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Biomedical subjects

T Muto

Publications and source records attributed to T Muto.

At least 19 recordsLinked to original sources
PubMed1999

Acquisition of glutamine synthetase expression in human hepatocarcinogenesis: relation to disease recurrence and possible regulation by ubiquitin-dependent proteolysis.

BACKGROUND: The authors previously reported increased ubiquitin (Ub) immunoreactivity in hepatocellular carcinomas (HCCs) and suggested a possible correlation between changes in ubiquitinated protein levels and multistep hepatocarcinogenesis. The current study was performed to identify one of these ubiquitinated proteins (42 kDa) and to analyze the clinical significance of its accumulation. METHODS: The protein was purified using two-dimensional gel electrophoresis and identified by amino acid sequence analysis. The authors studied the expression of this protein in 101 HCCs and 23 precancerous lesions by immunohistochemical methods and in 26 HCCs by immunoblot analysis. A survival analysis was performed on patients with advanced HCC using the Kaplan-Meier method with approximate chi-square statistics for the log rank test. RESULTS: The target protein for ubiquitination was identified as glutamine synthetase (GS). Accumulation of GS was found in 19 of 49 advanced HCCs (38.8%) by immunohistochemical methods and in 9 of 16 (56.3%) by immunoblot analysis, whereas the frequency was much lower in early HCCs (12.9% and 33.3%, respectively) and precancerous lesions (4.3% by immunostaining). In the Ub immunoblot analysis of strongly GS positive specimens, an intense 42-kDa ubiquitinated band was observed. Nine of 21 (42.9%) nodule-in-nodule type HCCs showed a GS positive, high-grade component within a GS negative, low-grade component, indicating the acquisition of GS expression during progression. Among 23 patients with a single advanced HCC nodule, the relapse free survival time was significantly shorter in the GS positive group than in the GS negative group. CONCLUSIONS: The results of this study demonstrate the acquisition of GS expression during hepatocarcinogenesis and the possible regulation of GS enzyme activity by a Ub-dependent proteolytic system. Moreover, GS might play a significant role in promoting the metastatic potential of HCC.

Amino Acid Sequence↗
PubMed1999

Association between duration of obesity and risk of non-insulin-dependent diabetes mellitus. The Sotetsu Study.

The authors investigated the association between duration of obesity (ordinary obesity as body mass index (BMI) (kg/m2) > or = 25.0 and extreme obesity as BMI > or = 27.8) and the risk of diabetes mellitus. Male employees of a railway company, aged 30 years or older, observed for 10 years or more, free from serious disease conditions, with initial BMI <25.0, aged 30 years or more at the time diabetes was diagnosed, and with complete data, were examined by univariate and multivariate analyses (n = 1,598). Age-adjusted odds ratios for diabetes were significantly increased among males who were obese for 10-19.9 years and >20 years (odds ratios = 2.10 and 2.84 for ordinary obesity and 6.14 and 4.15 for extreme obesity, respectively). Additional adjustment for current obesity, physical activity, smoking, drinking, family history, and observation period did not change the findings remarkably. In conclusion, > or = 10 years duration of ordinary obesity or > or = 1 year of extreme obesity was an important predictor for diabetes independent of age, current obesity, physical activity, smoking, drinking, family history, and observation period.

Adult↗
PubMed1999

Concomitant increase in neutrophil adhesion to inflammatory peritoneum and remote organs during peritonitis.

BACKGROUND: Neutrophils contribute to the host defense mechanism, but they can cause remote organ injury in peritonitis. The purpose of this study was to examine neutrophil adhesion to the peritoneum and remote organs simultaneously in peritonitis using a fluorescence microscopic method. STUDY DESIGN: Experiment 1: Sprague-Dawley rats (n = 16) were injected intraperitoneally (ip) with saline solution or 10(5), 10(7), or 10(9) Escherichia coli. Five hours after challenge, 1 x 10(6) fluorescein-labeled neutrophils were infused. Two minutes after neutrophil injection, five peritoneal samples (the greater omentum, mesentery, parietal peritoneum, colon, and ileum), both lungs, the liver, and the right kidney were harvested for counting of labeled neutrophils under epifluorescent microscopy. Lung myeloperoxidase (MPO) activity was also determined. Experiment 2: Rats (n = 23) were given 10(9) E. coli ip. Before challenge (0 h) or at 1, 5, or 10 h after challenge, labeled neutrophils were infused. Then, the labeled neutrophil numbers in organs and lung MPO activities were assessed as described for Experiment 1. Hemodynamic and arterial blood gas data were also obtained in another set of rats before and at 1, 5, 8 and 10 h after 10(9) E. coli ip challenge. RESULTS: Experiment 1: The labeled neutrophil numbers in the peritoneum, lungs, and kidney showed significant positive correlations with the injected bacterial numbers. Lung MPO also positively correlated with E. coli number and labeled neutrophil number in the lungs. Experiment 2: Labeled neutrophil numbers in the peritoneum and kidney peaked at 5 h. The pulmonary labeled neutrophil number rose, reaching a plateau at 5 h. No remarkable change was observed in the hepatic labeled neutrophil number. There was a positive correlation between lung MPO activity and pulmonary labeled neutrophil number. Hemodynamic and blood gas data reflected a hyperdynamic state. CONCLUSIONS: Concomitant dose-dependent increases in neutrophil adhesion in the peritoneum, lungs, and kidney were observed in this peritonitis model. Increased neutrophil adhesion was transient in the peritoneum and kidney but persistent in the lungs. Strategies modulating neutrophil adhesion in organs are anticipated to be useful for the treatment of peritonitis.

Animals↗
PubMed1999

Correlation of the therapeutic effect of activated tumor-draining lymph node cells with specific interferon-gamma production in vitro.

It has been established that lymphocytes obtained from tumor-draining lymph nodes (DLN) are sensitized to the tumor antigen in vivo. Moreover, after being activated in vitro, these cells can be utilized for adoptive immunotherapy. In the present study, DLN cells, obtained from C57BL/6 mice with fibrosarcoma (MC-1), were activated and expanded with anti-CD3 monoclonal antibody followed by culture with recombinant interleukin-2 (rIL-2). These CD4- CD8+ CD25+ CD44+ T-cells showed specific antitumor efficacy to the pulmonary micrometastases of an autologous tumor, against which lymphokine-activated killer cells were ineffective; however, they did not show cytolytic activity in vitro. The supernatant, obtained by coculturing the activated DLN cells with MC-1 cells, exhibited the specific production of interferon-gamma (IFN-gamma) which was enhanced by rIL-2. The therapeutic effect of the activated DLN cells correlated with the specific IFN-gamma production better than with the cytolytic activity.

Animals↗
PubMed1999

Organ-specific pancreatic tumor growth properties and tumor immunity.

We established a model of orthotopic injection of a syngeneic pancreatic tumor cell line in C57BL/6 mice and evaluated the effects of organ site on induction of immunity to a tumor-specific antigen, MUC1. Mice were challenged with a syngeneic pancreatic adenocarcinoma cell line that expressed MUC1 (Panc02-MUC1) by orthotopic injection into the pancreas, or by subcutaneous injection. Tumor cells injected into the pancreas grew much faster than those injected subcutaneously. Mice challenged subcutaneously with Panc02-MUC1 rejected tumors or developed slowly growing tumors that were negative for MUC1 expression. In contrast, mice challenged orthotopically into the pancreas developed progressive tumors that were positive for MUC1 expression. Sera from mice that rejected PancO2-MUC1 (tumor-immune mice) showed no detectable IgG1 and IgM titers against the MUC1 tandem-repeat peptide, whereas mice with progressive tumor growth had significant titers of IgG1 and IgM specific for MUC1. This suggests that the humoral immune response was ineffective in mediating tumor rejection. The results show that the growth properties and immunological rejection of pancreatic tumors is affected by the organ site at which the tumor grows.

Amino Acid Sequence↗
PubMed1999

Tachycardia as a potential risk indicator for coronary arterial lesions in Kawasaki disease.

UNLABELLED: Tachycardia is frequently observed in the acute phase of Kawasaki Disease (KD) patients. However, little is known about the association between the tachycardia in the acute phase of KD and the development of coronary arterial lesions (CAL). We examined the association between the mean 24 h heart rate in the acute phase of KD observed using 24 h ambulatory ECG monitoring (24 h-ECG) and the occurrence of CAL in patients. In a study conducted between 1994 and 1997, 26 patients with KD underwent 24 h-ECG within the febrile period and before the 9th day of illness. We compared the mean 24 h heart rate based on 24 h-ECG between patients with and those without CAL. Of 26 patients, 7 had CAL. The groups with and without CAL had similar baseline characteristics. The mean 24 h heart rate in the group with CAL was significantly higher than that in the group without CAL (144 +/- 14 vs. 124 +/- 22, P = 0.033). On multiple regression analysis, the mean 24 h heart rate was significantly correlated with the development of CAL (P = 0.019). CONCLUSION: Marked tachycardia detected by 24 h-ambulatory ECG monitoring in the acute phase of Kawasaki disease might provide important information on the development of coronary arterial lesions.

Acute Disease↗
PubMed1999

Enteral administration of glutamine in purulent peritonitis.

The intestinal hypomotility associated with purulent peritonitis is generally regarded as a contraindication to enteral nutrition. However, enteral nutrition may be feasible in suppurative peritonitis if administered with great caution, i.e., assuring the appropriate amount, delivery speed, and osmolality of the enteral formulation. Glutamine (Gln) increases muscle protein synthesis and decreases muscle protein degradation in sepsis, regardless of the route of administration. Therefore, administering small amounts of supplemental Gln via the enteral route to peritonitis patients may be beneficial. Two purulent peritonitis patients received L-Gln through a jejunostomy tube. The average amount of supplemental Gln was 16 g/d. Systemic inflammatory responses, i.e., high temperature and a high serum C-reactive protein level, persisted throughout the treatment period. Femoral arterial and venous blood samples were drawn simultaneously for determination of amino acid levels before and after 7 d of Gln supplementation. Enterally administered Gln was well-tolerated by both patients. There was an increase in plasma Gln levels after Gln supplementation. Moreover, the release of Gln, alanine, and phenylalanine from the lower extremities was lower after as compared to before Gln supplementation. Enteral administration of Gln may be feasible even in purulent peritonitis.

Amino Acids↗
PubMed1999

Effect of 5-fluorouracil on gastrointestinal carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

This study was undertaken to determine the effect of 5-fluorouracil on gastrointestinal carcinogenesis. Sixty rats were divided into three groups of 20 rats each. All rats were exposed to N-methyl-N'-nitro-N-nitrosoguanidine for the first 20 weeks. Group 1 rats received intraperitoneal injections of 5-fluorouracil for the first 20 weeks and were then observed for the second 20 weeks. Group 2 rats also received 5-fluorouracil injections, but for the second 20 weeks. Group 3 rats received no 5-fluorouracil treatment. Four of 20 rats in group 1 developed an invasive adenocarcinoma. In group 3, invasive squamous cell carcinoma and adenocarcinoma developed in one rat each. None of the group 2 rats had malignant lesions. These results suggested that 5-fluorouracil is not effective in suppressing the initial stage of gastrointestinal carcinogenesis with a coexisting carcinogen. Rather, the therapeutic effect is exerted in later stages of tumor progression.

Adenocarcinoma↗
PubMed1999

Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3.

Ulcerative colitis (UC), a common form of inflammatory bowel disease, is a multifactorial disorder with significant genetic influence. Recently, evidence of linkage on chromosome 7q near the intestinal mucin gene MUC3 was reported by an affected sib-pair analysis. Previous reports indicate a possible mucin abnormality in UC patients, but whether genetic differences in a specific mucin gene are associated with UC is unknown. Here we analysed polymorphisms of variable number of tandem repeats (VNTRs) within this gene using DNAs obtained from 243 Japanese (75 patients with UC and 168 controls), and to confirm the result we undertook a two-stage examination using 328 Caucasian samples (72 and 85 with UC in the first and second stages, respectively, and 171 controls). When the frequency of patients carrying one or two rare VNTR alleles was compared with that of controls, a significant increase was found first in Japanese patients (odds ratio 2.72, 95% CI 1.17-6.32, P = 0. 0308). In Caucasians, the odds ratio was 2.80 (95% CI 1.36-5.75, P = 0.0079) in the first stage, 2.43 (95% CI 1.20-4.92, P = 0.0196) in the second stage and 2.60 (95% CI 1.41-4.80, P = 0.0024) in total. The overall odds ratio was 2.64 (95% CI 1.60-4.33, P = 0.0001). This result suggests that rare alleles of the MUC3 gene may confer genetic predisposition to UC.

Alleles↗
PubMed1999

Histopathological prognostic factors influencing long-term prognosis after surgical resection for hepatic metastases from colorectal cancer.

OBJECTIVE: We aimed to present new histopathological features of metastatic liver nodules as more reliable prognostic factors after surgical resection for colorectal metastatic cancer. METHODS: Clinicopathological features, including newly proposed histopathological ones, of 63 consecutive patients were reviewed retrospectively to determine which most strongly correlated with long-term prognosis after hepatectomy for metastatic tumors from colorectal cancers, using univariate and multivariate analysis. RESULTS: The 1-, 3-, and 5-year cancer-related survival rates after hepatectomy were 87.8%, 55.2%, and 47.3%, respectively. New histopathological features we proposed, which are expansive growth, marginal fibrosis, and peritumorous lymphocytic infiltration of hepatic tumor, were significant prognostic factors for cancer-related survival after hepatectomy in an univariate analysis. Also in a multivariate analysis, i.e., a stepwise Cox regression analysis, infiltrative, i.e., not expansive, growth of hepatic tumor was one of significant and independent poor prognostic factors for survival after hepatectomy, with moderate to severe lymphatic vessel involvement of the primary colorectal lesion, microscopic cancer invasion at the surgical margin of hepatectomy, and extrahepatic distant metastases. CONCLUSIONS: Our results suggest that our proposed new histopathological features of hepatic metastases were good predictors of prognosis after surgical resection for hepatic metastases from colorectal cancer. Especially, infiltrative growth of hepatic tumor is strongly correlated with a poor prognosis after hepatectomy.

Colorectal Neoplasms↗
PubMed1999

Expression of vascular endothelial growth factor in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis.

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are proteins implicated in tumor-associated microvascular angiogenesis. Expressions of VEGF and bFGF in various stages of chemical-induced rat bladder carcinogenesis were immunohistochemically investigated. Thirty-two male 6-week-old Wistar rats were given drinking water containing 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 20 weeks. VEGF and bFGF were not detected in the normal bladder epithelium. In simple hyperplasia, intensive expression of VEGF was observed in a few epithelial cells, and the expression of epithelial VEGF became more pronounced in papillary or nodular (PN) hyperplasia and papilloma. In carcinoma, heterogeneous expression of VEGF was observed in focal tumor cells, intensely expressed in the invading tumor cells. Ultrastructurally, carcinoma cells showed VEGF immunoreactivity in the cytoplasmic matrix and some rough endoplasmic reticulum, and VEGF-positive and -negative carcinoma cells were also clearly defined. High levels of VEGF mRNA were observed in the carcinoma. However, bFGF was not detected in the epithelium throughout the carcinogenesis. Increased microvessel counts appeared at simple hyperplasia and became more pronounced in PN hyperplasia, papilloma, and carcinoma (F-test; P < 0.05). In the carcinoma, the microvessel counts of the VEGF-expressing tumor areas were significantly higher than that of the non-VEGF-expressing tumor areas (U-test; P < 0.05). The present study suggests that upregulation of epithelial VEGF may begin at a quite early stage in BBN-induced rat bladder carcinogenesis, but bFGF may not be involved.

Animals↗
PubMed1998

Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer.

Loss of heterozygosity (LOH) observed in human tumors strongly suggests the existence of (a) tumor-suppressor gene(s) at the concerned locus. A series of studies has revealed that LOH on the long arm of chromosome 5 (5q) frequently occurs in differentiated gastric adenocarcinomas. Furthermore, it has been shown that the interferon regulatory factor-1 (IRF-1) locus on chromosome 5q31.1 is one of the common minimal regions of LOH in these cancers. IRF-1 is a transcriptional activator that shows tumor-suppressor activity in the mouse. In the present study, we examined the sequence of the IRF-1 gene in 9 cases of histologically differentiated gastric adenocarcinomas, all of which exhibited LOH at the IRF-1 locus. We identified a mis-sense mutation in the residual allele in one case. This mutated form of IRF-1 showed markedly reduced transcriptional activity. In addition, overexpression of wild-type IRF-1 induced cell-cycle arrest, whereas such activity was attenuated in the mutant IRF-1. These results suggest that the loss of functional IRF-1 is critical for the development of human gastric cancers.

3T3 Cells↗
PubMed1998

Regular physical activity and coronary risk factors in Japanese men.

BACKGROUND: Physical activity decreases the risk of coronary heart disease (CHD), but its effects on risk factors require further exploration. METHODS AND RESULTS: The study included 3331 adult Japanese men in whom health benefits, especially CHD risk factors, were compared among those who were sedentary and those who were engaged in continuous physical activity of 30 minutes or more per day for 1, 2 and > or =3 days per week. Significantly higher HDL cholesterol values; lower triceps, scapula, and iliac subcutaneous fat thickness; and lower smoking rates were noted in all physically active groups compared with the sedentary group, whereas body mass index did not differ significantly. Waist-to-height ratios and the prevalence of fatty liver were significantly lower in the groups who exercised 2 or > or =3 days per week than in the sedentary group. The lowest triglyceride values were noted in the group who exercised > or =3 days per week. Multiple regression analysis revealed both the frequency of physical activity and smoking status to be independent positive and negative factors, respectively, for the HDL cholesterol value. The sum of the risk factor scores for hypertension, abnormal glucose tolerance, hypertriglyceridemia, hypercholesterolemia, and low HDL cholesterol level (one point for each if present) was highest in the sedentary group (1.38, 1.19, 1.19, 0.99 for the sedentary group and the groups who exercised 1, 2, and > or =3 days per week). CONCLUSIONS: Those who engaged in regular physical activity > or =3 days per week appeared to have the fewest coronary risk factors. However, even those engaged in physical activity once per week had fewer CHD risk factors than sedentary individuals.

Adult↗
PubMed1998

Nitric oxide donor decreases neutrophil adhesion in both lung and peritoneum during peritonitis.

BACKGROUND: As nitric oxide (NO) is an antiadhesive molecule, exogenous NO may modulate neutrophil adhesion in organs. This study was designed to examine the effects of the NO donor SNAP (S-nitroso-acetyl penicillamine) on neutrophil adhesion at the inflammatory site and in remote organs, in peritonitis using a fluorescent microscopic method. MATERIALS AND METHODS: In experiment 1, rats (n = 12) were given saline or 10 micrograms/kg of SNAP intravenously followed by continuous infusion of saline, or of 2, 20, or 200 micrograms/kg/h SNAP until sacrifice. Ten minutes after injection of saline or SNAP, 10(7) Escherichia coli were injected into the peritoneal cavity. Five hours after challenge, 10(6) fluorescein-labeled neutrophils were infused. Peritoneal samples, lungs, liver, and kidney were harvested for counting of labeled neutrophils under epifluorescent microscopy. In experiment 2, rats (n = 25) were treated with saline or 10 micrograms/kg of SNAP intravenously and infused with saline or 20 micrograms/kg/h SNAP; E. coli was injected as in experiment 1. Before or 5 h after challenge, hemodynamic data were obtained. Then, labeled neutrophils were infused for counting of neutrophil numbers in organs. Arterial blood gas data and the circulating neutrophil number were also determined. RESULTS: Experiment 1. Twenty and 200 micrograms/kg/h SNAP infusions tended to reduce labeled neutrophil numbers in lungs, while all three SNAP doses decreased the peritoneal labeled neutrophil numbers. RESULTS: Experiment 2. Five hours after bacterial injection, SNAP infusion simultaneously decreased both pulmonary and peritoneal labeled neutrophil numbers. SNAP had no effect on hemodynamic and blood gas data, or on circulating neutrophil numbers. CONCLUSION: NO donors may be useful for preventing neutrophil-associated lung injury, but should be used with caution in light of the possible adverse effects on host defense in the peritoneal cavity.

Animals↗
PubMed1998

Targeting strategy for gene delivery to carcinoembryonic antigen-producing cancer cells by retrovirus displaying a single-chain variable fragment antibody.

Cancer-specific antigens are promising targets for the specific delivery of certain drugs or genes to cancer cells in cancer therapy. Carcinoembryonic antigen (CEA) is one of the cancer-associated antigens predominantly detected in the gastrointestinal cancer of the colon and stomach. Targeting strategies for CEA-producing cancer cells have been thoroughly developed mainly by the production of monoclonal antibodies to CEA and further single-chain variable fragment (scFv) antibodies. Here, we have generated Moloney murine leukemia virus-derived retroviral vectors co-displaying an anti-CEA scFv-envelope chimeric protein and an unmodified envelope protein to deliver a gene for herpes simplex virus thymidine kinase (HSV-tk) or Escherichia coli beta-galactosidase. The harvested viruses successfully incorporated the chimeric envelope protein as well as the unmodified envelope into the viral particles, and specifically bound to and infected human CEA-producing cancer cells via recognition of CEA, depending on the CEA-producing phenotype of the target cells. These results may have significant implications for the use of scFv directed against tumor-specific antigens for targeting specific antigen-producing cancer cells, a potential step toward in vivo cancer therapy.

3T3 Cells↗
PubMed1998

Quantification and characterization of total cellular p53 protein in colorectal cancer.

Immunochemical methods were developed for the optimal detection and characterization of total cellular p53 protein expression, both in the nuclear-attached and soluble fractions of colorectal cancers, in order to improve the correlation between protein deregulation and gene status. Seventy colorectal carcinomas were studied using 3 monoclonal antibodies in a sensitive analyzing system combining flow cytometry (nuclear-bound fraction) and enzyme-linked immunosorbent assay (ELISA; soluble fraction). DNA indices were calculated on the DNA histograms and mutations of the p53 gene were searched for in a subset of 41 cases. Three p53 expression patterns were found: 35 tumors were classified as pattern "A," characterized by high p53 expression including "mutant" conformation and missense mutations of the gene (16/17 cases tested), pattern "B" consisted of 15 tumors with total absence of p53 expression corresponding to nonsense mutations of the gene (8/9 cases tested), and pattern "C" of 20 tumors presenting low or undetectable nuclear-bound p53 but intermediate p53 protein content (pAb (1801+) in the soluble fraction. The latter pattern was associated with wild-type genes (14/15 cases tested), and with tumors that were often localized in the right colon compared to pattern "A" and "B" tumors (45% versus 8%, P < 0.009) and were frequently near-diploid (80% versus 29%, P < 0.0002). No correlation was found between tumor stage and the patterns of p53 expression. The results indicate that both flow cytometry (FCM) and ELISA seem necessary for the proper characterization of the p53 expression pattern, thus achieving a high degree of concordance with molecular analysis of gene mutations.

Adenoma↗