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Kazuyoshi Saito

Publications and source records attributed to Kazuyoshi Saito.

At least 19 recordsLinked to original sources
PubMed2007

Engagement of CD44 up-regulates Fas ligand expression on T cells leading to activation-induced cell death.

Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent Ca(2+) mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.

Apoptosis↗
PubMed2006

Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system.

AIM: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious treatment-resistant phenotype of systemic lupus erythematosus. A standard treatment for NPSLE is not available. This report describes the clinical and laboratory tests of 10 patients with NPSLE before and after rituximab treatment, including changes in lymphocyte phenotypes. METHODS: Rituximab was administered at different doses in 10 patients with refractory NPSLE, despite intensive treatment. RESULTS: Treatment with rituximab resulted in rapid improvement of central nervous system-related manifestations, particularly acute confusional state. Rituximab also improved cognitive dysfunction, psychosis and seizure, and reduced the SLE Disease Activity Index Score at day 28 in all 10 patients. These effects lasted for >1 year in five patients. Flow cytometric analysis showed that rituximab down regulated CD40 and CD80 on B cells and CD40L, CD69 and inducible costimulator on CD4+ T cells. CONCLUSIONS: Rituximab rapidly improved refractory NPSLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings. The down regulation of functional molecules on B and T cells suggests that rituximab modulates the interaction of activated B and T cells through costimulatory molecules. These results warrant further analysis of rituximab as treatment for NPSLE.

Adult↗
PubMed2006

Fragmented hyaluronan induces transcriptional up-regulation of the multidrug resistance-1 gene in CD4+ T cells.

P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in multidrug resistance. We found previously that interleukin-2, a lymphocyte-activation cytokine, induces P-glycoprotein expression on lymphocytes. Lymphocyte activation involves adhesion with the extracellular matrix, such as hyaluronan, through adhesion molecules on lymphocytes. We investigated the transcriptional regulation of MDR-1 in lymphocytes by fragmented hyaluronan. Fragmented hyaluronan (especially the 6.9-kDa form), not native high molecular hyaluronan, induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into the nucleus and resulted in the transcription of MDR-1 and the expression of P-glycoprotein on lymphocytes in a dose-dependent manner. Transfection of YB-1 antisense oligonucleotides inhibited P-glycoprotein expression induced by fragmented hyaluronan. The fragmented hyaluronan induced significant P-glycoprotein expression on only activated CD4+ T cells, which highly expressed CD69, and resulted in excretion of intracellular dexamethasone added in vitro. Cyclosporin A, a competitive P-glycoprotein inhibitor, restored intracellular dexamethasone levels in CD4+ T cells. Anti-CD44 monoclonal antibody (Hermes-1) inhibited fragmented hyaluronan-induced YB-1 activation and P-glycoprotein expression in CD4+ T cells. We provide the first evidence that binding of fragmented hyaluronan to CD44 induces YB-1 activation followed by P-glycoprotein expression in accordance with activation of CD4+ T cells. Our findings imply that CD4+ T cell activation by fragmented hyaluronan, induced by characteristic extracellular matrix changes in inflammation, tumors, and other conditions, results in P-glycoprotein-mediated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Abnormal intracellular distribution of NFAT1 in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features.

Systemic lupus erythematosus (SLE) presents various clinical features; however, underlying mechanisms remain unclear. In the immunity of SLE, impaired T cell receptor (TCR) signaling and altered cytokine production are in the center of pathogenesis, although, little is known about NFAT (nuclear factor of activated T cells) in lupus T lymphocytes. TCR stimulation activates NFAT1 through Ca2+/calcineurin (Cn) pathway, facilitating nuclear translocation of NFAT1 from cytosol. Therefore, we investigated relationship of disease activity/features and intracellular NFAT1 localization in T lymphocytes from active lupus patients by fractionation. Results showed no significant relationship between disease activity and NFAT1 distribution. However, interestingly, we observed skewed NFAT1 distribution in pellet in patients with active lupus nephritis or pleuritis. In vitro cyclosporin A treatment suggested autonomously activated Ca2+/Cn pathway in lupus T lymphocytes. Considering these results, NFAT1 might be presenting the clinical heterogeneity in SLE.

Adult↗
PubMed2006

Significance of extensive surgery including resection of the pancreas head for the treatment of gallbladder cancer--from the perspective of mode of lymph node involvement and surgical outcome.

The present study aimed to clarify the efficacy of extensive surgery, including pancreas head resection, for more complete lymphadenectomy in the treatment of gallbladder carcinoma. The study involved retrospective analyses of 65 consecutive patients with gallbladder carcinoma who underwent surgical resection between 1982 and 2003. Of these 65 patients, 41.5% displayed node-positive disease and among them 23.1% had positive para-aortic nodes. Of six node-positive 5-year survivors, five underwent pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy. The 5-year survival rates were 76.2% for pN0, 30.0% for pN1, 45.8% for pN2, and 0% for pM1[lymph], respectively. Significant differences existed in survival rates. Postoperative recurrence was observed in 24.1% (13/54) of patients who underwent R0 resection. Of the four patients who displayed lymph node recurrence, two had pericholedocal and/or posterior pancreatoduodenal lymph node metastasis at the time of surgery and underwent pancreas-preserving regional lymphadenectomy. These results suggest that extensive resection, including resection of the pancreatic head, is effective in selected patients with up to pN2 lymph node metastasis, as long as complete removal of the cancer can be achieved. Pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy should be considered when lymph node metastasis is obvious and the patient is in good condition.

Aged↗
PubMed2005

Clinicopathological study of depth of subserosal invasion in patients with pT2 gallbladder carcinoma.

BACKGROUND: We examined whether depth of subserosal cancer invasion predicts lymph node involvement and survival in gallbladder carcinoma (GBC) patients with pathologicial subserosal invasion (pT2), to explore which patients benefit from radical second resection among patients with inapparent pT2 tumor. METHODS: Subjects comprised 31 patients with pT2 GBC. Thickness of the subserosal layer and vertical length of carcinoma invasion into the subserosa were measured under microscopy. Depth of subserosal invasion was divided subjectively into three categories: ss1, ss2, and ss3 (invasion of upper, middle, and lower thirds of the subserosal layer, respectively). Relationships between subserosal subclassification, histopathological factors, and prognosis were examined. RESULTS: Subserosal layers were significantly thicker (P < 0.001) in portions with cancer invasion (5.46 +/- 0.68 mm; range 1.0 approximately 13.75 mm) than those without cancer invasion (1.89 +/- 0.16 mm, range, 0.88 approximately 4.50 mm). Depth of carcinoma invasion into subserosa was 4.20 +/- 0.65 mm (range, 0.25 approximately 12.5 mm). Rate of lymphatic permeation, venous permeation, and lymph node involvement significantly increased with deeper subserosal invasion (P = 0.014, P = 0.027, P = 0.018, respectively). Among histopathological factors examined, only subserosal subclassification had a significant correlation with presence or absence of lymph node metastasis. Further, there was a significant correlation (P = 0.043) between the degree of subserosal invasion (ss1, ss2, and ss3) and involved nodal disease (pN0, pN1, and pM1 [lymph]). Although 5-year survival rates, according to the degree of subserosal invasion, tended to decrease with deeper invasion into the subserosal layer (ss1, 83.3%; ss2, 62.5%; ss3, 50.0%), no significant differences were noted. CONCLUSIONS: Pathological characteristics tend to become more aggressive with increasing depth of subserous carcinoma invasion in pT2 GBC. Depth of subserosal invasion is a predictor of presence and degree of lymph node metastasis in pT2 GBC. A sampling biopsy of the para-aortic nodes is recommended for inapparent pT2 GBC patients with subserosal invasion beyond one-thirds of the subserosal layer when they undergo radical second resection.

Carcinoma↗
PubMed2005

Glucocorticoid inhibits the human pro-interleukin lbeta gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer.

Elucidating the role of glucocorticoid in regulating gene expression is crucial to developing effective strategies against inflammatory diseases such as arthritis. In this report we demonstrate that glucocorticoid inhibits transcription directed by the IL-lbeta gene (IL1B) upstream induction sequence (UIS) enhancer, and to a much lesser extent by the tissue-specific basal promoter. Within the enhancer, three transcription factor binding sites, previously demonstrated by us to be important for the induction of IL1B by lipopolysaccharide, are now shown to be directly inhibited by the synthetic glucocorticoid, dexamethasone. We also previously showed that one of these sites could bind a novel STAT-like factor, while the other two bound heterodimers containing NF-IL6(C/EBPbeta). Although it has been reported by others that NF-IL6 homodimers can interact with glucocorticoid receptor (GR) to enhance transcription of the alpha1-acid glycoprotein gene, it now appears that glucocorticoid represses DNA binding of NF-IL6 heterodimers as well as the novel STAT-like factor to the critical sites within the IL1B UIS. Thus, GR likely disrupts the DNA binding capability of critical IL1B factors via transrepression.

Binding Sites↗
PubMed2005

Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts.

Rho is a major small GTP-binding protein that is involved in the regulation of various cell functions, including proliferation and cell migration, through activation of multiple signaling molecules in various types of cells. We studied its roles in synovial fibroblasts (SFs) in patients with rheumatoid arthritis (RA) and clarified its relevance to RA synovitis, with the following results. 1)We found that the thrombin receptor was overexpressed on RA synovial fibroblasts (RA SFs) and that thrombin induced a marked proliferation and progression of the cell cycle to the S phase in these cells. 2)We also found that thrombin efficiently activated Rho. 3)Rho activation and proliferation and the progression of the cell cycle to the S phase were completely blocked by p115RGS (an N-terminal regulator of the G-protein signaling domain of p115RhoGEF) and by the C-terminal fragments of Galpha13 (an inhibitor of the interaction of receptors with G13). 4)Thrombin induced the secretion of IL-6 by RA SFs, but this action was blocked by p115RGS or Galpha13. Our findings show that the actions of thrombin on the proliferation of RA SFs, cell-cycle progression to the S phase, and IL-6 secretion were mainly mediated by the G13 and RhoGEF pathways. These results suggest that p115RGS and Galpha13 could be potent inhibitors of such functions. A rational design of future therapeutic strategies for RA synovitis could perhaps include the exploitation of the Rho pathway to directly reduce the growth of synovial cells.

Aged↗
PubMed2005

Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus.

OBJECTIVE: P-glycoprotein (P-gp) of membrane transporters leads to drug resistance by the exclusion of intracellular drugs, including corticosteroids. Some patients with highly active systemic lupus erythematosus (SLE) show poor response to corticosteroids; however, the mechanisms of steroid resistance remain unclear. The aim of this study was to elucidate the clinical relevance of P-gp expression on lymphocytes to steroid resistance in patients with active SLE. METHODS: Flow cytometric analyses of the expression of P-gp on peripheral blood lymphocytes from 20 normal volunteers and 80 SLE patients were performed. Steroid-exclusion analysis of peripheral blood mononuclear cells (PBMCs) was conducted by using radioisotope-labeled dexamethasone. RESULTS: P-gp was expressed at significantly high levels on most of the peripheral blood lymphocytes from SLE patients, whereas normal lymphocytes had only marginal expression. The quantity of P-gp on SLE lymphocytes correlated with the disease activity in each patient, as estimated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Furthermore, in SLE patients whose SLEDAI scores were >12 despite taking >0.5 mg/kg/day of prednisolone, P-gp expression on lymphocytes was markedly increased, and intracellular dexamethasone in their PBMCs was significantly decreased. However, intensive immunosuppressive treatment in these SLE patients resulted in successful control of disease activity, which occurred in parallel with a marked reduction of P-gp on lymphocytes. CONCLUSION: The overexpression of P-gp on lymphocytes might lead to exclusion of corticosteroids from lymphocytes, resulting in steroid resistance in patients with highly active SLE. Reduction of P-gp expression achieved by intensive immunosuppressive treatment overcame the steroid resistance. We therefore propose that measurement of P-gp expression on lymphocytes is useful in the assessment of steroid resistance and is a good marker for indicating the need for intensive immunosuppressive treatment in patients with highly active SLE.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Experimental evaluation of bursting pressure in lymphatic vessels with ultrasonically activated shears.

To evaluate the ability of ultrasonically activated shears (USAS) to occlude lymphatic vessels, we investigated the bursting pressure of lymphatic vessels occluded with USAS and compared with pressures in an artery and a vein. The inguinal lymphatic vessels, testicular arteries, and testicular veins were removed from male pigs. The vessels were occluded by USAS at power level 2. The bursting pressures of the harvested vessels were measured ex vivo. The bursting pressure of the artery (average, 1154 mmHg; range, 1000-1341 mmHg) was significantly greater than that in the vein (average, 747 mmHg; range, 560-973 mmHg; p = 0.0024) or the lymphatic vessel (average, 610 mmHg; range, 491-996 mmHg; p = 0.0003). There was no significant difference of bursting pressure between the vein and lymphatic vessel (p = 0.2226). Although the bursting pressures of the vein and lymphatic vessel were significantly lower than that of the artery, they were much higher than that found in physiologic conditions. USAS is considered to be a powerful tool for lymph node dissection for malignant diseases in open surgery as well as laparoscopic surgery.

Animals↗
PubMed2005

Overcoming treatment unresponsiveness mediated by P-glycoprotein overexpression on lymphocytes in refractory active systemic lupus erythematosus.

P-glycoprotein (P-gp) expels various drugs from cells, resulting in multidrug resistance, including against glucocorticoids. Here, we present a case of systemic lupus erythematosus (SLE) that suggests the importance of initial intensive treatment in overcoming unresponsiveness due to P-gp overexpression on activated lymphocytes. A 28-year-old woman had been diagnosed with highly active SLE including severe pericarditis, hemolytic anemia, lupus nephritis, and retinopathy. The disease activity of SLE progressed despite 1 mg/kg per day oral prednisolone. At the time, P-gp expression was extremely high, as evaluated by flow cytometric analysis on peripheral lymphocytes. After intensive treatment with three courses of methylprednisolone pulse therapy and plasmapheresis, we succeeded in controlling disease activity in association with marked reduction of P-gp overexpression; namely, the clinical symptoms immediately improved along with the reduction of P-gp expression. These results imply that patients with highly active SLE might have drug unresponsiveness that is mediated by P-gp overexpression on lymphocytes. Therefore, downregulation of P-gp by initial intensive immunosuppressive therapy might be important for overcoming glucocorticoid resistance. We also propose that measurement of P-gp on lymphocytes is a useful test for prediction of drug resistance and may assist in the selection of appropriate initial treatment.

Journal Article↗
PubMed2005

Human urinary trypsin inhibitor bolus infusion improved severe interstitial pneumonia in mixed connective tissue disease.

Interstitial pneumonia (IP) with mixed connective tissue disease (MCTD) often progresses despite immunosuppressive therapies that caused serious infections. Human urinary trypsin inhibitor (UT) inhibits inflammatory factors associated with IP, without immunosuppression. UT bolus infusion rescued a female MCTD patient with refractory IP and severe opportunistic fungal pneumonia. Her IP diminished with monthly UT bolus infusion despite tapering of prednisolone, without UT-related side effects. UT pulse therapy could prove beneficial for refractory IP in MTCD even with opportunistic infections.

Journal Article↗
PubMed2005

Epigenetic status and aberrant expression of the maspin gene in human hepato-biliary tract carcinomas.

We examined expression of maspin and the epigenetic status of its gene in 40 primary hepato-biliary tract carcinomas and 11 cell lines originating from hepato-pancreatico-biliary tract carcinomas. Aberrant maspin expression was frequently observed immunohistochemically in biliary tract carcinomas (22/25, 88%) but not in hepatocellular carcinomas (HCCs) (0/15, 0%). Aberrant maspin expression by five pancreatico-biliary tract carcinoma cell lines was closely associated with demethylation at the maspin promoter. Five of six HCC cell lines were maspin-negative and exhibited extensive hypomethylation and hypoacetylation at the maspin promoter. Treatment with 5-aza-2'-deoxycytidine did not activate maspin expression in these five maspin-negative HCC cell lines, whereas treatment with Trichostatin A (TSA) activated maspin expression in two of them. Treatment with TSA increased histone acetylation in some HCC cell lines. These results suggest that aberrant maspin expression in biliary tract carcinomas is closely associated with demethylation at the promoter region, but that some HCC cell lines additionally require histone acetylation. In addition, the fact that maspin-negative HCC cell lines remain after treatment with TSA suggests the existence of other repressive factors controlling maspin expression.

Acetylation↗
PubMed2005

Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.

Envoplakin (EVPL) is a member of the desmosomal plaque proteins attached to desmosomal cadherin and keratin filaments. The EVPL gene has been mapped to the tylosis oesophageal cancer (TOC) locus on chromosome 17q25, where it has been demonstrated to be frequently deleted in both familial and sporadic forms of oesophageal squamous cell carcinoma (OSC). In this study, we examined EVPL gene mutations in 10 OSC cell lines and 20 sporadic OSCs using reverse transcription-polymerase chain reaction single-strand conformational analysis (RT-PCR SSCP) followed by direct sequencing. We observed one somatic mutation (GCG to ACG at codon 1104, Ala to Thr: 1/20, 5%) in the central rod domain and 5 intragenic polymorphic sites, where frequent loss of heterozygosity (LOH) (63%) was detected. No mutations were detected in the OSC cell lines. The rate of EVPL gene mutation was quite low in contrast to the frequency of LOH on the TOC locus in sporadic OSCs, and the high incidence of oesophageal cancer development in tylosis families. Our results suggest that EVPL might not be the target gene responsible for OSC, despite its strong candidacy in terms of character and localization.

Alleles↗
PubMed2005

[Endoscopic radiofrequency ablation for liver metastasis of colorectal cancer].

The application of radiofrequency ablation (RFA) for liver metastasis of colorectal cancer has not yet acquired an established status in clinical cancer therapy research. Removing as much tumor tissue as possible is desirable, but some cases do not allow optimal surgical ablation due to general condition of the patient and tumor status. We introduced endoscopic RFA for liver cancer in 2003, and have applied the procedure to 6 cases with H1 or H2 liver metastases of colorectal cancer to which surgical ablation could not be applied due to the poor general health of patients. Mean tumor diameter was 22.9 mm, and mean number of tumors per patient was 1.2. Tumor location was: S4, n = 2; S5, n = 1; S4, n = 1; S7, n = 2; and S8, n = 1. Mean frequency of session was 3.0. No complications occurred in any cases, and no reoperations were required. Although no recurrence of tumors in the vicinity of ablation was observed, 2 cases of each lung metastasis and intrahepatic recurrence were identified. Intrahepatic recurrence underwent hepatic arterial infusion (HAI) chemotherapy for simultaneous metastatic hepatic tumors (H2) prior to RFA, and relapses occurred in the metastatic focus where the efficacy of HAI was observed. At this point, 2 deaths were reported, 1 each from cancer and other diseases, and mean duration of survival after the procedure was 451.2 days. These results indicate that endoscopic RFA with good local control should be an available treatment for cases involving colorectal cancer with metastasis to the liver in which surgical ablation is difficult to apply.

Adult↗
PubMed2004

Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers.

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but the biological significance of DNA hypomethylation in carcinogenesis is less understood. The expression of Maspin (mammary serpin) in differentiated normal cells is regulated by epigenetic modifications in a cell-type-specific manner. Paradoxical Maspin expression due to epigenetic modification has been addressed in several cancer cell types. To elucidate the role of the Maspin gene in thyroid cancer, we studied methylation status in the promoter region and its expression in six human undifferentiated thyroid cancer cell lines and in specimens from 92 primary thyroid tumors, consisting of six follicular adenomas, 56 well-differentiated thyroid cancers (WDTCs), 17 poorly differentiated thyroid cancers (PDTCs) and 13 undifferentiated thyroid cancers (UDTCs). Three of the six cell lines overexpressed Maspin mRNA and its protein product, but the remaining three did not. The methylation status at the promoter region was inversely correlated with Maspin expression. In Maspin-negative cell lines, Maspin expression was induced by treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. Immunoreactivity for Maspin protein was frequently detected in UDTCs (8/13, 62%) and PDTCs (7/17, 41%). Immunoreactivity for Maspin was diffusely positive in UDTCs, and was restricted to dedifferentiated components of the tumor in PDTCs. Positive immunoreactivity was infrequent in WDTCs (1/56, 2%), and all follicular adenomas and normal thyroid glands were completely negative. Their methylation status evaluated by the methylation-specific PCR method showed a good inverse correlation with their immunoreactivity in surgically resected specimens. Our data suggest that overexpression of Maspin by DNA hypomethylation is closely associated with morphological dedifferentiation in thyroid cancers.

Adenoma↗