 5-hydroxytryptamine₃ (5-HT₃) receptors in state-dependent learning (SDL) induced by ethanol (EtOH) was investigated in the step-through passive avoidance task in rats. Pre-training injections of EtOH or MK-801 reduced step-through latency in the test session conducted 24 h after the training session. Pre-test as well as pre-training injections of EtOH failed to reduce the latency, while pre-training and pre-test injections of MK-801 reduced the latency. These results show that EtOH but not MK-801 produces SDL. SDL induced by EtOH was blocked by ICS205-930 injected before either the training or test session. However, ICS205-930 failed to block SDL induced by diazepam and muscimol. These results suggest that NMDA receptor complex may not be involved in SDL, and that 5-HT₃ receptors may contribute to SDL induced by EtOH but not by diazepam and muscimol.     

Adrenalectomy for Treatment of Cushing Syndrome: Results in 122 Patients and Long-Term Follow-up Studies

n = 122) who underwent adrenalectomy from 1957 through 1993 were reviewed for survival and complications. Of the 122 patients, 70 had adrenocortical adenoma, 30 Cushing’s disease, 6 primary pigmented nodular adrenocortical disease (PPNAD), 7 other types of primary nodular hyperplasia, 5 adrenocortical carcinoma, and 4 ectopic ACTH syndrome. Sixty-five patients with adrenocortical adenoma are alive, and the survival rate was equal to the age-matched control population, when patients who died of the postoperative complication were excluded. Of the patients with Cushing’s disease, 20 are alive; and 10 of 16 patients (63%) who were followed-up and evaluated had skin pigmentation. Four of sixteen patients (25%) developed Nelson’s syndrome. Four PPNAD patients and five with other types of nodular hyperplasia are alive. Most of these patients underwent bilateral total adrenalectomy, but some patients remitted after unilateral adrenalectomy. All of five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within 2 years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid cure of signs and symptoms of glucocorticoid excess after total adrenalectomy is ensured, and prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing’s disease.     

Esterase D phenotypes in north-eastern Japan

Summary Esterase D (EsD) was typed in 2,367 unrelated healthy blood donors from Yamagata and Miyagi districts, north-eastern area of Japan. The gene frequencies observed were: EsD¹=0.642, EsD²=0.358. In these blood donors two rare EsD phenotypes, EsD 3-2 and a new variant, were found. As for this new variant, the mode of hereditary transmission was discussed by family study.     

Entire colon aganglionosis,and extensive aganglionosis: Analysis of 94 cases in Japan

Incidence, sex distribution, length of the involved bowel, associated malformations, treatment and operative results were analysed in 94 cases of entire colon aganglionosis, 87 of which were collected from 42 institutions in Japan and seven treated in our department. In this series, 62 were entire colon aganglionosis and 32 were extensive aganglionosis. Incidence of entire colon aganglionosis was four per cent of all aganglionosis seen, and that of extensive aganglionosis was two per cent. Male: female ratio was 2∶1 in cases with entire colon aganglionosis and 1.3∶1 in extensive aganglionosis. Associated malformation was rare in both of entire colon, or extensive aganglionosis. Of the 94 cases, 41 cases survived neonatal period, and cure was obtained in 23 of entire colon aganglionosis and three of extensive aganglionosis.     

Repeated administration of alpha-galactosyl ceramide attenuates of natural killer T cells

alpha-Galactosyl ceramide (alpha-GalCer) is well known as a specific ligand which can activate natural killer T (NKT) cells. This drug potentially induces anti-tumor effect of NKT cells, and clinical trials for alpha-GalCer in cancer patients are ongoing in the world. The aim of this study is to investigate how repeated alpha-GalCer injection affects the activation of NKT cells in mice. The initial administration of alpha-GalCer triggered a rapid production of both IFN-gamma and IL-4 in NKT cells and induced subsequent apoptosis in the majority of those cells. Meanwhile, no increase in IFN-gamma production was observed after further injections, and NKT cells maintained the low level secretion of IL-4 since the first injection. After repeated alpha-GalCer administration, activation markers on NKT cells were down-regulated and autologous cytotoxicity against liver cells decreased, suggesting that repeated stimulation attenuates the response of NKT cells to the ligand. These data indicate that prudent discussion is required to determine the dosing interval of alpha-GalCer in clinical applications. A further study is needed for establishing effective methods of sustained NKT cell activation.