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Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors

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Cancer Communications 2023年第4期43卷 415-434页

作者： Hiroyuki Suzuki Hideki Iwamoto Takahiro Seki Toru Nakamura atsutaka masuda Takahiko Sakaue Toshimitsu Tanaka Yasuko Imamura Takashi Niizeki Masahito Nakano Shigeo Shimose Tomotake Shirono Yu Noda Naoki Kamachi Miwa Sakai Kazutoyo Morita Masamichi Nakayama Tomoharu Yoshizumi Ryoko Kuromatsu Hirohisa Yano Yihai Cao Hironori Koga Takuji Torimura Division of Gastroenterology Department of MedicineKurume University School of MedicineKurume CityFukuokaJapan Liver Cancer Research Division Research Center for Innovative Cancer TherapyKurume UniversityKurume CityFukuokaJapan Iwamoto Internal Medicine Clinic Kitakyushu CityFukuokaJapan Department of Microbiology Tumor and Cell biologyKarolinska InstitutetStockholmSweden Department of Surgery and Science Graduate School of Medical ScienceKyushu UniversityFukuoka CityFukuokaJapan Department of Pathology Kurume University School of MedicineKurume CityFukuokaJapan

Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not *** aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in ***:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC *** evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC *** on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were ***,in vivo genetic and pharmacological gain-and loss-of-function experiments were ***:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall ***,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor ***-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase ***,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib ***:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic *** TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 *** data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

关键词： hepatocellular carcinoma hypoxia IGFBP-1 lenvatinib molecular targeting resistance tyrosine kinase inhibitors

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STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury

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World Journal of Gastroenterology 2017年第37期23卷 6833-6844页

作者： Mitsuhiko Abe Takafumi Yoshida Jun Akiba Yu Ikezono Fumitaka Wada atsutaka masuda Takahiko Sakaue Toshimitsu Tanaka Hideki Iwamoto Toru Nakamura Michio Sata Hironori Koga Akihiko Yoshimura Takuji Torimura Division of Gastroenterology Department of Medicine Kurume University School of Medi-cine Liver Cancer Division Research Center for Innovative Cancer Therapy Kurume University Kurume Clinical pharmacology Clinic Department of Diagnostic pathology Kurume University hospital Department of Microbiology Immun--ology Keio University School of Medicine

AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to *** Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient *** STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.

关键词： Hepatocellular 癌 Ductular 反应表明抄写 3 的变换器和使活跃之物联系是的蛋白质决定区域 Y-box9 的性 Transdifferentiation

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铜氧化物母体在正负偏压下的选择性易失和非易失绝缘-超导转变

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Science Bulletin 2021年第1期66卷 1-2,M0003页

作者： atsutaka Maeda Department of Basic Sciences University of TokyoTokyo 153-8902Japan

Changing carrier density is one of the most remarkable but common aspects of unconventional *** for understanding the mechanism of exotic superconductivity and for novel technological applications,this“semiconductor-... 详细信息

关键词：超导转变铜氧化物负偏压

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Strength of plastic with various helical wheels meshed types of worms

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材料与冶金学报 2015年第3期14卷 232-235,238页

作者： Makoto Nomura Takao Koide Akio Ueda Yusuke Ishida atsutaka Tamura Tottori University 4 - 101 Minami Koyama - cho Tottori 680 - 8552 Japan Amtec INC. BayTower 2510 1-2-1 Minato-ku Benten Osaka 552-0007 Japan

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Hepatic clearance measured with ^(99m)Tc-GSA single-photon emission computed tomography to estimate liver fibrosis

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World Journal of Gastroenterology 2014年第44期20卷 16714-16720页

作者： Masahiko Taniguchi atsutaka Okizaki Kenji Watanabe Koji Imai Koichiro Uchida Takahiro Einama Noriyuki Shuke Naoyuki Miyokawa Hiroyuki Furukawa Division of Gastroenterologic and General Surgery Department of Surgery Asahikawa Medical College Department of Radiology Asahikawa Medical College Department of Pathology Asahikawa Medical College

AIM: To evaluate the clinical utility of hepatic clearance(HC) measured with technetium-99m-diethylenetriaminepenta-acetic acid-galactosyl human serum albumin(99mTc-GSA) single-photon emission computed tomography(SPECT) to estimate the degree of liver ***:Seventy-eight consecutive patients who underwent initial hepatectomy due to hepatocellular carcinoma were enrolled in this *** green clearance(ICG R15),quantitative indices estimated by 99mTc-GSA[the receptor index(LHL15 and HH15)and HC via SPECT analysis],and conventional liver function tests were performed before *** among the quantitative indices for liver functional reserve,conventional liver function tests,andthe degree of liver fibrosis were ***:The degree of liver fibrosis was correlated with ICG R15,HH15,LHL15,and *** showed the best correlation with conventional liver function *** to multivariate analysis,HC and LHL15 were significant independent predictors of severe *** was the most valuable index for predicting severe ***:HC measured with 99mTc-GSA SPECT is a reliable index for assessing liver fibrosis before hepatectomy.

关键词： Fibrosis Technetium-99m-diethylenetri-aminepenta-a

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路易体痴呆患者FP-CITSPECT显像定量分析中的测量者组间和组内的重复性研究

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中华核医学与分子影像杂志 2018年第6期38卷 455-456页

作者：唐军 atsutaka Okizaki Michihiro Nakayama Kaori Nakajima Takayuki Katayama Takahiro Uno Fumiyoshi Morikawa Juichiro Naoe Koji Takahashi 上海交通大学医学院附属苏州九龙医院核医学科 Department of Radiology Asahikawa Medical University

目的多巴胺转运体SPECT（DAT-SPECT）显像有益于评价路易体痴呆（DLB）。特异性结合比值（SBR）是测量DAT密度的指标。但在实际工作中不时会遇到SBR测量重复性差的情况。笔者假设距离加权直方图（DWH）可能有助于改善SBR测量的重复性。... 详细信息

目的多巴胺转运体SPECT（DAT-SPECT）显像有益于评价路易体痴呆（DLB）。特异性结合比值（SBR）是测量DAT密度的指标。但在实际工作中不时会遇到SBR测量重复性差的情况。笔者假设距离加权直方图（DWH）可能有助于改善SBR测量的重复性。该研究的目的是分析使用常规法和DWH法时测量者组间和组内测量SBR的重复性,并视觉评价使用2种方法设置参考感兴趣体素（VOI）时的精密度。方法. 共纳入50例疑似DLB的成年患者,均行脑MRI、DAT-SPECT和N-异丙基-p-[;I]碘安非他明(;I-IMP)脑血流灌注SPECT显像。使用常规法和DWH法测量纹状体SBR。由2位经验丰富的核医学医师独立使用常规法和DWH法测量SBR,以确认测量者组间的重复性;2周内由其中1位医师再次测量SBR,以评价测量者组内的重复性。结果使用常规法测量SBR时,60.0%的VOI设置准确;而使用DWH法时,98.0%的VOI设置准确。常规法和DWH法的测量者组间和组内的重复性均较好,但常规法测量者组间和组内的重复性差异仍有统计学意义。常规法测量SBR时,测量者组间和组内的平均错误率分别为7.9%和6.1%;而DWH法在所有患者的SBR测量中未出现错误。此外,常规法测量SBR中VOI设置不准确时,测量者组间和组内的平均错误率明显高于VOI设置准确时。结论尽管常规法和DWH法测量SBR的重复性均较好,但常规法的测量者组间和组内偏差不容忽视,尤其是在VOI设置不准确时。因此,DWH法也许有助于改善测量SBR时的测量者组间和组内的重复性。

关键词： FP-CIT SPECT 多巴胺转运体密度 SBR 直方图路易体痴呆

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不同类型塑料螺旋轮啮合强度研究（英文）

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材料与冶金学报 2015年第3期14卷 232-235+238页

作者：野村诚小出隆夫上田昭夫石田裕介田村笃敬 Tottori University

This study investigates the strength of plastic helical wheels meshed with enveloping and cylindrical worms whose tooth profiles mesh in line contact with helical wheels.R unning fatigue tests of plastic helical wheels together with a conventional cylindrical involute worm,a line contact enveloping worm,and a line contact cylindrical worm were conducted.T he tooth bearings,tooth temperatures,and fatigue lives of plastic helical wheels meshed with the different worms were examined at various center *** results obtained are as follows:T he lives of both line and point contact wheels depended upon backlash,but the lives of line contact wheels are more sensitive to backlash than those of point contact *** the backlash that maximizes the wheel life,the line contact wheels last longer than point contact wheels at smaller applied torques,but the influence of worm type on wheel life reduced at higher applied torque.

关键词： plastic gear worm wheel helical wheel temperature fatigue life

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无多重对照校正的SPECT正常人控尿脑区研究

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中国临床医学影像杂志 2008年第7期19卷 457-459页

作者：尹雅芙殷波李雪娜秀毛範至沖崎貴琢佐滕顺一油野民雄李亚明周久贸中国医科大学附属第一医院核医学科辽宁沈阳110001 中国医科大学附属盛京医院泌尿外科辽宁沈阳110004 旭川医科大学

目的:应用99Tcm-HMPAO SPECT和NEUROSTAT(Neurological Statistical Image Analysis Software)软件包分析无多重对照校正条件下正常人的控尿脑激活区。方法:对15例右利手的健康男性自愿者(24～45岁)进行了SPECT扫描,每位自愿者均在排空... 详细信息

目的:应用99Tcm-HMPAO SPECT和NEUROSTAT(Neurological Statistical Image Analysis Software)软件包分析无多重对照校正条件下正常人的控尿脑激活区。方法:对15例右利手的健康男性自愿者(24～45岁)进行了SPECT扫描,每位自愿者均在排空膀胱的静息状态和膀胱充满尿液的控尿状态下接受两次扫描。控尿图像是由两次采集的数据相减而获得的。图像分析采用NEUROSTAT分析软件包,无多重对照校正P<0.005。结果:无多重对照校正P<0.005条件下,与静息状态相比,控尿状态下额叶、颞叶、前扣带回、扣带回、丘脑、岛叶、顶叶、枕叶等皮质及皮质下的广泛区域均呈现放射性升高趋势。结论:应用SPECT显像和脑功能影像分析软件NEUROSTAT研究发现,在无多重对照校正条件下,正常健康男性控尿的大脑控制与大脑皮质及皮质下的广泛区域相关。

关键词：脑体层摄影术发射型计算机单光子

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逼尿肌过度活动症患者及男性健康成人控尿状态下大脑激活区的SPECT显像

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同位素 2009年第1期22卷 28-33页

作者：尹雅芙李雪娜秀毛範至沖崎貴琢佐滕顺一油野民雄李亚明中国医科大学附属第一医院核医学科辽宁沈阳110001 旭川医科大学放射科

利用神经学统计图像分析软件NEUROSTAT分析健康志愿者和逼尿肌过度活动患者的SPECT图像,探讨膀胱贮尿的大脑控制区及其控制机理。15例健康志愿者(Ⅰ组)和25例下尿道尿储存功能障碍患者接受了SPECT扫描。25例中19例患者为逼尿肌过度活动... 详细信息

利用神经学统计图像分析软件NEUROSTAT分析健康志愿者和逼尿肌过度活动患者的SPECT图像,探讨膀胱贮尿的大脑控制区及其控制机理。15例健康志愿者(Ⅰ组)和25例下尿道尿储存功能障碍患者接受了SPECT扫描。25例中19例患者为逼尿肌过度活动症(Ⅱ组),6例患者逼尿肌功能正常(Ⅲ组)。所有受检者均在排空膀胱的静息状态和控尿状态接受SPECT扫描。控尿状态的图像用第二次扫描后的图像减去第一次的图像获得。用NEUROSTAT对比分析3组受检者在静息状态下的脑血流(rCBF)情况及各组受检者控尿状态与静息状态rCBF的差异,进行多重对照校正。静息状态下Ⅱ组与Ⅲ组相比脑血流差异无统计学意义(P>0.05)。Ⅰ组和Ⅲ组控尿状态与静息状态相比,两侧额下回和右侧颞中回rCBF明显增高,其中右侧额下回在Z-值和病灶范围方面均最为明显(多重对照校正P4.476,Ⅲ组对应Z-值>4.414)。Ⅱ组控尿状态与静息状态相比,仅左侧颞中回和额中回rCBF明显增高(多重对照校正P4.35)。3组结果中,没有任何病灶脑血流降低达统计学标准。本研究结果表明两侧额下回和右侧颞中回与膀胱贮尿功能的大脑控制有关,特别是右侧额下回在膀胱贮尿的大脑控制中起重要作用,抑制控尿期逼尿肌的收缩。

关键词：膀胱贮尿功能逼尿肌过度活动症 SPECT

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