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Biomedical subjects

K Eguchi

Publications and source records attributed to K Eguchi.

At least 307 records · Page 17Linked to original sources
PubMed1995

Correlation of therapeutic outcome in non-small cell lung cancer and DNA damage assayed by polymerase chain reaction in leukocytes damaged in vitro.

A pilot study was conducted in patients with advanced non-small cell lung cancer to examine whether the gene-specific damage in mononuclear cells (MNCs) incubated with cisplatin in vitro correlates with chemotherapeutic outcome in cisplatin-based chemotherapy. Twenty-one patients received cisplatin-based chemotherapy, consisting of cisplatin (80 mg/m2 i.v. on day 1), vindesine (3 mg/m2 i.v. on days 1 and 8), with or without mitomycin (8 mg/m2 i.v. on day 1). MNCs from peripheral blood were obtained from each patient before chemotherapy. The cells were incubated with cisplatin for 3 h in vitro and the 2.7-kb fragment of the hypoxanthine phosphoribosyltransferase gene was amplified by PCR for quantitation of DNA damage. There was a 4-fold interpatient variation in DNA damage in MNCs. Seven of 21 patients had a partial response to chemotherapy. When the dose of cisplatin required to reduce amplification of the hypoxanthine phosphoribosyltransferase sequence by 63% (D63 value) of MNCs was compared in each patient (defined by a Poisson distribution as the dose that produced an average of one lesion per single strand of the 2.7-kb fragment), the mean D63 value in patients showing a partial response (n = 7; 52 +/- 11 micrograms/ml) was significantly lower than that in patients showing no change (n = 10; 81 +/- 20 micrograms/ml; P = 0.0045) and in patients with disease progression (n = 4; 115 +/- 34 micrograms/ml; P = 0.0012). The mean D63 in patients with no change was also significantly lower than that in the patients with disease progression (P = 0.0386). Seven (70%) of 10 patients with a D63 value < 70 micrograms/ml were responders. No relationship was observed between the D63 values and hematological and nonhematological toxicities. It is suggested that DNA damage in MNCs incubated by cisplatin treatment in vitro in responders was greater than that in nonresponders. Gene-specific damage in MNCs from peripheral blood incubated with cisplatin in vitro assayed by PCR may predict the chemotherapeutic response in cisplatin-based chemotherapy for non-small cell lung cancer.

Adult↗
PubMed1995

The role of protein kinase in human synovial fibroblast growth.

The histological features of rheumatoid arthritis (RA) consist of overgrowth of synovial cells. Several growth factors that cause synovial hyperplasia have been identified in RA synovium. The basic-fibroblast growth factor (b-FGF), representing one of these growth factors, may play an important role in the pathogenesis of RA. We examined the b-FGF-mediated intracellular signal pathway involved in synovial cell growth. b-FGF-induced synovial cell growth was inhibited by protein tyrosine kinase (PTK) inhibitors, herbimycin A and genistein, but not by H7 that inhibits protein kinase C (PKC). Stimulation of synovial cells with b-FGF resulted in tyrosine phosphorylation of cellular proteins and MAP kinase activation. Our results also demonstrated that b-FGF-mediated activation of MAP kinase was inhibited by herbimycin A indicating that protein tyrosine kinase may be involved in the activation of MAP kinase in human synovial cells. However, inhibition of b-FGF-mediated MAP kinase activation by PKC downregulation did not occur.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Transforming growth factor beta 1 induces apoptotic cell death in cultured human umbilical vein endothelial cells with down-regulated expression of bcl-2.

Transforming growth factor beta 1 (TGF-beta 1) is a potent growth inhibitor of human umbilical vein endothelial cells (HUVEC). We investigated whether apoptosis is involved in the TGF-beta 1 mediated HUVEC growth inhibition. Using immunofluorescence microscopy and staining by propidium iodide, we showed HUVEC treated with TGF-beta 1 contained characteristic apoptotic nuclei with condensation of chromatin. FACS analysis demonstrated that the number of cells with hypodiploid DNA contents were increased in HUVEC treated with TGF-beta 1. The DNA fragmentation assay exhibited typical ladder formation in TGF-beta 1-treated HUVEC. Using Western blot analysis, the expression of bcl-2 on HUVEC was down-regulated by TGF-beta 1-treatment. These findings suggest that TGF-beta 1 regulates the growth of HUVEC by inducing apoptosis accompanied with down-regulation of bcl-2 expression.

Apoptosis↗
PubMed1995

Serum cytokines in patients with rheumatoid arthritis. Correlation of interferon gamma and tumor necrosis factor alpha with the characteristics of peripheral blood mononuclear cells.

Serum cytokines such as interleukin 1 beta (IL-1 beta), interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF alpha) were measured in 40 patients with rheumatoid arthritis (RA). In the 40 patients studied, serum IL-1 beta was detected in 5 patients, IFN-gamma in 10 patients, and TNF alpha in 20 patients. The IL-1 beta-positive group showed increased values of activity indices compared to the IL-1 beta-negative group. Values of serum IFN-gamma correlated well with the number of peripheral blood lymphocytes and CD3+ cells and with the percentage of CD3+ CD26+ cells. Values of serum TNF alpha correlated positively with the number of peripheral blood monocytes and the percentage of CD3+ HLA-DR+ and CD3+ CD25+ cells. These results indicated that serum IL-1 beta in RA patients reflects the activity of RA, while the serum IFN-gamma and TNF alpha in RA patients may be related to circulating activated lymphocytes and monocytes, respectively.

Adult↗
PubMed1995

Experimental tracheal replacement using the esophagus and an expandable metallic stent.

An experimental study was conducted to investigate whether a segment of autogenous esophagus with its lumen supported by an expandable metallic stent (EMS) could be successfully used as a tracheal substitute. Seven rings of the cervical trachea were circumferentially removed and reconstructed by interposing a pedicled segment of the esophagus with an EMS in six mongrel dogs. The interposed esophagus was observed endoscopically at various stages after the operation. By 1 month, the EMS was found to be buried under the esophageal mucosa, and the lumen was patent. The dogs died 5, 17, 61, 92, 210, and 478 days after the operation, but the cause of death could not be determined by postmortem examination and no respiratory tract complications were detected. The results of this study indicated that a segment of the esophagus with its lumen supported by an EMS could work as a reliable tracheal substitute, though its practical use is not clinically feasible. Nevertheless, we conclude that some autogenous material other than the esophagus with its lumen supported by an EMS could provide a feasible method for tracheal replacement.

Anastomosis, Surgical↗
PubMed1995

The influence of ageing on cisplatin pharmacokinetics in lung cancer patients with normal organ function.

This study was performed to identify any relationship between age and cisplatin (CDDP) pharmacokinetics in lung cancer patients. CDDP was given at a dose of 80 mg/m2 by 1-h intravenous infusion to 23 lung cancer patients. All patients had normal renal, hepatic, and bone marrow functions. We measured ultrafilterable platinum (U-Pt) and total plasma platinum (T-Pt) using atomic absorption spectrometry. There was significant correlation between the age of the patients and U-Pt pharmacokinetic parameters such as the area under the plasma concentration versus time curve (AUC), total clearance (Cl), and peak plasma concentration (Cmax) as well as the AUC of T-Pt (P < 0.05). We performed univariate regression analysis to examine the influence of factors aside from age on the AUC of U-Pt and T-Pt. Creatinine and GPT levels were significantly related to the AUC of U-Pt, and creatinine clearance and creatinine concentrations were significantly related to the AUC of T-Pt. Therefore, stepwise multiple-regression models for the AUC of U-Pt and T-Pt were developed to assess an age effect. Age was consistently an independent and significant predictor of the AUC of U-Pt and T-Pt.

Adult↗
PubMed1995

Removal of LDL from plasma by adsorption reduces adhesion molecules on mononuclear cells in patients with arteriosclerosis obliterans.

BACKGROUND: There is increasing evidence that immune processes are important in the development of atherosclerosis. We investigated whether low density lipoprotein (LDL) adsorption therapy affected serum cytokine levels and the expression of adhesion molecules on peripheral blood mononuclear cells (lymphocytes and monocytes) in patients with arteriosclerotic obliterance (ASO). METHODS AND RESULTS: LDL adsorption therapy was repeated ten times over a period of three months in ten ASO patients. The total serum cholesterol and LDL cholesterol levels were significantly reduced at the end of therapy. This was associated with a significant improvement in Fontaine's classification and ankle pressure index. We also measured serum levels of inflammatory cytokines (interleukin-1 beta (IL-1 beta), IL-6 and tissue necrosis factor alpha (TNF-alpha)) and expression of adhesion molecules (lymphocyte function-associated antigen 1 alpha (LFA-1 alpha), LFA-1 beta, CD2, very late antigen (VLA)-4, VLA-5 and CD44) on mononuclear cells in the same patients and a group of healthy subjects. Serum levels of all inflammatory cytokines were markedly higher in ASO patients compared with healthy subjects, but there was no significant difference in the level before and after LDL adsorption. VLA-4 expression on CD3+ cells, but not of other adhesion molecules, was markedly higher in ASO patients compared with healthy subjects. LDL adsorption caused a significant reduction in CD2, VLA4 and VLA-5 expression on CD3+ cells. Furthermore, VLA-4 and VLA-5 expression on monocytes diminished significantly after LDL adsorption. CONCLUSIONS: Our results indicate that LDL adsorption-induced immunoregulation is mediated by an indirect stimulatory effect on the immune system. The results suggests that improved peripheral circulation produced by LDL adsorption may reflect improved immune dysfunctions of atherosclerotic lesions in ASO patients.

Aged↗
PubMed1995

Cellular immunity in autoimmune thyroid disease.

Autoimmune thyroid disease occurs in a genetically susceptible patient after triggering events including bacterial and viral infections, environmental insults, drugs or hormones. These triggering events may break the tolerance to self-antigen, leading to emergence of autoreactive T cells. One or more T cell clones that recognize the self-antigen is(are) assumed to be involved in initiating autoimmune processes. Following this, T cell clones expand and migrate from the peripheral blood into the thyroid gland. Migration of mononuclear cells is controlled by inflammatory cytokines and adhesion molecules. Intrathyroidal T cells may interact with dendritic-like cells, thyrocytes expressed with HLA-DR antigens, B cells and extracellular matrix, resulting in the proliferation of T cells, production of cytokines and autoantibodies. These interactions are also regulated by inflammatory cytokines and adhesion molecules. When the initial immune response is completed, a secondary immune response ensues, that may be of considerable complexity involving reaction of infiltrating T cells to a variety of tissue-specific and tissue-non-specific antigens. These immune responses may contribute to the recurring immunologic activity and maintenance of autoantibody overproduction.

Animals↗
PubMed1995

Comparative study of erythrocyte deformability in maternal and cord blood.

To elucidate the rheological difference in maternal and fetal blood by determining erythrocyte deformability, 20 pairs of mothers and newborns, and 20 nonpregnant women were studied. Erythrocyte deformability was measured by means of an electron spin resonance method. Erythrocyte deformability was dependent on the hematocrit, and there was an optimal hematocrit value at which the deformation was maximal. The hematocrit at which the deformability was maximal showed a lower value (32 to 35%) in maternal blood; conversely, a higher value (47 to 50%) occurred in fetal blood than that (40 to 43%) in nonpregnant control women. When the hematocrit of the red blood cell suspension in dextran solution was adjusted to 40% (nonpregnant blood), 35% (maternal blood), and 50% (fetal blood), the deformability of fetal erythrocytes was significantly higher than maternal blood (P < 0.05), and its value was almost similar to that of nonpregnant control women. Based on our results, erythrocyte deformability of fetal blood is much higher compared with the maternal blood, suggesting the effective oxygen supply to the fetal tissues even in the circumstances of lower oxygen tension.

Adult↗
PubMed1995

Management of chemotherapy-induced anemia.

Chronic anemia associated with cancer often causes poor quality of life and is often exacerbated by intensive treatment. In recent controlled trials, recombinant human erythropoietin (rhEpo) proved to be well tolerated and effective in amelioration and reduction of transfusion requirements of cancer-associated anemia. Double-blind placebo-controlled trials of rhEpo in patients undergoing allogenic, but not autologous, bone marrow transplantation showed significant acceleration of the reconstitution of erythropoiesis. Multivariate analysis revealed that serum erythropoietin levels of 100 mU/mL or greater and an increase in hemoglobin by at least 0.5 g/dL was a probable response; conversely, a serum ferritin level of 400 ng/mL or greater after 2 weeks indicated a poor response to rhEpo therapy. Further studies are needed to define patient populations in whom cost-effective rhEpo therapy is justified.

Anemia↗
PubMed1995

Efficient sampling strategies for forecasting pharmacokinetic parameters of irinotecan (CPT-11): implication for area under the concentration-time curve monitoring.

A linear two-compartment Bayesian pharmacokinetic model was developed using a standard two-stage population method for the novel anti-cancer agent CPT-11 from 11 adult patients with refractory cancer. The accuracy and efficiency of this Bayesian model for estimating pharmacokinetic parameters including the area under the concentration-time curve (AUC) was then evaluated using two different sampling strategies in a new study cohort of 13 patients with cancer. Sampling strategies included either one, two, or three nonsteady-state feedback levels determined empirically and from optimal sampling theory (D-optimality). All 24 patients in this study received CPT-11 (60 mg/m2) as a 90-min infusion. Pharmacokinetic parameters derived from the Bayesian model combined with these limited sampling strategies were compared with those parameters obtained from the full sample data sets (n = 10) analyzed by weighted nonlinear least squares regression (reference method). The least-bias and most precise sampling times for estimating AUC were 3.5; 3.5 and 9.5; and 0.5, 3.5, and 9.5 h, respectively. At these times, only marginal improvement in precision of the AUC estimate was observed using two versus three samples. However, the precision of the estimate of clearance was not improved using two versus three samples. The sampling times derived from optimal sampling theory were 0.25, 3.5, 8.5, and 24 h and correlated closely to the actual and best empirical sampling times of 0.5, 3.5, 9.5, and 24 h. These results strongly suggest that Bayesian estimation combined with only two optimally timed samples accurately predicts the AUC of CPT-11 and should be useful for implementing adaptive control dosing for monitoring CPT-11 systemic exposure in patients with cancer.

Adult↗
PubMed1995

A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38.

In the present study, an attempt was made to determine the precise pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). The relationship between pharmacokinetic parameters and pharmacodynamic effects was also investigated to elucidate the cause of interpatient variation in side effects. Thirty-six patients entered the study. CPT-11, 100 mg/m2, was administered by IV infusion over 90 min weekly for four consecutive weeks. The major dose-limiting toxicities were leukopenia and diarrhea. There was a positive correlation between the area under the concentration-time curve (AUC) of CPT-11 and percent decrease of WBC (r = 0.559). On the other hand, episodes of diarrhea had a better correlation with the AUC of SN-38 (r = 0.606) than that of CPT-11 (r = 0.408). Multivariate analysis revealed that the AUC of SN-38, AUC of CPT-11 and indocyanine green retention test were significant variables for the incidence of diarrhea and that both performance status and AUC of CPT-11 were significant variables for percent decrease of WBC. The large interpatient variability of the degree of leukopenia and diarrhea is due to a great plasma pharmacokinetic variation in CPT-11 or SN-38. The AUCs of CPT-11 and SN-38 obtained from the first administration of CPT-11 correlate with toxicities, but it is impossible to predict severe side effects before the administration of CPT-11 at the present time.

Adult↗
PubMed1995

Prospective evaluation of the feasibility of cisplatin-based chemotherapy for elderly lung cancer patients with normal organ functions.

A study was conducted to examine the feasibility of cisplatin-based chemotherapy in elderly patients (> or = 75 years old) with advanced non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). Thirty-four patients were enrolled between September 1993 and December 1994. Patients with normal organ function and good performance status (PS) received cisplatin-based chemotherapy (cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 2 and 8 for NSCLC, or cisplatin 80 mg/m2 on day 1 and etoposide 100 mg/m2 on days 2 to 4 for SCLC). Ten patients (29%) were eligible for this study, 7 with NSCLC and 3 with SCLC. Reasons for exclusion were ischemic heart disease in 14, poor PS (> or = 2) in 11, reduced creatinine clearance (Cer) in 10, abnormal electrocardiogram without ischemia in 9 and noncompliance with the protocol in 2 patients. Eight patients had two or more reasons. Nine of the 10 eligible patients were able to tolerate two or more courses of chemotherapy. All 3 patients with SCLC responded (1 complete response and 2 partial response), but only 1 of the patients with NSCLC achieved partial response. Toxicity was evaluated according to Japan Clinical Oncology Group criteria. All but one patient experienced grade 4 neutropenia, and 6 patients had infectious episodes requiring antibiotics. Grade 3 anemia and thrombocytopenia were observed in 1 and 2 patients, respectively. Non-hematological toxicities were mild. Only 10 of 34 patients (29%) satisfied our eligibility criteria and they experienced severe myelotoxicity. We conclude that chemotherapy should be given carefully to elderly patients even if they appear to have normal organ function.

Aged↗
PubMed1995

Synovial cells are potent antigen-presenting cells for superantigen, staphylococcal enterotoxin B (SEB).

There is ample evidence suggesting that superantigens may act as a triggering factor in the pathogenesis of rheumatoid arthritis (RA). We investigated whether superantigen could activate T cells in the presence of synovial cells. T cells were cultured with SEB in the presence of interferon-gamma (IFN-gamma)-treated synovial cells. T cell proliferation and activation were assessed by 3H-thymidine incorporation and IL-2 production. The expression of HLA class II antigens and adhesion molecules on synovial cells was detected by flow cytometer. In the presence of IFN-gamma-treated synovial cells, T cells proliferated vigorously and produced IL-2 in response to SEB. A low SEB-induced T cell response was noticed in the presence of untreated synovial cells. Allogeneic as well as autologous IFN-gamma-treated synovial cells markedly enhanced SEB-induced T cell proliferation. IFN-gamma-treated synovial cells had increased expression of HLA class II antigens and intercellular adhesion molecule-1 (ICAM-1) adhesion molecules. MoAbs towards these antigens markedly inhibited the SEB-induced T cell response. These results indicate that activated synovial cells are potent antigen-presenting cells for SEB to T cells, and that superantigens may play a critical role in the pathogenesis of RA through activated synovial cells.

Antibodies, Monoclonal↗
PubMed1995

Increased levels of serum IgM antibody to staphylococcal enterotoxin B in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the role of superantigen in rheumatoid arthritis (RA) by assaying the serum levels of staphylococcal enterotoxin B (SEB) antibodies. METHODS: Serum IgG and IgM SEB antibodies were measured using an enzyme linked immunosorbent assay (ELISA), and confirmed by Western blot analysis. The T cell receptor V beta (TCR V beta) repertoire was analysed using the reverse transcriptase polymerase chain reaction. RESULTS: RA patients had increased levels of serum IgM SEB antibody compared with normal subjects, patients with systemic lupus erythematosus, Sjögren's syndrome, and Behçet's disease. The titres of rheumatoid factor (RF) showed no correlation with the levels of IgM SEB antibodies, and the levels of SEB antibodies were not inhibited by the addition of human immunoglobulin, or after absorption of RF. RA patients whose disease duration was less than 10 years had greater levels of serum IgM SEB antibodies than those with disease duration more than 10 years. The levels of IgM and IgG SEB antibodies in synovial fluid from RA patients were correlated with those in their sera. Western blot analysis detected IgM and IgG SEB antibodies as a band of approximately 30 kDa molecular size. The percentage of TCR V beta 2, V beta 5.2, and V beta 12 in phytohaemagglutinin stimulated peripheral T cells correlated significantly with the levels of serum IgM SEB antibody in RA patients. CONCLUSION: These results suggest that SEB, one of the superantigens, may have a critical role in the pathogenesis of RA.

Adult↗
PubMed1995

Differential distribution of type IV collagen chains in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus.

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of human diabetic nephropathy. Renal tissues from 15 patients with type II (non-insulin-dependent) diabetes (NIDDM) were studied by immunofluorescence (IF) and immunogold electron microscopy (IEM) for the distribution of 2 type IV collagen peptides [alpha 3(IV) noncollagenous (NC) domain and alpha 4(IV) NC domain] and 2 classical type IV collagen chains [alpha 1(IV) NC domain and alpha 2(IV) domain]. There was intense staining for alpha 3(IV) NC and alpha 4(IV) NC domain in the GBM but not in the mesangial matrix of patients with overt diabetic nephropathy. In contrast, staining with antibodies to alpha 1(IV) NC and alpha 2(IV) NC domain reacted with mesangial matrix but was significantly decreased in the GBM in the patients with overt diabetic nephropathy. IEM confirmed the IF findings. These data suggest that expansion of the mesangial matrix and thickening of GBM in NIDDM involves separate and distinct type IV collagen components and that the site-specific matrix alterations in NIDDM and type I (insulin-dependent) diabetes are parallel.

Adult↗
PubMed1995

FK506 augments activation-induced programmed cell death of T lymphocytes in vivo.

FK506 is an immunosuppressive drug that inhibits T cell receptor-mediated signal transduction. This drug can induce immunological tolerance in allograft recipients. In this study, we investigated the in vivo effects of FK506 on T cell receptor-mediated apoptosis induction. Injection of anti-CD3 antibody (Ab) in mice resulted in the elimination of CD4+ CD8+ thymocytes by DNA fragmentation. FK506 treatment significantly augmented thymic apoptosis induced by in vivo anti-CD3 Ab administration. Increased thymic apoptosis resulted in the disappearance of CD4+ CD8+ thymocytes after anti-CD3 Ab/FK506 treatment. DNA fragmentation triggered by FK506 was induced exclusively in antigen-stimulated T cells, since enhanced DNA fragmentation induced by in vivo staphylococcal enterotoxin B (SEB) injection was confirmed in SEB-reactive V beta 8+ thymocytes but not in SEB-nonreactive V beta 6+ thymocytes. In addition to thymocytes, mature peripheral T cells also die by activation-induced programmed cell death. A similar effect of FK506 on activation-induced programmed cell death was observed in SEB-activated peripheral spleen T cells. In contrast, cyclosporin A treatment did not enhance activation-induced programmed cell death of thymocytes and peripheral T cells. Apoptosis is required for the generation and maintenance of self-tolerance in the immune system. Our findings suggest that FK506-triggered apoptosis after elimination of antigen-activated T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment.

Animals↗