M Sakurai

Osaka City University, Ōsaka, Ōsaka, Japan

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Publications (457)1201.83 Total impact

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    ABSTRACT: The phase S ratlo in cell cycles were analyzed in livers with hyperplastic foci (HPF) and in livers without HPF by nuclear DNA determinatlons using flow cytometry, and by stalning wlth argyrophilic protelns of the nucieolar organlzer reglon (AgNOR). Flow cytometric analysis was done on 50 fresh frozen speclmens of livers resected from 50 patients wlth hepatocellular carcinoma (HCC). Paraffin sections from the same patients were analyzed uslng AgNOR staining. There were 25 cases each wlth and without HPF. We examined the stage of fibrosis and the grade of inflammatory activity according to the modlfied Scheuer and Desmet scale. The incidence of HCC recurrence among these patlents was also studied. The average phase S ratio of the livers of the patients with HPF was 6.5+3.2%, and that of the livers of the patients without HPF was 4.0±2.5%. The ratio differed slgnificantly between the two groups (P<0.01). The average AgNOR score for HPF lesions of the HPF-positlve cases was 1.6020.34, that for non-HPF lesions In the HPF-positive cases was 1.2920.12, and that for the HPF-negative cases was 1.1920.14. Significant differences were found between the average AgNOR scores for HPF lesions of the HPF-posltive cases and the non-HPF lesions of the HPF-posltive cases (P<0.0l), as well as between the non-HPF lesions in the HPF-positive cases and the HPF-negatlve cases (P-cO.05). Severe fibrosis (stage 3) and cirrhosls (stage 4) were found In 76% of HPF-positive cases and 48% of HPF-negatlve cases. The llvers of HPF-posltlve patlents were slgnificantiy more cirrhotic than those of HPF-negative patients (R0.05). The association between HPF and the Inflammatory grade was not slgnlficant (Ao.05). The incldence of HCC recurrence among HPF-positive cases was significantly higher than that among the HPF-negative cases (P<0.05). The average phase S ratio of the recurrent HPF-positive patients was 7.48+3.48%, slgnlficantly higher than that of HPF negative cases (5.57*3.06%, Pc0.05). Hyperplastic foci of the llver was shown to be a hlghly prollferatlve lesion. The proliferative activity of the non-HPF lesions in the HPF-positive patients was also higher than that of the HPF-negative patients. Hyperplastic focl tended to be present in cirrhotic livers, but it was not associated wlth the grade of inflammatory activlty of the Iiver. Hyperplastic focl may represent an important predictor of recurrence after hepatic resection.
    Pathology International 12/2008; 47(8):547 - 552. · 1.72 Impact Factor
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    ABSTRACT: Particulate matters can enhance antigen-related airway inflammation and immunoglobulin production. The present study was designed to determine the effects of different sizes of nanoparticles on the antigen-presenting cells (APC) in the lung. ICR mice were exposed to vehicle, carbon black (CB) nanoparticles (14 nm or 56 nm), ovalbumin (OVA), or OVA + nanoparticles intratracheally. The expression of major histocompatibility complex (MHC) class II, costimulatory molecules (CD80, CD86, CD11c), and DEC205 (dendritic cell marker), F4/80 (macrophage marker), and CD19 (B-cell marker) in the lung cells was measured by flow cytometry. 14 nm nanoparticles, but not 56 nm nanoparticles, increased the number of the total lung cells. Combination of OVA and 14 nm or 56 nm nanoparticles increased the total lung cells. The expression of MHC class II and/or costimulatory molecules and the number of APC in the lung were increased by 14 nm nanoparticles in the presence or absence of OVA. The increases were more prominent with combination of OVA and 14 nm nanoparticles. 56 nm nanoparticles did not show any significant effects. 14 nm CB nanoparticles can increase the expression of MHC class II and costimulatory molecules and the number of APC in the lung, especially in the presence of antigen, which can result in subsequent antigen-related airway inflammation and immunoglobulin production.
    International journal of immunopathology and pharmacology 01/2008; 21(1):35-42. · 2.99 Impact Factor
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    ABSTRACT: We have previously demonstrated the protective role of interleukin (IL)-6 against septic lung injury induced by lipopolysaccharide (LPS) using IL-6 knock-out (-/-) mice. This protection is mediated, at least partly, through the inhibition of the enhanced local expression of proinflammatory cytokines. In the present study, we addressed whether IL-6 regulates oxidative stress in the lung generated by LPS exposure using IL-6 (-/-) and corresponding wild type (WT) mice. Intraperitoneal LPS (1 mg/kg) challenge induced transcriptional expressions of inducible nitric oxide synthase and heme oxygenase -1 in the lung of mice with both genotypes. In the presence of LPS, these expressions were significantly greater in IL-6 (-/-) than in WT mice. Immunohistochemistry also showed that LPS induced a significant increase in 8-hydroxy-2'-deoxyguanosine formation in the lung as compared to vehicle. Furthermore, the formation was more intense in IL-6 (-/-) than in WT mice in the presence of LPS challenge. In the presence of LPS, lipid peroxidation in the lung was significantly greater in IL-6 (-/-) than in WT mice. These data suggest that the possible mechanisms in which endogenous IL-6 protects against septic lung injury induced by LPS involve, at least in part, its antioxidative properties.
    International journal of immunopathology and pharmacology 01/2008; 21(3):501-7. · 2.99 Impact Factor
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    ABSTRACT: Effects of nano-sized materials (nanomaterials) on subjects with predisposing inflammatory disorders have not been well elucidated. This study examined the effects of pulmonary exposure to TiO2 nanomaterials on lung inflammation induced by lipopolysaccharide (LPS) and consequent systemic inflammation with coagulatory disturbance in mice, in particular regarding their size-dependency. Also, gene expression pattern in the lung was compared among the experimental groups using cDNA microarray analysis. ICR male mice were divided into 8 experimental groups that intratracheally received vehicle, three sizes (15, 50, 100 nm) of TiO2 nanomaterials (8 mg/kg), LPS (2.5 mg/kg), or LPS plus nanomaterials. Twenty four h after the treatment, these nanomaterials exacerbated the lung inflammation and vascular permeability elicited by LPS, with an overall trend of amplified lung expressions of cytokines such as interleukin (IL)-1beta, macrophage chemoattractant protein (MCP)-1, and keratinocyte chemoattractant (KC). LPS plus nanomaterials, especially of a size less than 50 nm, elevated circulatory levels of fibrinogen, IL-1beta, MCP-1, and KC, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. cDNA microarray analyses revealed that there was no difference in gene expression pattern between the LPS group and the LPS + nanomaterial. These results suggest that nanomaterials exacerbate lung inflammation related to LPS with systemic inflammation and coagulatory disturbance, and that the exacerbation is more prominent with smaller nanomaterials than with larger ones.
    International journal of immunopathology and pharmacology 01/2008; 21(1):197-206. · 2.99 Impact Factor
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    ABSTRACT: Percutaneous transhepatic biliary cytology and biopsy was carried out in 19 patients with a malignancy-related jaundice, using a percutaneous transhepatic biliary tube. The preoperative diagnosis was positive in 17 patients (89%). This simple and safe method will facilitate operative procedures, diagnosis, and palliative chemotherapy regimens.
    Journal of Surgical Oncology 07/2006; 22(2):121 - 124. · 2.64 Impact Factor
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    Comparative Hepatology 02/2004; 3 Suppl 1:S56. · 1.88 Impact Factor
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    ABSTRACT: Hepatitis C virus is a major causative agent of chronic liver disease and hepatocellular carcinoma and is considered to be a hepatotropic virus. It remains controversial whether hepatitis C virus exists in peripheral blood mononuclear cells and replicates there. In order to resolve this issue, we performed nested RT-PCR (reverse transcription polymerase chain reaction) and RT-PCR in situ hybridization in peripheral blood mononuclear cells of patients with chronic hepatitis C. We collected peripheral blood mononuclear cells from patients with chronic hepatitis C, extracted total RNA from the samples, and performed nested RT-PCR to detect hepatitis C virus RNA in the peripheral blood mononuclear cells lysates. We also fixed peripheral blood mononuclear cells of the patients in 4% paraformaldehyde and performed RT-PCR in situ hybridization with a digoxigenin-labeled RNA probe to detect hepatitis C virus RNA in the cells. Using these methods, we detected both positive- and negative-stranded hepatitis C virus RNA in peripheral blood mononuclear cells of hepatitis C patients. To determine in which cell population of peripheral blood mononuclear cells hepatitis C virus is present, we performed PCR in situ hybridization after incubation with fluorescent latex microbeads which could be phagocytozed by monocytes. We obtained positive signals of the replicative hepatitis C virus genome not only in lymphocytes but also in monocytes. RT-PCR in situ hybridization with a nonradioactive probe was found to be useful for in situ detection of hepatitis C virus RNA. Our findings suggest that peripheral blood mononuclear cells may be extrahepatic replication sites for hepatitis C virus.
    Hepato-gastroenterology 01/2003; 50(53):1301-4. · 0.77 Impact Factor
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    ABSTRACT: Unlike normal liver with the sinusoids, hepatocellular carcinomas (HCCs) possess capillaries. Whether these capillaries derive from the sinusoids remains unclear in human HCCs. This study aimed to examine sinusoidal capillarization in human HCCs and its relationship to the tumor size, arterialization and dedifferentiation. Thirty-eight HCCs with a diameter of 10 - 140 mm were pathologically and angiographically examined. By electron microscopy, the microvasculature of tumors was classified into sinusoidal, intermediate and capillary types, which were all negative, partially positive and all positive, respectively, for four parameters, i.e., endothelial defenestration, continuous basement membrane, lack of Kupffer cells, and lack of lipid-containing hepatic stellate cells. Well-, moderately and poorly differentiated HCCs displayed sinusoidal / intermediate / capillary types, intermediate / capillary types and only capillary type, respectively, suggesting the transition from the sinusoids to capillaries in well-differentiated (and probably moderately differentiated) HCCs. Furthermore, well-differentiated HCCs with a diameter of less than 30 mm often received preferential portal venous blood, while moderately and poorly differentiated ones were all supplied with arterial blood, indicating a relationship between dedifferentiation and arterialization. In contrast, the microvascular type displayed no significant relationship with tumor size or arterialization in well-differentiated HCCs. The present study has demonstrated that sinusoidal capillarization occurs in human well-differentiated HCCs and seems to be related to dedifferentiation of parenchymal tumor cells, but not to tumor size or arterialization.
    Japanese journal of cancer research: Gann 12/2001; 92(11):1207-13.
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    ABSTRACT: Several 5-fluorouracil (5-FU) derivatives, 1-hexylcarbamoyl-5-fluorouracil (HCFU), 5'-deoxy-5-fluorouridine (5'-DFUR) and UFT (mixed compound of tegafur and uracil), have been developed and clinically widely used. However, comparative pharmacokinetic studies of the parent compound and other fluorinated drivatives have not been precisely reported. The dosage of the oral clinical use for human cancer of 5-FU, HCFU, 5'-DFUR and UFT as tegafur (FT) is 200-300mg/d, 600mg/d, 800-1,200mg/d and 300-600mg/d respectively. These amounts of the drugs are almost equimolar. Previously, we reported the effect of oral equimolar administration of each four drugs on thymidilate synthase activity, deoxyribonucleotide metabolism and cell cycle progression in L1210 ascites tumor. (1,2) In this study, we examined the antitumor effect and 5-FU concentration in the plasma, intestine and tumor after oral equimolar administrations of each drug using BDF1 mice bearing L1210 ascites tumor. In our study, UFT showed the best life prolongation among these four drugs. The intestine 5-FU level was highest by treatment with 5-FU during the initial 4 h. The plasma 5-FU level was highest by treatment with HCFU for 4 h. But the tumor 5-FU level was highest by treatment with UFT over the 24 h. In spite of the high plasma 5-FU concentration after the treatment with HCFU, the 5-FU concentration in the tumor was below the detectable level until 24 h. These findings suggested that the highest specific accumulation of 5-FU in tumor cells may explain the best therapeutic results of UFT.
    Biological & Pharmaceutical Bulletin 12/2001; 24(11):1329-31. · 1.85 Impact Factor
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    ABSTRACT: Dendritic cell (DC) is the most potent activator of CD4+ T cells and has unique dendrites and veils. To explore the function of Rho in DC, exoenzyme C3 from Clostridium botulinum was used as a specific inhibitor of Rho. Treatment of DC with C3 (DC/C3) resulted in profound morphological changes by losing dendrites and emerging of shrunk membrane processes that were in parallel with marked reduction of polymerized actin in the marginal area. Inactivation of Rho-associated coiled coil-containing kinase (p160ROCK) by a specific ROCK inhibitor Y-27632 also led to disappearance of dendrites of DC with retaining large membrane expansions. In scanning electron microscopy, untreated DCs interacted with CD4+ T cells more efficiently than DC/C3. Conjugate formation assay showed that the number of DCs associated with CD4+ T cells was 2-fold higher in untreated DCs than that of DC/C3. Alloantigen-presenting capacity of DC/C3 was significantly suppressed in a dose-dependent manner. Because C3 treatment did not affect the surface expression of HLA, costimulatory, and adhesion molecules of DC, we examined cytokine production of DC and naive CD4+ T cells to further elucidate the inhibitory mechanism of MLR. Unexpectedly, DC/C3 increased IL-12 production after LPS stimulation. Naive CD4+ T cells cocultured with DC/C3 produced the increased percentage of IFN-gamma-producing cells, whereas the percentage of IL-2-producing T cells was decreased. These results demonstrate that Rho GTPase in DC controls both characteristic shape and immunogenic capacity.
    The Journal of Immunology 11/2001; 167(7):3585-91. · 5.52 Impact Factor
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    ABSTRACT: Monocytes as antigen-presenting cells play an important role in host defense and transplantation. However, there are little reports on cord blood monocytes, and the role of monocytes in cord blood transplantation is largely unknown. There are several cytokines affecting monocyte function. These include interferon-gamma, interleukin-4, interleukin-10, granulocyte macrophage-colony stimulating factor and hepatocyte growth factor (HGF). We investigated the effect of these cytokines on antigen-presenting capacity (APC) of cord and adult blood monocytes. Using either mononuclear cells or purified CD4+ T cells as responder cells, HGF enhanced APC of adult monocytes most effectively among these cytokines. In contrast, cord blood monocytes failed to respond to HGF. As HLA, costimulatory and adhesion molecules may affect APC function, we examined these antigens of monocytes following HGF stimulation. The HGF upregulated integrin alpha5 subunit (CD49e) and intercellular adhesion molecule-1 (CD54) was expressed in adult blood monocytes, but not in cord blood. In kinetic studies, HGF downregulated c-met protein/HGF receptor expression of adult monocytes in lower concentrations and at shorter incubation time as compared with that of cord blood. The results suggest that impaired response of cord blood monocytes to HGF may be responsible, in large part, for their functional immaturity.
    Pediatrics International 09/2001; 43(4):334-9. · 0.88 Impact Factor
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    ABSTRACT: Monocytes as antigen-presenting cells play an important role in host defence. There are several cytokines affecting monocyte function. We demonstrate that both adult and cord blood monocytes constitutively express hepatocyte growth factor (HGF) receptor, MET. HGF significantly down-regulated MET expression of adult blood monocytes, compared with cord blood monocytes, when cultured either in RPMI-1640 containing 10% FBS or serum-free medium. Surface levels of MET correlated with c-met mRNA levels both in adult and cord blood when cultured. MET expression was down-regulated by treating with actinomycin D or cycloheximide. HGF stimulated DNA synthesis of adult monocytes, but not cord blood. HGF enhanced antigen-presenting capacity of adult blood monocytes but not cord blood monocytes. HGF up-regulated HLA class I expression in adult monocytes but not in cord blood monocytes. The current results suggest that the failure of cord blood monocytes to respond to HGF may be responsible, in large part, for their functional immaturity.
    Clinical & Experimental Immunology 09/2001; 125(2):222-8. · 3.41 Impact Factor
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    ABSTRACT: Anthracyclines are effective anticancer drugs for childhood cancer with dose-limiting cardiotoxicity. Children who have received anthracyclines thus need periodical cardiac evaluation. The plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been shown to increase in proportion to severity of cardiac dysfunction. We examined whether plasma levels of ANP and BNP, in addition to echocardiographic evaluation, can be used as specific markers for doxorubicin-induced cardiotoxic effects in children. Consecutively, 34 patients (18 boys and 16 girls) who had previously received doxorubicin-containing chemotherapy were enrolled in this study. Plasma ANP and BNP were assayed simultaneously at the time of first cardiac function evaluation by echocardiography. Of the 34 patients, 8 (23.5%) had left ventricular dysfunction as assessed by echocardiography. Both ANP and BNP plasma levels in these patients were significantly elevated in comparison with healthy controls (P < 0.01) or patients with normal cardiac function (P < 0.05). It should be also noted that ANP and BNP levels were correlated significantly with cardiac systolic function, but not with diastolic function. These results suggest that plasma ANP and BNP levels could be markers for doxorubicin-induced cardiotoxicity in children. Measurement of natriuretic peptide levels during treatment may allow earlier-identification of individuals at risk for severe cardiac damage.
    Medical and Pediatric Oncology 08/2001; 37(1):4-9.
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    ABSTRACT: In the neonate, cellular immunity has generally been hypothesized as being incompetent. Accumulating evidence from several recent studies, together with our present report, contradicts this hypothesis. T-helper cell and T cytotoxic type 1 and 2 (Th1/Th2 and Tc1/Tc2, respectively) cytokine responses to polyclonal T cell receptor (TCR) activation were assessed in medium-term cultures of human cord blood T cells using intracellular cytokine staining, which could measure the frequencies of cytokine-producing cells. In this study, we examined the responses of cord blood CD4(+) and CD8(+) T cells in regard to the production of interferon (IFN)-gamma and interleukin (IL)-4 and compared the responses with those obtained from T cells of healthy adults. We found that the responses in cord blood T cells activated with TCR stimulation were comparable to those of their adult counterparts. Moreover, the Th/Tc cells that developed in cord blood were as competent as adult cells for both IFN-gamma and IL-4 secretion. In addition, IL-12 production, which is critical for both Th1 and Tc1 responses, was equally comparable in the two groups. The production of two major cross-regulatory cytokines, tumor necrosis factor-alpha and IL-10, was similarly comparable and not significantly different between the two groups. Taken together, these results indicate that, though naive, the neonatal T cell is competent to respond to TCR-mediated stimulation and to produce both type 1 and type 2 cytokines.
    Cellular Immunology 12/2000; 205(2):110-9. · 1.74 Impact Factor
  • Pediatrics International 09/2000; 42(4):383-5. · 0.88 Impact Factor
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    ABSTRACT: During an ongoing immune response, cytokines produced by T helper types 1 (Th1) and 2 (Th2) together with T cytotoxic types 1 (Tc1) and 2 (Tc2) are critical to the effectiveness of that response. Dysregulated expansion of one or the other subset may contribute to the impaired function of the T-cell-mediated immune system in cancer patients. In the present study we have investigated whether such dysregulation might exist in children with acute lymphoblastic leukemia (ALL). We analyzed 61 blood samples from 45 children with B cell precursor ALL and 16 healthy children. Interleukin(IL)-2, IL-4, and interferon gamma (IFN gamma) production of their respective purified CD4+ and CD8+ T cells were assessed at the single-cell level by intracellular-cytokine-staining flow cytometry. At the time of diagnosis, IL-2-producing cell populations in CD4+ and CD8+ T cells were reduced below the normal range in 31 of 44 (70.5%) and 23 of 38 (60.5%) cases respectively. Similarly, IFN gamma-producing cell populations in CD4+ and CD8+ T cells decreased in 17 of 44 (38.6%) and 18 of 38 (47.4%) cases respectively. Conversely cell populations capable of IL-4 production in CD4+ and CD8+ T cell subsets were increased in 13 of 30 (43.3%) and 15 of 30 (50.0%) cases respectively. Therefore, the Th1-to-Th2 and Tc1-to-Tc2 ratios (1.6 +/- 2.2 and 7.7 +/- 6.7 respectively) were significantly lower in peripheral blood T cells of ALL patients (n = 30) than those (6.0 +/- 2.9 and 20.1 +/- 10.3 respectively) in 15 healthy controls (P < 0.0001). Although both CD45RA+/CD4+ and CD45RA+/CD8+ cells significantly increased in 43 ALL patients (P < 0.05), there existed no apparent correlation between CD45 isoform expression and cytokine (IL-2 and IFN gamma) production. Interestingly, the ability to produce both IL-2 and IFN gamma was recovered in 8 cases examined, after complete remission had been achieved. These observations suggest that, in both CD4+ and CD8+ T cells of ALL patients, there is a dysregulation in the functionality of Th1 (Tc1) and Th2 (Tc2) cells with a gross reduction of Th1 (Tc1) cell populations and an expansion in Th2 (Tc2).
    Cancer Immunology and Immunotherapy 07/2000; 49(3):165-72. · 3.64 Impact Factor
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    ABSTRACT: Prostate cancers are resistant to many anticancer agents at the time of presentation. P-glycoprotein (P-gp) is believed to mediate multidrug resistance phenotype. To elucidate the possible role of P-gp in such an intrinsic drug resistance of prostate cancers, its expression was examined immunohisochemically using two P-gp isoform-specific monoclonal antibodies (mAbs) with the paraffin embedded prostate samples derived from five nonmalignant and 30 untreated prostate cancer patients. In all of five normal prostate tissues, P-gp was consistently detected with both mAbs in the epithelial cells, especially at their apical site, and the level of expression was higher in the inner zone than in outer zone. On the other hand, tumor cells expressed P-gp heterogeneously in distribution and intensity; in 25 of 30 malignant cases P-gp expression was clearly demonstrated, whereas its expression was only faintly detected in other cases. However, the staining intensities for P-gp in prostate cancer cells were generally lower than in normal prostate epithelial cells. Thus, not only normal prostate epithelial cells but prostate cancer cells express at least MDR1 P-gp isoform. These results suggest that P-gp expression might play some role in intrinsic drug resistance of prostate cancer cells to many cytotoxic drugs as well as in relative resistance of the inner zone cells to the prostate carcinogenesis.
    Cancer Letters 04/2000; 150(2):147-53. · 5.02 Impact Factor
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    ABSTRACT: Fas (Apo-1/CD95) is a cell membrane receptor involved in apoptotic cell death. Soluble variant forms (sFas) lacking the transmembrane domain due to alternative splicing have been identified. Up-regulation of sFas expression is reportedly implicated in prereceptorial blockage of Fas-induced apoptosis in a dose-dependent manner. We examined mRNA expression of Fas and sFas in fresh leukemia cells. All leukemia cells expressed both mRNAs of full-length Fas (FasFull) and sFas with deletion of exon6 (FasDel6). The ratio of FasFull/FasDel6 mRNA expression was not always correlated with Fas-mediated growth inhibition. Interestingly, in a 6-year-old boy with acute myelogenous leukemia, blast cells obtained at onset and at the time of bone marrow relapses expressed distinct amounts of FasDel6 mRNA. Furthermore, the level of FasDel6 expression appeared to be correlated with Fas-resistance in leukemia blasts. In addition, sFas protein levels were elevated in patients' sera at onset with subsequent return to normal levels after complete remission. These results indicated that sFas could be synthesized and released by leukemia blasts and suggested that up-regulation of Fas variant transcript might render leukemia blasts resistant to Fas-mediated growth inhibition in certain cases.
    American Journal of Hematology 12/1999; 62(3):150-8. · 4.00 Impact Factor
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    ABSTRACT: Fas (CD95) is a cell surface glycoprotein that mediates apoptotic cell death when cross-linked with agonistic anti-Fas monoclonal antibodies (MAbs) or the endogenous Fas ligand. In this study, we investigated the in vitro biological properties of a panel of anti-human Fas MAbs. We found that five anti-Fas MAbs of IgG1 subclass (B.E28, B.G30, B.L25, DX2, and B.G34) induced marked apoptotic cell death in Fas-expressing leukemia cells, although this killing was delayed when compared to the cytolytic effect mediated by the prototypic anti-Fas MAb of IgM subclass (clone CH-11). On the other hand, four clones (ZB4, B.G27, B.D29, and B.K14) efficiently blocked apoptotic cell death induced by the CH-11 MAb or Fas ligand. The ability of these MAbs to inhibit cell death appeared to correlate with their relative affinity for the Fas molecule. Furthermore, different clones recognized the same epitope and elicited different effects (induction or inhibition of cell killing); conversely, different clones elicited the same effect but recognized different epitopes. These results suggest that the different biological effects of anti-Fas MAbs would not be mediated in an epitope-restricted manner. The relative binding affinity might correlate to some extent with the biological properties of the MAb.
    Hybridoma 11/1999; 18(5):391-8.
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    ABSTRACT: Many protocol studies have shown that low dose 6-mercaptopurine (6MP) in maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL) can be utilized to cure the disease. Mitotic or reproductive cell death has been recognized after G2 arrest when cells are treated with antitumor agents. The precise mechanism of mode of action of 6MP still remains unclear. We found delayed cytotoxic effect of 6MP in P388 murine leukemic cells. Morphological study showed that 6MP induced delayed death was characterized by an enlargement of cell size and multinucleated nuclei. Agarose gel electrophoresis of fragmented DNA from cells treated with 6MP showed the typical ladder pattern. These findings were compatible with mitotic death. Our results make us hypothesize that the delayed cytotoxicity of 6MP is one of the drug induced mitotic deaths caused by DNA damage due to incorporation of 6-thioguanine (6TG) into DNA as thioguanine nucleotide (TGN). Mitotic death may be a mechanism for killing the cycling cells from residual leukemic cells in G0 or long G1 phases in the treatment of childhood ALL.
    Journal of experimental & clinical cancer research: CR 10/1999; 18(3):417-24. · 1.50 Impact Factor

Publication Stats

4k Citations
1,201.83 Total Impact Points


  • 1991–2004
    • Osaka City University
      • • Department of Hepato-Biliary-Pancreatic Surgery
      • • Department of Orthopaedic Surgery
      Ōsaka, Ōsaka, Japan
    • Kyoto Prefectural University of Medicine
      • Department of Pediatrics
      Kyoto, Kyoto-fu, Japan
  • 2001
    • Mie-chuo Medical Center
      Matsusaka, Mie, Japan
  • 1990–2001
    • Social Insurance Chukyo Hospital
      Nagoya, Aichi, Japan
  • 1986–2001
    • Mie University
      • • Department of Pediatrics
      • • Faculty of Medicine
      • • School of Medicine
      Tsu-shi, Mie-ken, Japan
    • St. Jude Children's Research Hospital
      • Department of Pathology
      Memphis, Tennessee, United States
  • 2000
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
  • 1978–1999
    • Saitama Cancer Center
      • Saitama Cancer Center Hospital
      Saitama, Saitama, Japan
  • 1998
    • Gifu University
      • Department of Pediatrics
      Gihu, Gifu, Japan
  • 1997
    • Shizuoka Hospital
      Sizuoka, Shizuoka, Japan
    • Osaka Central Hospital
      • Department of Internal Medicine
      Ōsaka, Ōsaka, Japan
  • 1991–1995
    • Noguchi Memorial Institute for Medical Research
      Akra, Greater Accra, Ghana
  • 1985–1991
    • Osaka University
      • • Department of Oral Pathology
      • • School of Medicine
      • • Department of Internal Medicine
      Ibaraki, Osaka-fu, Japan