研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Acute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report. 査読有り国際誌

Ohara Y, Ito T, Ito M, Yamashita K, Toyokuni S

Medical mycology case reports 20 巻頁： 39 - 42 2018年6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：Medical Mycology Case Reports

A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.

DOI： 10.1016/j.mmcr.2018.02.002

An autopsy case report: Differences in radiological images correlate with histology in Erdheim–Chester disease 査読有り国際誌 Open Access

Ohara Y., Kato S., Yamashita D., Satou A., Shimoyama Y., Hamaie C., Sato M., Ban N., Yamamoto K., Yamada T., Kawai H., Ohshima K., Nakamura S., Toyokuni S.

Pathology International 68 巻 ( 6 ) 頁： 374 - 381 2018年6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：Pathology International

p16 activation caused by oncogenic mutations may represent oncogene-induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim–Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD.

DOI： 10.1111/pin.12663

タルクへの曝露は卵巣表層上皮細胞内の2価鉄イオンの増加に寄与し卵巣癌の発癌に関わる

本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

Biomedical Research on Trace Elements 29 巻 ( 1 ) 頁： 71 - 71 2018年6月

Ferroptosis in carcinogenesis and tumor biology 国際誌

Toyokuni Shinya

FREE RADICAL BIOLOGY AND MEDICINE 120 巻頁： S19-S19 - S19 2018年5月

Expression of P-REX2a is associated with poor prognosis in endometrial malignancies. 国際誌

Takeshita S, Yamashita Y, Shiomi K, Suzuki N, Yoshida J, Naiki-Ito A, Suzuki S, Akatsuka S, Toyokuni S, Takahashi T, Mase S, Arakawa A, Sugiura-Ogasawara M, Takahashi S

Oncotarget 9 巻 ( 37 ) 頁： 24778 - 24786 2018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：Oncotarget

P-REX2a is a PTEN inhibitor that also activates Rac 1. No associations with P-REX2a and human endometrial cancers have been reported to date. In this study, we immunohistochemically analyzed 155 uterine endometrial malignancies for P-REX2a expression. The P-REX2a-positive tumors displayed worse prognosis independent of PTEN expression. Then, we transduced either P-REX2a expression vector or short hairpin RNAs targeting P-REX2a into 2 uterine endometrioid carcinoma cell lines, OMC-2 and JHUEM-14. Ectopic expression of P-REX2a led to increased cell proliferation only in the PTEN-expressing OMC-2 cells but did not show any change in the PTEN-negative JHUEM-14 cells or the P-REX2a-knockdown cells. Induction of P-REX2a increased and knockdown of P-REX2a decreased cell migration in both cell lines. Then, we performed expression microarray analysis using these cells, and pathway analysis revealed that the expression of members of the GPCR downstream pathway displayed the most significant changes induced by the knockdown of P-REX2a. Immunohistochemical analysis revealed that Vav1, a member of the GPCR downstream pathway, was expressed in 139 of the 155 endometrial tumors, and the expression levels of Vav1 and P-REX2a showed a positive correlation (r = 0.44, p < 0.001). In conclusion, P-REX2a enhanced cell motility via the GPCR downstream pathway independently of PTEN leading to progression of uterine endometrioid malignancies and poor prognosis of the patients.

DOI： 10.18632/oncotarget.25349

Superiority of rat over murine model for studies on the evolution of cancer genome. Open Access

Akatsuka S, Li GH, Toyokuni S

Free radical research 頁： 1-5 2018年5月

Effect of molecular hydrogen on uterine inflammation during preterm labour. 査読有り国際誌

Nakano T, Kotani T, Imai K, Iitani Y, Ushida T, Tsuda H, Li H, Iwase A, Toyokuni S, Kikkawa F

Biomedical reports 8 巻 ( 5 ) 頁： 454 - 460 2018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：Biomedical Reports

Intrauterine inflammation causes preterm birth and is associated with complications in preterm neonates. Thus, strategies aimed at suppressing inflammation are expected to be effective for reducing the risk of preterm birth and associated complications. Our previous studies demonstrated that molecular hydrogen (H2), an anti-inflammatory agent, prevented inflammation-induced impairment in foetal brain and lung tissues in lipopolysaccharide (LPS)-induced rodent models. However, it remains unclear whether H2 is capable of inhibiting preterm labour. The aim of the current study was therefore to investigate the effect of H2 on inflammation-induced preterm labour. Pregnant ICR (CD-1) mice were divided into three groups: Control, LPS and H2 water (HW) + LPS. In the control and LPS groups, vehicle and LPS, respectively, were intraperitoneally injected on embryonic day 15.5. In the HW + LPS group, HW was administered 24 h prior to LPS injection. The time from LPS administration to parturition was compared between the LPS and HW + LPS groups. Maternal uterus was collected 6 h after LPS injection and the transcript levels of pro-inflammatory cytokines, contractile-associated proteins (CAPs), matrix metalloproteinase-3 (Mmp3) and endothelin-1 (Et1) were assessed by reverse transcription-quantitative polymerase chain reaction. The protein levels of cyclooxygenase-2 (Cox2) were also evaluated by immunohistochemistry. The time from LPS administration to parturition in the HW + LPS group was significantly increased compared with that in the LPS group (33.5±3.4 vs. 18.3±8.8 h, respectively, P=0.020). H2 administration also resulted in significantly higher progesterone levels compared with LPS treatment alone (P=0.002). The transcript levels of pro-inflammatory cytokines, CAPs, Mmp3 and Et1 in the uteri of the LPS group were significantly higher than those in the control group (all P<0.05). In turn, all these levels with the exception of interleukin-8 and Mmp3 were significantly lower in the HW + LPS group compared with those in the LPS group (all P<0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P<0.001) and HW + LPS (P=0.003) groups. These results suggest that inflammation-induced changes in the uterus may be ameliorated through maternal H2 administration. Preventive H2 administration may therefore represent an effective strategy for the suppression of inflammation during preterm labour.

DOI： 10.3892/br.2018.1082

Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model. 査読有り国際誌

Ohara Y, Chew SH, Misawa N, Wang S, Somiya D, Nakamura K, Kajiyama H, Kikkawa F, Tsuyuki Y, Jiang L, Yamashita K, Sekido Y, Lipson KE, Toyokuni S

Oncotarget 9 巻 ( 26 ) 頁： 18494 - 18509 2018年4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：Oncotarget

Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

DOI： 10.18632/oncotarget.24892

Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. 査読有り国際誌

Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H, Ito I, Takahashi M, Inoue T, Ito M, Ohara Y, Oda Y, Toyokuni S

Histopathology 72 巻 ( 5 ) 頁： 729 - 738 2018年4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：Histopathology

Aims: Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. Methods and results: We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). Conclusions: The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes.

DOI： 10.1111/his.13421

脱分化型脂肪肉腫における骨形成の特徴と予後との関連

山下享子, 孝橋賢一, 山田裕一, 伊藤以知郎, 小田義直, 豊國伸哉

日本病理学会会誌 107 巻 ( 1 ) 頁： 291 - 291 2018年4月

Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 査読有り国際誌

Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S

Cancer science 109 巻 ( 2 ) 頁： 330 - 339 2018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：Cancer Science

Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial–mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

DOI： 10.1111/cas.13460

Phlebotomy attenuates the growth of malignant mesothelioma on rat model

Ohara, Y; Toyokuni, S

CANCER SCIENCE 109 巻頁： 781 - 781 2018年1月

Molecular mechanisms in oxidative stress-induced carcinogenesis

Toyokuni, S

CANCER SCIENCE 109 巻頁： 163 - 163 2018年1月

Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice

Akatsuka, S; Li, GH; Sakumi, K; Nakabeppu, Y; Futakuchi, M; Suzuki, H; Toyokuni, S

CANCER SCIENCE 109 巻頁： 167 - 167 2018年1月

Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice 国際誌

Akatsuka Shinya, Li Guang-Hua, Sakumi Kunihiko, Nakabeppu Yusaku, Futakuchi Mitsuru, Suzuki Hiromu, Toyokuni Shinya

CANCER SCIENCE 109 巻頁： 167-167 2018年1月

Molecular mechanisms in oxidative stress-induced carcinogenesis 国際誌

Toyokuni Shinya

CANCER SCIENCE 109 巻頁： 163-163 2018年1月

Phlebotomy attenuates the growth of malignant mesothelioma on rat model 国際誌

Ohara Yuuki, Toyokuni Shinya

CANCER SCIENCE 109 巻頁： 781-781 2018年1月

Glioblastoma Cell Lines Display Different Sensitivities to Plasma-Activated Medium 国際誌

Tanaka H., Mizuno M., Ishikawa K., Takeda K., Hashizume H., Nakamura K., Utsumi F., Kajiyama H., Okazaki Y., Toyokuni S., Akiyama S., Maruyama S., Kikkawa F., Hori M.

IEEE Transactions on Radiation and Plasma Medical Sciences 2 巻 ( 2 ) 頁： 99 - 102 2018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：IEEE Transactions on Radiation and Plasma Medical Sciences

Plasma-activated medium (PAM) is a novel chemotherapy that induces reactive oxygen species (ROS) and cell death in a wide range of cancer cell types, suggesting that PAM may be a promising therapeutic option for cancer treatment. However, dose response experiments suggest that PAM sensitivity is cell line specific. We examined the sensitivities of three glioblastoma cell lines to PAM, and found a wide variation in cell killing that was linked to differences in PAM induced ROS and apoptosis. These results indicate that the PAM sensitivity of glioblastoma cells, and potentially cancer cells more generally, is heterogeneous and likely to be dependent on the regulation of apoptosis and antioxidant pathways in target cells.

DOI： 10.1109/trpms.2017.2721973

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State of the art in medical applications using non-thermal atmospheric pressure plasma 査読有り国際誌

Tanaka H., Ishikawa K., Mizuno M., Toyokuni S., Kajiyama H., Kikkawa F., Metelmann H.R., Hori M.

Reviews of Modern Plasma Physics 1 巻 ( 1 ) 2017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：Reviews of Modern Plasma Physics

Plasma medical science is a novel interdisciplinary field that combines studies on plasma science and medical science, with the anticipation that understanding the scientific principles governing plasma medical science will lead to innovations in the field. Non-thermal atmospheric pressure plasma has been used for medical treatments, such as for cancer, blood coagulation, and wound healing. The interactions that occur between plasma and cells/tissues have been analyzed extensively. Direct and indirect treatment of cells with plasma has broadened the applications of non-thermal atmospheric pressure plasma in medicine. Examples of indirect treatment include plasma-assisted immune-therapy and plasma-activated medium. Controlling intracellular redox balance may be key in plasma cancer treatment. Animal studies are required to test the effectiveness and safety of these treatments for future clinical applications.

DOI： 10.1007/s41614-017-0004-3

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Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 査読有り国際誌

Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S

Cancer Science 2017年11月

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