研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

分割表示 1,236 件中 361 - 380 件目／全件表示 >>

Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. 招待有り国際誌

Toyokuni S

J Clin Biochem Nutr 56 巻頁： 165 2015年

Application of intermittent microwave irradiation to western blot analysis. 査読有り国際共著国際誌

Liu YT, Toyokuni S

Methods Mol Biol 1314 巻頁： 185-190 2015年

Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury. 査読有り国際誌

Hattori Y, Kotani T, Tsuda H, Mano Y, Tu L, Li H, Hirako S, Ushida T, Imai K, Nakano T, Sato Y, Miki R, Sumigama S, Iwase A, Toyokuni S, Kikkawa F

Free radical research 49 巻 ( 8 ) 頁： 1026 - 37 2015年

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

Maternal inflammation is associated with spontaneous preterm birth and respiratory impairment among premature infants. Recently, molecular hydrogen (H2) has been reported to have a suppressive effect on oxidative stress and inflammation. The aim of this study was to evaluate the effects of H2 on fetal lung injury caused by maternal inflammation. Cell viability and the production of interleukin-6 (IL-6) and reactive oxygen species (ROS) were examined by treatment with lipopolysaccharide (LPS) contained in ordinal or H2-rich medium (HM) using a human lung epithelial cell line, A549. Pregnant Sprague Dawley rats were divided into three groups: Control, LPS, and HW + LPS groups. Rats were injected with phosphate-buffered saline (Control) or LPS intraperitoneally (LPS) on gestational day 19 and provided H2 water (HW) ad libitum for 24 h before LPS injection (HW + LPS). Fetal lung samples were collected on day 20, and the levels of apoptosis, oxidative damage, IL-6, and vascular endothelial growth factor (VEGF) were evaluated using immunohistochemistry. The number of apoptotic cells, and levels of ROS and IL-6 were significantly increased by LPS treatment, and repressed following cultured with HM in A549 cells. In the rat models, the population positive for cleaved caspase-3, 8-hydroxy-2′-deoxyguanosine, IL-6, and VEGF was significantly increased in the LPS group compared with that observed in the Control group and significantly decreased in the HW + LPS group. In this study, LPS administration induced apoptosis and oxidative damage in fetal lung cells that was ameliorated by maternal H2 intake. Antenatal H2 administration may decrease the pulmonary mobility associated with inflammation in premature infants.

DOI： 10.3109/10715762.2015.1038257

Minimal inflammogenicity of pristine single-wall carbon nanotubes 査読有り国際誌

Toyokuni S., Jiang L., Kitaura R., Shinohara H.

Nagoya Journal of Medical Science 77 巻 ( 1-2 ) 頁： 195 - 202 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nagoya Journal of Medical Science

Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi-wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 μg/cm2 SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low-risk material with respect to mesothelial carcinogenesis.

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Application of Intermittent Microwave Irradiation to Western Blot Analysis. 査読有り国際誌

Liu YT, Toyokuni S

Methods in molecular biology (Clifton, N.J.) 1314 巻頁： 185 - 90 2015年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Methods in Molecular Biology

We established a shortened protocol for Western blot analysis using intermittent microwave irradiation. With this method, the procedure is completed within 1 h after applying the primary antibody, and thus greatly saves time. This procedure appears to be applicable to any antibody based on our experience of several years.

DOI： 10.1007/978-1-4939-2718-0_20

Receptor role of annexin A2 in the mesothelial endocytosis of crocidolite fibers. 査読有り

Yamashita K, Nagai H, Toyokuni S

Lab Invest 95 巻頁： 749-764 2015年

アスベストによる中皮腫発がん機構の解明とナノマテリアルのリスク評価

豊國伸哉

日本毒性学会学術年会 42 巻 ( 0 ) 頁： S4 - 2 2015年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

現在、日本人死因の第１位はがんである。産業・経済の発展を重視するあまり、リスク評価が十分になされないまま、ナノマテリアルが社会に多量に持ち込まれ、がんの原因となったことを忘れてはならない。それがアスベストであり、白石綿・青石綿・茶石綿が世界中で多量に使用された。日本では2006年に全面禁止となったが、アジア諸国を中心に現在も産生・使用されている。日本の中皮腫発生ピークは2025年と予想されており、今後10万人以上が中皮腫で死亡すると試算され、現在発生数が増加している。ラットで上記３種のアスベストの腹腔内10mg投与により中皮腫発がん実験を行った。２年の経過でほぼ全動物に中皮腫が発生した。アスベスト投与部の中皮細胞や貪食細胞に著明な鉄沈着を認め、Fenton反応促進性のニトリロ三酢酸の追加投与により、中皮腫発生が有意に早くなった。93％の腫瘍でCdkn2a/2bのホモ欠損を認めた。アスベスト発がんでは局所の過剰鉄病態が重要なことが示唆された。このような背景のもと、すでに中皮腫の危険性の報告のあった多層カーボンナノチューブ（MWCNT）の評価を行った。MWCNTは軽量・高強度で熱伝導性が高く、導体・半導体になることからすでに使用されているが、物理的形状は石綿に酷似している。直径が15/50/115/150 nmのMWCNTを使用し中皮細胞毒性実験ならびに、上記と同様のラットを使用した発がん実験を行った。中皮細胞への毒性と発がん性はほぼ一致し、直径50 nmのMWCNTの発がん性が最も高かった。Cdkn2a/2bのホモ欠損をほぼ全例で認めた。このことは、剛性が高い50 nm直径のMWCNTは特に注意して扱うべきことを示唆している(IARC Group 2B)。ヒトにおいて体腔に繊維が到達することはそう容易ではないと考えられるが、感染症が克服され、ますます長寿化が進む現在、新素材の十分なリスク評価とリスク管理は重要と考える。参考文献：1. Nagai H et al. Proc Natl Acad Sci USA 108: E1330, 2011; 2. Jiang L, et al. J Pathol 228: 366, 2012; 3. Toyokuni S. Adv Drug Deliv Rev 65: 298, 2013

DOI： 10.14869/toxpt.42.1.0_S4-2

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１-ブロモプロパン神経毒性のマウスモデルの確立

宗才, Edwin GARNER, 黄晋彦, 張霊逸, 張堯, 櫻井敏博, 豊國伸哉, 市原佐保子, 市原学

日本毒性学会学術年会 42 巻 ( 0 ) 頁： P - 13 2015年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

【目的】オゾン層破壊物質代替物質1-ブロモプロパン（1BP）はヒトとラットで神経毒性と生殖毒性を引き起こすことがわかっている。雄ラットは1000 ppmの1BPに1日8時間、５から７週間の曝露でも生存するのに対し、最近の我々の研究で雄C57BL6/JJclマウスは300 ppmの1BPに7日間曝露後、肝臓の壊死を引き起こし、結果として生存できず、神経毒性影響が検出できなかった。本研究はサイトクロームP450の阻害剤、1ーアミノベンゾトライアゾール（ABT）を用い、1BPが引き起こす肝障害作用を抑制することによって、マウスを用いた1BP神経毒性モデルの確立を試みるとともに、P450による1BPの酸化が生殖毒性のパラメータにあたる影響を明らかにする。 【方法】42匹のC57BL/6JJclマウスを6匹ずつ7群に分け、4群にABT 50mg/kgを皮下注射で1日2回投与し、0、50、250、1200 ppmで1BP８時間の曝露を28日間行った。残る3群には生理食塩水を注射し、0、50、250 ppmの1BPに1日8時間、28日間曝露した。曝露終、麻酔下で臓器を剖出した。 【結果】ABT-・1BP 250 ppm群で、肝臓で壊死、炎症、肝臓細胞の変性像が見られた。一方、ABT+マウスでは、1200 ppmを含むすべての群で病理的な変化が見られなかった。脳重量は、ABT＋・1200ppm群でABT＋・0ppm群に比して有意に減少した。ABT-・1BP250 ppmのグループで、精子数がABT-・1BP 0ppm群に比して減少したが、ABT＋・1BP250ppm群およびABT＋・1BP50ppm群においてABT＋・1BP0ppm群に比して精子数の変化は無かった。精嚢と前立腺はABTの投与の有無に関わらず、250 ppmの濃度で、それぞれの0ppm群に対して重量が減少した。 【考察】ABT投与は1-BPによる肝毒性を抑制した。本研究はP450が1-BPの代謝と毒性発現において重要な役割を担っていることを明らかにした。この方法によりマウスの1-BP神経毒性モデルの作成が期待される。

DOI： 10.14869/toxpt.42.1.0_P-13

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グルタチオンＳ－トランスフェラーゼの肝臓内における分布は、 1，2－ジクロロプロパン曝露による胆管癌誘導作用におけるヒトとげっ歯類の違いを説明できない国際誌

Lingyi ZHANG, Cai ZONG, 市原佐保子, 内藤久雄, 豊國伸哉, 熊谷信二, 市原学

日本毒性学会学術年会 42 巻 ( 0 ) 頁： P - 165 2015年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

Purpose: 1,2-Dichloropropane(DCP) is thought to induce cholangiocarcinoma(CCA) among Japanese printing workers in 2013. However no studies have shown DCP-induced CCA in rodents. Five kinds of rodents were exposed to DCP to find an appropriate animal model for DCP-induced CCA. Methods: First, 12 C57BL/6J mice, Balb/cA mice, F344 rats, Syrian Hamsters and Guinea Pigs were divided into 4 groups equally and exposed to DCP at 0, 300, 1000 and 3000 ppm respectively. Then 32 Balb/cA mice and Syrian Hamsters were divvied into 4 groups equally and exposed to DCP at 0, 200, 400 and 800ppm respectively. After the last exposure livers were dissected out for immunohistochemistry with anti- GSTT1, GSTM1, GSTPi antibodies. Result: Either in control or exposed group all of the animals expressed GSTT1 both at liver cells and bile duct cells. Conclusion: GSTT1 expression cannot explain the gap between human and rodents in the case of DCP inducing CCA.

DOI： 10.14869/toxpt.42.1.0_P-165

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鉄過剰症による発がんの分子機構　特集：鉄代謝制御機構と鉄過剰症

豊國伸哉

病理と臨床 70 巻頁： 337 - 242 2015年

Minimal inflammogenicity of pristine single-wall carbon nanotubes 査読有り国際誌

Toyokuni S

Nagoya Journal of Medical Science 77 巻 ( 1-2 ) 頁： 195 - 202 2015年

Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus. 査読有り国際誌

Yoshihara M, Jiang L, Akatsuka S, Suyama M, Toyokuni S

DNA research : an international journal for rapid publication of reports on genes and genomes 21 巻 ( 6 ) 頁： 603 - 12 2014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：DNA Research

8-Oxoguanine (8-oxoG) is one of the most common DNA lesions generated by reactive oxygen species. In this study, we analysed the genome-wide distribution profile of 8-oxoG by combining immunoprecipitation by antibodies specific for the DNA fragments containing 8-oxoG with a microarray that covers rat genome. Genome-wide mapping of 8-oxoG in normal rat kidney revealed that 8-oxoG is preferentially located at gene deserts. We did not observe differences in 8-oxoG levels between groups of genes with high and low expression, possibly because of the generally low 8-oxoG levels in genic regions compared with gene deserts. The distribution of 8-oxoG and lamina-associated domains (LADs) were strongly correlated, suggesting that the spatial location of genomic DNA in the nucleus determines the susceptibility to oxidative modifications. One possible explanation for high 8-oxoG levels in LADs is that the nuclear periphery is more susceptible to the oxidative damage caused by the extra-nuclear factors. Moreover, LADs have a rather compact conformation, which may limit the recruitment of repair components to the modified bases.

DOI： 10.1093/dnares/dsu023

Plasma Medical Science for Cancer Therapy: Toward Cancer Therapy Using Nonthermal Atmospheric Pressure Plasma 査読有り国際誌

Tanaka, H; Mizuno, M; Ishikawa, K; Takeda, K; Nakamura, K; Utsumi, F; Kajiyama, H; Kano, H; Okazaki, Y; Toyokuni, S; Maruyama, S; Kikkawa, F; Hori, M

IEEE TRANSACTIONS ON PLASMA SCIENCE 42 巻 ( 12 ) 頁： 3760 - 3764 2014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：IEEE Transactions on Plasma Science

We have been developing novel ultrahigh density atmospheric pressure plasma sources and succeeded in the selective killing ovarian cancer cells against normal ones. Furthermore, we have found out the plasma-activated medium (PAM) also killed glioblastoma brain tumor cells selectively against normal ones and the chemical products in the PAM have long lifetime healing effects. To clarify the mechanism, interactions of plasma with the organism and the medium where the organism belongs were investigated on the viewpoint of intracellular molecular mechanism.

DOI： 10.1109/TPS.2014.2353659

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Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules. 査読有り国際誌

Okazaki Y, Wang Y, Tanaka H, Mizuno M, Nakamura K, Kajiyama H, Kano H, Uchida K, Kikkawa F, Hori M, Toyokuni S

Journal of clinical biochemistry and nutrition 55 巻 ( 3 ) 頁： 207 - 15 2014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：一般社団法人　日本酸化ストレス学会

Thermal plasmas and lasers are used in medicine to cut and ablate tissues and for coagulation. Non-equilibrium atmospheric pressure plasma (NEAPP) is a recently developed, non-thermal technique with possible biomedical applications. Although NEAPP reportedly generates reactive oxygen/nitrogen species, electrons, positive ions, and ultraviolet radiation, little research has been done into the use of this technique for conventional free radical biology. Recently, we developed a NEAPP device with high electron density. Electron spin resonance spin-trapping revealed .OH as a major product. To obtain evidence of NEAPP-induced oxidative modifications in biomolecules and standardize them, we evaluated lipid peroxidation and DNA modifications in various in vitro and ex vivo experiments. Conjugated dienes increased after exposure to linoleic and α-linolenic acids. An increase in 2-thiobarbituric acid-reactive substances was also observed after exposure to phosphatidylcholine, liposomes or liver homogenate. Direct exposure to rat liver in saline produced immunohistochemical evidence of 4-hydroxy-2-nonenal- and acrolein-modified proteins. Exposure to plasmid DNA induced dose-dependent single/double strand breaks and increased the amounts of 8-hydroxy-2′-deoxyguanosine and cyclobutane pyrimidine dimers. These results indicate that oxidative biomolecular damage by NEAPP is dose-dependent and thus can be controlled in a site-specific manner. Simultaneous oxidative and UV-specific DNA damage may be useful in cancer treatment.

DOI： 10.3164/jcbn.14-40

Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. 査読有り国際誌

Mukaide T, Hattori Y, Misawa N, Funahashi S, Jiang L, Hirayama T, Nagasawa H, Toyokuni S

Free radical research 48 巻 ( 9 ) 頁： 990 - 5 2014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：Free Radical Research

Iron overload of a chronic nature has been associated with a wide variety of human diseases, including infection, carcinogenesis, and atherosclerosis. Recently, a highly specific turn-on fluorescent probe (RhoNox-1) specific to labile ferrous iron [Fe(II)], but not to labile ferric iron [Fe(III)], was developed. The evaluation of Fe(II) is more important than Fe(III) in vivo in that Fe(II) is an initiating component of the Fenton reaction. In this study, we applied this probe to frozen sections of an established Fenton reaction-based rat renal carcinogenesis model with an iron chelate, ferric nitrilotriacetate (Fe-NTA), in which catalytic iron induces the Fenton reaction specifically in the renal proximal tubules, presumably after iron reduction. Notably, this probe reacted with Fe(II) but with neither Fe(II)-NTA, Fe(III) nor Fe(III)-NTA in vitro. Prominent red fluorescent color was explicitly observed in and around the lumina of renal proximal tubules 1 h after an intraperitoneal injection of 10-35 mg iron/kg Fe-NTA, which was dose-dependent, according to semiquantitative analysis. The RhoNox-1 signal colocalized with the generation of hydroxyl radicals, as detected by hydroxyphenyl fluorescein (HPF). The results demonstrate the transformation of Fe(III)-NTA to Fe(II) in vivo in the Fe-NTA-induced renal carcinogenesis model. Therefore, this probe would be useful for localizing catalytic Fe(II) in studies using tissues. © 2014 Informa UK, Ltd.

DOI： 10.3109/10715762.2014.898844

FREE FERROUS IRON IN AMNIOTIC FLUID AS A PREDICTIVE MARKER OF FETAL DISORDERS IN PREGNANCY 査読有り国際誌

Hattori, Y; Kotani, T; Nakano, T; Mano, Y; Sumigama, S; Tsuda, H; Usida, T; Nagasawa, H; Toyokuni, S; Kikkawa, F

PLACENTA 35 巻 ( 9 ) 頁： A71 - A71 2014年9月

Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. 査読有り国際誌

Jiang L, Yamashita Y, Chew SH, AKatsuka S, Ukai S, Wang S, Nagai H, Okazaki Y, Takahashi T, Toyokuni S

J Pathol 233 巻 ( 4 ) 頁： 402 - 414 2014年8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：Journal of Pathology

Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the β-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3β-β-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.4377

Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation. 査読有り国際誌

Shinjo K, Yamashita Y, Yamamoto E, Akatsuka S, Uno N, Kamiya A, Niimi K, Sakaguchi Y, Nagasaka T, Takahashi T, Shibata K, Kajiyama H, Kikkawa F, Toyokuni S

International journal of cancer 135 巻 ( 2 ) 頁： 308 - 18 2014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：International Journal of Cancer

Ovarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell-cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression-free survival rates of the CBX7-positive patients were significantly shorter than those of the CBX7-negative patients (p < 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that cell viability was significantly reduced compared to the control cells (p < 0.001). Expression microarray analysis revealed that apoptosis-related genes, particularly tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p < 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL-induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy. What's new? Ovarian cancer is the most lethal gynecologic malignancy, with clear celladenocarcinoma of the ovary (OCCA) having a particularly poor prognosis due to high chemoresistance. Chromobox homolog 7 (CBX7) is a polycomb group transcriptional repressor whose role in human cancer remains controversial. Here, the authors showed for the first time that CBX7 expression is related to worse prognosis in OCCA. Furthermore, knockdown of CBX7 in vitro induced apoptosis in OCCA cell lines, possibly via regulation of the TRAIL-pathway. The findings thus indicate CBX7 as a good prognostic marker, andthe TRAIL-pathway as a potential target for OCCA diagnosis and therapy. © 2013 UICC.

DOI： 10.1002/ijc.28692

Lack of presence of the human cytomegalovirus in human glioblastoma. 査読有り国際誌

Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S, Tsurumi T

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 27 巻 ( 7 ) 頁： 922 - 9 2014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：Modern Pathology

Recent reports have indicated human cytomegalovirus (HCMV) to be associated with human glioblastoma carcinogenesis. In established examples of viral carcinogenesis, viral DNA and one or more of its products have been detected in most tumor cells of biopsies in the majority of cases. To test whether HCMV is associated with human glioblastoma based on this criterion, we measured the number of viral DNA molecules per cell in both frozen and paraffin-embedded tumor biopsies from 58 patients using real-time quantitative PCR (QPCR). Immunohistochemical and fluorescence in situ hybridization (FISH) to detect HCMV proteins and genome was performed in 10 cases using formalin-fixed paraffin-embedded glioblastoma tissues. Southern blotting using DNA extracted from four glioblastoma cell lines together with immunoblotting using the four cell lines and five glioblastoma tissue samples were also performed. We further confirmed the immunoblot bands using liquid chromatography-tandem mass spectrometry assay. As a result, HCMV DNA was not detected in the tumor cells from any of the glioblastoma cases by QPCR detecting two different HCMV genes, in clear contrast to samples from patients with HCMV infection. Southern blotting and immunoblotting of cell lines and FISH using paraffin sections were all negative. However, immunoblotting and immunohistochemistry using tissue samples were partly positive, but HCMV proteins were not detected by proteomic analysis, suggesting false positivity of the analyses. As our QPCR analysis could detect 10 copies of HCMV DNA mixed with DNA extracted from 10 4 HCMV-negative cells, we conclude that HCMV is not persistent, at least in the tumor cells, of developed human glioblastoma. © 2014 USCAP, Inc All rights reserved.

DOI： 10.1038/modpathol.2013.219

Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions. 査読有り国際誌

Nishiwaki S, Nakayama T, Murata M, Nishida T, Terakura S, Saito S, Kato T, Mizuno H, Imahashi N, Seto A, Ozawa Y, Miyamura K, Ito M, Takeshita K, Kato H, Toyokuni S, Nagao K, Ueda R, Naoe T

PloS one 9 巻 ( 5 ) 頁： e96252 2014年5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：PLoS ONE

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type. © 2014 Nishiwaki et al.

DOI： 10.1371/journal.pone.0096252

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