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Biomedical subjects

Sumio Kawata

Publications and source records attributed to Sumio Kawata.

At least 37 records · Page 2Linked to original sources
PubMed2005

A case of primary biliary cirrhosis accompanied with fibrinogen storage disease.

We report the first case of primary biliary cirrhosis (PBC) accompanied by fibrinogen storage disease (FSD). A 50-year-old Japanese woman had been treated for numbness of her right-side extremities for 5 years. Mildly elevated serum levels of alkaline phosphatase and gamma-glutamyl transferase were detected. The titers of both anti-mitochondrial (x 320) and anti-mitochondrial M2 (x 84) antibodies were elevated. The biopsied liver specimen showed mononuclear cell infiltrate densely encircling the bile ducts, poorly developed epithelioid cell granuloma, and loss of integrity of bile duct organization, which permitted a diagnosis of stage I PBC according to Scheuer's histologic classification. In addition, round to oval, eosinophilic, homogenous intracytoplasmic inclusions, several microm in average size, with a surrounding halo were found in the vast majority of hepatocytes. These inclusions were negative for the periodic acid-Schiff reaction. In immunohistochemistry, the inclusions were positive for fibrinogen and complement C3c, but not for HBs antigen and alpha1-antitrypsin. These findings were identical to FSD. To investigate the mechanism(s) of abnormal fibrinogen storage, immunostaining for heat shock protein 70 and ubiquitin was performed. The former was detected in all intracytoplasmic inclusions, whereas the latter was detected in only some inclusions, suggesting a partial loss of ubiquitin expression.

Alkaline Phosphatase↗
PubMed2005

Expression of tumor suppressor and tumor-related proteins in differentiated carcinoma, undifferentiated carcinoma with tubular component and pure undifferentiated carcinoma of the stomach.

BACKGROUND: The recent development of tissue microarray (TMA) technology allows high-throughput protein expression profiling of cancer tissues by immunohistochemistry. We attempted to clarify the derivation of undifferentiated-type gastric carcinoma with tubular component by using TMA. METHODS: We constructed a TMA system composed of six paraffin blocks in which 274 samples of formalin-fixed gastric carcinoma tissue from 274 patients were embedded. Using this system, we performed immunohistochemical stains for five tumor suppressor and tumor-related proteins, i.e. p53, p16, hMLH1, c-erbB-2 and carcinoembryonic antigen (CEA). The 274 gastric carcinomas were histopathologically divided into the following three groups according to the degree of differentiation: differentiated-type (D-type), undifferentiated-type with tubular component (UT-type) and pure undifferentiated-type (UP-type). Immunohistochemical results were then compared with histological types. RESULTS: The percentages of abnormal expression of each protein in D-type, UT-type and UP-type carcinomas were as follows: 27% (38/143), 17% (17/98) and 15% (5/33) for p53; 27% (39/143), 19% (19/98) and 18% (6/33) for p16; 38% (54/143), 44% (43/98) and 24% (8/33) for hMLH1; 15% (22/143), 5% (5/98) and 0% (0/33) for c-erbB-2; and 22% (31/143), 35% (34/98) and 70% (23/33) for CEA. UP-type carcinomas exhibited the lowest frequencies of abnormal expression for p53, p16, hMLH1 and c-erbB-2, but the highest frequencies for CEA. UT-type carcinomas generally showed intermediate frequencies between those of D-type and UP-type carcinomas. Differences between D-type and UP-type for c-erbB-2 (P < 0.05) and CEA (P < 0.001) were significant, as were differences between D-type and UT-type for c-erbB-2 (P < 0.05) and CEA (P < 0.05), and differences between UT-type and UP-type for hMLH1 (P < 0.05) and CEA (P < 0.001). CONCLUSIONS: These findings reveal that gastric carcinomas have distinct expression profiles for tumor suppressor and tumor-related proteins depending on histological types, and support the hypothesis that UT-type carcinomas are derived not only from D-type but also from UP-type carcinomas. We also found significant differences between abnormal protein expression and other clinicopathological parameters such as gender, age and status of tumor and nodes.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Expression of Notch signalling markers in bone marrow cells that differentiate into a liver cell lineage in a rat transplant model.

Notch signalling pathway plays an important role in cell differentiation. To investigate the implications of Notch signalling in the differentiation of rat bone marrow (BM) cells into a liver cell lineage, we used cultured BM cells to examine the mRNA expression of Musashi-1, which positively regulates Notch signalling, and made a transplant model to examine the protein expression of Notch signalling markers. For the in vivo experiment, BM cells were collected from transgenic rats expressing green fluorescence protein (GFP) and transplanted into the spleens of recipient rats, in which liver damage had been induced with carbon tetrachloride. The expression of Notch receptor 1 (Notch-1), Jagged-1 and Musashi-1, in the transplanted GFP-positive BM cells was investigated by immunohistochemistry. The expression of the liver-specific proteins, alpha-fetoprotein and cytokeratin19 was also investigated. Musashi-1 mRNA became detectable in the BM cells on culture day 7 in vitro. After transplantation, GFP-positive BM cells were observed in the portal areas of the recipient's livers. Notch-1, Jagged-1, Musashi-1, alpha-fetoprotein and cytokeratin19 were all expressed in the transplanted BM cells. These results suggest that the Notch signalling pathway plays a role in the differentiation of BM cells into a liver cell lineage.

Journal Article↗
PubMed2004

Hypermethylation of Chfr and hMLH1 in gastric noninvasive and early invasive neoplasias.

Human tumors are genetically unstable, and the instability exists at two distinct levels-the chromosomal level and the nucleotide level. Chfr and hMLH1 hypermethylation, which may lead to chromosomal instability (CIN) and microsatellite instability (MSI), respectively, was analyzed in gastric noninvasive neoplasias (NIN, Padova international classification) and submucosal invasive adenocarcinomas and in their corresponding non-neoplastic gastric epithelia. Results were compared with microsatellite status, p53 immunoreactivity, and cellular phenotype. Hypermethylation of Chfr and hMLH1 was observed in: 10% (1/10) and 0% (0/10) of low-grade NIN (L-NIN); 63% (5/8) and 63% (5/8) of high-grade NIN, including suspicion for carcinoma without invasion (H-NIN); 36% (5/14) and 57% (8/14) of high-grade NIN, including carcinoma without invasion; and 35% (7/20) and 25% (5/20) of submucosal invasive adenocarcinomas, respectively. Hypermethylation was less frequent in L-NIN than H-NIN (P<0.05) for Chfr and was also less frequent in L-NIN than the others (P<0.05) for hMLH1. We failed to find a significant correlation between Chfr hypermethylation and chromosomal loss of heterozygosity, although hypermethylation of hMLH1 was significantly associated with high-frequency MSI (P<0.01). Expression of p53 was not associated with Chfr or hMLH1 methylation. As for cellular phenotype, hypermethylation of Chfr and hMLH1 was frequent in tumors exhibiting the foveolar epithelial phenotype (50%, 2/4 and 75%, 3/4, respectively) and the ordinary phenotype (40%, 16/40 and 38%, 15/40, respectively), but never in those with the complete-type intestinal metaplastic phenotype (0%, 0/8 for both). In addition, hypermethylation of Chfr and hMLH1 occurred concurrently (P<0.01); methylation was more frequent in patients over 70 years of age (P<0.01), and it was also present in some samples of non-neoplastic gastric epithelia from elderly patients. Thus, some gastric tumors with the foveolar or ordinary phenotype may develop as a result of age-related methylation of Chfr and hMLH1, although Chfr methylation was not associated with CIN.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy.

BACKGROUND: The objective of the current study was to determine the characteristic features of sustained responders who develop hepatocellular carcinoma after treatment with interferon for chronic hepatitis C. METHODS: This study included 3626 patients with chronic hepatitis C who had received interferon monotherapy. Cox proportional hazards analysis was used to compare sustained responders who did and did not develop hepatocellular carcinoma, and nonsustained responders who developed hepatocellular carcinoma in a multicenter, retrospective cohort study. RESULTS: Among 1197 sustained responders, 27 patients developed hepatocellular carcinoma (2.3%). Compared with sustained responders who did not develop hepatocellular carcinoma, patients who developed disease more often were male (P = 0.0212), were older (P = 0.0068), and had advanced-stage histologic disease before interferon therapy (P = 0.0345). Conversely, compared with patients with hepatocellular carcinoma who were not sustained responders, patients who were sustained responders tended to be older at the time of the initiation of interferon therapy (P = 0.0552) and at the time hepatocellular carcinoma was detected (P = 0.0593), and they also were predominantly male (P = 0.0507). The histologic staging and serum aminotransferase levels at the initiation of interferon therapy, the interval to the detection of tumor, and the tumor size showed no significant differences between the two groups. CONCLUSIONS: Sustained responders in the group at high risk for developing hepatocellular carcinoma after interferon therapy were older, more often were male, and had more advanced histologic disease stage. Such patients should be followed carefully periodically for > 10 years after they complete interferon therapy.

Age Factors↗
PubMed2004

Genetic variations in humans associated with differences in the course of hepatitis C.

The outcome of hepatitis C virus (HCV) infection varies among individuals, but the genetic factors involved remain unknown. We conducted a population-based association study in which 238 Japanese individuals positive for anti-HCV antibody were genotyped for 269 single nucleotide polymorphisms (SNPs) in 103 candidate genes that might influence the course of infection. Altogether, 50 SNPs in 32 genes were listed. Genetic polymorphisms in IL4, IL8RB, IL10RA, PRL, ADA, NFKB1, GRAP2, CABIN1, IFNAR2, IFI27, IFI41, TNFRSF1A, ALDOB, AP1B1, SULT2B1, EGF, EGFR, TGFB1, LTBP2, and CD4 were associated with persistent viremia (P < 0.05), whereas those in IL1B, IL1RL1, IL2RB, IL12RB1, IL18R1, STAT5A, GRAP2, CABIN1, IFNAR1, Mx1, BMP8, FGL1, LTBP2, CD34, and CD80 were associated with different serum alanine aminotransferase levels in HCV carriers (P < 0.05). The sorted genes allow us to draw novel hypotheses for future studies of HCV infection to ultimately identify bona fide genes and their variations.

Adult↗
PubMed2004

Interferon therapy for aged patients with chronic hepatitis C: improved survival in patients exhibiting a biochemical response.

BACKGROUND: In Japan, generally, patients with chronic hepatitis C are aged. The aim of this study was to investigate the effect of interferon (IFN) therapy on the mortality of chronic hepatitis C patients over age 60. METHODS: Seven-hundred and seven patients with histologically proven chronic hepatitis C were enrolled in this study; 649 received IFN therapy (IFN group) and 58 did not (control group). The standardized mortality ratio (SMR) and Cox proportional hazard regression analysis were used to evaluate the effect of IFN on the survival of the patients. RESULTS: Mean follow-up periods in the IFN and control groups were 5.7 and 6.7 years, respectively. During follow-up, 13 patients in the control group died (7 of liver-related diseases) and 42 in the IFN group died (29 of liver-related diseases). The SMRs of the control and IFN groups were 1.40 (95% confidence interval [CI], 0.76-2.45) and 0.73 (95% CI, 0.52-0.98) for overall death, and 10.70 (95% CI, 4.29-22.05) and 5.05 (95% CI, 3.38-7.26) for liver-related death, respectively. Sustained and transient biochemical responders in the IFN group (SMR, 0.53; 95% CI, 0.01-2.97 and SMR, 3.25; 95% CI, 0.87-8.32, respectively) showed lower liver-related mortality compared with the control group. In patients with sustained virological response, liver-related mortality was also very low (SMR, 0.65; 95% CI, 0.01-3.61). The risk for liver-related death of sustained and transient biochemical responders was also low compared with that of the control group (adjusted risk ratios 0.10 [95% CI, 0.01-0.95] and 0.50 [95% CI, 0.11-2.21], respectively). CONCLUSIONS: These results suggest that IFN treatment could reduce liver-related mortality in chronic hepatitis C patients over age 60, notably in patients showing a biochemical response and in those showing a sustained virological response.

Aged↗
PubMed2004

Transmission of hepatitis C virus quasispecies between human adults.

To elucidate how hepatitis C virus (HCV) with multiple variants (quasispecies) is transmitted and adapts to the host during infection, we compared nucleotide and deduced amino acid sequences from hypervariable region1 (HVR1) of the E2 gene of HCV between a donor and a recipient who developed hepatitis after a needlestick accident. Thirty clones from each subject were sequenced after PCR amplification, cloning, and purification of plasmid DNA from single colonies of transformed bacteria. Genetic analysis revealed that the recipient's viral sequences were much less diverse than the donor's. We found a single predominant HCV HVR1 clone of the recipient in 22/30 isolates with the same amino acid sequence, and mimic clones in 8/30 isolates with only one amino acid substitution. These were all absent in the donor, who had 21 highly diverse sequences. Phylogenetic analysis of virus E1/E2 gene sequences showed that the recipient's unique sequences were related to the population of variants from the donor, in whom one isolate had 96% similarity to the recipient's predominant amino acid sequence. These results suggest that a minor subset of the donor's HCV variants is selectively transmitted to the recipient, and that the selection determines the predominant variant in the new host.

Journal Article↗
PubMed2004

Hepatitis B virus genotype G is an extremely rare genotype in Japan.

BACKGROUND:: Hepatitis B virus (HBV) has been classified into seven genotypes (A-G). HBV genotypes have a geographically characteristic distribution. Since HBV genotype G (HBV/G) was identified recently, little is known about the distribution of HBV/G in Japan. The aim of this study was to clarify this issue. PATIENTS AND METHODS:: Seven hundred and twenty-one serum samples obtained from patients with HBV in Japan were investigated. The patients included 149 asymptomatic carriers, 325 with chronic hepatitis, 129 with liver cirrhosis, and 118 with hepatocellular carcinoma. Six HBV genotypes (A-F) were determined by restriction fragment length polymorphim targeting to the S region of the HBV genome. Furthermore, HBV/G was investigated by polymerase chain reaction with hemi-nested primers derived from an HBV/G-specific nucleotide sequence. RESULTS:: Of the 721 serum samples investigated, 12 subjects were classified as having HBV/A, 88 HBV/B, 610 HBV/C, 3 HBV/D, and 1 HBV/F. Seven subjects had a mixed infection with distinct genotypes, two with HBV/A and HBV/D, and five with HBV/B and HBV/C. HBV/G was not identified among the 721 samples. CONCLUSION:: HBV/G was not identified in a large cohort of patients with HBV, either single or dual infection. HBV/G seems to be an extremely rare genotype in Japan.

Journal Article↗
PubMed2004

Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients.

To clarify the clinicopathological significance of promoter hypermethylation of tumor suppressor and tumor-related genes in biliary tract carcinomas, we examined the promoter methylation status of multiple genes in primary biliary tract carcinomas. These consisted of carcinomas of the bile duct, gallbladder, and duodenal ampulla. Surgical specimens were obtained from a total of 37 patients with biliary tract carcinoma. The cohort consisted of 23 patients with bile duct carcinoma, 9 patients with gallbladder carcinoma, and 5 patients with ampullary carcinoma. The methylation status of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 was examined by methylation-specific polymerase chain reaction (MSP). The correlation between methylation status and clinicopathological characteristics was then assessed. The methylation frequencies of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 genes were 16.2%, 21.4%, 27.0%, 8.1%, 24.3%, 27.0%, and 56.8%, respectively, in primary biliary tract carcinomas. The number of methylated genes per sample was 2.17 +/- 0.28 (average +/- SD) in bile duct carcinomas, 1.80 +/- 0.97 in ampullary carcinomas, and 0.89 +/- 0.35 in gallbladder carcinomas, with a statistically significant difference between bile duct carcinomas and gallbladder carcinomas (P = 0.02). As for clinicopathological significance, patients with a methylated RUNX3 promoter were significantly older than those with unmethylated RUNX3 (P = 0.01), and DAP-kinase methylation was more frequent in poorly differentiated tumors than in well to moderately differentiated ones (P = 0.04). The overall survival rate was significantly lower in patients with methylated DAP-kinase (P = 0.009) or RUNX3 (P = 0.034) compared to those with unmethylated genes. Furthermore, DAP-kinase methylation-positive status was independently associated with poor survival in multivariate analyses (hazard ratio = 8.71, P = 0.024). A significant proportion of primary biliary tract carcinomas exhibited promoter hypermethylation of tumor suppressor and tumor-related genes, although bile duct carcinomas are more prone to being affected by promoter methylation than are gallbladder carcinomas. Hypermethylation of DAP-kinase appears to be a significant prognostic factor in primary biliary tract carcinomas.

Age Distribution↗
PubMed2004

Possible contribution of circulating transforming growth factor-beta1 to immunity and prognosis in unresectable hepatocellular carcinoma.

Transforming growth factor-beta1 (TGF-beta1) has been implicated in tumor progression. The relationship of this cytokine as measured in plasma to anti-tumor immunity and prognosis was investigated. This study consisted of 70 consecutive patients with unresectable hepatocellular carcinoma (HCC) (median age, 65 years). Forty-four healthy age-matched subjects and 32 patients with cirrhosis but no carcinoma served as controls. Patients with HCC were divided into those with plasma TGF-beta1 concentrations above (group A, n=21) or below (group B, n=49) 10 ng/ml (the mean concentration+2SD in the concentrations of the controls with cirrhosis was 8.7 ng/ml). Age, gender, Child-Pugh grade, and tumor stage distributions were similar in groups A and B. Considering all tumor stages together and individually, group A had a significantly shorter survival (median for all stages, 2 months) than group B (median for all stages, 10 months; P<0.01, generalized Wilcoxon's test). Groups A and B had significantly shorter survival than controls with cirrhosis (P<0.001 for each). Lymphokine-activated killer (LAK) activity in group A was significantly lower than that in group B (P<0.001). Natural killer (NK) activity in group A was also significantly lower than that in group B (P<0.05). Plasma TGF-beta1 concentration was a significant predictor of survival by Cox's proportional-hazards regression analysis (multivariate analysis, P<0.01). LAK and NK activities were also weak but significant predictors (P<0.05 and <0.05, respectively). These data suggest that plasma TGF-beta1 concentration is a predictor of outcome of patients with unresectable HCC. Circulating TGF-beta1 supposedly contributes to the suppression of anti-tumor immunity in the advanced disease.

Aged↗
PubMed2003

Histogenesis of hepatoid adenocarcinoma of the stomach: molecular evidence of identical origin with coexistent tubular adenocarcinoma.

Hepatoid adenocarcinoma of the stomach is a highly malignant neoplasm. Most gastric hepatoid adenocarcinomas coexist with tubular adenocarcinoma. However, the relationship between hepatoid adenocarcinoma and tubular adenocarcinoma is still unclear. In the present study, the characteristics of the coexistent tubular adenocarcinomas were determined by examining their profiles of mucin production. Subsequently, molecular pathological techniques were applied to determine the clonality of 15 mixed hepatoid and tubular adenocarcinomas of the stomach. Mucin analysis suggested that the coexistent tubular adenocarcinomas with hepatoid adenocarcinoma were of the intestinal type. The patterns of chromosome X inactivation were identical between the hepatoid adenocarcinoma component and tubular adenocarcinoma component in all of 3 informative female cases. Mutations in the p53 gene were found in 5 cases. The sequences were identical within both tumor components in all 5 cases. Microsatellite analysis indicated more than 3 common patterns of loss of heterozygosity in 8 cases. These observations strongly suggested that hepatoid adenocarcinomas were of identical origin to coexistent tubular adenocarcinomas.

Adenocarcinoma↗
PubMed2003

Differentiation of bone marrow cells into cells that express liver-specific genes in vitro: implication of the Notch signals in differentiation.

Bone marrow (BM) stem cells have been shown to differentiate into liver cells. It remains difficult to sort and culture BM stem cells, and the gene expression of liver-specific proteins in these cells has not been fully investigated. We used a negative selective magnetic cell separation system to obtain stem cell-enriched BM cells. The cells obtained were cultured with hepatocytes or with hepatocyte growth factor (HGF), and the differentiation of BM cells into cells expressing liver-specific genes, hepatocyte nuclear factor (HNF) 1alpha, cytokeratin (CK) 8, alpha-fetoprotein (AFP), and albumin was investigated by the reverse transcription-polymerase chain reaction. We also investigated the gene expressions of Notch receptor-1 (Notch-1) and its ligand Jagged-1 in BM cell differentiation. Sorted BM cells showed positive for Sca-1 (Ataxin-1) by immunofluorescence staining. Fluorescence activated cell sorter analysis showed that 32.6% of sorted BM cells had a high level of expression of the hematopoietic stem cell marker CD90 (Thy-1). When cultured with hepatocytes, these cells expressed the liver-specific genes HNF1alpha and CK8 on culture day 3, AFP and albumin on culture day 7. When cultured with HGF (20ng/ml), the cells expressed HNF1alpha on day 3 and CK8 on day 7. Gene expressions of Notch-1 and Jagged-1 were detected in cultured BM cells on day 3. These results suggest that the negative selective magnetic cell separation system is useful for the rapid preparation of stem cell-enriched BM cells, and that the Notch signaling pathway plays a role in BM cell differentiation into a hepatocyte lineage in vitro.

Animals↗