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Tetsuji Sawada

Publications and source records attributed to Tetsuji Sawada.

At least 19 recordsLinked to original sources
PubMed2006

Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine.

PURPOSE: The purpose of the present study was to evaluate whether trastuzumab has antitumor effect against pancreatic cancer and whether this effect is concordant with levels of HER-2, which is reportedly overexpressed in pancreatic cancer. We also investigated whether the effect is potentiated in combined therapy with gemcitabine. EXPERIMENTAL DESIGN: Using immunohistochemistry and FACScan, we analyzed HER-2 expression in 16 pancreatic cancer cell lines. The in vitro antiproliferative effect of trastuzumab, alone and in combination with gemcitabine, was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vitro antibody-dependent cell-mediated cytotoxicity of trastuzumab was investigated by (51)Cr release assay. The in vivo antitumor effect of trastuzumab, alone and in combination with gemcitabine, was evaluated in nude mouse xenograft growth. The survival benefit was evaluated in a Capan-1 orthotopic implanted nude mouse model. RESULTS: HER-2 expression of 2+ or more was observed in 10 and of 3+ in 2 of the 16 cell lines. No in vitro growth-inhibitory effect of trastuzumab was found in any cell line, but trastuzumab induced antibody-dependent cell-mediated cytotoxicity in proportion to HER-2 expression level. Trastuzumab inhibited tumor growth in Capan-1 (HER-2: 3+) xenografts and prolonged survival in the orthotopic model. These effects were increased by combined therapy with gemcitabine. In contrast, trastuzumab exhibited no antitumor effect against PANC-1 (HER-2: 1+) or SW1990 (HER-2: 2+) xenografts. CONCLUSIONS: The antitumor effect of trastuzumab in pancreatic cancer with high HER-2 expression was shown in vitro and in vivo. Clinical application of trastuzumab is expected in pancreatic cancer with 3+ HER-2 expression.

Animals↗
PubMed2006

A synergic inhibitory-effect of combination with selective cyclooxygenase-2 inhibitor and S-1 on the peritoneal metastasis for scirrhous gastric cancer cells.

An inhibitory-effect of a selective cyclooxygenase-2 (COX-2) inhibitor on peritoneal metastasis of scirrhous gastric carcinoma was investigated in vivo. Peritoneal metastasis had developed after intraperitoneal inoculation of scirrhous gastric cancer cells, OCUM-2MD3, in nude mice. COX-2 inhibitor and/or S-1 were administered orally in nude mice with peritoneal metastasis. Oral administration of COX-2 inhibitor and S-1 significantly prolonged survival rates of these nude mice, compared with either alone. These findings suggested that combining S-1 and COX-2 inhibitor administration obtain a synergistic inhibitory-effect on the peritoneal metastasis of scirrhous gastric carcinoma.

Adenocarcinoma, Scirrhous↗
PubMed2006

Identification of citrullinated eukaryotic translation initiation factor 4G1 as novel autoantigen in rheumatoid arthritis.

Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis. We previously reported that functional variants of the gene encoding peptidylarginine deiminase type 4 were closely associated with RA. The purpose of this study was to investigate the citrullinated autoantigens recognized by serum samples from patients with RA. The human chondrocyte cDNA expression library was citrullinated by PADI4 and was immunoscreened with anti-modified citrulline antibodies and sera from patients with rheumatoid arthritis. One immunoreactive cDNA clone containing a 2480-base pair insert was isolated and sequence analysis revealed that the cDNA included a part of the eukaryotic translation initiation factor 4G1. Immunoreactivity against a recombinant citrullinated eIF4G1 fragment was observed with high specificity in 50.0% of RA patients. The levels of antibodies against citrullinated eIF4G1 were correlated with those of anti-CCP antibodies. Citrullinated eIF4G1 was identified as a candidate citrullinated autoantigen in RA patients. Citrullination of eIF4G1 may thus be involved in the pathogenesis of RA.

Adult↗
PubMed2006

Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases.

IL-32 is a newly described cytokine in the human found to be an in vitro inducer of tumor necrosis factor alpha (TNFalpha). We examined the in vivo relationship between IL-32 and TNFalpha, and the pathologic role of IL-32 in the TNFalpha-related diseases - arthritis and colitis. We demonstrated by quantitative PCR assay that IL-32 mRNA was expressed in the lymphoid tissues, and in stimulated peripheral T cells, monocytes, and B cells. Activated T cells were important for IL-32 mRNA expression in monocytes and B cells. Interestingly, TNFalpha reciprocally induced IL-32 mRNA expression in T cells, monocyte-derived dendritic cells, and synovial fibroblasts. Moreover, IL-32 mRNA expression was prominent in the synovial tissues of rheumatoid arthritis patients, especially in synovial-infiltrated lymphocytes by in situ hybridization. To examine the in vivo relationship of IL-32 and TNFalpha, we prepared an overexpression model mouse of human IL-32beta (BM-hIL-32) by bone marrow transplantation. Splenocytes of BM-hIL-32 mice showed increased expression and secretion of TNFalpha, IL-1beta, and IL-6 especially in response to lipopolysaccharide stimulation. Moreover, serum TNFalpha concentration showed a clear increase in BM-hIL-32 mice. Cell-sorting analysis of splenocytes showed that the expression of TNFalpha was increased in resting F4/80+ macrophages, and the expression of TNFalpha, IL-1beta and IL-6 was increased in lipopolysaccharide-stimulated F4/80+ macrophages and CD11c+ dendritic cells. In fact, BM-hIL-32 mice showed exacerbation of collagen-antibody-induced arthritis and trinitrobenzen sulfonic acid-induced colitis. In addition, the transfer of hIL-32beta-producing CD4+ T cells significantly exacerbated collagen-induced arthritis, and a TNFalpha blockade cancelled the exacerbating effects of hIL-32beta. We therefore conclude that IL-32 is closely associated with TNFalpha, and contributes to the exacerbation of TNFalpha-related inflammatory arthritis and colitis.

Adoptive Transfer↗
PubMed2006

Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway.

Cancer found in the post-operative remnant stomach includes both newly developed cancer after surgery for benign-disease (PRC) and metachronous multiple cancer (MRC). Differences in the carcinogenic pathway between PRC and MRC have been suspected from clinical studies. However, no study has demonstrated the difference in molecular alteration between these diseases. P16 is inactivated predominantly by epigenetic change, rather than genetic alteration. We analyzed the methylation status and protein expression of the p16 gene in cancers of the remnant stomach. Eleven lesions of PRC, 24 lesions of MRC and corresponding non-cancerous tissue, as well as 13 primary gastric cancer (PC) lesions were examined. DNA was extracted by the micro-dissection method from paraffin-embedded surgical specimens. The methylation status of the promoter CpG island of the p16 gene was examined by using a methylation-specific polymerase chain reaction technique. To detect protein expression, immunohistochemical staining was employed. p16 promoter hypermethylation was observed more often in remnant gastric cancer than in PC. A significantly more frequent hypermethylation in the p16 gene was found in PRC (64%) than in MRC (21%) or PC (23%). Moreover, a significant correlation was found between p16 promoter hypermethylation and diminishment of protein expression in cancers of the remnant stomach. Silencing of the p16 gene by methylation of its promoter CpG island was suggested as a unique molecular mechanism in the carcinogenesis of PRC compared with MRC or PC.

Aged↗
PubMed2006

[An autopsied case of a woman with rheumatoid arthritis attacked by multiple cerebral emboli].

A 45-year-old woman, who had had rheumatoid arthritis for 12 years, had three attacks of cerebral embolism over two months and died after the final attack. Intensive clinical laboratory investigations did not disclose any specific origins of emboli, but an autopsy revealed a nodule at the base of the aortic valve which was pathologically proved to be a rheumatoid nodule. The thrombi were present from the distal part of left internal carotid artery up to the proximal part of the left middle cerebral artery. They were rich in fiber, but poorly organized endothelial cell, raising the possibility that they originated from other parts and have recently reached there. On the top of the rheumatoid nodule, a thrombus was present. It was easily ablated and a small amount of fibrin stuck the nodule. Based on these results, we concluded that cerebral emboli were originally generated at the top of a rheumatoid nodule in the heart. In patients with RA, rheumatoid nodules are rarely seen in the heart. If present, they usually cause cardiac failure or atrioventricular block, and seldom result in cerebral infarction. This is the first case in which an autopsy proved rheumatoid nodule in the heart which had caused multiple cerebral emboli. We should consider the possibility of rheumatoid nodules in the heart as an origin of cerebral emboli in patients with rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2006

[A case of advanced gastric cancer with malignant ascites responding to weekly paclitaxel therapy].

A 54-year-old woman with scirrhous gastric cancer in the upper third area was admitted to our hospital. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal metastasis, so weekly paclitaxel (PTX) therapy was carried out. After 2 courses, malignant ascites completely disappeared and bilateral hydronephrosis improved. After 4 courses, no ascites or hydronephrosis were seen. Only neutropenia (grade 2) and alopecia (grade 1) were observed as adverse events during the therapy, but no major adverse events were noted. We also investigated the concentration of paclitaxel in ascites. Two hours after intravenous injection of PTX, the concentration of PTX in ascites rose over the reported cytotoxic dose of PTX, and this available concentration was maintained after 48 hours. Weekly paclitaxel therapy is suggested to be one of the safe and useful treatments for advanced gastric cancer with malignant ascites.

Adenocarcinoma, Scirrhous↗
PubMed2005

Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, but its autoimmune mechanisms are not clearly understood. Recently, anti-citrullinated peptide antibodies have been specifically observed in sera of RA patients. Furthermore, we identified RA-susceptible variant in a gene encoding citrullinating enzyme, peptidylarginine deiminase type 4 (PADI4). Therefore, we hypothesized that proteins which are modified in RA synovium by PADI4 act as autoantigens. Subsequently, we obtained human collagen type I (huCI) as one of the autoantigens using a RA synoviocyte cDNA library by immunoscreening. We also investigated that the levels of anti-citrullinated huCI were significantly higher in RA patient sera than in normal control sera with high specificity (99%) and positively correlated with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies. We concluded that huCI is a novel substrate protein of PADIs and that citrullinated huCI is a candidate autoantigen of RA.

Adult↗
PubMed2005

A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities.

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-kappaB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.

Arthritis, Rheumatoid↗
PubMed2005

[A case of gastric cancer with peritoneal recurrence which developed during adjuvant administration of TS-1 showing complete response by weekly docetaxel regimen].

A 62-year old man had undergone total gastrectomy for Borrmann type 4 gastric cancer. No peritoneal dissemination was observed at the laparotomy. Pathological examination revealed that the tumor involved the subserosal layer, and that the lymph node metastasis extended to the left gastric nodes. Vascular and lymphatic involvement was also observed. One hundred mg/body of TS-1, an oral 5-fluorouracil (5-FU) anticancer agent, which consisted of tegafur (a prodrug of 5-FU), and two modulators (gimeracil and oteracil potassium) was given from the 16th post-operative day. A course of TS-1 consisted of consecutive administration for 4 weeks followed by 2 weeks rest. The patient complained of abdominal fullness after administration of the second course of TS-1. Computed tomography (CT) revealed massive ascites. The serum carcinoembryonic antigen (CEA) titer was elevated to 13.5 ng/ml. From these findings, the occurrence of peritoneal dissemination was suspected. Weekly docetaxel of 30 mg/m2 (40 mg/body) was given for 3 weeks followed by a week cessation. At the start of the 6th course, the serum CEA was normalized, and CT scan detected the disappearance of ascites without any new lesion. Administration of docetaxel was continued until the 10th course then stopped without relapse of the disease. No dose reduction or postponement of administration were required. The patient has survived without disease one year after cessation of the treatment. Weekly docetaxel is a safe and effective regimen for gastric cancer worth using for a second-line therapy after failure of the 5-FU-based regimen.

Adenocarcinoma↗
PubMed2005

Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis.

OBJECTIVE: The nuclear factor-kB (NF-kB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, such as rheumatoid arthritis (RA). In particular, IkB kinase (IKK) is considered an important molecular target because the majority of inflammatory signaling pathways mediated by NF-kB involve IKK activation. We investigated the effect of NF-kB inhibition on rheumatoid fibroblast-like synoviocytes (FLS) and collagen induced arthritis. METHODS: We evaluated the effect of IMD-0560, an inhibitor of IKK, on rheumatoid FLS in vitro and on collagen type II induced arthritis in mice. RESULTS: IMD-0560 suppressed the nuclear translocation of NF-kB and phosphorylation of IkBa induced by tumor necrosis factor-a in FLS. In addition, this compound suppressed the production of inflammatory cytokines, including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1. IMD-0560 also inhibited the proliferation of FLS without showing cellular toxicity. Finally, this compound was effective against collagen induced arthritis in mice. CONCLUSION: Based on these results, IMD-0560 could be a new therapeutic agent for RA.

Animals↗
PubMed2005

Plasminogen activator inhibitor-1 (PAI-1) gene transfection inhibits the liver metastasis of pancreatic cancer by preventing angiogenesis.

Plasminogen activator inhibitor-1 (PAI-1) is a unique type of serine protease inhibitor and one of the key regulators of tumor invasion and metastasis. The purpose of this study was to elucidate the effect of PAI-1 gene transfection on liver metastasis and its mechanism by using the human high liver metastasis pancreatic cancer cell line, SW1990. PAI-1-transfected SW1990 (SW/PAI-1) produced a significantly higher level of PAI-1 in supernatant than parental cells. While no difference was observed for the production of u-PA and u-PA activity in the supernatant, cell proliferation of SW/PAI-1 was slightly suppressed on the 7th day of incubation compared to parental cells. Cellular invasion, in vivo tumorigenesis in xenograft and liver metastasis were significantly suppressed in SW/PAI-1 cells compared to parental cells. The angiogenesis of xenograft by detecting microvascular density and the production of metastasis-related factors, such as VEGF and TGF-beta1, were also decreased in SW/PAI-1 cells. These findings suggested that PAI-1 gene transfection might have the ability to prevent the liver metastasis of pancreatic cancer by modulating angiogenesis.

Animals↗
PubMed2004

Is a lymph node detected by the dye-guided method a true sentinel node in gastric cancer?

PURPOSE: A sentinel node is defined as the initial lymph node, to which cancer cells metastasize from a primary tumor. Recently, sentinel node navigation surgery has been done using the dye-guided method. However, no study has shown that a lymph node detected by the dye-guided method is the true sentinel node from the viewpoint of micrometastasis. Micrometastases of lymph nodes, in which no metastasis was found by H&E staining, were examined to establish whether a lymph node detected by the dye-guided method is the true sentinel node. EXPERIMENTAL DESIGN: Isosulfan blue was injected endoscopically as the dye-guided method at a submucosal lesion of early gastric cancer. Total 345 lymph nodes, including 150 blue-dyed lymph nodes and 195 nondyed lymph nodes were collected from 57 patients and each was quartered. Two quarters were examined histologically by H&E staining and cytokeratin staining. The other specimens were used for quantitative reverse transcription-PCR of CEA and CK20 mRNAs. RESULTS: Lymph node disease was not found in any of 345 lymph nodes from the 57 patients by routine H&E staining. By contrast, either CEA or CK20 mRNA expression was detected in 21 of 345 lymph nodes obtained from the 10 (18%) of 57 patients by quantitative reverse transcription-PCR. Eight of the 21 micrometastasis-positive lymph nodes were confirmed to be positive for cytokeratin staining. Although micrometastasis of nondyed lymph nodes was found in three cases, these were included in the 10 cases with micrometastasis of blue-dyed nodes, such that there was no patient who only had micrometastasis in nondyed nodes. Six of 10 cases were micrometastasis-positive in a single node; all six were blue-dyed nodes. CONCLUSION: A lymph node detected by the dye-guided method should be a true sentinel node to which cancer cells metastasize initially.

Adult↗
PubMed2004

Inhibition and mechanism of action of a protease inhibitor in human pancreatic cancer cells.

OBJECTIVES: Tumor-associated trypsinogen (TAT), urokinase-type plasminogen activator (u-PA), matrix metalloproteinase-2 (MMP-2), and MMP-9 each play a dominant role in the degradation of extracellular matrix (ECM) during the invasion process of pancreatic cancer. Transforming growth factor beta1 (TGF-beta1) is a multifunctional poly-peptide that regulates cell growth and differentiation, ECM deposition, cellular adhesion properties, angiogenesis, and also immune functions. We previously reported that TGF-beta1 up-regulated vascular endothelial growth factor (VEGF) production and protease production of MMP-2 and of u-PA in the highly metastatic pancreatic cancer cell lines SW1990 and CAPAN-2. In this study, we examined the inhibitor effects of a protease inhibitor, gabexate mesilate (GM), on cell invasion, cell proliferation, growth factor production, and ECM degradation. We also examined the effect of GM on the production of growth factor and ECM degradation by these cell proteases and enzymatic activities. RESULTS: GM down-regulated the invasiveness and liver metastasis potential of SW1990 and CAPAN-2 cells, but it did not affect the proliferation of these cells. GM inhibited not only the enzymatic activities of TAT and u-PA but also the production of MMP-2, and u-PA, all of which have been known to be secondarily down-regulated by TGF-beta1. CONCLUSIONS: These findings suggested that GM has very good potential for use in the treatment against invasion and metastasis of pancreatic cancer.

Adenocarcinoma↗
PubMed2004

A role for protease-activated receptor-2 in pancreatic cancer cell proliferation.

The protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin and tryptase. The purpose of this study was to clarify the role of PAR-2 in proliferation of human pancreatic cancer cells. PAR-2 mRNA and protein expression were detected by RT-PCR and Western blotting in three cell lines, SW1990, Capan-2, and Panc-1. The PAR-2 agonist peptide, SLIGKV (25, 50 micro g/ml) and trypsin (10, 100 ng/ml) significantly increased cell proliferation. Enhancement of MAP kinase also was observed in cancer cells treated with SLIGKV and trypsin. In vivo, subcutaneous xenografted tumors showed significantly enhanced growth after treatment with SLIGKV. Tumor-associated trypsinogen (TAT) mRNA and protein expression was detected in SW1990 and Capan-2, suggesting autocrine trypsin production. PAR-2 activated by trypsin plays an important role in promoting proliferation of pancreatic cancer.

Animals↗
PubMed2003

An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis.

Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

Animals↗
PubMed2003

Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.

Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.

Adult↗