研究者詳細 - 大内田　守

論文 - 大内田　守

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SYT, a partner of SYT-SSX oncoprotein in synovial sarcomas, interacts with mSin3A, a component of histone deacetylase complex 国際誌

T Ito, M Ouchida, S Ito, Y Jitsumori, Y Morimoto, T Ozaki, A Kawai, H Inoue, K Shimizu

LABORATORY INVESTIGATION 84 ( 11 ) 1484 - 1490 2004年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Synovial sarcomas are soft-tissue tumors predominantly affecting children and young adults. They are molecular-genetically characterized by the SYT-SSX fusion gene generated from chromosomal translocation t(X; 18) (p11.2; q11.2). When we screened new gene products that interact with SYT or SSX proteins by yeast two-hybrid assay, we found that mSin3A, a component of the histone deacetylase complex, interacts with SYT but not with SSX. These results were confirmed by mammalian two-hybrid and pull-down assays. Analyses with sequential truncated proteins revealed a main mSin3A-interaction region on the SYT amino-terminal 93 amino acids, and another one on the region between 187th amino acid and break point. In luciferase assay, mSin3A repressed the transcriptional activity of reporter promoter mediated by SYT and hBRM/BRG1. Our results suggest that the histone deacetylase complex containing mSin3A may regulate the transcriptional activation mediated by SYT.

DOI： 10.1038/labinvest.3700174

高齢にて発症したQT延長症候群の1例同一家系内で異なる発症様式を示したLQT1の1家系

三浦大志, 中村一文, 久松研一, 森田宏, 森田志保, 永瀬聡, 齋藤博則, 草野研吾, 江森哲郎, 大江透, 大内田守, 清水憲二, 西内崇将, 幡芳樹, 水尾浩三, 大杉保

Therapeutic Research 25 ( 11 ) 2137 - 2141 2004年11月

記述言語：日本語出版者・発行元：ライフサイエンス出版(株)

症例は81歳,男性.生来失神歴はなかった.80歳の時に意識レベルが低下し,CT上脳萎縮,多発性脳梗塞を指摘された.このとき心電図でQT間隔の延長を指摘された(QTc=0.54).その後も誤嚥性肺炎を繰り返し近医に入退院を繰り返していた.81歳の時,肺炎で入院中に失神発作をきたし,著明なQT間隔の延長(QTc=0.64),Torsades de Pointes(TdP)を認めた.発作の誘因としては低カリウム血症が増悪因子となったと考えられ,電解質補正で心室性不整脈は再発を認めていない.孫(12歳,男性)にKCNQ1遺伝子の変異(V254M)によるQT延長症候群患者がおり,遺伝子検査にて同じ変異が認められた.本症例は高齢になるまでTdPや失神を発症せず,LQT1(V254M)の同一家系内でも,発症には電解質や自律神経など後天的な因子も大きく関与していると考えられた(著者抄録)

Tumor-specific exon creation of the HELLS/SMARCA6 gene in non-small cell lung cancer 国際誌

M Yano, M Ouchida, H Shigematsu, N Tanaka, K Ichimura, K Kobayashi, Y Inaki, S Toyooka, K Tsukuda, N Shimizu, K Shimizu

INTERNATIONAL JOURNAL OF CANCER 112 ( 1 ) 8 - 13 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-LISS

To identify tumor-suppressor genes on chromosome 10 in non-small cell lung cancers, we isolated 10 types of splicing variant of the HELLS/SMARCA6 gene transcripts. HELLS/SMARCA6 is a novel member of SNF2 family, which is implicated in cellular functions like chromatin remodeling. Variant I was an alternatively spliced isoform containing an insertion of a 44 ntd intronic sequence between exons 3 and 4, giving rise to a premature termination of translation. Expression of variant I was detected exclusively in lung cancer specimens (I I of 43 cases, 26%) but was not detected in corresponding normal tissues. The D10S520 marker in the proximity of the HELLS/SMARCA6 gene showed prevalent allelic loss (41%) compared to flanking markers (25-31%). These results suggest that loss of function of HELLS/SMARCA6 by allelic loss and aberrant proteins by tumor-specific exon creation may result in epigenetic deregulation, leading lung cells to malignancy or its progression. (C) 2004 Wiley-Liss, Inc.

DOI： 10.1002/ijc.20407

Severity dependent up-regulations of LOX-1 and MCP-1 in early sclerotic changes of common carotid arteries in spontaneously hypertensive rats

Y Hamakawa, N Omori, M Ouchida, M Nagase, K Sato, Nagano, I, M Shoji, T Fujita, K Abe

NEUROLOGICAL RESEARCH 26 ( 7 ) 767 - 773 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MANEY PUBLISHING

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) and monocyte chemoattractant protein- I (MCP-1) are molecules involving in the initiation and progression of atherosclerosis. In order to examine a possible difference in LOX-1 and MCP-1 expressions depending on the severity of early stage of atherosclerosis, we investigated atherosclerotic changes by exposure to hypertension and hyperlipidemia in common carotid arteries (CCAs) of stroke-prone spontaneously hypertensive rat (SHR-SP). Three rat model groups such as control [Wistar Kyoto rat (WKY) group], hypertension (SHR-SP group) and hypertension + hyperlipidemia [SHR-SP+high fat and cholesterol (HFC) group] were used. Body weights, brain weights, systolic blood pressures and serum levels of total cholesterol, low-density lipoprotein and triglyceride were measured at 0, 5, 10 and 15 days after appropriate diet. Immunohistochemistry showed that the positive area and the strength of LOX-1 and MCP-1 were larger in the SHR-SP+ HFC group than in the SHR-SP group, while no immunoreactivities were found in the WKY group. Conventional RT-PCR and real-time PCR analyses showed that mRNAs of those in the SHR-SP group were higher with greater up-regulation in the SHR-SP+ HFC group. LOX-1 and MCP-1 expressions were coordinately up-regulated at mRNA and protein levels in an early stage of sclerosis depending on the severity of atherosclerotic stress. Activations of LOX-1 and MCP-1 are collectively involved in the early stage of atherosclerosis.

DOI： 10.1179/016164104225016074

Loss of heterozygosity on chromosome 10q associated with malignancy and prognosis in astrocytic tumors, and discovery of novel loss regions 国際誌

S Daido, S Takao, T Tamiya, Y Ono, K Terada, S Ito, M Ouchida, Date, I, T Ohmoto, K Shimizu

ONCOLOGY REPORTS 12 ( 4 ) 789 - 795 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PROFESSOR D A SPANDIDOS

Certain tumor suppressor genes (TSG) residing on human chromosome 10q are implicated in astrocytic tumors. We thoroughly examined loss of heterozygosity (LOH) on chromosome 10q in astrocytic tumors to determine the extent of deletion and their relation to prognostic variables of patients. We analyzed 63 astrocytic tumors, including 9 diffuse astrocytomas, 36 anaplastic astrocytomas, and 18 glioblastomas. DNAs from tumors and leukocytes were analyzed for LOH at 18 microsatellite loci by polymerase chain reaction using fluorescence-labeled primers. Then correlation between LOH and clinicopathological variables was examined statistically. Twenty-four (66.7%) anaplastic astrocytomas and 15 (83.3%) glioblastomas had at least one LOH on chromosome 10q. However, diffuse astrocytomas exhibited no LOH. Nineteen tumors (10 anaplastic astrocytomas and 9 glioblastomas) were believed to have a total loss of one chromosome 10. Analyses on 20 tumors with interstitial LOH revealed that most of the high LOH regions matched the location of known TSGs, while some novel LOH regions were found preferentially in anaplastic astrocytoma. The median survivals of the total, partial, and no loss groups were 10.1, 14.8, and 46.8 months, respectively, indicating a significant difference in the survivals of these groups (P=0.0289). Thus, analyzing chromosome 10q loss is helpful for diagnosing malignancy in astrocytic tumors and for predicting patients' survival. Our data also suggested that there are novel TSGs for anaplastic astrocytoma at 10q24 and 10q26.

Prevalent hyper-methylation of the CDH13 gene promoter in malignant B cell lymphomas 国際誌

Y Ogama, M Ouchida, T Yoshino, S Ito, H Takimoto, Y Shiote, F Ishimaru, M Harada, M Tanimoto, K Shimizu

INTERNATIONAL JOURNAL OF ONCOLOGY 25 ( 3 ) 685 - 691 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PROFESSOR D A SPANDIDOS

CDH13 (H-cadherin) is a member of the cadherin superfamily, which plays an important role in cell recognition and adhesion. We examined the expression and methylation status of the CDH13 gene in diffuse large B cell lymphomas (B-DLCLs). We found decreased expression of the CDH13 gene in all of 6 hematopoietic cell lines by reverse transcription-polymerase chain reaction (RT-PCR). Promoter hypermethylation of the gene was detected in all 6 cell lines and in 13 of 19 (68%) B-DLCL samples by methylation-specific PCR. Interestingly, the methylation frequency of the CDH13 gene was comparable to those of the tumor suppressor genes p15 (68%) and p16 (74%) detected in B-DLCLs. Sequencing of bisulfite-treated DNA revealed hyper-methylation of the CpG islands of the CDH13 promoter in B-DLCLs and the cell lines. Treatment with 5-aza-2'-deoxycytidine restored CDH13 gene expression in a cell line in which promoter hyper-methylation and impaired expression of the CDH13 gene were observed. Loss of heterozygosity (LOH) around the CDH13 genes on chromosome 16q24 was detected in 6 of 15 (40%) informative cases with microsatellite marker D16S507 and in 6 of 15 (40%) cases with D16S422 in B-DLCLs. In all of 4 B-DLCL cases which showed both promoter methylation and LOH at the two marker loci, expression of the CDH13 gene was significantly low. These results suggest that silencing of the CDH13 gene by aberrant promoter methylation and allelic deletion is associated with tumorigenesis in a subset of B-DLCL.

Positive correlation between allelic loss at chromosome 14q24-31 and poor prognosis of patients with renal cell carcinoma 国際誌

H Kaku, S Ito, S Ebara, M Ouchida, Y Nasu, T Tsushima, H Kumon, K Shimizu

UROLOGY 64 ( 1 ) 176 - 181 2004年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Objectives. To report our development of a new application of the inter-AN long polymerase chain reaction (PCR) for genomic scanning to screen for tumor-specific alterations in tumor DNA. Using this method, we detected a rearranged chromosomal region in renal cell carcinomas (RCCs). We then examined tumor-specific allelic loss in this region using microsatellite markers and determined whether a relationship was present between this allelic loss and the clinicopathologic features of the patients.
Methods. The inter-Alu long PCR genomic scan method was performed using RCC DNA samples and primers specific for a minor subset of the human repeat sequence Alu. We analyzed DNA samples from 42 pairs of matched normal and nonpapillary RCC tissues with seven microsatellite markers.
Results. The inter-Alu long PCR genomic scan method revealed an altered DNA region on chromosome 14q24-31, which is the location of several putative tumor suppressor genes. At least one of seven microsatellite markers on chromosome 14q24-31 showed loss of heterozygosity in 23 (54.8%) of 42 informative cases of RCC. The prevalent loss region was confined to a 2-Mb region around D14S67. We found a positive correlation between the presence of the loss of heterozygosity on 14q24-31 and tumor stage (P < 0.05). We also found that cases with allelic loss at 14q24-31 had a poor prognosis (P = 0.045).
Conclusions. Our inter-Alu long PCR genomic scan method is a powerful method for the screening of DNA alterations, and our data suggest that the chromosome 14q24-31 region contains likely tumor suppressor genes associated with the progression of RCC. (C) 2004 Elsevier Inc.

DOI： 10.1016/j.urology.2004.03.015

Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer 国際誌

H Dote, S Toyooka, K Tsukuda, M Yano, M Ouchida, H Doihara, M Suzuki, H Chen, JT Hsieh, AF Gazdar, N Shimizu

CLINICAL CANCER RESEARCH 10 ( 6 ) 2082 - 2089 2004年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC CANCER RESEARCH

Purpose: Human DOC-2/DAB2 interactive protein (hDAB21P) gene is a novel member of the Ras GTPaseactivating family and has been demonstrated to be a tumor suppressor gene inactivated by methylation in prostate cancer. We analyzed methylation and expression status of hDAB21P in breast cancer.
Experimental Design: The promoter region of hDAB21P was divided into two regions (m2a and m2b) following our previous report on prostate cancer, and methylation status was determined in breast cancer cell lines with bisulfited DNA sequencing. Expression was semiquantified with real-time reverse transcription-PCR to rind that aberrant methylation showed the inverse relationship with expression. On the basis of sequence data, we developed methylation-specific PCR for m2a and m2b regions and applied to samples.
Results: Aberrant methylation was detected in 11 of 25 breast cancer cell lines (44%) and 15 of 39 primary tumors (38%) at the m2a region and in 12 of 25 cell lines (48%) and 13 of 39 tumors (33%) at the m2b region. In addition, gene expression was restored in methylated cell lines with 5-aza2'-deoxycytidine, confirming that methylation caused gene down-regulation. We also examined the relationship between hDAB21P methylation and clinicopathologic features in primary tumors and found that methylation in the m2b region was associated with progressive nodal status of tumors.
Conclusions: We developed methylation-specific PCR for hDAB21P and examined its methylation status in breast cancer. Our results demonstrate that hDAB2IP methylation frequently is present in breast cancer and plays a key role in hDAB21P inactivation, suggesting the relationship between hDAB2IP methylation and lymph node metastasis of breast cancer.

DOI： 10.1158/1078-0432.CCR-03-0236

Establishment and characterization of a biphasic synovial sarcoma cell line, SYO-1 国際誌

A Kawai, N Naito, A Yoshida, Y Morimoto, M Ouchida, K Shimizu, Y Beppu

CANCER LETTERS 204 ( 1 ) 105 - 113 2004年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

We describe here the establishment of a new synovial sarcoma cell line, SYO-1, derived from a biphasic synovial sarcoma that developed in the groin of a 19-year-old female. The cell line was maintained for more than 70 passages (more than 24 months) in vitro. The SYO-1 cells in monolayer culture exhibited a spindle shape without conspicuous pleomorphism. Immunohistochemically, the cells were positive for vimentin, type IV collagen, S-100, mdm2, bcl-2, c-Met and c-Kit. Tumors developed by their implantation in nude mice histologically showed biphasic features that were composed of areas of fascicles of spindle cells and areas of compact proliferation of polygonal to ovoid cells, which occasionally formed epithelial plaque and expressed cytokeratin and EMA. SYO-1 cells harbored the characteristic t(X;18)(p11.2;q11.2) translocation by chromosome analysis and SYT-SSX2 chimeric transcript by RT-PCR. The SYO-1 cells, the first characterized cell line derived from biphasic synovial sarcoma retaining the characteristic genetic and phenotypic features of the tumor, will be useful for various investigations on synovial sarcoma, especially for its epithelial differentiation. (C) 2003 Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.canlet.2003.09.031

高齢にて発症したQT延長症候群の一例

三浦大志, 中村一文, 久松研一, 森田宏, 森田志保, 永瀬聡, 齋藤博則, 草野研吾, 江森哲朗, 大江透, 大内田守, 清水憲二, 西内崇将, 幡芳樹, 水尾浩三, 大杉保

Therapeutic Research 68 ( Suppl.III ) 946 - 946 2004年

Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation 国際誌

M Koyama, T Oka, M Ouchida, Y Nakatani, R Nishiuchi, T Yoshino, K Hayashi, T Akagi, Y Seino

LABORATORY INVESTIGATION 83 ( 12 ) 1849 - 1858 2003年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Previously we showed reduced protein and mRNA expression of the SHP1 gene in lymphoma/leukemia cell lines and patient specimens by Northern blot, RT-PCR, Western blot, and immunohistochemical analyses. In this study, aberrant methylation in the SHP1 gene promoter was detected in many B-cell leukemia/lymphoma cell lines as well as in patient specimens, including diffuse large B-cell lymphoma (methylation frequency 93%), MALT lymphoma (82%), mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%) by methylation-specific PCR, bisulfite sequencing, and restriction enzyme-mediated PCR analyses. The methylation frequency was significantly higher in high-grade MALT lymphoma cases (100%) than in low-grade MALT lymphoma cases (70%), which correlated well with the frequency of no expression of SHP1 protein in high-grade (80%) and low-grade MALT lymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpG methylation relates to the lymphoma progression. SHP1 protein expression was recovered in B-cell lines after the treatment of the demethylating reagent: 5-aza-2'-deoxycytidine. Transfection of the intact SHP1 gene to the hematopoietic cultured cells, which show no expression of the SHP1 gene, induced growth inhibition, indicating that gene silencing of the SHP1 gene by aberrant methylation plays an important role to get the growth advantage of the malignant lymphoma/leukemia cells. The extraordinarily high frequency (75 to 100%) of CpG methylation of the SHP1 gene in B-cell lymphoma/leukemia patient specimens indicates that the SHP1 gene silencing is one of the critical events to the onset of malignant lymphomas/leukemias as well as important implications for the diagnostic or prognostic markers and the target of gene therapy. These data support the possibility that the SHP1 gene is one of the tumor suppressor genes.

DOI： 10.1097/01.LAB.0000106503.65258.2B

Frequent deletion and increased mRNA expression of a candidate tumor suppressor gene at 19p13 region, BRG1, in oral cancers(2nd ASIAN SCIENCE SEMINAR IN OKAYAMA 2003)

Gunduz Esra, Gunduz Mehmet, Nagatsuka Hitoshi, Tsujigiwa Hidetsugu, Ouchida Mamoru, Shinnou Yasuo, Cengiz Beyhan, Shimizu Kenji, Nagai Noriyuki

Journal of hard tissue biology 12 ( 2 ) 73 - 73 2003年12月

Single nucleotide polymorphism in fibroblast growth factor receptor 4 at codon 388 is associated with prognosis in high-grade soft tissue sarcoma 国際誌

Y Morimoto, T Ozaki, M Ouchida, N Umehara, N Ohata, A Yoshida, K Shimizu, H Inoue

CANCER 98 ( 10 ) 2245 - 2250 2003年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS INC

BACKGROUND. A recent study revealed that single nucleotide polymorphism (SNP) at codon 388 (Gly or Arg) of fibroblast growth factor receptor 4 (FGFR4) was associated with prognosis in patients with carcinoma of the breast and colorectal carcinoma. The purpose of the current study was to investigate the correlation between codon 388 SNIP and clinical prognosis in patients with sarcoma of the bone and soft tissues.
METHODS. Tumor samples were obtained from 143 patients with high-grade bone and soft tissue sarcomas at Okayama University Hospital between 1986-2002, and from 102 healthy volunteers. SNP of codon 388 was detected by sequencing and fragment length of polymerase chain reaction products digested by restriction enzyme. The chi-square test was used to compare genotype distribution and the Kaplan-Meier method was used for survival analysis. 2
RESULTS. With regard to FGFR4 genotypes in the 143 patients studied, 54 (37.8%) were Gly/Gly, 72 (50.3%) were Gly/Arg, and 17 (11.9%) were Arg/Arg, findings that were not significantly different from those of controls (P = 0.97). With regard to cumulative overall and metastasis-free survival, patients with the Gly/Gly genotype were found to have a better prognosis (P = 0.085 and P = 0.27, respectively). FGFR4 SNIP was found to be correlated significantly with overall and metastasis-free survival in patients with soft tissue sarcomas (P = 0.029 and P = 0.045, respectively), but not in those patients with bone sarcomas (P = 0.88 and P = 0.75, respectively).
CONCLUSIONS. In the current study, the authors found a significant correlation between FGFR4 SNP and prognosis in patients with soft tissue sarcoma, although the samples were comprised of various histologic types. This SNP might be used to improve the prediction of clinical prognosis and lead to new treatment strategies in patients with soft tissue sarcomas. (C) 2003 American Cancer Society.

DOI： 10.1002/cncr.11778

現代医学の焦点(254)広範な悪性リンパ腫・白血病発症に関連するSHP1遺伝子に関する最新知見

岡剛史, 大内田守

日本臨床 61 ( 11 ) 2025 - 2032 2003年11月

[Recent progress in the protein-tyrosine phosphatase SHP1 gene: the significant correlation of the SHP1 gene silencing with the onset of lymphomas/leukemias].

Takashi Oka, Mamoru Ouchida

Nihon rinsho. Japanese journal of clinical medicine 61 ( 11 ) 2025 - 32 2003年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Using cDNA expression array and tissue microarray, we comprehensively and systematically analyzed the expression profile to investigate the lymphomagenesis. We detected the significant decrease of hematopoietic cell specific protein-tyrosine phosphatase SHP1 gene expression in various malignant lymphomas and leukemias. High-frequent silencing of the SHP1 gene by promoter methylation was detected in various kinds of leukemias and lymphomas as well as in many hematopoietic cell lines. The promoter methylation of the SHP1 gene was significantly correlated with the clinical stage. Loss of heterozygosity with microsatellite markers around the SHP1 gene was detected in 79% of informative ALL cases. These results suggest that loss of functional SHP1 is closely associated with the pathogenesis of leukemias/lymphomas.

Is phenotype difference in severe myoclonic epilepsy in infancy related to SCN1A mutations? 国際誌

Ohmori, I, Y Ohtsukaa, M Ouchida, T Ogino, S Maniwa, K Shimizu, E Oka

BRAIN & DEVELOPMENT 25 ( 7 ) 488 - 493 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

We classified 28 patients with severe myoclonic epilepsy in infancy (SME) according to the presence or absence of myoclonic seizures and/or atypical absences. Eleven of the patients had myoclonic seizures and/or atypical absences, and we refer to this condition as 'typical SME (TSME)'. Seventeen of the patients had only segmental myoclonias, and we refer to this condition as 'borderline SME (BSME)'. We then analyzed the electroclinical and genetic characteristics of these two groups. Ten of the 11 TSME patients had a photoparoxysmal response at some time during their clinical course, while none of the BSME patients showed this response. TSME and BSME showed a significant difference in regard to gender ratio: female dominance in TSME and male dominance in BSME (P = 0.008). The detection rate of the voltage-gated sodium channel alpha1-subunit (SCN1A) gene mutations was 72.7 and 88.2% in TSME and BSME, respectively. There was no difference in the type or rate of mutation between TSME and BSME. We conclude that TSME and BSME show distinct differences in photoparoxysmal response and gender, which might be caused by some genetic mechanism(s) other than the SCN1A gene mutation. (C) 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0387-7604(03)00038-X

Paroxysmal movement disorders in severe myoclonic epilepsy in infancy 国際誌

Y Ohtsuka, Ohmori, I, T Ogino, M Ouchida, K Shimizu, E Oka

BRAIN & DEVELOPMENT 25 ( 6 ) 401 - 405 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

We report on the electroclinical findings and the results of a molecular genetic study of a patient with typical severe myoclonic epilepsy ill infancy (TSME) and three with borderline SME (BSME) who showed paroxysmal movement disorders, such as choreoathetosis, dystonia and ballismus, during their clinical course. BSME was defined as a clinical entity that shares common characteristics with TSME but lacks myoclonic seizures associated with ictal EEG changes. When the paroxysmal movement disorders were first observed, all the patients in this study were being treated with polytherapy including phenytoin (PHT), and these abnormal movements disappeared when PHT was discontinued or reduced. However, on other occasions, two of our cases also showed the same abnormal movements even when not being treated with PHT. One patient with TSME and two of the three patients with BSME had SCN1A gene mutations that lead to truncation of the associated protein. We conclude that paroxysmal movement disorders seen in SME patients were closely related to their AED therapy, especially the use of PHT. It is thought that patients with both TSME and BSME have some predisposition toward paroxysmal movement disorders, and that this predisposition is partly related to sodium channel dysfunction, although some other factors might influence the occurrence of this phenomenon. (C) 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0387-7604(03)00025-1

Detection of codon 61 point mutations of the K-ras gene in lung and colorectal cancers by enriched PCR

S Toyooka, K Tsukuda, M Ouchida, M Tanino, Y Inaki, K Kobayashi, M Yano, J Soh, T Kobatake, N Shimizu, K Shimizu

ONCOLOGY REPORTS 10 ( 5 ) 1455 - 1459 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PROFESSOR D A SPANDIDOS

Mutation of the Kirsten ras (K-ras) gene is one of most common alterations in solid tumors including lung and colorectal cancers. We developed new enriched PCR-RFLP assay to detect mutations of K-ras codon 61 at the 1st and 2nd letters and non-enriched PCR-RFLP assay to detect the 3rd letter mutation. One mutant allele among 103 wild-type alleles was detected by enriched PCR-RFLP assay, while one mutant in 10 wild-type alleles was detected by non-enriched PCR-RFLP assay for codon 61 3rd letter. We then examined K-ras codon 12, 13 and 61 mutations in lung and colorectal cancers using these assays. K-ras codon 12 mutation was detected in 10 of 109 (9%) lung cancer and 19 of 83 (23%) colorectal cancer cases: K-ras codon 13 mutation was detected in 2 of 83 (2%) colorectal and 0 of 109 NSCLC cases, respectively. There was no K-ras codon 61 mutation in either type of cancer. Our results demonstrate that enriched PCR-RFLP is a sensitive assay to detect K-ras codon 61 mutation, however, it was extremely rare in lung and colorectal cancers, suggesting organ-specific pathways in mutagenesis of the ras gene family.

Splicing isoform of SYT-SSX fusion protein accelerates transcriptional activity and cell proliferation 国際誌

Y Morimoto, M Ouchida, T Ozaki, A Kawai, T Ito, A Yoshida, H Inoue, K Shimizu

CANCER LETTERS 199 ( 1 ) 35 - 43 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

The human SYT-SSX gene has two splicing isoforms (type N and 1), the latter of which contains an additional insertion of 93 bases. In the present study, we found increased transcriptional activity of the SYT-SSX type I protein in luciferase assay. When the SYT-SSX cDNAs were transfected to NIH3T3 cells, the type I transformant grew faster than the type N transformant. Furthermore, we evaluated the isoform ratio of the SYT or SYT-SSX transcripts in various tissues. Our results suggest that the SYT-SSX type I protein plays a critical role in the tumorigenesis of synovial sarcomas through increased transcriptional activity. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3835(03)00314-8

Genome-wide analyses on loss of heterozygosity in head and neck squamous cell carcinomas 国際誌

LB Beder, M Gunduz, M Ouchida, K Fukushima, E Gunduz, S Ito, A Sakai, N Nagai, K Nishizaki, K Shimizu

LABORATORY INVESTIGATION 83 ( 1 ) 99 - 105 2003年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor survival rate. Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. We therefore performed comprehensive analyses on loss of heterozygosity (LOH) using a genome-wide panel of 191 microsatellite markers in 22 HNSCC samples. We found 53 markers with significantly high LOH (>30%) on 21 chromosomal arms; the highest values of those were observed on 3p, 9p, 13q, 15q, and 17p, corresponding to D3S2432 (67%), D9S921-D9S925 (67%) and GATA62F03 (86%), D13S1493 (60%), D15S211 (62%), and D17S1353 (88%), respectively. Fifteen hot spots of LOH were defined in 13 chromosomal arms: 2q22-23, 4p15.2, 4q24-25, 5q31, Sp23, 9p23-24, 9q31.3, 9q34.2, 10q21, 11q21-22.3, 14q11-13, 14q22.3, 17p13, 18q11, and 19q12 as loci reported previously in HNSCCs. Furthermore, we identified five novel hot spots of LOH on three chromosomal arms in HNSCC at 2q33 (D2S1384), 2q37 (D2S125), 8q12-13 (D8S1136), 8q24 (D8S1128), and 15q21 (D15S211). In conclusion, our comprehensive allelotype analyses have unveiled and confirmed a total of 20 possible TSG loci that could be involved in the development of HNSCC. These results provide useful clues for identification of putative TSGs involved in HNSCC by fine mapping of the suspected regions and subsequent analysis for functional genes.

DOI： 10.1097/01.LAB.0000047489.26246.E1

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