[Ovarian cancer with swelling of the right upper arm, amyopathic dermatomyositis, and elevated serum KL-6].
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Aged↗
Biomedical subjects
Isao Matsumoto
Publications and source records attributed to Isao Matsumoto.
Diagnosis of chlamydia-induced reactive arthritis.
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Arthritis, Reactive↗
Overexpression of phosphorylated STAT-1alpha in the labial salivary glands of patients with Sjögren's syndrome.
OBJECTIVE: To clarify the molecular mechanisms of Sjögren's syndrome (SS), we analyzed the functional role of the STAT-1 gene, one of the interferon-gamma (IFNgamma)-inducible genes, in labial salivary glands (LSGs) from SS patients. METHODS: The expression of STAT-1 messenger RNA (mRNA) was examined by real-time polymerase chain reaction (PCR) analysis, and the phosphorylation of STAT-1 protein (Tyr(701) and Ser(727) pSTAT-1) was investigated by Western blot and immunohistochemical analyses. The expression of IFNgamma-inducible 10-kd protein (IP-10), IFN regulatory factor 1 (IRF-1), and Fas was also examined by real-time PCR and immunohistochemical analyses. RESULTS: STAT-1alpha and STAT-1beta mRNA were highly expressed in LSGs from SS patients. The level of STAT-1alpha protein in SS LSGs was higher than that in 3 control LSGs, whereas STAT-1beta protein was not clearly detected by Western blot analysis. Moreover, Tyr(701) and Ser(727) pSTAT-1alpha proteins were specifically detected in SS LSGs. Immunohistochemical analysis showed localization of Tyr(701) pSTAT-1 in infiltrating lymphocytes and the adjacent ductal epithelium from SS patients. Ser(727) pSTAT-1 was localized only in the ductal epithelium of SS LSGs. The STAT-1-inducible genes IP-10 and IRF-1 and the Fas genes were highly expressed in SS LSGs and were colocalized with Ser(727) pSTAT-1-positive, but not Tyr(701) pSTAT-1-positive, cells. CONCLUSION: We found evidence of the up-regulation of STAT-1alpha mRNA and protein in LSGs from SS patients, as well as the presence of pSTAT-1alpha in ductal epithelium from SS patients. Our findings suggest that STAT-1alpha, especially Ser(727) pSTAT-1, may function as a key molecule in the pathogenesis of SS.
Gene Expression↗
Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay, and comparison with other antiphospholipid antibody assays.
Antibodies against prothrombin are detected by enzyme immunoassays (EIA) in sera of patients with antiphospholipid syndrome (APS). However, there are two methods for antiprothrombin EIA; one that uses high binding plates (aPT-A), and another that utilizes phosphatidylserine bound plates (aPS/PT). We aimed to evaluate and compare aPT-A and aPS/PT in a clinical setting. We performed EIA for anti-PT, anti-PS/PT, IgG, and IgM anticardiolipin antibodies (aCL), and IgG beta2-glycoprotein I-dependent aCL (abeta2GPI/CL) with serum samples from 139 systemic lupus erythematosus (SLE) patients (16 with history of at least one thrombotic episode) and 148 controls. We observed that: (1) although titers of anti-PT and anti-PS/PT were significantly related with each other (P < 0.0001, rho = 0.548), titer of anti-PT and anti-PS/PT differed greatly in some samples; (2) odds ratio and 95% confidence interval for each assay was 3.556 (1.221-10.355) for aPT-A, 4.591 (1.555-15.560) for aPS/PT, 4.204 (1.250-14.148) for IgG aCL, 1.809 (0.354-9.232) for IgM aCL, and 7.246 (2.391-21.966) for abeta2GPI/CL. We conclude that, while all EIA performed in this study except IgM aCL are of potential value in assessing the risk of thrombosis, aPS/PT and abeta2GPI/CL seemed to be highly valuable in clinical practice, and that autoantibodies detected by anti-PT and anti-PS/PT are not completely identical.
Antibodies, Antiphospholipid↗
Altered peptide ligands control type II collagen-reactive T cells from rheumatoid arthritis patients.
We previously reported that peripheral blood mononuclear cells from HLA-DRB1*0101 Japanese patients with rheumatoid arthritis (RA) were highly reactive to 256-271 peptide of type II collagen (CII). In this report, we tried to regulate the CII reactivity of T cells from RA patients with HLA-DRB1*0101 by altered peptide ligand (APL), which is a single amino acid substitution of the T-cell epitope on CII 256-271 peptide. Antagonistic activity of 21 APLs was assessed using three different T-cell lines. Results showed that 262 (G-->A) APL of CII 256-271 exhibited antagonistic activity in all T-cell lines and it was suggested that the application of CII APL might be a new therapeutic strategy in the regulation of RA.
Amino Acid Sequence↗
Results of initial operations in non-small cell lung cancer patients with single-level N2 disease.
BACKGROUND: There is still debate regarding the use of surgery in the management of non-small cell lung cancer patients with N2 disease. The primary aim of the present study was analysis of the results of initial operations in non-small cell lung cancer patients with single-level N2 disease. METHODS: Ninety-four patients with the disease who underwent initial surgery consisting of complete resection of the primary site plus systematic lymphadenectomy were examined. We also immunohistochemically examined lymphatic vessel density and vascular endothelial growth factor-C expression. RESULTS: The overall 5- and 10-year survival rates for the 94 patients were 27.1% and 12.1%, respectively, with a median survival of 22 months. When stratified by skipping status, the 5-year survival rates for the patients in skip-N2 and non-skip-N2 groups were 33.4% and 19.8%, respectively (p = 0.0189). Skip metastasis, T factor, subcarinal lymph node metastasis, and adjuvant chemotherapy were recognized as independent prognostic indicators. In both skip-N2 and non-skip-N2 groups, distant relapse was the dominant pattern of recurrence. Although the peritumoral lymphatic vessel density was associated with vascular endothelial growth factor-C expression in tumors, the lymphangiogenic profile appeared to be different between skip-N2 and non-skip-N2 tumors, suggesting different nodal metastatic process. CONCLUSIONS: Lung cancer patients with single-level N2 disease are an oncologically heterogeneous cohort. Although further studies involving randomized comparisons are required, the poor outcomes found here indicate that the initial operation has yet to be validated for patients with this disease.
Adult↗
Pathologic and biological assessment of lung tumors showing ground-glass opacity.
BACKGROUND: We evaluated the pathologic and biological aspects of lung tumors 3.0 cm or less in diameter with the appearance of ground-glass opacity (GGO). METHODS: Of 988 patients with non-small cell lung cancer who underwent operations at our institute between January 1994 and December 2004, 87 resected lung tumor specimens that showed GGO appearance on helical computed tomography were obtained from 81 patients. Forty-four lesions were pure GGO with no solid component in the tumor and 43 lesions were mixed GGO consisting of areas of attenuation with a solid component. Together with histological features, MIB1 and nm23 expression within tumors were examined immunohistochemically. RESULTS: The mean tumor size in the pure GGO group was significantly smaller than that in the mixed GGO group. The composition of pathologic subtypes and biological characteristics were clearly different between the two groups. Although atypical adenomatous hyperplasia and localized bronchioloalveolar cell carcinoma of Noguchi's A and B were the predominant pathologic subtypes and nm23 negativity was rare in the pure GGO group, a high score for expression of MIB1 was often found in pure GGO tumors even though the tumors were less than 10 mm in diameter. CONCLUSIONS: If the tumor is 2 cm or less in diameter, the ability of invasion and metastasis seems to be low in pure GGO tumors. However, the proliferation ability of these tumors suggests the necessity of a careful follow-up schedule if the tumor is greater than 5 mm in diameter. For mixed GGO tumors, surgical resection instead of observation is justified.
Carcinoma, Non-Small-Cell Lung↗
Surgical results in T2N0M0 nonsmall cell lung cancer patients with large tumors 5 cm or greater in diameter: what regulates outcome?
BACKGROUND: We assessed the surgical results along with the clinical and biological features of nonsmall-cell lung cancer (NSCLC) patients with localized large tumors. METHODS: The study population consisted of 86 NSCLC patients who underwent complete resection of tumors 5 cm or larger in diameter in stage IB (T2N0M0). We immunohistochemically assessed the expression of angiostatin and endostatin. RESULTS: The median tumor size was 6.0 cm (range, 5 to 14 cm). The operative procedures used were lobectomy in 71 cases, bilobectomy in 8 cases, and pneumonectomy in 11 cases. Fifty patients (58.1%) relapsed during the mean follow-up period of 33.6 +/- 4.5 months. The median disease-free interval was 9 months. Of 44 recurrent patients whose disease-free interval could be identified, 25 patients (56.8%) relapsed within 12 months after the operation. The overall 5- and 10-year survival rates were 42.0% and 24.2%, respectively. Multivariate analysis showed that the degree of pleural involvement and angiostatin expression within the tumor were independent prognostic indicators. The endostatin expression within tumors also had a weaker relationship with outcome. CONCLUSIONS: Long-term surgical results were poor and early relapse was common in this cohort. In addition to pleural involvement, the tumor-induced expression of angiostatin and endostatin merit further investigation to gain possible insights into selection of patients who will benefit from surgery as the first line treatment.
Aged↗
Critical role of M. tuberculosis for dendritic cell maturation to induce collagen-induced arthritis in H-2b background of C57BL/6 mice.
Collagen-induced arthritis (CIA) can be induced even in CIA-resistant H-2(b) background of C57BL/6 mice when these mice are immunized with type II collagen (CII) emulsified in complete Freund's adjuvant (CFA) containing high, but not low, dose of Mycobacterium tuberculosis. Here, we investigated the pathogenesis of CIA in C57BL/6 mice induced by the immunizing protocol. We examined expressions of cytokines, costimulatory molecules and major histocompatibility complex (MHC) class II in draining lymph nodes (DLN) in CIA-induced C57BL/6 mice by quantitative reverse transcription-polymerase chain reaction. We also examined an effect of M. tuberculosis on the expression of these molecules on dendritic cells (DC) in vitro by flow cytometry. We finally examined an effect of M. tuberculosis in CFA used for immunization with CII antigen on priming of CD4+ helper T cells specific to CII in DLN of CIA-induced C57BL/6 mice. The expression of interferon-gamma (IFN-gamma), Interleukin-12p40 (IL-12p40), costimulatory molecules CD40, CD80 and CD86 and MHC class II were up-regulated in DLN of CIA-induced C57BL/6 mice. Expressions of these costimulatory molecules were also up-regulated on DC after stimulation with high, but not low, dose of M. tuberculosis in vitro. Furthermore, priming of CD4+ helper T cells specific to CII antigen in DLN required immunization with CII using CFA containing high, but not low, dose of M. tuberculosis. These results suggested that high dose of M. tuberculosis were required for maturation of DC enough to prime CD4+ helper T cells specific to CII antigen in DLN of H-2b background of C57BL/6 mice.
Adjuvants, Immunologic↗
T cell receptor BV gene repertoire of lymphocytes in bronchoalveolar lavage fluid of polymyositis/dermatomyositis patients with interstitial pneumonitis.
We analyzed the T cell receptor (TCR) repertoire of bronchoalveolar lavage fluid (BALF) lymphocytes from polymyositis (PM) and dermatomyositis (DM) patients with interstitial pneumonitis (IP) to elucidate the pathogenic mechanisms of IP in these disorders. Samples from 2 PM patients, 1 DM patient and 3 healthy controls were used. RNA was isolated from BALF, cDNAs were synthesized, and family PCR and Southern blot analysis were performed by primers specific for TCR BV1-25 and TCR BC to determine TCR repertoire. We examined single-strand conformation polymorphism (SSCP) to evaluate T cell clonality. The CDR3 region of TCR BV genes in BALF T cells were determined by DNA sequencer. Our examination showed that TCR repertoire of T cells in BALF was heterogeneous both in patients with PM/DM and control subjects. SSCP analysis demonstrated an increased number of accumulated T cell clones in BALF of three PM/DM patients, but not in the healthy subjects and the junctional sequence analysis showed the presence of conserved amino acid motifs (RGS, GLA, LQG, SGG, DRG, GTS, TSGR, GGS, GQA, GAG, GTG) in the TCR-CDR3 region of BALF lymphocytes from PM/DM patients, which were not detected in the control. Our findings suggest that T cells in BALF may recognize the restricted antigen and accumulate via antigen-driven stimulation, suggesting that T cells may play a crucial role in the development of IP in patients with PM/DM.
Adult↗
Gene transduction of tristetraprolin or its active domain reduces TNF-alpha production by Jurkat T cells.
Tristetraprolin (TTP) is a physiological regulator of tumor necrosis factor (TNF)-alpha production. It destabilizes TNF-alpha mRNA by binding to the AU-rich element located in the 3' region of TNF-alpha mRNA. We wished to determine how transducing the TTP gene or its fragment gene encoding its biological active site, the tandem zinc finger (TZF) domain, affects TNF-alpha production, cell viability and growth of Jurkat T cells. Jurkat T cells were transduced with either the TTP or the TZF gene using retrovirus vectors. Cell growth and apoptosis was analyzed. Expression of genes before or after appropriate stimuli was measured by real-time PCR. In addition, production of the TNF-alpha protein was measured by enzyme immunoassay. The transduction of either gene reduced TNF-alpha mRNA levels under unstimulated conditions, and reduced the response to phytohemagglutinin stimulation. Production of TNF-alpha protein upon stimulation was also decreased in TTP/TZF-transduced cells. Transduction of either gene also affected the expression of granulocyte-macrophage colony-stimulating factor mRNA in a similar fashion, but not that of c-myc. The growth rate of TTP-transduced Jurkat T cells tended to be slower than that of TZF- or mock-transduced cells. TTP-transduced cells were more susceptible to campthothecin-induced apoptosis than others. Our results indicate that either TTP or TZF gene transduction using retrovirus vectors can reduce the production of TNF-alpha in Jurkat T cells although some differences were noted between TTP and TZF in cell growth and occurrence of apoptosis. These results suggest that TTP may be a potential target for new therapies against RA.
Animals↗
In vitro sensitivity to platinum-derived drugs is associated with expression of thymidylate synthase and dihydropyrimidine dehydrogenase in human lung cancer.
Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are critical enzymes in nucleic acid metabolism. Proliferating cell nuclear antigen (PCNA) is a specific protein that is correlated with proliferative activity of cells. The TS gene has a variable number of tandem repeats (VNTR) in its 5'-untranslated region and a single nucleotide polymorphism (SNP) in the VNTR area. We examined the association of in vitro sensitivity to anticancer drugs with TS polymorphism, TS, DPD, and PCNA mRNA expression using human lung cancer tissues. Seventy-eight surgically resected lung cancer tissues were tested for in vitro sensitivity to 5-fluorouracil, cisplatin (CDDP), carboplatin (CBDCA), irinotecan, docetaxel, and gemcitabine by histoculture and MTT assay. The TS polymorphisms were analyzed by PCR and PCR-RFLP. TS, DPD, and PCNA mRNA expression levels were quantified by real-time RT-PCR and normalized relative to beta-actin mRNA expression. The inhibition rates (IRs) of CDDP and CBDCA were significantly correlated with TS/PCNA, the ratio of TS/actin and PCNA/actin, and DPD/PCNA, the ratio of DPD/actin and PCNA/actin. This correlation was further explored by subgroup analyses according to TS VNTR or TS functional type, in which 2R/3G, 3C/3G, or 3G/3G were classified into H-type group and 2R/2R, 2R/3C, or 3C/3C into L-type group. The associations of TS/PCNA and DPD/PCNA with the IRs of CDDP, CBDCA remained significant in the 3R/3R group and H-type group. These results suggest that in vitro sensitivity to platinum-derived drugs, CDDP and CBDCA, is associated with PCNA-normalized mRNA expression of TS and DPD in human lung cancer tissues, as affected by the TS polymorphism. The clinical significance of these pharmacogenomic markers for chemotherapy regimens with platinum-derived drugs should be investigated further for personalized treatment of lung cancer.
Adult↗
Expression of TNF-alpha, tristetraprolin, T-cell intracellular antigen-1 and Hu antigen R genes in synovium of patients with rheumatoid arthritis.
Post-transcriptional regulation through the AU-rich element (ARE) by ARE binding proteins (ARBPs) has an important role in controlling the production of cytokines, including tumor necrosis factor (TNF)-alpha. Therefore, expression of ARBPs may influence, or may be influenced, by the severity of rheumatoid arthritis (RA). We measured the gene expression of ARBPs, including tristetraprolin, T-cell intracellular antigen (TIA)-1 and Hu antigen R (HuR), in synovial tissues from RA and osteoarthritis patients. cDNA was constructed from synovial tissues obtained from 21 patients with RA, and those from 12 patients with osteoarthritis. Gene expression was measured using the TaqMan PCR real-time quantification method. No significant differences were observed in the expression of tristetraprolin, TIA-1 or HuR genes between RA and osteo-arthritis synovium samples. No significant relationships between expression of tristetraprolin, TIA-1 or HuR genes and TNF-alpha gene expression serum CRP levels in samples from RA patients were observed. A significant positive relationship was observed between gene expression levels of TIA-1 and HuR. While HuR stabilizes TNF-alpha mRNA and enhances TNF-alpha production, TIA-1 acts as a post-transcriptional silencer, and suppresses the production of the TNF-alpha protein. The clear positive relationship between the expression of these two ARBPs may imply that the expression of either gene affects the expression of the other, or the mechanisms that control the expression of these genes have some factors in common.
Aged↗
Retrospective review of lung cancer patients with pleural dissemination after limited operations combined with parietal pleurectomy.
BACKGROUND AND OBJECTIVES: The long-term control of malignant effusion is necessary to achieve long-term survival in lung cancer patients with carcinomatous pleuritis. This report describes our results of limited operations including parietal pleurectomy (pl) on a hypothesis that the most effective target area for controlling malignant pleural effusion is the parietal pleura. METHODS: Forty-two patients with pleural dissemination with/without malignant pleural effusion were analyzed retrospectively. The operative procedures used were partial resection of the primary site with pl in 20 cases, segmentectomy with pl in 2 cases, lobectomy with pl in 19 cases, and pl only in 1 case. Postoperative adjuvant treatment was performed in 31 patients. RESULTS: Adenocarcinoma was the dominant histology, and the pathological stages were IIIB in 34 cases and IV (intrapulmonary metastasis) in 8 cases. The overall 3-, 5-, and 10-year survival rates were 30.1%, 17.2%, and 10.3%, respectively. When stratified by the TNM classification, the overall 3-, 5-, and 10-year survival rates were 56.3%, 32.1%, and 24.1%, respectively, in the T4N0M0 group and 21.1%, 7.0%, and 0%, respectively, in the T4N1-2M0 group (P = 0.0257). Among the 24 patients whose recurrent patterns could be identified, only 2 patients developed recurrent malignant effusion. CONCLUSIONS: With appropriate patient selection, the use of limited surgery combined with pl followed by intrapleural and systemic chemotherapy appears to be effective in management of the disease.
Adult↗
A functional variant of Fcgamma receptor IIIA is associated with rheumatoid arthritis in individuals who are positive for anti-glucose-6-phosphate isomerase antibodies.
Anti-glucose-6-phosphate isomerase (GPI) antibodies are known to be arthritogenic autoantibodies in K/BxN mice, although some groups have reported that few healthy humans retain these antibodies. The expression of Fcgamma receptors (FcgammaRs) is genetically regulated and has strong implications for the development of experimental arthritis. The interaction between immune complexes and FcgammaRs might therefore be involved in the pathogenesis of some arthritic conditions. To explore the relationship between functional polymorphisms in FcgammaRs (FCGR3A-158V/F and FCGR2A-131H/R) and arthritis in individuals positive for anti-GPI antibodies, we evaluated these individuals with respect to FCGR genotype. Genotyping for FCGR3A-158V/F and FCGR2A-131H/R was performed by PCR amplification of the polymorphic site, followed by site specific restriction digestion using the genome of 187 Japanese patients with rheumatoid arthritis (including 23 who were anti-GPI antibody positive) and 158 Japanese healthy individuals (including nine who were anti-GPI antibody positive). We report here on the association of FCGR3A-158V/F functional polymorphism with anti-GPI antibody positive status. Eight out of nine healthy individuals who were positive for anti-GPI antibodies possessed the homozygous, low affinity genotype FCGR3A-158F (odds ratio = 0.09, 95% confidence interval 0.01-0.89; P = 0.0199), and probably were 'protected' from arthritogenic antibodies. Moreover, among those who were homozygous for the high affinity genotype FCGR3A-158V/V, there were clear differences in anti-human and anti-rabbit GPI titres between patients with rheumatoid arthritis and healthy subjects (P = 0.0027 and P = 0.0015, respectively). Our findings provide a molecular model of the genetic regulation of autoantibody-induced arthritis by allele-specific affinity of the FcgammaRs.
Adult↗
Effective 6-hour preservation in non-heart-beating donor canine lungs with topical cooling: assessment from histopathological aspects.
PURPOSE: This study assesses the possibility of preserving and transplanting non-heart-beating donor (NHBD) lungs under topical cooling for 6 h. METHODS: The donor dogs were killed and heparinized after cardiac arrest. After 10 min of cardiac massage, the bilateral lungs were deflated. In group 1 (n = 6), the recipient dogs were transplanted and the lungs preserved at 4 degrees C for 6 h. In group 2 (n = 2), the recipients received lungs preserved at room temperature for 4 h. In both groups the right main bronchus, pulmonary artery, and pulmonary vein were clamped and ventilated to examine the lung function. RESULTS: The mean total ischemic time before reperfusion was 7 h 48 min (group 1) and 5 h 55 min (group 2). All dogs in group 1 survived with excellent hemodynamics and gas exchange function. Both dogs in group 2 revealed congestion immediately after reperfusion, and consequently died. CONCLUSIONS: We concluded that it is possible to use NHBD lungs for clinical lung transplantation if topical cooling can be initiated soon after irreversible cardiac arrest. Topical cooling of NHBD lungs allows at least 6 h for preparation before transplantation.
Analysis of Variance↗
Clinical characteristics of anti-glucose-6-phosphate isomerase antibody-positive Japanese patients with rheumatoid arthritis.
Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are known to be arthritogenic in mice. These Abs are elevated in several forms of arthritic condition in humans, although their prevalence in rheumatoid arthritis (RA) patients is still in debate. Some RA patients have increased levels of anti-GPI Abs, but their clinical manifestation and relevance to other Abs are not clearly elucidated. The aims of this study were to explore the clinical and hematological characteristics of RA with anti-GPI Abs, and to compare their prevalence in RA patients, systemic lupus erythematosus (SLE) patients, and healthy subjects (HS) in a Japanese population. Anti-GPI Abs were positive in 16 patients with RA (12%, n = 137), in 10 patients with SLE (8%, n = 131), and in 6 HS (4%, n = 139). C-reactive protein (CRP), immunoglobulin G, and the antinuclear antibody titer were higher in anti-GPI-positive patients than in those who were negative (P = 0.049, P = 0.0003, and P = 0.002, respectively). Moreover, the positivity of anti-GPI Abs was correlated with CRP more than with rheumatoid factor in RA patients. It is unclear whether anti-GPI Abs can predict the progress of disease, but the prevalence of these Abs was higher in active RA patients with severe arthritis, suggesting that anti-GPI Abs may be related to the pathogenesis of severe forms of arthritis.
Journal Article↗
Identification of three novel peptides that inhibit CD40-CD154 interaction.
The CD40-CD154 interaction is an attractive target for therapeutic intervention in various autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and myasthenia gravis. In this study, to develop a new disruption strategy of the CD40-CD154 interaction, we screened for peptides with inhibitory effects on such ligation. 2 x 10(11) phage display libraries displaying liner peptides of 12-mer amino acids were screened by CD40-Ig binding assay and eight phages which expressed a different respective peptide (40BP-1 to -8) were able to specifically bind to CD40. Competitive inhibition analyses showed that 3 of the 8 peptides (40BP-N1-1 - APELPNMTPSWT; 40BP-N1-2 - APRPHTSYSPLP; and 40BP-N1-3 - GMTAPPPPRLTQ) blocked CD40-CD154 interaction when used at high concentrations. A consensus sequence (APxPPxxT) was conserved in these three peptides. These peptides may constitute a useful and novel strategy for the inhibition of the interaction between CD40 and CD154 molecules.
Journal Article↗