論文 - 西原　広史

中枢神経系原発びまん性大細胞型B細胞性リンパ腫におけるDNAメチル化に関する解析

畑中佳奈子, 畑中豊, 小林浩之, 菅野宏美, 西原広史, 田中伸哉, 三橋智子, 松野吉宏

日本病理学会会誌 103 （ 1 ） 211 2014年03月

共著,  ISSN  0300-9181

C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma

Kawamata F., Homma S., Kamachi H., Einama T., Kato Y., Tsuda M., Tanaka S., Maeda M., Kajino K., Hino O., Takahashi N., Kamiyama T., Nishihara H., Taketomi A., Todo S.

Journal of Gastroenterology （Journal of Gastroenterology）  49 （ 1 ） 81 - 92 2014年01月

研究論文（学術雑誌）, 共著,  ISSN  09441174

　概要を見る

Background: Lymph node metastasis is a key event of colorectal cancer (CRC) progression. Mesothelin is expressed in various types of malignant tumor and associated with an unfavorable prognosis. The full-length mesothelin (Full-ERC) is cleaved by protease into membrane-bound C-ERC/mesothelin and N-ERC/mesothelin which is secreted into the blood. The aim of this study was to examine the biological role of mesothelin in CRC by clinicopathological analysis and in vitro lymphatic invasion assay. Methods: Ninety-one cases of CRC specimens were immunohistochemically examined and the localization of mesothelin in luminal membrane and/or cytoplasm was also evaluated. Lymphatic invasion assay was also performed using the human CRC cell line, WiDr, which was transfected with Full-, N- and C-ERC/mesothelin expression plasmids (Full-WiDr, N-WiDr and C-WiDr). Results: Immunohistochemically, "luminal membrane positive" of mesothelin was identified in 37.4 %, and correlated with lymphatic permeation and lymph node metastasis, but not with patients' prognosis. Interestingly, among the patients with lymph node metastasis (N = 38), "luminal membrane positive" of mesothelin significantly correlated with unfavorable patients' outcome. In addition, lymphatic invasion assay revealed that Full-WiDr and C-WiDr more significantly invaded human lymphatic endothelial cells than the Mock-WiDr (P < 0.01). Conclusion: The luminal membrane expression of mesothelin was associated with unfavorable prognosis of CRC patients with lymph node metastasis. Moreover, this is the first report to prove the biological function of C-ERC/mesothelin associated with lymphatic invasion of cancer in vitro. © 2013 Springer Japan.

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Clinicopathological evaluation of cyclooxygenase-2 expression in meningioma: Immunohistochemical analysis of 76 cases of low and high-grade meningioma

Kato Y., Nishihara H., Mohri H., Kanno H., Kobayashi H., Kimura T., Tanino M., Terasaka S., Tanaka S.

Brain Tumor Pathology （Brain Tumor Pathology）  31 （ 1 ） 23 - 30 2014年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14337398

　概要を見る

Tumorigenic activity of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the production of prostaglandins (PGs), has been proved for some types of cancer, including brain tumors. We evaluated expression of COX-2 in meningioma, one of the most common intracranial tumors in adults which accounts for 24-30% of intracranial tumors. We performed immunostaining for COX-2 in 76 cases of meningioma consisting of 44 cases of low-grade (WHO Grade I) and 32 cases of high-grade (29 cases of Grade II and 3 cases of Grade III) meningioma, and evaluated COX-2 expression levels on the basis of staining intensity and proportion in tumor cells. The expression level of COX-2 in meningioma cells was significantly correlated with WHO grade ( P = 0.0153). In addition, COX-2 expression was significantly correlated with MIB-1 labeling index for all 76 cases of meningioma (P = 0.0075), suggesting tumor promotion by COX-2 in meningioma progression. Our results may indicate the therapeutic value of non-steroidal anti-inflammatory drugs against meningioma, especially for patients with elevated proliferation, to regulate the tumorigenic activity of COX-2 in meningioma cells. © The Japan Society of Brain Tumor Pathology 2012.

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Autophagy in the placenta of women with hypertensive disorders in pregnancy

Akaishi R., Yamada T., Nakabayashi K., Nishihara H., Furuta I., Kojima T., Morikawa M., Fujita N., Minakami H.

Placenta （Placenta）  35 （ 12 ） 974 - 980 2014年

研究論文（学術雑誌）, 共著,  ISSN  01434004

　概要を見る

Copyright © 2014 Elsevier Ltd. All rights reserved. Introduction: Autophagy has not been studied extensively in the human placenta. This study was performed to determine whether autophagy is increased in the placentas of women with hypertensive disorders in pregnancy compared to normotensive pregnancies. Methods: LC3-II and p62 protein expression were examined by quantitative Western blotting analysis in 40 placentas from women not experiencing labor pains. The 40 placentas were from 13, 8, and 19 women with preeclampsia, gestational hypertension, and normal pregnancy, respectively. Hypertensive disorders in pregnancy included preeclampsia and gestational hypertension. Results: LC3-II expression was significantly increased, while that of p62 was significantly reduced in 21 placentas of women with hypertensive disorders compared to those with normal blood pressure irrespective of the presence or absence of fetal growth restriction (FGR). LC3-II expression was also significantly increased in 13 placentas of women with preeclampsia irrespective of the presence or absence of FGR. Discussion: The results of this study suggested that autophagy is active in the placenta of hypertensive disorders even in the absence of FGR.

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Rapid immunohistochemistry based on alternating current electric field for intraoperative diagnosis of brain tumors

Tanino M., Sasajima T., Nanjo H., Akesaka S., Kagaya M., Kimura T., Ishida Y., Oda M., Takahashi M., Sugawara T., Yoshioka T., Nishihara H., Akagami Y., Goto A., Minamiya Y., Tanaka S.

Brain Tumor Pathology （Brain Tumor Pathology）  32 （ 1 ） 12 - 19 2014年

研究論文（学術雑誌）, 共著,  ISSN  14337398

　概要を見る

© 2014, The Japan Society of Brain Tumor Pathology. Rapid immunohistochemistry (R-IHC) can contribute to the intraoperative diagnosis of central nervous system (CNS) tumors. We have recently developed a new IHC method based on an alternating current electric field to facilitate the antigen–antibody reaction. To ensure the requirement of R-IHC for intraoperative diagnosis, 183 cases of CNS tumors were reviewed regarding the accuracy rate of diagnosis without R-IHC. The diagnostic accuracy was 90.7 % (168/183 cases) in which definitive diagnoses were not provided in 17 cases because of the failure of glioma grading and differential diagnosis of lymphoma and glioma. To establish the clinicopathological application, R-IHC for frozen specimens was compared with standard IHC for permanent specimens. 33 gliomas were analyzed, and the Ki-67/MIB-1 indices of frozen specimens by R-IHC were consistent with the grade and statistically correlated with those of permanent specimens. Thus, R-IHC provided supportive information to determine the grade of glioma. For discrimination between glioma and lymphoma, R-IHC was able to provide clear results of CD20 and Ki-67/MIB-1 in four frozen specimens of CNS lymphoma as well as standard IHC. We conclude that the R-IHC for frozen specimens can provide important information for intraoperative diagnosis of CNS tumors.

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Rectal obstruction due to endometriosis: A case report and review of the Japanese literature

Ono H., Honda S., Danjo Y., Nakamura K., Okabe M., Kimura T., Kawakami M., Nagashima K., Nishihara H.

International Journal of Surgery Case Reports （International Journal of Surgery Case Reports）  5 （ 11 ） 845 - 848 2014年

研究論文（学術雑誌）, 共著,  ISSN  22102612

　概要を見る

© 2014 The Authors. Published by Elsevier Ltd. INTRODUCTION Colorectal obstructive endometriosis is relatively rare in Japan and its differentiation from malignancy is often difficult. We report a case of rectal obstructive endometriosis. PRESENTATION OF CASE A 37-year-old woman was referred to our hospital with a suspected ileus. Her chief symptoms were left lower abdominal pain and vomiting. Colonoscopy showed an intraluminal mass of redness in the upper rectum. A proctectomy was performed because of the bowel obstruction. The rectum was filled with an intraluminal mass measuring 5 cm × 4 cm, and endometriosis was diagnosed pathologically. DISCUSSION A preoperative diagnosis of colorectal obstructive endometriosis is often difficult because of the lack of definite diagnostic, clinical, sonographic, or radiological findings that are characteristic of this disease. Medical treatment is not always effective for colorectal obstructive endometriosis, and surgery is often performed. CONCLUSION Colorectal obstructive endometriosis should be considered as a differential diagnosis in cases of various gastrointestinal symptoms in women who are of reproductive age.

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Erratum to: Rapid immunohistochemistry based on alternating current electric field for intraoperative diagnosis of brain tumors [Brain Tumor Pathol, (2014), DOI:10.1007/s10014-014-0188-y]

Mishie Tanino, Toshio Sasajima, Hiroshi Nanjo, Shiori Akesaka, Masami Kagaya, Taichi Kimura, Yusuke Ishida, Masaya Oda, Masataka Takahashi, Taku Sugawara, Toshiaki Yoshioka, Hiroshi Nishihara, Yoichi Akagami, Akiteru Goto, Yoshihiro Minamiya, Shinya Tanaka

Brain Tumor Pathology （Springer-Verlag Tokyo）  32 （ 1 ） 20 - 21 2014年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1861-387X

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Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors

Nanjo S., Yamada T., Nishihara H., Takeuchi S., Sano T., Nakagawa T., Ishikawa D., Zhao L., Ebi H., Yasumoto K., Matsumoto K., Yano S.

PLoS ONE （PLoS ONE）  8 （ 12 ） e84700 2013年12月

共著

　概要を見る

Purpose: Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. Experimental Design: Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. Results: The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFRT790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. Conclusions: Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically. © 2013 Nanjo et al.

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NS1-binding protein abrogates the elevation of cell viability by the influenza A virus NS1 protein in association with CRKL

Miyazaki M., Nishihara H., Hasegawa H., Tashiro M., Wang L., Kimura T., Tanino M., Tsuda M., Tanaka S.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications）  441 （ 4 ） 953 - 957 2013年11月

研究論文（学術雑誌）, 共著,  ISSN  0006291X

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The influenza A virus non-structural protein 1 (NS1) is a multifunctional virulence factor consisting of an RNA binding domain and several Src-homology (SH) 2 and SH3 binding motifs, which promotes virus replication in the host cell and helps to evade antiviral immunity. NS1 modulates general host cell physiology in association with various cellular molecules including NS1-binding protein (NS1-BP) and signaling adapter protein CRK-like (CRKL), while the physiological role of NS1-BP during influenza A virus infection especially in association with NS1 remains unclear. In this study, we analyzed the intracellular association of NS1-BP, NS1 and CRKL to elucidate the physiological roles of these molecules in the host cell. In HEK293T cells, enforced expression of NS1 of A/Beijing (H1N1) and A/Indonesia (H5N1) significantly induced excessive phosphorylation of ERK and elevated cell viability, while the over-expression of NS1-BP and the abrogation of CRKL using siRNA abolished such survival effect of NS1. The pull-down assay using GST-fusion CRKL revealed the formation of intracellular complexes of NS1-BP, NS1 and CRKL. In addition, we identified that the N-terminus SH3 domain of CRKL was essential for binding to NS1-BP using GST-fusion CRKL-truncate mutants. This is the first report to elucidate the novel function of NS1-BP collaborating with viral protein NS1 in modulation of host cell physiology. In addition, an alternative role of adaptor protein CRKL in association with NS1 and NS1-BP during influenza A virus infection is demonstrated. © 2013 Elsevier Inc.

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Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier

Miura Y., Takenaka T., Toh K., Wu S., Nishihara H., Kano M., Ino Y., Nomoto T., Matsumoto Y., Koyama H., Cabral H., Nishiyama N., Kataoka K.

ACS Nano （ACS Nano）  7 （ 10 ） 8583 - 8592 2013年10月

研究論文（学術雑誌）, 共著,  ISSN  19360851

　概要を見る

Ligand-mediated drug delivery systems have enormous potential for improving the efficacy of cancer treatment. In particular, Arg-Gly-Asp peptides are promising ligand molecules for targeting αvβ3/ αvβ5 integrins, which are overexpressed in angiogenic sites and tumors, such as intractable human glioblastoma (U87MG). We here achieved highly efficient drug delivery to U87MG tumors by using a platinum anticancer drug-incorporating polymeric micelle (PM) with cyclic Arg-Gly-Asp (cRGD) ligand molecules. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma compared with the PM having nontargeted ligand, "cyclic-Arg-Ala-Asp" (cRAD). As both cRGD/m-and cRAD-linked polymeric micelles have similar characteristics, including their size, surface charge, and the amount of incorporated drugs, it is likely that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant antitumor effects in an orthotopic mouse model of U87MG human glioblastoma. © 2013 American Chemical Society.

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Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET

Mitamura T., Watari H., Wang L., Kanno H., Hassan M., Miyazaki M., Katoh Y., Kimura T., Tanino M., Nishihara H., Tanaka S., Sakuragi N.

Oncogenesis （Oncogenesis）  2 2013年07月

研究論文（学術雑誌）, 共著,  ISSN  2157-9024

　概要を見る

Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX) is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative (KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3′-UTR of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore, co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX will increase PTX efficacy. © 2013 Macmillan Publishers Limited All rights reserved.

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Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma

Kanno H., Nishihara H., Wang L., Yuzawa S., Kobayashi H., Tsuda M., Kimura T., Tanino M., Terasaka S., Tanaka S.

Neuro-Oncology （Neuro-Oncology）  15 （ 7 ） 853 - 864 2013年07月

研究論文（学術雑誌）, 共著,  ISSN  15228517

　概要を見る

Background: CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression. Methods: First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo. Results: Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Conclusions: To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma. © 2013 The Author(s).

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Immunohistochemical molecular expression profile of metastatic brain tumor for potent personalized medicine

Kato Y., Nishihara H., Yuzawa S., Mohri H., Kanno H., Hatanaka Y., Kimura T., Tanino M., Tanaka S.

Brain Tumor Pathology （Brain Tumor Pathology）  30 （ 3 ） 167 - 174 2013年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14337398

　概要を見る

Recent progress in molecule-targeting therapy may yield personalized therapeutic strategies for patients with metastatic brain tumors (MBT), the most frequently encountered intracranial tumors. For this purpose, we investigated the molecular expression profile of MBT to establish the pathological basis for personalized diagnosis. We studied 166 MBT specimens including 70 cases of lung cancer and 34 cases of breast cancer, and performed immunostaining for EGFR, COX-2, and O-6-methylguanine-DNA methyltransferase (MGMT), among others, which could be target molecules for therapeutic agents or enable prediction of drug efficacy. Loss of MGMT expression was observed in approximately 20-40 % of MBT derived from lung, breast, and gastrointestinal cancers, indicating the possibility of treatment of MBT patients with temozolomide. In addition, MBT expressed a variety of receptor tyrosine kinases, for example EGFR and HER2, and signal transduction molecules, for example phospho-mTOR and COX-2, irrespective of tumor origin, enabling individualized medication with molecule-targeting drugs. We also identified alteration of molecular expression profile in 4 MBT cases during recurrence. Our results not only reveal the molecular characteristics of MBT but also suggest the possibility of potent personalized medicine for MBT patients. © 2012 The Japan Society of Brain Tumor Pathology.

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Inhibition of GSH synthesis potentiates temozolomide-induced bystander effect in glioblastoma

Kohsaka S., Takahashi K., Wang L., Tanino M., Kimura T., Nishihara H., Tanaka S.

Cancer Letters （Cancer Letters）  331 （ 1 ） 68 - 75 2013年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03043835

　概要を見る

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor prognosis. Current standard treatment includes chemotherapy using DNA alkylating agent temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, GBM patients exhibit various levels of the elevated expression of DNA repair enzyme, due to MGMT causing resistance to TMZ. Determination of the MGMT-positive population of primary tumor is important to evaluate the therapeutic efficacy of TMZ. Here we generated TMZ-resistant GBM cells by introducing MGMT into TMZ-sensitive GBM cell line KMG4, and established a model to assess the TMZ-induced bystander effect on TMZ-resistant cells. By mixing TMZ-resistant and -sensitive cells, GBM tumors with MGMT positivity as 50%, 10%, and 1% were generated in vivo. We could not observe any bystander effect of TMZ-induced cell death in tumor with 50% MGMT positivity. Although the bystander effect was observed within 20. days in the case of tumor with 1% MGMT positivity, final tumor size at day 28 was the same as control without sensitive cells. This bystander effect was observed in vitro using conditioned medium of TMZ-damaged GBM cells, and PCR array analysis indicated that the conditioned medium stimulated stress and toxicity pathway and upregulated anti-oxidants genes expression such as catalase and SOD2 in TMZ-resistant cells. In addition, the reduction of the activity of anti-stress mechanism by using inhibitor of GSH synthesis potentiated TMZ-induced bystander effect. These results suggest that GSH inhibitor might be one of the candidates for combination therapy with TMZ for TMZ-resistant GBM patients. © 2012 Elsevier Ireland Ltd.

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Intracranial mass-forming lesion associated with dural thickening and hypophysitis

Kanno H., Tanino M., Watanabe K., Ozaki Y., Itoh T., Kimura T., Nishihara H., Itoh T., Narita T., Nagashima K., Tanaka S.

Neuropathology （Neuropathology）  33 （ 2 ） 213 - 216 2013年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09196544

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脳腫瘍の現代病理学 BRAF異常とグリオーマ

田中 伸哉, 谷野 美智枝, 津田 真寿美, 石田 雄介, 木村 太一, 西原 広史, 長嶋 和郎

日本病理学会会誌 （(一社)日本病理学会）  102 （ 1 ） 203 - 203 2013年04月

ISSN  0300-9181

術中迅速脳腫瘍診断における電解非接触撹拌技術を搭載した迅速免疫染色装置使用の有用性

谷野 美智枝, 明坂 詩織, 石田 雄介, 木村 太一, 西原 広史, 田中 伸哉

日本病理学会会誌 （(一社)日本病理学会）  102 （ 1 ） 349 - 349 2013年04月

ISSN  0300-9181

Relationship between Methyl CpG binding protein 2 and JC viral proteins

Takahashi K., Orba Y., Kimura T., Wang L., Kohsaka S., Tsuda M., Tanino M., Nishihara H., Nagashima K., Sawa H., Tanaka S.

Japanese Journal of Infectious Diseases （Japanese Journal of Infectious Diseases）  66 （ 2 ） 126 - 132 2013年03月

研究論文（学術雑誌）, 共著,  ISSN  13446304

　概要を見る

JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy (PML). Methyl CpG binding protein 2 (MeCP2) is a transcriptional control nuclear protein that is abundantly expressed in neurons. We previously observed that the MeCP2 protein is expressed in JCV large T antigen (TAg)-expressing glial cells in PML brains. To investigate the relationship between MeCP2 and JCV TAg, we examined the promoter activity and mRNA and protein expression levels of MeCP2 in JCV TAg-expressing cells. We found that JCV TAg enhances the promoter activity of MeCP2, but does not enhance the mRNA and protein levels of MeCP2. These results suggest that post-transcriptional mechanisms may play a role in MeCP2 expression.

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Clinical implications of luminal membrane expression of mesothelin in intraductal papillary mucinous neoplasms

Takahiro Einama, Hirofumi Kamachi, Hiroshi Nishihara, Shigenori Homma, Futoshi Kawamata, Munenori Tahara, Masahiko Taniguchi, Hiroyuki Furukawa, Toshiya Kamiyama, Akinobu Taketomi, Yoshihiro Matsuno, Satoru Todo

JOURNAL OF CLINICAL ONCOLOGY （AMER SOC CLINICAL ONCOLOGY）  31 （ 4 ）  2013年02月

共著, 査読有り,  ISSN  0732-183X

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Expression of O⁶-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors

Kanno H., Nishihara H., Oikawa M., Ozaki Y., Murata J., Sawamura Y., Kato M., Kubota K., Tanino M., Kimura T., Nagashima K., Itoh T., Tanaka S.

Neuropathology （Neuropathology）  32 （ 6 ） 647 - 653 2012年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09196544

　概要を見る

Pineal parenchymal tumors (PPTs) are rare neoplasms which occupy less than 1% of primary CNS tumors. Because of their rare incidence, previous reports on PPTs are limited in number and the useful molecular markers for deciding histological grading and even selecting chemotherapy are undetermined. In this study, we conducted immunohistochemical analysis of 12 PPT specimens, especially for expression of O6-methylguanine DNA methyltransferase (MGMT) to assess whether temozolomide (TMZ) could serve as a possible alternative therapy for PPTs. We analyzed 12 PPTs, consisting of three pineocytomas, six PPTs of intermediate differentiation (PPTIDs), and three pineoblastomas. Immunohistochemical analysis was performed using antibodies against MGMT, synaptophysin, neurofilament protein (NF), p53, and neuronal nuclear antigen (NeuN). Immunohistochemically, 11 out of 12 cases were positive for MGMT. The mean MIB-1 labeling index was less than 1% in pineocytoma, 3.5% in PPTID, and 10.5% in pineoblastoma. All 12 cases were positive for synaptophysin and 11 cases, except one PPTID case, showed positive for NF. Nuclear staining of NeuN was negative in all cases although cytoplasmic staining of NeuN was observed in five cases. No case was positive for p53. Eleven out of 12 cases of PPTs demonstrated MGMT expression, suggesting chemoresistancy to TMZ treatment. This is the first report showing MGMT expression in PPTs. In addition, MIB-1 labeling index correlated with WHO grade, although the immunoreactivity of synaptophysin, NF, NeuN and p53 did not correlate with the histological grade. © 2012 Japanese Society of Neuropathology.

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