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Biomedical subjects

M Takahama

Publications and source records attributed to M Takahama.

At least 37 records · Page 2Linked to original sources
PubMed1999

Systemic granulomatous arteritis associated with Epstein-Barr virus infection.

A 61-year-old woman initially presented with symptoms and findings reminiscent of infectious mononucleosis, and her illness then took a rapidly fatal course. Autopsy revealed widespread granulomatous arteritis, with multinucleated giant cells but without eosinophils and fibrinoid necrosis, affecting small arteries and arterioles and infiltration of haemophagocytic histiocytes into many organs. In situ hybridization with Epstein-Barr virus (EBV)-specific oligonucleotide probes showed positive signals in the infiltrating immune cells and epithelial and endothelial cells of the affected organs. EBV-associated haemophagocytic syndrome (EBV-AHS) with systemic granulomatous arteritis was diagnosed. From the immunophenotypes of the infiltrating immune cells, a possible role of CD4+ T-cells in the pathogenesis of this haemophagocytic syndrome and granulomatous vasculitis was suggested.

Arteritis↗
PubMed1999

Overexpression of midkine in lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine in rats and its increase with progression.

The expression of midkine (MK) in lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats was examined. The animals were administered 2000 p.p.m. of BHP in their drinking water for 12 weeks, then maintained without further treatment until being killed 20-28 weeks after the beginning of the experiment. MK mRNA expression of adenocarcinomas and squamous cell carcinomas assessed by means of the reverse transcriptase-polymerase chain reaction and northern blot analysis was significantly higher than in rat embryonic tissues (positive controls) and contrasted strongly with the lack in normal lungs. MK protein was detected immunohistochemically in 58.3% of alveolar hyperplasias, 92.3% of adenomas and 100% of adenocarcinomas and squamous cell carcinomas. The extent of staining significantly increased along with malignant progression in adenomatous (pre-)neoplastic lesions and tended to become more pronounced with malignant progression in squamous lesions. The results suggest that MK may play some essential roles in the development and progression of lung tumors induced by BHP in rats.

Adenocarcinoma↗
PubMed1999

Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine.

In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, and membrane-type 1 MMP (MT1-MMP) and MT2-MMP in ductal lesions in a rapid-production model for pancreatic duct carcinomas (PCs) in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) and in subcutaneous transplantable tumors of hamster pancreatic duct carcinoma (HPDs) was investigated. Northern analysis revealed MMP-2, MMP-9, TIMP-2 and MT1-MMP mRNAs to be overexpressed in PCs. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in both of primary and HPD tumors, the MT1-MMP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001). In our rapid production model, 0.1 and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that overexpression of MMP-2, TIMP-2 and MT1-MMP, and cell surface activation of proMMP-2 by MT1-MMP, are involved in the development of PCs, and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. OPB-3206 may be a candidate chemopreventive agent for pancreatic ductal adenocarcinomas.

Adenocarcinoma↗
PubMed1999

Rubrimonas cliftonensis gen. nov., sp. nov., an aerobic bacteriochlorophyll-containing bacterium isolated from a saline lake.

Phenotypic and phylogenetic studies were performed with two strains (OCh 317T and OCh 318; T = type strain) of aerobic chemoheterotrophic bacteriochlorophyll-containing bacteria isolated from water of a saline lake located on the west coast of Australia. Both strains were Gram-negative, short rods and were motile by means of polar flagella. Catalase, oxidase, nitrate reductase, phosphatase and urease were produced. The cells utilized D-glucose, citrate, glycolate, pyruvate and ethanol. Acids were produced from L-arabinose, D-fructose, D-galactose, D-glucose, D-ribose and D-xylose. The strains could grow in media containing 0.5-7.5% NaCl. Bacteriochlorophyll a was synthesized under aerobic conditions. The results of 16S rRNA gene sequence comparisons revealed that strain OCh 317T represented a new lineage in the alpha-3 group of the class Proteobacteria. Strains OCh 317T and OCh 318 were identified as strains of the same species because of their very similar phenotypic characteristics and their previously described high DNA-DNA homology. Therefore, it was concluded that the two strains should be assigned to a new genus and species, for which the name Rubrimonas cliftonensis is proposed. The type strain is OCh 317T (= JCM 10189T).

Bacteria, Aerobic↗
PubMed1999

Roseivivax halodurans gen. nov., sp. nov. and Roseivivax halotolerans sp. nov., aerobic bacteriochlorophyll-containing bacteria isolated from a saline lake.

Phenotypic and phylogenetic studies were performed with two strains (OCh 239T and OCh 210T, T = type strain) of aerobic bacteriochlorophyll-containing bacteria isolated from the charophytes and the epiphytes on the stromatolites, respectively, of a saline lake located on the west coast of Australia. Both strains were chemoheterotrophic, Gram-negative and motile rods with subpolar flagella. Catalase and oxidase were produced. ONPG reaction was positive. Cells utilized D-glucose, acetate, butyrate, citrate, DL-lactate, DL-malate, pyruvate, succinate, L-aspartate and L-glutamate. Acids were produced from D-fructose and D-glucose. Bacteriochlorophyll a was synthesized under aerobic conditions. Strain OCh 239T had nitrate reductase and phosphatase. Acids were produced from L-arabinose, D-galactose, lactose, maltose, D-ribose and sucrose. The strain could grow in 0-20.0% (w/v) NaCl. Strain OCh 210T had urease. Hydrolysis of gelatin was positive. Acids were produced from D-xylose. The strain could grow in 0.5-20.0% (w/v) NaCl. The results of 16S rRNA sequence comparisons revealed that strains OCh 239T and OCh 210T formed a new cluster within the alpha-3 group of the alpha subclass of the class Proteobacteria. The similarity value of the 16S rRNA sequences between strains OCh 239T and OCh 210T was 95.8%. Therefore, it was concluded that these two strains should be placed in a new genus, Roseivivax gen. nov., as the new species Roseivivax halodurans sp. nov. and Roseivivax halotolerans sp. nov. The type species of the genus is Roseivivax halodurans. The type strains of Roseivivax halodurans and Roseivivax halotolerans are OCh 239T (= JCM 10272T) and OCh 210T (= JCM 10271T), respectively.

Bacteria, Aerobic↗
PubMed1999

Inhibition of spontaneous rat osteosarcoma lung metastasis by 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydroc arbostyril, a novel matrix metalloproteinase inhibitor.

In the present experiment, we examined the effects of OPB-3206, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4- dihydrocarbostyril, a novel metalloproteinase inhibitor, on the growth and metastasis of transplantable osteosarcomas (spontaneous osteosarcoma, selected lung metastatic lesions; S-SLM), which were previously established in rats. OPB-3206 inhibited the activities of interstitial collagenase, gelatinases A and B, and stromelysin in vitro. After oral administration to rats, its serum concentration peaked at 40 min and the drug was no longer detectable at 8 h. When OPB-3206 was orally administered at 0%, 0.1% and 0.4% in the diet for 4 weeks, starting 7 days after subcutaneous transplantation of osteosarcomas to male Fischer 344 rats, numbers of lung metastatic nodules were significantly reduced by the highest dose, while the growth of subcutaneous tumors was not affected. Zymographic analysis showed the presence of pro matrix metalloproteinase (proMMP)-2, proMMP-9 and MMP-9 activities in S-SLM. In animals fed 0.4% OPB-3206, the activity of proMMP-9 was increased, but that for MMP-9 had become undetectable. The results thus suggest that OPB-3206 selectively inhibits lung metastasis of rat transplantable osteosarcomas by inhibiting MMP-9 activation.

Administration, Oral↗
PubMed1999

Hypomethylation of CpG sites and c-myc gene overexpression in hepatocellular carcinomas, but not hyperplastic nodules, induced by a choline-deficient L-amino acid-defined diet in rats.

We have investigated aberrant methylation of CpG nucleotides (CpG sites) and gene expression of c-myc during hepatocarcinogenesis induced by a choline-deficient, L-amino acid-defined (CDAA) diet in rats. Male Fischer 344 rats, 6 weeks old, were continuously given a CDAA diet for 50 and 75 weeks and then killed. Macroscopically detectable nodules, which were histologically confirmed to be hyperplastic nodules (HNs) or well-differentiated hepatocellular carcinomas (HCCs), were dissected free from the surrounding tissue. Normal control liver was obtained from 6-week-old rats. Methylation of CpG sites of the c-myc gene was investigated in bisulfite-treated DNA isolated from normal liver, HNs and HCCs. All 33 cytosines in the 5'-upstream region of the c-myc gene were fully methylated in control liver and the 4 HNs. In contrast, these cytosines were completely unmethylated in 5 HCCs. Examination of the c-myc expression by reverse transcription-polymerase chain reaction (RT-PCR) analysis also showed a marked increase as compared to the low levels in normal livers and HNs. These results suggest that hypomethylation of the c-myc gene might play a critical role in malignant transformation from HN to HCC during CDAA diet-induced hepatocarcinogenesis in rats.

Amino Acids↗
PubMed1999

Expression of vascular endothelial growth factor and its receptors during lung carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine in rats.

The expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), VEGFR-1/Flt-1 and VEGFR-2/Flk-1, was investigated by immunohistochemical and northern blot analysis during lung carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine (BHP) in male Wistar rats. After BHP was given in the drinking water for 12 wk, the rats were maintained without further treatment until they were killed at 20-28 wk. Immunohistochemical studies revealed VEGF expression in almost all malignancies, the reaction being strongly positive in most adenocarcinomas (15 of 18; 83.3%) and squamous cell carcinomas (four of five; 80.0%), but less so in a total of 120 adenomas and 136 alveolar hyperplasias. In addition, VEGF mRNA and VEGFR mRNAs were found to be overexpressed in most adenocarcinomas and squamous cell carcinomas as well as in one to three of the five adenomas tested. The results indicated that VEGF and VEGFRs play important roles in the acquisition of malignant potential by preneoplastic lung lesions induced by BHP in rats. Moreover, overexpression of VEGF was related to upregulation of VEGFR-1/Flt-1 and VEGFR-2/Flk-1 expression in malignant and premalignant lung lesions.

Adenocarcinoma↗
PubMed1999

Enhanced expression of Tie2, its ligand angiopoietin-1, vascular endothelial growth factor, and CD31 in human non-small cell lung carcinomas.

Expression of angiogenesis-associated genes was compared in 32 primary non-small cell lung carcinoma samples (14 adenocarcinomas, 17 squamous cell carcinomas, and 1 large cell carcinoma) and paired adjacent noncancerous lung tissues using a multiprobe RNase protection assay. Levels of Tie2, angiopoietin (Ang)-1, vascular endothelial growth factor (VEGF), and CD31 mRNAs were higher in cancers than in adjacent noncancerous tissues, in contrast to the fms-like tyrosine kinase (Flt)-1, Flt-4, Tie1, thrombin receptor, endoglin, and VEGF-C, for which no differences were evident. Overexpression did not seem to differ with histological type and pathological stage. Significant positive correlations were found between mRNA expression of Ang-1 and those of Tie2 and CD31, and that of VEGF and those of Flt-1 and CD31. These findings suggest that Ang-1 and VEGF are important angiogenic factors in human non-small cell lung carcinomas.

Adult↗
PubMed1998

Increased telomerase activity in intrahepatic cholangiocellular carcinomas induced by N-nitrosobis(2-oxopropyl)amine in hamsters.

Telomerase activities in intrahepatic cholangiocarcinomas induced by N-nitrosobis(2-oxopropyl)amine (BOP) in female hamsters were determined using a telomeric repeat amplification protocol (TRAP) assay followed by densitometric quantification. Each determination was repeated to confirm the results and telomerase activity was also detected by gel electrophoresis. An increase was evident in all of 10 cholangiocarcinomas examined, with levels ranging from 2.48 to 4.40 times the normal liver value by densitometric quantification. This finding of a consistent increase suggests that telomerase activation is involved in the development of intrahepatic cholangiocarcinomas and immortalization of cancer cells.

Adenocarcinoma↗
PubMed1998

Chemopreventive effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on the development of rat urinary bladder carcinomas initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The chemopreventive potential of a selective cyclooxygenase-2 inhibitor, nimesulide (NIM), against the development of rat superficial urinary bladder carcinomas after initiation with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Six-week-old Fischer 344 male rats were given 0.05% BBN in their drinking water for 8 weeks, followed by diets supplemented with 0, 100, 200, or 400 ppm NIM for 12 weeks, and they were then sacrificed. NIM decreased, in a dose-dependent manner, the incidence of transitional cell carcinoma (TCC) to 12 of 20 (60.0%), 8 of 16 (50.0%), and 5 of 19 (26.3%) and the multiplicity of TCCs to 0.75 +/- 0.79, 0.56 +/- 0.63, and 0.37 +/- 0.78 per rat at 100, 200, and 400 ppm, respectively, as compared with the BBN alone group values of 18 of 20 (90.0%) and 2.35 +/- 1.23. NIM did not significantly affect the cell differentiation or invasiveness of TCCs. These results indicate clear chemopreventive potential of a selective cyclooxygenase-2 inhibitor against postinitiation development of superficial rat urinary bladder carcinomas.

Animals↗
PubMed1998

Increased telomerase activity and absence of p53 mutation in oligoastrocytomas induced by N-ethyl-N-nitrosourea in rats.

The question of whether the changes in telomerase activity and/or the alteration of the p53 gene are involved in the development of oligo-astrocytomas induced by N-ethyl-N-nitrosourea (ENU) in rats was addressed. Telomerase activity levels of oligo-astrocytomas, including early neoplastic lesions, were significantly increased as compared to the normal controls, correlating with the degree of malignancy. In contrast, no mutations of p53 exons 5-7 were found in early neoplastic lesions or oligo-astrocytomas. These results indicate that the activation of telomerase occurs during astrocytoma carcinogenesis and contributes to the development of brain tumors, but the alterations of p53, at least on exons 5-7, may not be involved in this process.

Animals↗
PubMed1998

Induction of telomerase activity during regeneration after partial hepatectomy in the rat.

The regulation of telomerase activity during regeneration induced by two-thirds partial hepatectomy (PH) was investigated in 6-week-old male F344 rats. Groups of animals were serially sacrificed 0, 6, 16, 24, 36 and 72 h after the operation and telomerase activity was determined by the telomeric repeat amplification protocol (TRAP) assay followed by densitometric quantification. DNA synthesis was immunohistochemically quantified in terms of bromodeoxyuridine (BrdU) incorporation. The expression levels of telomerase RNA were examined by Northern blot analysis. Telomerase activity was increased significantly from 6 to 36 h but had decreased to close to the normal levels after 72 h. DNA synthesis reached a maximum 24 h after PH. However, the expression levels of telomerase RNA did not change during regeneration. The results suggest that telomerase is actively regulated by unknown mechanisms throughout the cell cycle in regenerating rat hepatocytes.

Animals↗
PubMed1998

Frequent expression of the vascular endothelial growth factor in human non-small-cell lung cancers.

BACKGROUND: Angiogenesis is an essential factor for progression and metastases in solid tumors. It has been reported that several angiogenic factors play a role in the regulation of angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most important molecules in angiogenesis. We investigated expressions of VEGF in a series of lung carcinomas with regard to clinicopathological factors. METHOD: VEGF expression was investigated by use of immunohistochemical studies and Northern blot analysis, using 155 primary and 26 metastatic lung carcinomas for the immunohistochemical studies and 10 primary and two metastatic lung carcinomas for the Northern blot analysis. All lesions were resected at surgery. RESULTS: The frequencies for positive VEGF expression were 64 of 74 (86.5%) adenocarcinomas, 38 of 67 (56.7%) squamous cell carcinomas, four of four (100%) large cell carcinomas, two of three (66.7%) adenosquamous carcinomas and one of five (20%) small-cell carcinomas, the degree of positivity generally being greater in well differentiated tumors. The majority of metastatic foci from adenocarcinomas and squamous cell carcinomas at other sites were also positive (76.5 and 66.7%, respectively). VEGF expression did not correlate with clinicopathological factors such as tumor size or pathological stage, but pathological stage I adenocarcinoma cases positive for VEGF demonstrated a shorter disease-free period when followed up for 48 months than those cases expressing VEGF negatively. CONCLUSIONS: The results indicated that VEGF expression was frequently detected in non-small-cell lung cancers and suggested that VEGF might relate to the disease-free period of the patients with early adenocarcinomas.

Adenocarcinoma↗
PubMed1998

Telomerase activity correlates with growth of transplantable osteosarcomas in rats treated with cis-diammine dichloroplatinum or the angiogenesis inhibitor AGM-1470.

To determine the role of telomerase activity in the growth of tumors in rats undergoing chemotherapy, a comparison of the volumes of telomerase-positive transplantable osteosarcomas was made in rats treated with the antineoplastic agent cis-diammine dichloroplatinum (CDDP) or the angiogenesis inhibitor O-(chloroacetylcarbamoyl)fumagillol (AGM-1470). Male F344 rats, 8 weeks old, received transplants of macroscopic lung metastatic nodules into the subcutaneous back space and treatment was started on day 14 thereafter. CDDP was injected i.v. at doses of 0, 0.625, 1.25 and 2.5 mg/kg body weight (b.w.) and AGM-1470 was administered at total doses of 0, 2.5, 5 and 10 mg/kg b.w. over 2 weeks by osmotic pumps, also implanted into the subcutaneous back space, but remote from the transplanted tumors. On day 28, all animals were killed for measurement of transplanted tumor size and determination of telomerase activities by telomeric repeat amplification protocol (TRAP) assay. The results showed telomerase activity to be highly correlated with the treated/non-treated (T/C) tumor size ratio (r = 0.96, P < 0.0001). In a second experiment, CDDP at 2.5 mg/kg b.w. and AGM-1470 at 10 mg/kg b.w., these being the most effective doses, were given as in the first experiment, and animals were serially killed on days 14, 21, 28, 35 and 42. Tumors in rats treated with CDDP and AGM-1470 showed 18.2% and 20.5% of the control telomerase activity on days 35 and 21, respectively, when tumor growth was inhibited. However, on day 42, the activities increased to 46.5% and 92.5%, this correlating with re-growth (r = 0.73, P < 0.0001). These results suggest that decline of telomerase activity may be involved in tumor growth retardation induced by chemotherapeutic agents. This possibility clearly warrants further mechanistic studies.

Animals↗
PubMed1998

Recovery and limitation of exercise capacity after lung resection for lung cancer.

OBJECTIVE: To assess the effects of pulmonary resection for lung cancer on postoperative recovery and limitation of exercise capacity. METHODS: Eighty-two patients (20 pneumonectomies, 62 lobectomies) underwent spirometric pulmonary tests and exercise capacity tests preoperatively, and at 3 months and more than 6 months after the operation. RESULTS: In the lobectomy group, FEV1 vital capacity (VC), and maximum oxygen consumption (VO2max) decreased significantly 3 months after the operation and improved after more than 6 months, but did not reach the preoperative values. In the pneumonectomy group, FEV1 VC, and VO2max decreased 3 months after the surgery and the values did not recover thereafter. In comparison with preoperative values, the functional percentage losses after more than 6 months for lobectomies and pneumonectomies were 11.2% and 36.1% for FEV1, 11.6% and 40.1% for VC, and 13.3% and 28.1% for VO2max, respectively. Postoperatively, maximal minute ventilation (VEmax), the maximal heart rate percentage, and maximal O2 pulse during the exercise test significantly decreased in both the lobectomy and pneumonectomy groups. Nevertheless, VEmax and O2 pulse improved more than 6 months after lobectomy compared with the value at 3 months, but not after pneumonectomy. Breathing reserve did not differ before and after surgery in the lobectomy group, although it decreased significantly after surgery in the pneumonectomy group. Subjectively, postoperative exercise after lobectomy was limited by leg discomfort (64% at more than 6 months after surgery); after pneumonectomy, exercise was limited by dyspnea (60%). CONCLUSIONS: These results suggest that there are differences between lobectomy and pneumonectomy for lung cancer in terms of recovery and limitation of exercise capacity.

Exercise Test↗
PubMed1997

Increased telomerase activity is not directly related to metastatic potential in rat transplantable osteosarcomas.

Previously, we reported the establishment of two transplantable osteosarcomas in rats, one induced by local application of a carcinogen, 4-hydroxyamino quinoline 1-oxide (4-HAQO), and another which developed spontaneously, and their subdivision into four lines with high and low metastatic potential to the lung. In the present study, activation of telomerase was investigated by the telomeric repeat amplification protocol (TRAP) assay followed by densitometric quantification. Telomerase activity was found to be elevated in all four lines without any link to the metastatic potential. Thus the spontaneous osteosarcoma (SOS) and derived metastatic lesions (S-SLM) demonstrated a 20.1-23.5-fold increase and the chemical carcinogen (4HAQO)-induced osteosarcoma (COS) and metastatic lesions (C-SLM) were 18.4-19.1-fold elevated as compared to the value for abdominal muscle. The results suggest that activation of telomerase occurs in rat osteosarcomas but that it is not directly involved in determining their metastatic potential.

Animals↗