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Biomedical subjects

M Seto

Publications and source records attributed to M Seto.

At least 19 recordsLinked to original sources
PubMed2006

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein.

At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-kappaB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-kappaB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-kappaB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-kappaB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10.

Animals↗
PubMed2004

Calcium hydroxyapatite ceramic implants in bone tumour surgery. A long-term follow-up study.

We reviewed the results of 51 patients with benign bone tumours treated by curettage and implantation of calcium hydroxyapatite ceramic (CHA). The mean follow-up was 11.4 years (10 to 15.5). Post-operative fractures occurred in two patients and three had local recurrences; three had slightly limited movement of the adjacent joint and one had mild osteoarthritis. There were no allergic or neoplastic complications. In all cases, radiographs showed that the CHA was well incorporated into the host bone. Statistical analysis showed that absorption of the implanted CHA was greater in males (odds ratio, 6.2; 95% CI, 1.6 to 23.7) and younger patients (odds ratio, 0.6 for increase in age of 10 years; 95% CI, 0.91 to 0.99). However, the implanted CHA was not completely absorbed in any patient. We conclude that CHA is a useful and safe bone substitute for the treatment of benign bone tumours.

Adolescent↗
PubMed2004

The expression and prognostic significance of bone morphogenetic protein-2 in patients with malignant fibrous histiocytoma.

We investigated the rates of expression of bone morphogenetic protein-2 (BMP-2) in 29 adult patients with high-grade malignant fibrous histiocytoma of soft tissue, using the BMP-2-specific monoclonal antibody, AbH3b2/17, and found that they ranged from 1.9% to 78.9%. The survival at five years of the groups expressing high (> or = 30%) and low (< 30%) levels of BMP-2 was 85.7% and 36.3%, respectively. Multivariable analysis showed that only BMP-2 had prognostic significance for continuous disease-free survival and for overall survival (p < 0.05). Our findings indicate that over-expression of BMP-2 in malignant fibrous histiocytoma of soft tissue is the most reliable prognostic indicator of the parameters assessed.

Adult↗
PubMed2003

Heterogeneous copy numbers of API2-MALT1 chimeric transcripts in mucosa-associated lymphoid tissue lymphoma.

T(11;18)(q21;q21) results in a chimeric transcript between API2 at 11q21 and MALT1 at 18q21 and is a characteristic chromosomal aberration of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). API2-MALT1 chimeric transcripts are present in approximately one-third of all cases of MALT lymphoma. MALT lymphoma is also known to have variations in histological features and tumor cell proportions. Real-time polymerase chain reaction (PCR) was used to examine number of API2-MALT1 copies in clinical samples for further investigation of the pathophysiology of MALT lymphoma. A total of 13 samples of MALT lymphoma contained API2-MALT1 transcripts from 1.7 x 10(-2) to 1.0 copies/beta-actin copy. These findings were compared to the proportions of tumor cells in genomic VDJ PCR products determined by Southern blotting. Tumor cell ratios varied widely among the patients' samples, and no significant correlation was found between transcript copy number and tumor cell ratio. These results suggest that copy numbers of API2-MALT1 do not reflect tumor cell proportions, and that the number of copies of API2-MALT1 in a tumor cell is different for each clinical sample.

Adult↗
PubMed2001

Century of Jackson-Weiss syndrome: further definition of clinical and radiographic findings in "lost" descendants of the original kindred.

Jackson-Weiss syndrome (JWS) is a condition consisting of craniosynostosis characterized by premature fusion of the cranial sutures and/or characteristic radiographic anomalies of the feet. The condition is inherited as an autosomal dominant trait with high penetrance and variable expressivity. Six different mutations in the fibroblast growth factor receptor 2 have been identified in patients with the clinical diagnosis of JWS. Jabs et al. [1994: Nat Genet 8:275-279] identified an Ala344Gly substitution in two branches of the family in which the clinical syndrome was originally described. This is the only publication to document this mutation in a family with the clinical diagnosis of JWS. In this study, we have identified a previously unrecognized branch of the original family with individuals that meet the clinical criteria for the diagnosis of JWS. We demonstrate that a mutation that produces the Ala344Gly substitution is present in affected members. This family illustrates the widely variable expression of the mutation, including a novel phenotype in the proband with a leg-length discrepancy and unilateral absence of the fifth digital ray in her right foot. We identify the clinical and detailed radiographic features of each affected individual and offer considerations when making the diagnosis of JWS.

Acrocephalosyndactylia↗
PubMed2001

Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma.

Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C-->T and MTHFR1298 A-->C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A-->G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospital-based case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. Further studies to confirm the association and detailed biologic mechanisms are now required.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2001

Target genes downregulated by the BCL-6/LAZ3 oncoprotein in mouse Ba/F3 cells.

The BCL-6/LAZ3 gene encodes a zinc-finger transcriptional repressor and is located at the breakpoint of the 3q27-associated translocations that occur most frequently in non-Hodgkin's lymphomas (NHLs). A number of chromosomal translocations involving BCL-6 have been analyzed, but the biological functions of this protein remain obscure. To examine cell responses and target genes related to the BCL-6 signaling pathway, we established Ba/F3 pro-B cells carrying a human BCL-6 transgene that is inducible under control of the lactose operon. Using a cDNA array hybridization technique, we found that the induced BCL-6 protein can downregulate the expressions of the genes, cyclin A2, chemokine receptor CXCR4, and insulin-like growth factor binding protein-4 (IGFBP-4) in the Ba/F3 cells. Northern blot analysis established that the expressions of these genes were indeed downregulated by the induced BCL-6 protein but in a somewhat different manner. The induced BCL-6 protein also inhibited cell proliferation of Ba/F3 cells. These findings strongly suggest that three key genes, namely cyclin A2, CXCR4, and IGFBP-4 may play a role in the downstream of the BCL-6 signaling pathway during B-lymphoid differentiation.

Animals↗
PubMed2001

Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway.

At least two distinct recurrent chromosomal translocations have been implicated in the pathogenesis of MALT lymphoma. The first, t(1;14), results in the transfer of the entire Bcl10 gene to chromosome 14 wherein Bcl10 expression is inappropriately stimulated by the neighboring Ig enhancer. The second, t(11;18), results in the synthesis of a novel fusion protein, API2-MALT1. Until now, no common mechanism of action has been proposed to explain how the products of these seemingly unrelated translocations may contribute to the same malignant process. We show here that Bcl10 and MALT1 form a strong and specific complex within the cell, and that these proteins synergize in the activation of NF-kappaB. The data support a mechanism of action whereby Bcl10 mediates the oligomerization and activation of the MALT1 caspase-like domain. This subsequently activates the IKK complex through an unknown mechanism, setting in motion a cascade of events leading to NF-kappaB induction. Furthermore, the API2-MALT1 fusion protein also strongly activates NF-kappaB and shows dependence upon the same downstream signaling factors. We propose a model whereby both the Bcl10.MALT1 complex and the API2-MALT1 fusion protein activate a common downstream signaling pathway that originates with the oligomerization-dependent activation of the MALT1 caspase-like domain.

Adaptor Proteins, Signal Transducing↗
PubMed2001

GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24).

We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C-terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoint analysis showed potential in vitro topoisomerase-II DNA-binding sites spanning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL-GPHN may have been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks, followed by error-prone DNA repair via non-homologous end joining. Gephyrin was originally identified as a submembraneous scaffold protein that anchors and immobilizes postsynaptic membrane neurotransmitter receptors to underlying cytoskeletal elements. It also is reported to bind to phosphatidylinositol 3,4,5-triphosphate binding proteins involved in actin dynamics and downstream signaling and interacts with ATM-related family member RAFT1. Gephyrin domains in the chimeric protein therefore could contribute novel signal sequences or might modify MLL activity by oligomerization or intracellular redistribution.

Amino Acid Sequence↗
PubMed2001

Detection of cyclin D1 overexpression by real-time reverse-transcriptase-mediated quantitative polymerase chain reaction for the diagnosis of mantle cell lymphoma.

The diagnosis of mantle cell lymphoma (MCL) is particularly important for clinical management because of a remarkable prognostic difference between MCL and other types of B-cell lymphoma. In addition to immunohistochemical analysis, we have established a 5' exonuclease-based real-time reverse transcriptase-mediated quantitative polymerase chain reaction (RQ-PCR) method to detect cyclin D1 overexpression for the diagnosis of MCL. The RQ-PCR could detect cyclin D1 overexpression in all nine examined MCL cases, in contrast genomic PCR detected t(11;14) in only two of nine cases. By RQ-PCR the expression of G6PDH was significantly higher in myeloid leukemias than those in B-cell lymphomas (P = 0.018). As a result, cyclin D1/G6PDH ratio ranged from 0.78 to 12.4 (mean, 1.83) in MCL, exclusively higher than those in other B-cell lymphoma (0.00009 approximately 0.16) and myeloid leukemia (0.00011 approximately 0.085). The high expression of cyclin D1 in certain myeloid leukemias was identified to reflect their proliferative activity and not to represent the oncogenic overexpression. The 95% confidence interval of the cyclin D1/G6PDH ratio was 0.29 approximately 11.1 for MCL, 0.014 approximately 0.25 for other B-cell lymphomas and 0.000014 approximately 0.083 for myeloid leukemia, suggesting that a cutoff value can be set at 0.25. The RQ-PCR of cyclin D1 is convenient and especially useful for the diagnosis of MCL.

Biomarkers, Tumor↗
PubMed2001

API2-MALT1 fusion transcripts involved in mucosa-associated lymphoid tissue lymphoma: multiplex RT-PCR detection using formalin-fixed paraffin-embedded specimens.

Malignant lymphoma of mucosa-associated lymphoid tissue (MALT) type is a distinct clinicopathological disease entity in the category of extranodal marginal zone B-cell lymphoma. Recently, we and others have shown that the API2 gene on chromosome 11 and the MALT1 gene on chromosome 18 are fused as a result of t(11;18)(q21;q21) in MALT lymphomas. Here we report a detection assay that can be used for formalin-fixed, paraffin-embedded specimens. It consists of a multiplex one-tube reverse transcriptase-polymerase chain reaction (RT-PCR) followed by three parallel multiplex nested polymerase chain reactions. Eight variants of the fusion transcripts have been reported to date. When these variants were used as positive controls, all were successfully detected. The subsequent direct sequencing confirmed the results. Using this rapid and simple method, we could detect API2-MALT1 fusion transcripts in 5 of 15 (33%) archival cases of MALT lymphoma for a frequency comparable with those of RT-PCR assays using frozen materials. The lung was the preferential anatomical site of origin of MALT lymphomas harboring API2-MALT1 fusion. No fusion transcript was detected in any of 20 high-grade B-cell lymphomas. Our multiplex RT-PCR assay, which can be used for routinely-processed paraffin samples, should serve as a useful molecular tool for clarifying the clinicopathological significance of API2-MALT1 fusion in MALT lymphoma.

Adult↗
PubMed2001

Spontaneous intracranial hypotension during pregnancy.

BACKGROUND: Spontaneous intracranial hypotension is characterized by postural headache associated with low cerebrospinal fluid pressure. CASE: A 37-year-old Japanese woman, gravida 3, para 2, had sudden onset of severe postural headache at 8 weeks' gestation, accompanied by nausea and vomiting. Results of medical and neurologic examinations were normal, and there was no measurable cerebrospinal fluid pressure on lumbar puncture. Brain magnetic resonance imaging showed diffuse subdural fluid collection and a narrowing of the ambient cistern, confirming the diagnosis of spontaneous intracranial hypotension. After a month of bed rest and intravenous fluid infusion, all symptoms subsided gradually and did not recur. CONCLUSION: Obstetricians should be aware that spontaneous intracranial hypotension can occur in pregnancy.

Adult↗
PubMed2001

Interphase detection of immunoglobulin heavy chain gene translocations with specific oncogene loci in 173 patients with B-cell lymphoma.

To detect immunoglobulin heavy chain (IGH) gene translocations with specific oncogene loci, we established an interphase cytogenetic approach using double-color fluorescence in situ hybridization (DC-FISH), which we used to analyze 173 patients with B-cell lymphoma. DC-FISH using the IGH gene (14q32.3) in combination with c-MYC (8q24.1), BCL1 (11q13.3), BCL2 (18q21.3), BCL6 (3q27), and PAX-5 (9p13) gene probes detected IGH translocations in 70 (40.5%) of 173 patients. The partner genes involved in IGH translocations were identified in 56 (80%) of 70 patients, and fusion of the IGH gene with specific oncogenes was detected in 53 of 56 patients, particularly in interphase nuclei of 28 patients for whom cytogenetic analysis was not informative. The most common partner gene was BCL2 (19 patients; 27% of IGH translocation-positive patients), followed by BCL6 (16; 23%), BCL1 (11; 16%), c-MYC (7; 10%), and PAX-5 (2; 3%). These oncogenes were closely associated with subtypes of B-cell lymphoma. The other partners were 19q13 (BCL3), 6p25 (MUM1/IRF4), 1q36, and chromosome 8 identified in one patient each. Six of the nine patients with add(14)(q32) showed a BCL6/IGH translocation. Double translocations of the IGH gene were found in three patients; c-MYC+BCL1, c-MYC+BCL2, and c-MYC+BCL6 in each one. Interphase FISH using specific IGH-translocation probes is valuable for defining clinically meaningful subgroups of B-cell lymphoma.

Adolescent↗
PubMed2001

Establishment of a follicular lymphoma cell line (FLK-1) dependent on follicular dendritic cell-like cell line HK.

A novel cell line, FLK-1, was established from bone marrow cells of a patient with follicular lymphoma by means of co-culture with follicular dendritic cell (FDC)-like cell line HK. Immunophenotypic analysis showed that FLK-1 expressed CD10, CD19, CD20, CD38, IgG and HLA-DR, which is a typical feature of germinal center B cells. Cytogenetic analysis of FLK-1 demonstrated t(14;18)(q32;q21) translocation involving BCL2 and immunoglobulin heavy chain genes. Especially noteworthy is that the growth of FLK-1 was found to be dependent on a FDC line, HK. When HK cells were removed from the culture, FLK-1 cells stopped growing and eventually died. An apoptotic mechanism appeared to be involved as indicated by the presence of chromosome condensation and DNA ladder formation. The culture experiment using micropore membranes showed that soluble factor(s) of HK cells supported the growth, while direct cell-to-cell contact appeared to be necessary for longterm cell proliferation. These findings suggest the importance of the micro-environment for follicular lymphoma cells to grow. The FLK-1 cell line may thus prove to be useful for studying the growth mechanism of follicular lymphoma and provide new insights into the pathogenesis of follicular lymphoma.

Cell Communication↗
PubMed2001

Detection of AP12-MALT1 chimaeric gene in extranodal and nodal marginal zone B-cell lymphoma by reverse transcription polymerase chain reaction (PCR) and genomic long and accurate PCR analyses.

t(11;18)(q21;q21) has been recognized as a characteristic chromosomal translocation in mucosa-associated lymphoid tissue (MALT)-type lymphoma, and recent studies have demonstrated that this translocation results in the chimaeric transcript of API2 (apoptosis inhibitor 2)-MALT1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1). In this study, we used reverse transcription polymerase chain reaction (RT-PCR) to analyse the incidence of this fusion product in a large series of MALT lymphoma, nodal marginal zone B-cell lymphoma (nMZBCL) and extranodal diffuse large B-cell lymphoma (DLBL) cases. RT-PCR analysis revealed that 17 of the 95 (17.9%) MALT lymphomas but none of the nine nMZBCLs or 16 DLBLs had API2-MALT1 fusion transcripts. The incidence of API2-MALT1 varied among MALT lymphomas arising from different sites and was highest for pulmonary MALT lymphomas (10 out of 16 cases, 62.5%). The presence of the API2-MALT1 fusion gene was also confirmed by long and accurate (LA)-PCR with genomic DNA, and the result correlated well with that obtained with the RT-PCR assay, thus demonstrating the usefulness of LA-PCR for the detection of the API2-MALT1 fusion gene.

Humans↗