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M Seto

Publications and source records attributed to M Seto.

At least 37 records · Page 2Linked to original sources
PubMed2001

Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases.

Immunostaining for cyclin D1 is essential for reliable diagnosis of mantle cell lymphoma (MCL). However, a small number of cyclin D1-positive lymphomas other than MCL have been encountered. Our goal was to investigate the morphological spectrum of MCL as a disease entity, based on cyclin D1 overexpression. We reviewed 181 biopsy specimens obtained from 168 cases of cyclin D1-positive MCL. Typical findings were the presence of nodular (53.9% of cases) or diffuse (46.1%) histological patterns, containing mantle zone patterns (16.8%), naked germinal centers (33.5%) and perivascular hyaline deposition (83.2%). Unusual findings of residual germinal centers with a mantle cuff (four cases) and follicular colonization (two cases) were seen. High magnification showed a monotonous proliferation of tumor cells with cytological diversity including small (3.0%), intermediate (43.1%), medium (34.1%), medium-large (13.2%) and large (6.6%) cells. Pleomorphic and blastic/blastoid variants were encountered in 9.6 and 7.2% of cases, respectively. Three cases had foci of cells of considerable size, with a moderately abundant pale cytoplasm resembling marginal zone B cells. Two cases showed an admixture of cells which appeared transformed and mimicked the histology of chronic lymphocytic leukemia/small lymphocytic leukemia. In one, neoplastic mantle zones were surrounded by sheets of mature plasma cells, resembling the plasma cell type of Castleman's disease. An admixture of areas characteristic of MCL and of other larger cells, indicating histological progression or a composite lymphoma, were observed in seven cases. In high-grade lesions of five cases, nuclear staining of cyclin D1 was rarely detected. In our experience, cyclin D1 expression was also found in nine lymphomas other than MCL (five plasma cell myelomas, three Hodgkin's disease and one anaplastic large cell lymphoma). The application of cyclin D1 staining prompted us to recognize the broad morphological spectrum of MCL. MCL can be diagnosed with the application of cyclin D1 immunostaining, if careful attention is given to architectural and cytological features.

Adult↗
PubMed2001

Different susceptibilities of postmitotic checkpoint-proficient and -deficient Balb / 3T3 cells to ICRF-193, a catalytic inhibitor of DNA topoisomerase II.

Two distinct types of Balb / 3T3 cells were isolated which exhibit either 4 N DNA or both 4 N and 8 N DNA after exposure to colcemid for 48 h. They were found to differ with respect to the postmitotic checkpoint, but not the mitotic checkpoint. Firstly, the checkpoint-proficient and -deficient cells exhibited the same accumulation and subsequent decrease in the number of mitotic cells following exposure to microtubule inhibitors. Secondly, after exit from abnormal mitosis in the presence of ICRF (Imperial Cancer Research Fund)-193, the checkpoint-proficient cells were arrested in the next cycle G1, while the checkpoint-deficient cells progressed into S and G2 phase. When either mitotic or asynchronous cells were exposed to ICRF-193, the checkpoint-proficient cells proved more sensitive to the cytotoxic effect of this agent than the checkpoint-deficient cells. The different susceptibilities of the two types of cells to ICRF-193 were not caused by variation in topoisomerase (topo) II function since both the biochemical activity of this enzyme and chromosome segregation were inhibited by similar concentrations of ICRF-193 in both checkpoint-proficient and -deficient cells. We propose that the inhibition of chromosome segregation by ICRF-193 is monitored by the next G1 checkpoint, resulting in an irreversible G1 block in the case of postmitotic checkpoint-proficient cells. As the checkpoint-deficient cells can escape this G1 block, these cells have an increased survival capacity. In summary, ICRF-193 may prove to be a very useful drug for examination of the postmitotic checkpoint.

3T3 Cells↗
PubMed2001

Myosin light chain kinase regulates capacitative ca(2+) entry in human monocytes/macrophages.

Monocytes/macrophages are present in all stages of atherosclerosis. Although many of their activities depend to various extents on changes in intracellular Ca(2+) concentration ([Ca(2+)](i)), mechanisms regulating [Ca(2+)](i) in these cells remain unclear. We aimed to explore the role of myosin light chain kinase (MLCK) in Ca(2+) signaling in freshly isolated human monocytes/macrophages. Large capacitative Ca(2+) entry (CCE) was observed under fura 2 fluoroscopy in human monocytes/macrophages treated with thapsigargin and cyclopiazonic acid. ML-9 and wortmannin, 2 structurally different inhibitors of MLCK, dose-dependently (1 to 100 micromol/L) prevented CCE and completely did so at 100 micromol/L, whereas inhibitors of tyrosine kinase and protein kinase C had only partial effects. Western blotting showed that thapsigargin significantly caused myosin light chain phosphorylation, which was almost completely blocked by ML-9 (100 micromol/L) and wortmannin (100 micromol/L). ML-9 also dose-dependently (1 to 100 micromol/L) inhibited this phosphorylation, which was well correlated with its inhibition of CCE. Transfection with MLCK antisense completely prevented CCE in response to thapsigargin and cyclopiazonic acid, whereas MLCK sense had no effect. These data strongly indicate that MLCK regulates CCE in human monocytes/macrophages. The study suggests a possible involvement of MLCK in many Ca(2+)-dependent activities of monocytes/macrophages.

Androstadienes↗
PubMed2001

Mitotic specific phosphorylation of serine-1212 in human DNA topoisomerase IIalpha.

It is known that topoisomerase IIalpha is phosphorylated by several kinases. To elucidate the role of phosphorylation of topoisomerase IIalpha in the cell cycle, we have examined the cell cycle behavior of phosphorylated topoisomerase IIalpha in HeLa cells using antibodies against several phospho-oligopeptides of this enzyme. Here we demonstrate that serine1212 in topoisomerase IIalpha is phosphorylated only in the mitotic phase. Using an antibody against an oligopeptide containing phosphoserine-1212 in topoisomerase IIalpha (PS1212), subcellular localization of topoisomerase IIalpha phosphorylated at serine1212 was examined by indirect immunofluorescence staining, and compared with that of overall topoisomerase IIalpha. Serine1212-phosphorylated topoisomerase IIalpha was localized specifically on mitotic chromosomes, but not on interphase chromosomes; this result contrasts with overall topoisomerase IIalpha which was observed on chomosomes in both interphase and mitosis. Serine1212-phosphorylated topoisomerase lIalpha first appeared on chromosome arms in prophase, became concentrated on the centromeres in metaphase, and disappeared in early telophase. In addition, ICRF-193, a catalytic inhibitor of topoisomerase II, prevented accumulation of serine1212-phosphorylated topoisomerase IIalpha at the centromeres. These results indicate that serine1212 of topoisomerase IIalpha is phosphorylated specifically during mitosis, and suggest that the serine1212-phosphorylated topoisomerase IIalpha acts on resolving topological constraint progressively from the chromosome arm to the centromere during metaphase chromosome condensation.

Antibodies, Monoclonal↗
PubMed2001

Characterization of a processed pseudogene of human psiHSP40 on chromosome 2q32.

A pseudogene for the human Hsp40 gene has been characterized (psiHSP40). The pseudogene sequence shows 90% similarity to the human Hsp40 mRNA at the nucleotide level. No introns were found in the region corresponding to the human Hsp40 cDNA, and two direct repeats flank this same region. Because of these features, the pseudogene can be classified as a processed pseudogene. PsiHSP40 was assigned to chromosome 2q32 by in situ hybridization. This is the first report of a pseudogene for a member of the DnaJ (Hsp40) family protein gene.

Base Sequence↗
PubMed2001

No substantial difference in genotype frequencies of interleukin and myeloperoxidase polymorphisms between malignant lymphoma patients and non-cancer controls.

BACKGROUND AND OBJECTIVES: The functional polymorphisms regulating immunologic responses may influence the proliferation or suppression of malignant lymphoma. We examined the association between malignant lymphoma risk and the polymorphisms of the IL-1 gene family [IL-1B -31 C/T, IL-1A -889 C/T, and IL-1RN 86-bp variable number of terminal repeat (VNTR)] and myeloperoxidase (MPO -463 G/A). DESIGN AND METHODS: The hospital-based case-control study was conducted in Japan. Genotypes were examined in a total of 372 lymphoma cases and 241 non-cancer control subjects. The relative risks were estimated by unconditional logistic regression analysis. RESULTS: The overall allele distribution of these polymorphisms did not differ substantially between patients and controls; the odds ratios were 0.73 (95% confidence interval, 0.48-1.11) for the T allele carriers of IL-1B relative to the non-carriers, 1.01 (0.56-1.82) for the 2-repeat allele (allele 2) carriers of IL-1RN, 0.96 (0.62-1.48) for the T allele carriers of IL-1A, and 1.04 (0.70-1.57) for the A allele carriers of MPO. Subgroup analyses according to histology [diffuse large B-cell lymphoma (DLBL), follicular lymphoma, low-grade lymphoma of mucosa associated lymphoid tissue, and others] failed to illustrate differences except for DLBL which showed a possible association with IL-1A and IL-1B polymorphisms. INTERPRETATION AND CONCLUSIONS: Our data show a limited association between these polymorphisms and malignant lymphoma risk in total. The possible association of the IL-1A and IL-1B polymorphisms with DLB-needs further clarification.

Adolescent↗
PubMed2000

Myosin light-chain kinase regulates endothelial calcium entry and endothelium-dependent vasodilation.

Activation of smooth muscle myosin light-chain kinase (MLCK) causes contraction. Here we have proven that MLCK controls Ca2+ entry (CE) in endothelial cells (ECs): MLCK antisense oligonucleotides strongly prevented bradykinin (BK)- and thapsigargin (TG)-induced endothelial Ca2+ response, while MLCK sense did not. We also show that the relevant mechanism is not phosphorylation of myosin light-chain (MLC): MLC phosphorylation by BK required CE, but MLC phosphorylation caused by the phosphatase inhibitor calyculin A did not trigger Ca2+ response. Most important, we provide for the first time strong evidence that, in contrast to its role in smooth muscle cells, activation of MLCK in ECs stimulates the production of important endothelium-derived vascular relaxing factors: MLCK antisense and MLCK inhibitors abolished BK- and TG-induced nitric oxide production, and MLCK inhibitors substantially inhibited acetylcholine-stimulated hyperpolarization of smooth muscle cell membrane in rat mesenteric artery. These results indicate that MLCK controls endothelial CE, but not through MLC phosphorylation, and unveils a hitherto unknown physiological function of the enzyme: vasodilation through its action in endothelial cells. The study discovers a counter-balancing role of MLCK in the regulation of vascular tone.

Acetylcholine↗
PubMed2000

The involvement of protein kinase C in myosin phosphorylation and force development in rat tail arterial smooth muscle.

Myosin light-chain phosphorylation is the primary mechanism for activating smooth-muscle contraction and occurs principally at Ser-19 of the 20 kDa light chains of myosin (LC(20)). In some circumstances, Thr-18 phosphorylation may also occur. Protein kinase C (PKC) can regulate LC(20) phosphorylation indirectly via signalling pathways leading to inhibition of myosin light-chain phosphatase. The goal of this study was to determine the relative importance of myosin light-chain kinase (MLCK) and PKC in basal and stimulated LC(20) phosphorylation in rat tail arterial smooth-muscle strips (RTA). Two MLCK inhibitors (ML-9 and wortmannin) and two PKC inhibitors (chelerythrine and calphostin C) that have different mechanisms of action were used. Results showed the following: (i) basal LC(20) phosphorylation in intact RTA is mediated by MLCK; (ii) alpha(1)-adrenoceptor stimulation increases LC(20) phosphorylation via MLCK and PKC; (iii) Ca(2+)-induced LC(20) phosphorylation in Triton X-100-demembranated RTA is catalysed exclusively by MLCK, consistent with the quantitative loss of PKCs alpha and beta following detergent treatment; (iv) very little LC(20) diphosphorylation (i.e. Thr-18 phosphorylation) occurs in intact or demembranated RTA at rest or in response to contractile stimuli; and (v) the level of LC(20) phosphorylation correlates with contraction in intact and demembranated RTA, although the steady-state tension-LC(20) phosphorylation relationship is markedly different between the two preparations such that the basal level of LC(20) phosphorylation in intact muscles is sufficient to generate maximal force in demembranated preparations. This may be due, in part, to differences in the phosphatase/kinase activity ratio, resulting from disruption of a signalling pathway leading to myosin light-chain phosphatase inhibition following detergent treatment.

Animals↗
PubMed2000

Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype.

Anaplastic large cell lymphoma (ALCL) is a distinct entity of non-Hodgkin lymphoma, characterized by a proliferation of pleomorphic large lymphoid cells that express CD30. Recent studies have found that a subset of ALCL aberrantly expresses a chimeric anaplastic lymphoma kinase (ALK) protein as a result of t(2;5)(p23;q35) or variant translocations. ALK-positive ALCLs feature good prognosis, but some of them lead to poor outcomes. Since CD56 is expressed in some ALCLs, its clinical significance was examined in a series of T/null cell type ALCLs. Of 143 patients, 83 (58%) showed ALK-positive staining, and of 140 patients, 25 (18%) expressed CD56. The ALK-positive subgroup was characterized by a younger age of onset (P <.0001), lower serum lactate dehydrogenase level (P =.01), better performance status (P =.03), less frequent extranodal involvement (P =.01), lower international prognostic index (IPI) categories (P =.002), and superior survival (P =.0009) in comparison with the ALK-negative group, suggesting that ALK is a specific marker defining a distinct subtype. CD56(+) cases showed a significantly poor prognosis overall (P =.002) as well as in both ALK-positive and ALK-negative subgroups (P =.02 and P =.04, respectively). Multivariate analysis confirmed that CD56 is independent of other prognostic factors, including IPI. Although CD56(+) cases showed a higher incidence of bone involvement, no other differences in clinicopathologic parameters were found between the CD56(+) and CD56(-) groups. These findings suggest that CD56 is not a marker to identify a distinct subtype of ALCL, but a strong clinical prognostic factor. Effective therapeutic approaches should be explored for high-risk ALCL patients, who can be identified by means of a prognostic model, including CD56.

Adolescent↗
PubMed2000

Observation of nuclear excitation by electron transition in 197Au with synchrotron X rays and an avalanche photodiode

We have succeeded in observing nuclear excitation by electron transition (NEET) in 197Au by a new method. Monochromatic x-rays of synchrotron radiation were used to ionize the K shell of gold atoms in a target foil. The internal-conversion electrons emitted from excited nuclei were detected with a silicon avalanche photodiode. At a photon energy of 80.989 keV, the NEET probability in 197Au was determined to be (5.0+/-0.6)x10(-8) from a comparison of the event number per photon between NEET and the nuclear resonance at 77.351 keV.

Journal Article↗
PubMed2000

Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety.

The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [(125)I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivatives 1 with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compounds, we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6, 7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydr o-2 H-pyran-4-aminium chloride (1r, TAK-779) as a highly potent and selective nonpeptide CCR5 antagonist with a IC(50) value of 1.4 nM in the binding assay. Compound 1r also inhibited the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC(50) values of 1.2 and 3.7 nM, respectively. The synthesis and structure-activity relationships of 1r and its related compounds are detailed.

Amides↗
PubMed2000

The Ikaros gene, a central regulator of lymphoid differentiation, fuses to the BCL6 gene as a result of t(3;7)(q27;p12) translocation in a patient with diffuse large B-cell lymphoma.

The BCL6 gene, isolated from the breakpoints of 3q27-associated chromosomal translocations, has been implicated in diffuse large B-cell lymphomas (DLBL). Here we describe the molecular characterization of novel t(3;7)(q27;p12) translocations in 2 patients with DLBL. Molecular genetic analysis of the breakpoint area involving BCL6 revealed the presence of the Ikaros gene, a central regulator of lymphoid differentiation that had been mapped to human chromosome 7 band p13-p11.1. As a molecular consequence of the translocation, the 5' regulatory region of the BCL6 gene was replaced by the putative 5' regulatory region of the Ikaros gene, probably leading to deregulated expression of the BCL6 gene throughout B-cell differentiation. Reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) analyses of a patient sample established that the t(3;7)(q27;p12) results in fusion of the Ikaros and BCL6 genes. This study provides the first evidence that the Ikaros gene is rearranged in human hematopoietic malignant disorders. (Blood. 2000;95:2719-2721)

Base Sequence↗
PubMed2000

Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma.

Mantle cell lymphoma (MCL) is a distinct clinicopathologic entity of non-Hodgkin's lymphoma, characterized by a monotonous proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and frequent t(11;14)(q13;q32) translocation. We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry. 128 cases (85%) showed positive nuclear staining for cyclin D1, while the remaining 23 (15%) were negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1-positive and -negative groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1-positive group showed a higher age distribution (P =.04), larger cell size (P =.02), higher mitotic index (P =.01), more frequent gastrointestinal involvement (P =.05), higher international prognostic index score (P =.05), and lower p27(KIP1) expression (P <.0001). Of particular interest is that cyclin D1-positive MCL showed significantly worse survival than cyclin D1-negative lymphoma (5-year survival: 30% versus 86%, P =.0002), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1-positive and -negative groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL. We therefore propose that cyclin D1-positivity should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored on the basis of the new criteria.

Adult↗
PubMed2000

Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex.

The serine proteinase alpha-thrombin causes blood clotting through proteolytic cleavage of fibrinogen and protease-activated receptors and amplifies its own generation by activating the essential clotting factors V and VIII. Thrombomodulin, a transmembrane thrombin receptor with six contiguous epidermal growth factor-like domains (TME1-6), profoundly alters the substrate specificity of thrombin from pro- to anticoagulant by activating protein C. Activated protein C then deactivates the coagulation cascade by degrading activated factors V and VIII. The thrombin-thrombomodulin complex inhibits fibrinolysis by activating the procarboxypeptidase thrombin-activatable fibrinolysis inhibitor. Here we present the 2.3 A crystal structure of human alpha-thrombin bound to the smallest thrombomodulin fragment required for full protein-C co-factor activity, TME456. The Y-shaped thrombomodulin fragment binds to thrombin's anion-binding exosite-I, preventing binding of procoagulant substrates. Thrombomodulin binding does not seem to induce marked allosteric structural rearrangements at the thrombin active site. Rather, docking of a protein C model to thrombin-TME456 indicates that TME45 may bind substrates in such a manner that their zymogen-activation cleavage sites are presented optimally to the unaltered thrombin active site.

Amino Acid Sequence↗
PubMed2000

Nuclear resonance scattering of synchrotron radiation by 40K

We have observed the excitation of the 29.83 keV nuclear level of the radioactive 40K nuclide, which level is not populated by any radioactive source, by synchrotron radiation for the first time. The absolute energy of the level of 29.834+/-0.011 keV and the half-life of 4.13+/-0.12 ns were obtained from our measurements. Our success in observing the nuclear excitation of radioactive 40K in a KCl powder sample shows the possibility for study of the local vibrational states and the electronic states of potassium in various areas of research.

Journal Article↗