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Biomedical subjects

M Seto

Publications and source records attributed to M Seto.

At least 109 records · Page 6Linked to original sources
PubMed1998

Translocation (10;11)(p13;q13) and MLL gene rearrangement in a case of AML (M5a) with aggressive leukemia cutis.

A male patient with a secondary acute monocytic leukemia whose leukemia cells had a t(10;11)(p13;q13) chromosomal abnormality is described. Gene analysis disclosed that the patient's leukemia cells had MLL gene rearrangement. His leukemia cells responded poorly to chemotherapy, and the patient developed an unusual aggressive leukemia cutis. A t(10;11)(p13;q13) chromosomal abnormality that expresses MLL gene rearrangement has not been reported previously in secondary leukemia.

Aged↗
PubMed1998

A small deletion in the 3'-untranslated region of the cyclin D1/PRAD1/bcl-1 oncogene in a patient with chronic lymphocytic leukemia.

The cyclin DI/PRAD1 oncogene, a key regulator of the G1 phase of the cell cycle, has been incriminated in the pathogenesis of human neoplasia. Cyclin D1 was also demonstrated to be identical to the long-sought bcl-1 oncogene in B-cell malignancies with the t(11;14)(q13;q32) translocation. We report here a small deletion in the 3'-untranslated portion of the cyclin D1 gene in leukemia cells of a patient diagnosed with B-chronic lymphocytic leukemia (CLL), associated with overexpression of the corresponding cyclin D1 mRNA. During a Northern blot survey of B-cell malignancies, we identified a patient whose CLL cells showed a marked increase in 1.5-1.6 kb cyclin D1 mRNA species. Subsequent Southern blot analysis showed that genomic DNA from the patient's cells contained an extra band in the EcoRI digest, suggesting that one allele of the cyclin D1 gene may be altered. Polymerase chain reaction (PCR) analysis of the genomic DNA and direct DNA sequencing clearly disclosed that one allele of the cyclin D1 gene was deleted in the 3'-untranslated region, which would contribute to an increased stability of its mRNA. Reverse transcription-polymerase chain reaction (RT-PCR) analysis and direct DNA sequencing revealed that the cyclin D1 mRNA was deleted at the corresponding region. This finding provides further evidence for a critical role of cyclin D1 in the pathogenesis of B-cell malignancies and highlights a novel mechanism, a small deletion in the 3'-untranslated region, responsible for deregulation of the cyclin D1 gene in oncogenesis.

Base Sequence↗
PubMed1998

Microsatellite instability is rare in the clinical course of myelodysplastic syndrome studied with DNA from fresh and paraffin-embedded tissues.

Microsatellite instability (MSI) has been reported to occur in various types of malignant neoplasms. We performed a polymerase-chain-reaction-based assay for MSI between the initial and the most recently available ("latest") samples from 23 patients with myelodysplastic syndrome (MDS). Of these patients, 15 were informative at more than three microsatellite loci. Seven patients showed an increase in leukemic cells while 8 patients did not during the interval between the two analyses. Only 1 of the patients, who had refractory anemia with excess blasts, which changed to acute myelogenous leukemia, showed microsatellite alteration at the analysis times. Among all 23 patients, two alterations were detected in the 42 informative paired samples that showed an increase in leukemic cells (4.8%), while none was detected in the 59 paired samples without such an increase. In total, therefore only two alterations were detected among 101 informative paired samples (2%). This indicates that MSI is rare in the clinical course of MDS irrespective of disease status, and is consequently not a critical genetic event for disease progression in most MDS patients.

Adult↗
PubMed1998

Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary.

[3H]Spiperone-binding assay to D2 receptors and quantitative ribonuclease protection assay for both isoforms (D2L and D2S receptor) of the D2 receptor mRNA and the prolactin mRNA were performed on pituitaries from the control rat and from the rat injected orally daily with either haloperidol (2 mg/kg) or aripiprazole (24 mg/kg) for 21 days. Haloperidol treatment increased the [3H]spiperone-binding by 28%, the levels of D2L and D2S receptor mRNA by 41% and 38%, respectively, and the level of prolactin mRNA by 26%. In contrast, the treatment with aripiprazole, a newly developed atypical antipsychotic with reduced side effects, decreased the [3H]spiperone-binding by 24% and the levels of D2L and D2S receptor mRNA by 23% and 23%, respectively, and did not have any effect on the level of prolactin mRNA. The same treatment with sulpiride (100 mg/kg) increased the levels of D2L and D2S receptor mRNA by 59% and 62%, respectively, but treatment with clozapine (25 mg/kg) did not cause any effect. Neither treatment changed the ratio of the level of D2S receptor mRNA to the level of D2L receptor mRNA in the pituitary. These findings indicate that D2 receptor densities in the pituitary are influenced differentially by the treatment with these antipsychotics, which could be induced at least partly by the changes in the levels of mRNA without any effects on the splicing mechanisms and thus affect the plasticity of the prolactin mRNA expression. The inhibitory effects of chronic aripiprazole treatment on D2 receptors in the pituitary might underlie this drug's clinical property of reduced hyperprolactinemia side effect.

Administration, Oral↗
PubMed1998

Progression from myelodysplastic syndrome with monosomy 7 to acute monoblastic leukemia with MLL gene rearrangement.

We report a case of myelodysplastic syndrome (MDS) with the 11q23 translocation at its leukemic transformation. Southern blot analysis demonstrated that the MLL gene on chromosome 11 was rearranged during the progression from MDS to acute leukemia. The clinical observation in this case supports the notion that leukemic transformation involves multiple cytogenetic evolutionary progresses, and that MLL gene rearrangement corresponds to the final step of leukemogenesis.

Child↗
PubMed1998

Truncated c-Myb expression in the human leukemia cell line TK-6.

The c-MYB proto-oncogene encodes a transcription factor which plays an important role in hematopoiesis. We detected truncated c-MYB mRNA (2.0 kb) and c-Myb protein (55 kDa) in the TK-6 cell line, which was established from a patient with chronic myelogenous leukemia in T cell blast crisis. Mutated c-MYB cDNA clone (WTK-1) was isolated from a TK-6 cell cDNA library and sequenced in its entirety. Compared with the wild-type human c-MYB sequence, the WTK-1 sequence diverged at the 3' ends of exons 9. A termination codon was present as the second codon downstream from the point of divergence and was followed by a previously unknown rearranged sequence. The conceptual protein encoded by WTK-1 (Myb(TK-6)) comprises 402 amino acids and lacks the negative regulatory domain of the normal c-Myb, reminiscent of the activated form of Myb protein. Luciferase reporter assay in NIH3T3 cells showed that the expression vector encoding Myb(TK-6) stimulated Myb-regulated mim-1 promoter more effectively than that encoding wild-type human c-Myb, suggesting that Myb(TK-6) is functional as a transcription factor, and thus as a potential transforming protein. Southern blot and mutant allele-specific polymerase chain reaction analyses showed that the same rearrangement of the c-MYB gene in TK-6 was present in late, but not in early, specimens obtained from the patient, indicating that this mutation had been acquired during disease progression.

Adult↗
PubMed1998

Establishment of an IL-2-dependent cell line derived from 'nasal-type' NK/T-cell lymphoma of CD2+, sCD3-, CD3epsilon+, CD56+ phenotype and associated with the Epstein-Barr virus.

A novel interleukin-2 (IL-2)-dependent cell line, HANK1, was established from a patient with CD56+ NK/T-cell lymphoma arising in the retroperitoneum. Morphologically, HANK1 is a pleomorphic large cell line with irregular nuclei, which contains azurophilic granules in the cytoplasm. Immunophenotypic analysis showed that HANK1 expressed CD2, CD3epsilon, CD56, TIA-1, granzyme B, and HLA-DR, but no other T-lineage markers. These features were the same as seen in the original tumour, and are highly characteristic of nasal and 'nasal-type' NK/T-cell lymphoma as described in the proposed W.H.O. classification. Genotypically, this cell line also demonstrated the germline configuration of the T-cell receptor beta, gamma and the immunoglobulin heavy chain genes and clonal integration of the Epstein-Barr virus (EBV) together with antigen expression with a type II latency pattern (LMP-1+ and EBNA2-). Furthermore, Southern blot analysis using the EBV termini as probes confirmed its derivation from the original lymphoma, and revealed that it contained multiple copies of the EBV genome. Dose-dependent growth on IL-2 was observed in an in vitro study with a doubling time of 3 d at maximal stimulation. These data indicate that HANK1 seemed to preserve the biological characteristics of the original tumour and therefore may serve as a good model for the further analysis of unusual 'nasal-type' NK/T-cell lymphoma.

Blotting, Southern↗
PubMed1998

Multiple polypoid lesions of primary mucosa-associated lymphoid-tissue lymphoma of colon.

AIMS: This study was focused on unusual cases of mucosa-associated lymphoid tissue (MALT) lymphoma presenting with multiple polypoid lesions of the colon and rectum with a special reference to the differential diagnosis of mantle cell lymphoma. METHODS AND RESULTS: The lesions of these five cases grossly showed a segmental distribution of nodular protrusions in three patients and of innumerable small polyps in two. These patterns of involvement simulated those of multiple lymphomatous polyposis, known as the gastrointestinal presentation of mantle cell lymphoma (MCL), and caused a differential diagnostic problem between MALT lymphoma and MCL, which have different prognostic and therapeutic implications. Their histological features are almost indistinguishable from each other, especially in the small biopsy specimens via endoscope. The most important procedure for their differentiation is cyclin D1 immunohistochemistry and its negative reaction provides strong indication of MALT lymphoma. Of interest, one case showed a rare karyotypic abnormality of t(11;18)(q21;q21), which has been reported specifically in MALT lymphoma. CONCLUSIONS: This study has indicated that the multiple polypoid lesions of the colon occur not only in MCL, but also in MALT lymphoma, making differential diagnosis between the two entities necessary, and cyclin D1 immunohistochemistry is indispensable for distinguishing between them.

Adult↗
PubMed1998

An essential role of myosin light-chain kinase in the regulation of agonist- and fluid flow-stimulated Ca2+ influx in endothelial cells.

Cytosolic Ca2+ ([Ca2+]i) plays an important role in endothelial cell signaling. Although it has been suggested that the influx of Ca2+ can be triggered by depletion of intracellular Ca2+ stores, the mechanism (or mechanisms) underlying this phenomenon needs further elaboration. In the present study, involvement of myosin light-chain kinase (MLCK) in the regulation of Ca2+ signaling was investigated in agonist- and fluid flow-stimulated endothelial cells loaded with Ca2+-sensitive dyes. Bradykinin (BK) and thapsigargin caused an increase in [Ca2+]i followed by a sustained rise due to Ca2+ influx from extracellular space and shifted total myosin light-chain (MLC) from the unphosphorylated to the diphosphorylated form. ML-9 (100 microM), an inhibitor of MLCK, abolished Ca2+ influx and prevented MLC diphosphorylation in BK- and thapsigargin-treated cells, but did not affect Ca2+ mobilization from internal stores. Fluid flow stimulation (shear stress=5 dynes/cm2) increased [Ca2+]i and enhanced MLC phosphorylation. ML-9 also inhibited Ca2+ response and MLC phosphorylation in fluid flow-stimulated cells. The Ca2+ influx in response to BK was linearly correlated with the diphosphorylation of MLC in ML-9 treated cells. Effects of ML-5 and ML-7, analogs of ML-9, to inhibit Ca2+ influx paralleled their potencies to inhibit MLCK activity. These findings demonstrate that MLCK plays an essential role in regulating the plasmalemmal Ca2+ influx in agonist- and fluid flow-stimulated endothelial cells. This study is the first to report the close relationship between Ca2+ influx and MLC diphosphorylation.

Animals↗
PubMed1998

Expression of the TCL1 gene at 14q32 in B-cell malignancies but not in adult T-cell leukemia.

The TCL1 gene was recently cloned as a candidate target within the 14q32.1 breakpoint cluster region observed in T-cell malignancies. We examined the TCL1 gene expression in 21 patients with adult T-cell leukemia (ATL) and 5 cell lines, because ATL is reported to have frequent chromosome 14 band q32 aberrations. However, 20 of the ATL patients and all 5 cell lines lacked any TCL1 expression on northern blot analysis, and TCL1 transcripts were only very faintly detected in the remaining one patient. Expansion of our analysis to include other types of hematopoietic malignancies revealed strong expression of the TCL1 gene in almost all tumor cells of B-cell lineage except myelomas. However, no TCL1 signals were encountered in cells of T-cell or myeloid lineages. In normal human tissues TCL1 was found to be expressed in the spleen, lymph nodes and B-lymphocytes of peripheral blood. These results indicate that TCL1 is not a major target gene for ATL, but that it may play a role in B-cell differentiation and proliferation.

Adult↗
PubMed1998

Growth inhibition of CD20-positive B lymphoma cell lines by IDEC-C2B8 anti-CD20 monoclonal antibody.

Treatment with IDEC-C2B8 (C2B8), the chimeric anti-CD20 antibody, was shown in a phase I-II study to be very effective for the treatment of low-grade B-cell lymphoma, in contrast to the results of most previous immunotherapies with monoclonal antibodies. In a study designed to elucidate the reason for this efficacy, two cell lines derived from lymphomas with BCL2 gene rearrangement (SU-DHL-4 and SU-DHL-6) showed remarkable growth inhibition and cell-death, and two other cell lines derived from a diffuse lymphoma (RC-K8) and a mantle cell lymphoma (SP-49) showed moderate growth inhibition, but neither a CD20 weakly positive cell line (NALL-1) nor a negative cell line (MOLT-4) showed any growth inhibition. An examination of the intensity of cell-surface CD20 expression showed no correlation between intensity and degree of growth inhibition among the four cell lines showing growth inhibition. Morphological examination revealed condensed and fragmented nuclei and budding of the plasma membrane, both characteristic of apoptosis, with some cells in these cell lines showing growth inhibition by C2B8. Such apoptosis was also confirmed by flow cytometric analysis, suggesting that, at least in part, apoptosis plays a role in this growth inhibition. This growth-inhibitory mechanism may thus account for the effectiveness of C2B8 antibody therapy.

Animals↗
PubMed1998

Dynamics of myosin light chain phosphorylation at Ser19 and Thr18/Ser19 in smooth muscle cells in culture.

Using the specific antibodies pLC1 and pLC2 for mono- and diphosphorylated 20-kDa myosin light chain (MLC20) at Ser19 and at both Thr18 and Ser19, respectively, we visualized the dynamics of the MLC20 phosphorylation in rabbit aortic smooth muscle cells (cell line SM-3) stimulated with PGF2alpha. In the resting state, the diphosphorylated form was located in the peripheral region of the cell, such as the leading edge or the adhesion plaque, and the monophosphorylated form was located not only in the peripheral region but also on a discontinuous fibrillary structure along the long axis of the cell. After stimulation with 30 microM PGF2alpha, although localization of the monophosphorylated form changed little, the content of the diphosphorylated form increased and the distribution spread along the fibrillary structure to an extent the same as or similar to that of the monophosphorylated form, which colocalized with actin filament bundles. The diphosphorylation of MLC20 was more sensitive to protein kinase inhibitors, HA-1077, HA-1100, staurosporine, wortmannin, and ML-9, than was the monophosphorylation. In light of these observations, we propose that MLC20 diphosphorylation and monophosphorylation are regulated by different mechanisms.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Effects of prednisolone on glomerular signal transduction cascades in experimental glomerulonephritis.

In vitro data support that activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) regulate the gene expression of numerous growth factors and cytokines involved in the development of glomerulonephritis (GN). However, the in vivo activation and role of these transcription factors are poorly understood. This study examines whether these transcription factors are activated in antithymocyte serum (ATS)-induced GN in vivo and whether prednisolone suppresses activation of them. As assessed by gel mobility shift assay, glomerular DNA binding activity of AP-1 containing both c-Jun and c-Fos and NF-kappaB composed of P-50 and P-65 subunits was significantly increased after ATS injection. Furthermore, as estimated by in-gel kinase assay, glomerular activity of extracellular signal-regulated kinases (ERK) and c-jun NH2-terminal kinases (JNK), which are mitogen-activated protein kinases (MAPK) known to activate AP-1 and NF-kappaB in vitro, was significantly increased after ATS injection, preceding the increase in AP-1 activity. Prednisolone treatment significantly prevented the increase in urinary protein and albumin excretion and glomerular cell proliferation in ATS-induced GN, indicating the beneficial effects of prednisolone on this GN. Prednisolone significantly suppressed the increased glomerular ERK and JNK activities and AP-1 binding activity, but not glomerular NF-kappa binding activity. This study provides the first evidence of the marked increase in glomerular MAPK activities, and AP-1 and NF-kappa binding activities in ATS-induced GN. The beneficial effect of prednisolone on this GN may be partially mediated by the suppression of MAPK, followed by the suppression of AP-1.

Animals↗
PubMed1998

[A clinical study on the background of patients with nontuberculous pulmonary mycobacteriosis--predisposing factor and environment].

We studied the background of 78 patients with pulmonary nontuberculous mycobacteriosis from 1992 to 1996, and 56 patients (71.8%) were diagnosed as primary infection type and 22 patients (28.2%) as secondary infection type. The former consisted of 17 males and 39 females (mean age +/- SD; 67.4 +/- 12.9 years), and the latter consisted of 13 males and 9 females (mean age +/- SD; 74.0 +/- 7.5 years). Out of all 83 strains, 67 strains (80.7%) were M. avium complex, and out of 36 strains identified either M. avium or M. intracellulare, 34 strains (94.4%) were M. intracellulare and 2 strains (5.6%) were M. avium. Many patients lived in farming areas along the coast, and 35 patients (62.5%) of primary infection type and 11 patients (50%) of secondary infection type were or used to be farmers. Nine patients (16.1%) of primary infection type and 6 patients (27.3%) of secondary infection type had history of gastroduodenal ulcer, while only 3 of all 78 patients had sinusitis. There was a married couple who lived in a same house and 2 sisters who lived apart who were proved to have primary infection type but cross infection was not demonstrated in either case. The development of this disease seems to be related to a genetic susceptibility and environmental factors.

Adult↗
PubMed1998

Amplification on double-minute chromosomes and partial-tandem duplication of the MLL gene in leukemic cells of a patient with acute myelogenous leukemia.

Partial-tandem duplication (PTD) of an internal portion of MLL occurs in some cases of acute myelogenous leukemia (AML) with trisomy 11 or a normal karyotype. This type of MLL rearrangement may be transcribed into an mRNA species that is capable of encoding a partially duplicated protein associated with leukemogenesis. However, although several kinds of oncogenes, especially MYC, are often amplified on double-minute chromosomes (dmins) in hematological malignancies, no amplification of MLL has been reported in AML. Here, we report the first documented case of a patient with AML whose leukemic cells exhibited amplification of MLL on dmins. Furthermore, in this patient, MLL was rearranged in a PTD manner, with in-frame fusion of exons 2 and 6.

Chromosome Aberrations↗
PubMed1997

Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta.

BACKGROUND: Although coronary artery spasm plays an important role in a wide variety of ischemic heart diseases, the intracellular mechanism for the spasm remains to be clarified. We examined the role of myosin light chain (MLC) phosphorylations, a key mechanism for contraction of vascular smooth muscle, in our swine model with interleukin-1beta (IL-1beta). METHODS AND RESULTS: IL-1beta was applied chronically to the porcine coronary arteries from the adventitia to induce an inflammatory/proliferative lesion. Two weeks after the operation, intracoronary serotonin repeatedly induced coronary hyperconstrictions at the IL-1beta-treated site both in vivo and in vitro, which were markedly inhibited by fasudil, an inhibitor of protein kinases, including protein kinase C and MLC kinase. Western blot analysis showed that during serotonin-induced contractions, MLC monophosphorylation was significantly increased and sustained in the spastic segment compared with the control segment, whereas MLC diphosphorylation was noted only in the spastic segment. A significant correlation was noted between the serotonin-induced contractions and MLC phosphorylations. Both types of MLC phosphorylation were markedly inhibited by fasudil. In addition, MLC diphosphorylation was never induced by a simple endothelium removal in the normal coronary artery, whereas enhanced MLC phosphorylations in the spastic segment were noted regardless of the presence or absence of the endothelium. CONCLUSIONS: These results indicate that enhanced MLC phosphorylations in the vascular smooth muscle play a central role in the pathogenesis of coronary spasm in our swine model.

Animals↗
PubMed1997

CAG repeat length and disease duration in Machado-Joseph disease: a new clinical classification.

To evaluate the clinical characteristics of Machado-Joseph disease (MJD) with reference to CAG repeat length and disease duration, we analyzed neurologic findings in 108 patients from 84 families. The majority of MJD patients presented with an ataxic gait as the initial symptom. Dysarthria and nystagmus were observed from an early stage. Bulging eyes, muscle atrophy and bradykinesia developed later. Patients with a shorter CAG repeat length or later onset had more frequent involvement of proprioceptive sensory deficit. Incidence of abnormal reflexes, tones, and proprioceptive sensation was not associated with disease duration, but with CAG repeat length. Based on these results, we propose a new clinical classification: type A (juvenile type), with hyperreflexia and dystonia, but without a proprioceptive sensory deficit; type C (adult type), with hyporeflexia and a proprioceptive sensory deficit, but without dystonia; and type B (intermediate type), the remaining patients with a mixed presentation.

Adult↗