Biomedical subjects
T Matsuda
Publications and source records attributed to T Matsuda.
A computer simulation of motion in turbo FLASH imaging and echo-planar imaging.
We have experimentally demonstrated motion effects in a turbo FLASH imaging (TFI) using a small cylindrical phantom moving at constant velocity. To further verify these experimental results, image blurring is assessed by using a computer simulation in this study. By applying the same acquisition parameters as phantom experiments, the simulation images are reconstructed to compare with the experimental results. Several kinds of configurations are applied to the simulation of the TFI. A computer simulation of an echo-planar imaging (EPI) is also used to compare the motion effects with TFI.
Shorter interval between cycles of cyclophosphamide, doxorubicin, cisplatin using recombinant human granulocyte colony-stimulating factor for urothelial cancer--phase I/II study.
BACKGROUND: Despite improvement in the response rate and protraction of the progression-free period of urothelial cancer produced by chemotherapy, severe bone marrow suppression often results in delays in the initiation of treatment cycles and/or decreases in drug dosages. Reduction of leukopenia during chemotherapy has been demonstrated by the combined administration of granulocyte colony-stimulating factor (G-CSF) in various malignancies. METHODS: A phase I/II study was conducted to assess whether the interval between cycles of CISCA (cyclophosphamide, doxorubicin, cisplatin) chemotherapy could be shortened under support of recombinant human granulocyte colony-stimulating factor (rhG-CSF) for urothelial cancer. Three or more patients with transitional cell carcinoma of the urinary tract were allocated to each of four different treatment intervals (step 1: 28 days, step 2: 21 days, step 3: 17 days, and step 4: 14 days) by reducing the interval in a step-wise manner. Two mg/kg/day of a rhG-CSF, lenograstim, was injected subcutaneously on days 3 to 16 (until day 14 for the 14-day interval group). RESULTS: Sixteen patients were enrolled, four patients were treated with the step 1 protocol, five with step 2, four with step 3, and three with step 4. Leukopenia/neutropenia was the most severe toxic reaction, but none of the patients at any step manifested neutropenia of WHO grade 4 for more than four days. There were no significant differences in the hematological and nonhematological toxicities among the 4 steps. Seven of eight patients with measurable diseases were treated with CISCA on shortened schedules (steps 2-4), and one complete remission (CR) and four partial responses (PR) were demonstrated. CONCLUSIONS: CISCA chemotherapy supported by rhG-CSF was safely shortened to a 14-day interval in the pilot study. The potential role of rhG-CSF in shortening the interval of CISCA, as well as the benefit of the intensified schedule, remains to be clarified.
[Effect of clarithromycin on symptoms and mucociliary transport in patients with sino-bronchial syndrome].
The effect of clarithromycin on symptoms and on mucociliary transport (as assessed by the saccharin test) were studied in 32 patients with sino-bronchial syndrome. Before treatment with clarithromycin, the nasal clearance time was significantly longer in these patients (70.3 +/- 64.7 min, mean +/- SD) than in control subjects (11.9 +/- 5.3 min, p < 0.001). By the end of 4 weeks of treatment with oral clarithromycin (400 mg/day), nasal clearance time in the patients had improved significantly (30.4 +/- 39.5 min, p < 0.001). Before clarithromycin therapy, bacteria were found in cultures of sputum from 15 patients. After clarithromycin therapy, bacteria were found in cultures of sputum from only 3 of those 15 patients. Cough frequency, volume of sputum, and dyspnea on exertion were significantly improved by clarithromycin therapy. These findings suggest that mucociliary transport is abnormal in patients with sino-bronchial syndrome, and that clarithromycin can be clinically useful in these patients.
[Bilateral simultaneous spontaneous pneumothoraces associated with Alport's syndrome].
A 45-year-old man with Alport's syndrome presented with chest pain and dry coughing. A chest roentgenogram showed bilateral simultaneous spontaneous pneumothoraces. Possible causes such as pulmonary bullae were not detected. A partial defect in type IV collagen, which is involved in repair of the basement membrane, may have played a role in the etiology of pneumothoraces in this patient.
Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia.
Hematopoietic function of some aplastic anemia (AA) patients is dependent on the administration of cyclosporine (CyA). To investigate whether certain HLA class II genes are associated with susceptibility to such CyA-dependent AA, we determined the HLA class II alleles of 59 AA patients treated with CyA. Among 26 patients successfully treated with CyA, 13 required a small dose of CyA to maintain stable hematopoiesis. Of these 13 AA patients, 10 shared an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602. None of the 13 responders who obtained a sustained remission off CyA therapy possessed this haplotype. In the 10 patients who shared the HLA class II haplotype, single-strand conformation polymorphism analysis of each gene fragment of this haplotype failed to detect a polymorphism in the nucleotide sequence. When the AA patients were assessed for their likelihood to respond to CyA therapy, the response rate in patients with this haplotype (71%) was significantly higher than that of patients with another haplotype associated with HLA-DR2, DRB1*1502-DQA1*0103-DQB1*0601 (36%) and that of patients without HLA-DR2 (35%). These findings indicate that the CyA-dependent response of AA is closely related to an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602 and suggest that, in AA patients with this haplotype, immune mechanisms play an important role in the pathogenesis of bone marrow failure.
Characterization of interactions between transducin alpha/beta gamma-subunits and lipid membranes.
The gamma-subunits of heterotrimeric guanine nucleotide-binding regulatory proteins (G-proteins) are isoprenylated and alpha-carboxyl methylated at their COOH-terminal cysteine residues. These modifications are necessary for membrane attachment of the beta gamma complex, but a requirement of an additional factor has been proposed for the stable binding. We explored a possible contribution of the blocked amino terminus of beta-subunits of bovine photoreceptor G-protein, transducin (T alpha/T beta gamma = Gt alpha/beta 1 gamma 1), and of three beta gamma complexes (beta 1 gamma 2, beta 1 gamma 3, and beta 1 gamma 7) purified from bovine brains. Structural analyses revealed that every beta 1-subunit has an N-acetylated serine, which is unlikely to contribute to the membrane association. Since neither protease nor heat treatment of photoreceptor membranes affected the membrane binding of T beta gamma, it seems unlikely that rhodopsin (or other membrane proteins) serves as an anchor protein for accepting T beta gamma. In fact, T beta gamma bound to phospholipid large unilamellar vesicles (LUVs), of which the polar head groups strongly influenced the binding: T beta gamma alone showed 2-fold higher binding for negatively charged phosphatidylserine-LUVs than for neutral phosphatidylcholine (PC)-LUVs, while the affinity of T alpha/T beta gamma complex for the phosphatidylserine-LUVs was lower than that for the PC-LUVs. These results indicate that 1) an ionic interaction between T beta gamma and membrane surface plays an important role in the stable membrane association, and 2) the domain(s) of T beta gamma responsible for the association would be different between trimeric and dissociated states. We also found that synthetic peptides corresponding to the COOH-terminal region of T gamma inhibited T alpha-T beta gamma interaction only when the peptides were isoprenylated. This suggests that the isoprenyl moiety is located at the contact site between the subunits, not at the membrane-binding domain, when T beta gamma is complexed with T alpha.
Dose-dependent inhibition of glutathione S-transferase placental form-positive hepatocellular foci induction in the rat by methyl propyl disulfide and propylene sulfide from garlic and onions.
Two organosulfur compounds, methyl propyl disulfide (MPD) and propylene sulfide (PS) from garlic and onions, were studied for their modifying effects on hepatocarcinogenesis in the F344 rats. Modifying potential was scored by comparing the number and area per cm2 of induced glutathione S-transferase placental form (GST-P)-positive foci in the liver. MPD and PS significantly reduced both these parameters of GST-P-positive foci in a dose-dependent manner. To investigate possible mechanisms of inhibition, ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SAT) activities were measured. In MPD and PS-high dose-treated liver tissue there was a tendency for their decrease, albeit non-significant, which suggested that the inhibitory effect might have been caused by decreased cell proliferation associated with decreased polyamine biosynthesis. In evaluating relationships between diet and cancer, it is thus necessary to consider various effects in assessing possible protective roles of garlic and onions.
DT-diaphorase as a determinant of sensitivity to adriamycin in non-small-cell lung-cancer cell lines.
We have reported the establishment of a mitomycin-C (MMC)-resistant non-small-cell lung-cancer cell line, PC-9/MC4. As determined by an MTT assay, this resistant cell line was found to be 4 times more sensitive to adriamycin (ADM) than was the parental PC-9. There were no significant differences in sensitivity to etoposide, mitoxantrone, daunomycin, epirubicin, pirarubicin, 9-aminoanthracycline or 3'-deamino-3'-morpholino-13-deoxo-10-hydroxy carminomycin. These data suggest that neither qualitative or quantitative changes in DNA topoisomerase II nor the enhanced repair of DNA can explain the differing sensitivity to ADM observed. No significant differences were found in the accumulation of ADM and glutathione (GSH) in these cell lines. Although total glutathione-S-transferase (GST) activity in PC-9/MC4 cells was lower than that observed in PC-9 cells and treatment with ethacrynic acid (EA) reduced sensitivity to ADM in both cell lines, relative resistance was unaffected. NADH-cytochrome b5 reductase (B5R) activity in PC-9/MC4 cells showed a 3-fold greater decrease than that in PC-9 cells, and DT-diaphorase (DTD) activity in PC-9/MC4 cells showed an approximately 200-fold greater decrease than that in PC-9 cells. Addition of dicumarol, an inhibitor of DTD, decreased the sensitivity of ADM of PC-9 but not of PC-9/MC4. DTD activity in the PC-9 cell line was inhibited by treatment with dicumarol while in PC-9/MC4 it remained unchanged. These data suggest that DT-diaphorase is a determinant of sensitivity to ADM in the 2 cell lines.
Vasodilating actions of cromakalim in resting and contracting states of carotid arteries from spontaneously hypertensive rats.
To determine the properties of cromakalim-opened K+ channels in arterial smooth muscle of spontaneously hypertensive rats (SHR), the effects of cromakalim on tension and 86Rb efflux were compared in endothelium-denuded strips of carotid arteries from 13-week-old SHR and normotensive Wistar-Kyoto rats (WKY). The addition of cromakalim or of nifedipine to resting strips caused a relaxation only in SHR. When strips from both strains were contracted with 15.9 mM K+, the magnitude of the precontraction was greater in SHR than in WKY. Under these conditions, relaxant responses to lower concentrations of cromakalim were decreased and those to higher concentrations of cromakalim were increased in SHR. When strips from both strains were contracted with a different concentration of K+ to an equivalent magnitude (78% of the maximum) relaxant responses to cromakalim were greater in SHR than in WKY. When strips were contracted with 10(-7) M norepinephrine, the precontraction was similar between SHR and WKY, and relaxant responses to cromakalim were greater in SHR. In both strains, the relaxant responses to cromakalim were competitively antagonized by glibenclamide, a blocker of ATP-sensitive K+ (KATP) channels, with a pA2 value of approximately 7.3. Charybdotoxin (10(-7) M), a blocker of Ca(2+)-activated K+ (KCa) channels, did not inhibit the relaxant responses to cromakalim in both strains. Charybdotoxin alone elicited a contraction, which was greater in SHR than in WKY. In resting strips preloaded with 86Rb, the basal 86Rb efflux rate constant was higher in SHR than in WKY. The addition of cromakalim (10(-5) M) to the resting strips increased the 86Rb efflux rate constant in both strains to a similar peak value. The addition of nifedipine (10(-7) M) to the resting strips decreased the basal 86Rb efflux rate constant only in SHR, and concomitantly affected the action of cromakalim in SHR. The results suggest that (1) cromakalim caused arterial relaxation via the opening of KATP channels in both SHR and WKY, (2) although the relaxant effects of cromakalim tended to be greater in SHR than in WKY, the differences were rather small, depended on the precontraction tone and varied with the concentration of the vasoconstrictors, and (3) there was an increased basal Ca2+ influx and a high activation of KCa channels in the resting state of SHR arteries, and these changes might influence the effects of cromakalim.
The role of basement membrane in colorectal cancer invasion and liver metastasis.
BACKGROUND: Basement membrane (BM) is a specialized extracellular matrix component that plays a key role in tumor invasion and metastasis. METHODS: Immunohistochemical staining for two major components of BM, type IV collagen (C IV), and laminin (LN), utilizing avidin-biotin-peroxidase complex detection to examine 182 primary colorectal cancers (pT2 or greater) and 20 liver metastases. RESULTS: The distribution of C IV was the same as of LN in colorectal cancer tissue, and in normal tissue. Both C IV and LN staining were more frequently positive in the superficial zone but infrequently in the deep zone of the primary tumor. BM preservation, C IV and LN staining in both the superficial and deep zones, was seen in 18.7% of the subjects. The rate of BM preservation significantly decreased with increasing histologic grade (P < 0.01). No correlation was observed between pT number and BM preservation. The rate of BM preservation in cases of liver metastasis was 84.4%, significantly higher than the rate in cases without liver metastasis (P < 0.001). BM was observed even at the advancing front of tumor invasion and was preserved in 95.0% of the liver metastases. CONCLUSIONS: BM is a functional substance that appears to accompany cancer rather than function as a structural barrier against cancer invasion and liver metastasis.
Establishment of the ELISA for murine soluble gp130, a signal transducer for the IL-6 family cytokine, and its detection in the ascitic fluids of tumor-bearing mice.
Interleukin-6 (IL-6) signal is transduced through a membrane glycoprotein gp130, which associates with the IL-6 receptor alpha chain (IL-6R alpha) in the presence of IL-6. We prepared monoclonal antibodies (mAbs) specific to murine gp130 by immunizing rats and hamsters with a chimeric molecule consisting of the extracellular domain of murine gp130 and human immunoglobulin (Ig) G1 Fc (m130Ig). Furthermore, we developed a sandwich ELISA for detection of murine soluble gp130 (sgp130) and showed that sgp130 was present in the ascitic fluids of tumor-bearing mice. Because sgp130 can inhibit the biological activities of the IL-6-related cytokine subfamily that can enhance anti-tumor immune response and also has both growth inducing and growth inhibitory activities on various tumors, the results suggest that sgp130 in tumor-bearing host modulates tumor progression.
Immunologically cross-reactive 57 kDa and 53 kDa glycoprotein antigens of bovine milk fat globule membrane: isoforms with different N-linked sugar chains and differential glycosylation at early stages of lactation.
Two glycoprotein antigens with molecular masses of 57 kDa (MGP57) and 53 kDa (MGP53) were co-purified from bovine milk fat globule membrane (MFGM) by immunoaffinity chromatography using a monoclonal antibody raised against the MFGM. Their N-terminal sequences of 22 amino acids determined were identical, and the sequence was homologous (about 60% identical) to the deduced amino acid sequence of mouse milk fat globule epidermal growth factor (EGF) factor 8 (MFG-E8) (Ref. [12], Stubbs, J.D. et al., Proc. Natl. Acad. Sci. USA, 87, 8417-8421, 1990). This suggests that MGP57/53 are bovine MFGM components 15/16 (PAS-6 and PAS-7), which have recently been reported to be bovine homologs of MFG-E8. N-Glycanase treatment of these glycoproteins reduced their molecular masses, and consequently the enzymatically deglycosylated MGP57 and MGP53 converged on a single band of 50 kDa as measured by SDS-PAGE, indicating that the polypeptide portions of these two distinct glycoprotein antigens are very similar or identical and that their N-linked sugar chains contributed to minor difference in their molecular masses. Western blot analyses using lectins also revealed that they were differentially glycosylated; MGP57 was stained with concanavalin A (Con A) more strongly than MGP53, whereas MGP 53 was stained well with soybean agglutinin (SBA). Reactivity with SBA remarkably increased during early stages of lactation. Two-dimensional gel electrophoresis showed that MGP57 and MGP53 were electrically heterogeneous; from day 9 after parturition, both glycoproteins fell in almost the same range of isoelectric points between 6.4 and 7.6, also, such glycoproteins from day 1 after parturition were more acidic, probably due to terminal sialylation of their sugar chains.
Direct measurement of single-vortex diameters by electron holography.
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Association of p72 tyrosine kinase with Stat factors and its activation by interleukin-3, interleukin-6, and granulocyte colony-stimulating factor.
Hematopoietic cytokines, including interleukin-3 (IL-3), IL-6, and granulocyte colony-stimulating factor (G-CSF), induce the proliferation, differentiation, and activation of hematopoietic lineage cells. These cytokines activate the Jak/Stat-mediated signal transduction pathway that is important in the biologic activities of these cytokines. In this study, we showed that hematopoietic cytokines, such as IL-3, IL-6, and G-CSF, all induced tyrosine-phosphorylation of Stat family proteins and Stat-associated 150-kD and 72-kD molecules in hematopoietic lineage cell lines. Furthermore, we showed that the 72-kD molecule had tyrosine kinase activity. The tyrosine kinase activity of the 72-kD molecule was enhanced by the stimulation through an IL-6 signal transducer, gp130, that was shared among the receptors for the IL-6-related cytokine subfamily, such as leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotrophic factor. Because 72-kD tyrosine kinase was distinct from Syk, Tec, and Btk and coimmunoprecipitated with anti-Stat antiserum, we termed it Stat-associated 72-kD tyrosine kinase (p72sak). p72sak may directly activate Stat family proteins or other signal transducing molecules for IL-3, G-CSF, and the IL-6-related cytokine subfamily.
Enhancement by organosulfur compounds from garlic and onions of diethylnitrosamine-induced glutathione S-transferase positive foci in the rat liver.
Ten organosulfur compounds from garlic and onions were studied for their modifying effects on diethylnitrosamine-induced neoplasia of liver in male F344 rats using the medium-term bioassay system of Ito based on the two-step model of hepatocarcinogenesis. Carcinogenic potential was scored by comparing the number and area per cm2 of induced glutathione S-transferase placental form-positive foci in the liver with those of the corresponding control group given diethylnitrosamine alone. In experiments 1 and 2, high doses of diallyl sulfide, diallyl trisulfide, allyl methyl sulfide, allyl methyl trisulfide, and dipropyl sulfide had enhancing effects on focus formation. In contrast, high doses of methyl propyl disulfide and propylene sulfide significantly decreased the number of glutathione S-transferase placental form-positive foci. In the third experiment, combined treatment with the five chemicals that had enhancing activity were fed at low doses and increased the induction of glutathione S-transferase placental form-positive foci. To investigate the mechanism of the modifying effect on hepatocarcinogenesis, ornithine decarboxylase activity was measured in diallyl sulfide-, allyl methyl sulfide-, and dipropyl sulfide-treated liver tissue without prior initiation with diethylnitrosamine, and its activity was increased compared to controls. Spermidine/spermine N1-acetyltransferase activity was not significantly changed. Formation of 8-hydroxydeoxyguanosine, a DNA adduct generated by activated oxygen species, and lipid peroxidation (2-thiobarbituric acid-reacting substance production) were also not changed. These results suggest that the promoting effect could be caused by increased cell proliferation with increased polyamine biosynthesis. In evaluating relationships between diet and cancer, it is appropriate to consider not only the possible protective role of garlic and onions but also their enhancing effects.
Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells.
Interleukin-6 (IL-6) is a multifunctional cytokine playing various roles in the immune system, hematopoiesis and acute phase reactions. To elucidate the intracellular signal transduction mechanism through the IL-6 receptor, we investigated IL-6-induced protein tyrosine phosphorylation in murine hematopoietic cell lines, BAFm130 and Y6. IL-6 stimulated tyrosine phosphorylation of multiple cellular proteins, such as gp130, an IL-6 signal transducer; Jak family of the cytoplasmic tyrosine kinases; and the latent cytoplasmic signal transducer and activator of transcription. We showed that the pattern of these tyrosine-phosphorylated molecules was different between BAFm130 and Y6 cells on which IL-6 exhibited different biological activities.
Clonal hematopoiesis detected in an allogeneic marrow transplant recipient with poor engraftment.
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