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Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions

Translational Neurodegeneration 2020年第1期9卷 66-80页

作者： Seiji Kaji Takakuni Maki tomoyuki ishimoto Hodaka Yamakado Ryosuke Takahashi Department of Neurology Graduate School of MedicineKyoto University54 Shogoin-Kawahara-choSakyo-kuKyotoJapan

Multiple system atrophy(MSA)is a debilitating and fatal neurodegenerative disorder.The disease severity warrants urgent development of disease-modifying therapy,but the disease pathogenesis is still enigmatic.Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions(GCIs),which are insoluble α-synuclein accumulations within oligodendrocytes(OLGs).Thus,preventive strategies against GCI formation may suppress disease progression.However,although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation,difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs;asynuclein and OLGs.The difficulty originates from several enigmas:1)what triggers the initial generation and possible propagation of pathogenic α-synuclein species?2)what contributes to OLG-specific accumulation of α-synuclein,which is abundantly expressed in neurons but not in OLGs?and 3)how are OLGs and other glial cells affected and contribute to neurodegeneration?The primary pathogenesis of GCIs may involve myelin dysfunaion and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism.We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein.This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells.In this review,in order to discuss the pathogenesis of GCIs,we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies.Furthermore,we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains,in the light of our data from the experiments with primary oligodendrocyte lineage cell culture.While various reports have focused on the mysterious source of α-synuclein in GCIs,insights into the mechanism wh

关键词： Multiple system atrophy a-synuclein Glial cytoplasmic inclusion Prion Neurodegeneration Oligodendrocyte Microglia Astrocyte Oligodendrocyte precursor cell

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Inverse relationship between platelet Akt activity and hippocampal atrophy:A pilot case-control study in patients with diabetes mellitus

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World Journal of Clinical Cases 2024年第2期12卷 302-313页

作者： Haruhiko Tokuda Takamitsu Hori Daisuke Mizutani tomoyuki Hioki Kumi Kojima Takashi Onuma Yukiko Enomoto Tomoaki Doi Rie Matsushima-Nishiwaki Shinji Ogura Hiroki Iida Toru Iwama Takashi Sakurai Osamu Kozawa Department of Metabolic Research Research InstituteNational Center for Geriatrics and GerontologyObu 474-8511Japan Department of Clinical Laboratory National Center for Geriatrics and GerontologyObu 474-8511Japan Department of Pharmacology Gifu University Graduate School of MedicineGifu 501-1194Japan Department of Neurosurgery Gifu University Graduate School of MedicineGifu 501-1194Japan Department of Dermatology Central Japan International Medical CenterMinokamo 505-8510Japan Department of Anesthesiology and Pain Medicine Gifu University Graduate School of MedicineGifu 501-1194Japan Department of Emergency Medicine Faculty of MedicineUniversity of ToyamaToyama 930-0194Japan Department of Emergency and Disaster Medicine Gifu University Graduate School of MedicineGifu 501-1194Japan Research Institute National Center for Geriatrics and GerontologyObu 474-8511Japan

BACKGROUND Akt plays diverse roles in humans.It is involved in the pathogenesis of type 2 diabetes mellitus(T2DM),which is caused by insulin resistance.Akt also plays a vital role in human platelet activation.Furthermore,the hippocampus is closely associated with memory and learning,and a decrease in hippocampal volume is reportedly associated with an insulin-resistant phenotype in T2DM patients without dementia.AIM To investigate the relationship between Akt phosphorylation in unstimulated platelets and the hippocampal volume in T2DM patients.METHODS Platelet-rich plasma(PRP)was prepared from the venous blood of patients with T2DM or age-matched controls.The pellet lysate of the centrifuged PRP was subjected to western blotting to analyse the phosphorylation of Akt,p38 mitogen-activated protein(MAP)kinase and glyceraldehyde 3-phosphate dehydrogenase(GAPDH).Phosphorylation levels were quantified by densitometric analysis.Hippocampal volume was analysed using a voxel-based specific regional analysis system for Alzheimer’s disease on magnetic resonance imaging,which proposes the Z-score as a parameter that reflects hippocampal volume.RESULTS The levels of phosphorylated Akt corrected with phosphorylated p38 MAP kinase were inversely correlated with the Z-scores in the T2DM subjects,whereas the levels of phosphorylated Akt corrected with GAPDH were not.However,this relationship was not observed in the control patients.CONCLUSION These results suggest that an inverse relationship may exist between platelet Akt activation and hippocampal atrophy in T2DM patients.Our findings provide insight into the molecular mechanisms underlying T2DM hippocampal atrophy.

关键词： Akt Platelet Hippocampal atrophy Magnetic resonance imaging Diabetes mellitus

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Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

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Cancer Communications 2024年第2期44卷 287-293页

作者： Kouya Shiraishi Atsushi Takahashi Yukihide Momozawa Yataro Daigo Syuzo Kaneko Takahisa Kawaguchi Hideo Kunitoh Shingo Matsumoto Hidehito Horinouchi Akiteru Goto Takayuki Honda Kimihiro Shimizu Masahiro Torasawa Daisuke Takayanagi Motonobu Saito Akira Saito Yuichiro Ohe Shun-ichi Watanabe Koichi Goto Masahiro Tsuboi Katsuya Tsuchihara Sadaaki Takata Tomomi Aoi Atsushi Takano Masashi Kobayashi Yohei Miyagi Kazumi Tanaka Hiroyuki Suzuki Daichi Maeda Takumi Yamaura Maiko Matsuda Yoko Shimada Takaaki Mizuno Hiromi Sakamoto Teruhiko Yoshida Yasushi Goto Tatsuya Yoshida Taiki Yamaji Makoto Sonobe Shinichi Toyooka Kazue Yoneda Katsuhiro Masago Fumihiro Tanaka Megumi Hara Nobuo Fuse Satoshi S.Nishizuka Noriko Motoi Norie Sawada Yuichiro Nishida Kazuki Kumada Kenji Takeuchi Kozo Tanno Yasushi Yatabe Kuniko Sunami tomoyuki Hishida Yasunari Miyazaki Hidemi Ito Mitsuhiro Amemiya Hirohiko Totsuka Haruhiko Nakayama tomoyuki Yokose Kazuyoshi Ishigaki Toshiteru Nagashima Yoichi Ohtaki Kazuhiro Imai Ken Takasawa Yoshihiro Minamiya Kazuma Kobayashi Kenichi Okubo Kenji Wakai Atsushi Shimizu Masayuki Yamamoto Motoki Iwasaki Koichi Matsuda Johji Inazawa Yuichi Shiraishi Hiroyoshi Nishikawa Yoshinori Murakami Michiaki Kubo Fumihiko Matsuda Yoichiro Kamatani Ryuji Hamamoto Keitaro Matsuo Takashi Kohno Division of Genome Biology National Cancer Center Research InstituteTokyoJapan Department of Clinical Genomics National Cancer Center Research InstituteTokyoJapan Laboratory for Statistical Analysis Center for Integrative Medical SciencesRIKENYokohamaJapan Department of Genomic Medicine Research InstituteNational Cerebral and Cardiovascular CenterOsakaJapan Laboratory for Genotyping Development Center for Integrative Medical SciencesRIKENYokohamaJapan Center for Antibody and Vaccine Therapy Research HospitalInstitute of Medical ScienceThe University of TokyoTokyoJapan Department of Medical Oncology and Cancer Center and Center for Advanced Medicine against CancerShiga University of Medical ScienceOtsuJapan Division of Medical AI Research and Development National Cancer Center Research InstituteTokyoJapan Center for Genomic Medicine Graduate School of MedicineKyoto UniversityKyotoJapan Department of Medical Oncology Japanese Red Cross Medical CenterTokyoJapan Department of Thoracic Oncology National Cancer Center Hospital EastJapan Department of Thoracic Oncology National Cancer Center HospitalTokyoJapan Department of Cellular and Organ Pathology Graduate School of MedicineAkita UniversityAkitaJapan Department of Respiratory Medicine Tokyo Medical and Dental UniversityBunkyo-kuTokyoJapan Division of General Thoracic Surgery Department of SurgeryShinshu University School of MedicineMatsumotoNaganoJapan Department of General Surgical Science Division of General Thoracic SurgeryGunma University Graduate School of MedicineIntegrative Center of General SurgeryGunma University HospitalGunmaJapan Department of Gastrointestinal Tract Surgery Fukushima Medical University School of MedicineFukushimaJapan StaGen Co. LtdTokyoJapan Division of Thoracic Surgery National Cancer Center HospitalTokyoJapan Department of Thoracic Surgery National Cancer Center Hospital EastChibaJapan Division of Translational Informatics Exploratory Oncology Research and Clinical Trial Center(EPOC

Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.

关键词： adenocarcinoma lung Lung

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Involvement of A5/A7 noradrenergic neurons and B2 serotonergic neurons in nociceptive processing:a fiber photometry study

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Neural Regeneration Research 2022年第4期17卷 881-886页

作者： Shunpei Moriya Akira Yamashita Daiki Masukawa Junichi Sakaguchi Yoko Ikoma Yoshimune Sameshima Yuki Kambe Akihiro Yamanaka tomoyuki Kuwaki Department of Physiology Kagoshima University Graduate School of Medical and Dental ScienceKagoshimaJapan Department of Molecular Pharmacologyand Neurobiology Yokohama City University Graduate School of MedicineYokohamaJapan Department of Pharmacology Kagoshima University Graduate School of Medical and Dental ScienceKagoshimaJapan Research Institute of Environmental Medicine Nagoya UniversityNagoyaJapan

In the central nervous system,the A6 noradrenaline(NA)and the B3 serotonin(5-HT)cell groups are well-recognized players in the descending antinociceptive system,while other NA/5-HT cell groups are not well characterized.A5/A7 NA and B25-HT cells project to the spinal horn and form descending pathways.We recorded G-Ca MP6 green fluorescence signal intensities in the A5/A7 NA and the B25-HT cell groups of awake mice in response to acute tail pinch stimuli,acute heat stimuli,and in the context of a non-noxious control test,using fiber photometry with a calcium imaging system.We first introduced G-Ca MP6 in the A5/A7 NA or B25-HT neuronal soma,using transgenic mice carrying the tetracycline-controlled transactivator transgene under the control of either a dopamineβ-hydroxylase or a tryptophan hydroxylase-2 promoters and by the site-specific injection of adeno-associated virus(AAV-Tet O(3 G)-G-Ca MP6).After confirming the specific expression patterns of G-Ca MP6,we recorded G-Ca MP6 green fluorescence signals in these sites in awake mice in response to acute nociceptive stimuli.G-Ca MP6 fluorescence intensity in the A5,A7,and B2 cell groups was rapidly increased in response to acute nociceptive stimuli and soon after,it returned to baseline fluorescence intensity.This was not observed in the non-noxious control test.The results indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA or B25-HT neurons but the non-noxious stimuli do not.The present study suggests that A5/A7 NA or B25-HT neurons play important roles in nociceptive processing in the central nervous system.We suggest that A5/A7/B2 neurons may be new therapeutic targets.All performed procedures were approved by the Institutional Animal Use Committee of Kagoshima University(MD17105)on February 22,2018.

关键词： A5 NA neurons A7 NA neurons B25-HT neurons DBH-tTA mice fiber photometry G-CaMP6 mCherry monoaminergic signaling nociception TPH-t TA mice

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Characteristics of In-Hospital Patients with Congenital Heart Disease Requiring Rapid Response System Activations: A Japanese Database Study

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Congenital Heart Disease 2022年第1期17卷 31-43页

作者： Taiki Haga tomoyuki Masuyama Yoshiro Hayashi Takahiro Atsumi Kenzo Ishii Shinsuke Fujiwara Department of Pediatric Critical Care Medicine Osaka City General HospitalOsaka534-0021Japan Department of Emergency and Critical Care Medicine Jichi Medical University Saitama Medical CenterSaitama330-8503Japan Department of Intensive Care Medicine Kameda Medical CenterChiba296-8602Japan Department of Emergency Medicine Seirei Hamamatsu General HospitalShizuoka430-8558Japan Department of Anesthesiology Intensive Care UnitFukuyama City HospitalHiroshima721-8511Japan Department of Emergency Medicine NHO Ureshino Medical CenterSaga843-0393Japan

Objectives:This study aimed to study the characteristics of in-hospital deterioration in patients with congenital heart disease who required rapid response system activation and identify risk factors associated with 1-month mortality.Methods:We retrospectively analysed data from a Japanese rapid response system registry with 35 participating hospitals.We included consecutive patients with congenital heart disease who required rapid response system activation between January 2014 and March 2018.Logistic regression analyses were performed to examine the associations between 1-month mortality and other patient-specific variables.Results:Among 9,607 patients for whom the rapid response system was activated,only 82(0.9%)had congenital heart disease.Only few patients with congenital heart disease were being treated at the cardiology and cardiovascular surgery departments(12.3%and 9.9%,respectively).Moreover,the incidences of rapid-response events after intensive care unit discharge or surgery were low(6.8% and 12.2%,respectively).The most common reason for rapid response system activation was respiratory dysfunction(desaturation:35.4%,tachypnoea:25.6%,and new dyspnoea:19.5%).Rapid response system interventions and intensive care unit transfers were required for 65.9% and 20.7%of patients,respectively.The mortality rate was 1.2% at the end of the rapid response system intervention and 11.0% after 1 month.Moreover,decreased respiratory rate and decreased heart rate at rapid response system activation were associated with increased 1-month mortality.The adjusted odds ratio was 1.10(95% confidence interval 1.02–1.19)and 1.02(95% confidence interval,1.00–1.04) for respiratory rate and heart rate,respectively.Conclusions:Rapid response systems were rarely activated after cardiac surgery and intensive care unit discharge,which were situations with a high risk of sudden deterioration in patients with congenital heart disease.Therefore,encouraging the use of the rapid response system in these departments will enable interventio

关键词： Heart defects congenital emergencies clinical deterioration hospital rapid response team critical care This

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Therapeutic targets against gastric cancer stem cells interacting with tumor microenvironment

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 110-117页

作者： tomoyuki Uchihara Takatsugu ishimoto Atsuko Yonemura Hideo Baba Department of Gastroenterological Surgery Graduate School of Medical ScienceKumamoto UniversityKumamoto 860-8556Japan

Gastric cancer(GC)is a major cause of cancer-related deaths worldwide.The existe nee of cancer stem cells(CSCs)is known to be the main reas on for resista nee to an ticanceragents as well as for the development of distant metastases.Although CSCs themselves harbor self-renewal and differentiation abilities,the tumor microenvironment that surrounds CSCs provides secreted factors and supports angiogenesis and is thus responsible for the maintenance of their CSC properties.The current review provides information regarding the impact of the tumor microenvironment on gastric CSCs,which will support the development of novel therapeutic strategies for targeting gastric CSCs.

关键词： Gastric cancer stem cells stem cell markers tumor microenvironment gastric cancer treatment

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Research on Lightning Protection of Overhead Power Distribution Lines

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高电压技术 2013年第10期39卷 2317-2328页

作者： Shigeru Yokoyama tomoyuki Sato Graduate School of Engineering Shizuoka University Shizuoka 4228526 Japan Tohoku Electric Power Company Sendai 9808550 Japan

There are two major protective methods against lightning outages on overhead distribution lines.One is a surge arrester,and the other is an overhead ground wire.The surge arresters have rather constant effect regardless of the cause of the lightning outage.On the other hand,the effect of an overhead ground wire is quite different in two major causes,the direct lightning hit and the induced overvoltage.It is sufficient to provide surge arresters with an interval of 300 m for protection against the induced overvoltage caused by the nearby lightning stroke.Use of an overhead ground wire together with surge arresters is effective for lightning protection against the direct lightning hit to a distribution line.Puncture of surge arresters is the popular outage when the outage caused by the insulation break decreases sufficiently.Also,the existence of nearby trees leads to the line break due to the side flash from a tree.Advanced lightning protection equipment with ZnO arrester components is popular in Japan.Modeling of a pole transformer and application of an electromagnetic analysis method,such as FDTD method,to surge phenomena is considerably advanced.

关键词：架空配电线路防雷保护雷击感应过电压时域有限差分方法架空地线避雷器防护方法直接雷击

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Body composition changes following chemotherapy for testicular germ cell tumor:obesity is the long-term problem

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Asian Journal of Andrology 2022年第5期24卷 458-462页

作者： Yuki Takai Sei Naito Hidenori Kanno Atsushi Yamagishi Mayu Yagi Toshihiko Sakurai Hayato Nishida Takuya Yamanobe tomoyuki Kato Norihiko Tsuchiya Department of Urology Yamagata University Faculty of MedicineYamagata 990-9585Japan

Metabolic syndrome is a long-term complication of systemic chemotherapy for testicular germ cell tumor(TGCT).It is believed to be caused by secondary hypogonadism or toxic medicines because of orchidectomy followed by systemic chemotherapy.In this study,changes in the body composition of patients over time were quantitatively analyzed up to 24 months after chemotherapy.This study retrospectively analyzed 44 patients with TGCT who underwent chemotherapy at our institution from January 2008 to December 2016.Subcutaneous and visceral fat areas and psoas and skeletal muscle areas were measured by computed tomography before and immediately after chemotherapy as well as 3 months,6 months,12 months,and 24 months after chemotherapy.The subcutaneous and visceral fat indices and psoas and skeletal muscle indices were calculated as each area divided by body height squared.The total fat area had already significantly increased 3 months after the initiation of chemotherapy(P=0.004).However,it did not return to prechemotherapeutic levels even at 24 months after chemotherapy.The skeletal muscle area was significantly decreased at the end of chemotherapy(P<0.001);however,the value returned to baseline within 12 months.In multivariable analysis,the prechemotherapeutic skeletal muscle index and number of chemotherapy cycles were independently associated with the reduction of skeletal muscle at the end of chemotherapy(P=0.001 and P=0.027,respectively).In patients with TGCT,skeletal muscle mass decreased during chemotherapy and recovered within 12 months,whereas fat mass progressively increased from the initiation of chemotherapy until 24 months after chemotherapy.

关键词： body composition chemotherapy obesity sarcopenia secondary hypogonadism testicular cancer

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A durable complete response resulting from treatment with nivolumab plus ipilimumab for metastatic collecting duct carcinoma of the kidney

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Asian Journal of Urology 2023年第3期10卷 376-378页

作者： Keisuke Funajima Sei Naito Takanobu Kabasawa Hayato Nishida tomoyuki Kato Mitsuru Futakuchi Norihiko Tsuchiya Department of Urology Yamagata University Faculty of Medicine2-2-2 Iida-nishiYamagataJapan Department of Pathology Yamagata University Faculty of Medicine2-2-2 Iida-nishiYamagataJapan

Dear Editor,Collecting duct carcinoma(CDC)or Bellini carcinoma originates in the distal collecting ducts.CDC is a markedly aggressive subtype of renal cell carcinoma and accounts for less than 1%of all renal cell carcinomas[1].We described a patient with CDC and psoriasis,who showed complete response(CR)after being treated with combination therapy of nivolumab and ipilimumab(NI).The study was conducted in accordance with and approved by the Ethics Committee of Yamagata University Faculty of Medicine(approval no.2019-35).The need for patient consent was waived by the same institutional review board;all the patients provided written informed consents.

关键词： markedly nivolumab approval

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Origin and Evolution of Ultramafic Rocks along the Sagaing Fault, Myanmar

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Journal of Earth Science 2023年第1期34卷 122-132页

作者： Tomoaki Morishita Hnin Min Soe Hla Htay Than Htut Lwin Juan Miguel Guotana Akihiro Tamura tomoyuki Mizukami Khin Zaw 无 Faculty of Geosciences and Civil Engineering Kanazawa UniversityKanazawa920-1192Japan Lamont-Doherty Earth Observatory Columbia UniversityPalisadesNY10964USA Volcanoes and Earth’s Interior Research Center Japan Agency for Marine-Earth Science and Technology2-15 NatsushimaKanagawa237-0061Japan Geology Department University of MandalayMandalay05092Myanmar Geology Department Dagon UniversityNorth Dagon11422Myanmar Taunggoke Degree College TaunggokeTaunggoke Township07161Myanmar Graduate School of Natural Science and Technology Kanazawa UniversityKanazawaIshikawa920-1192Japan CODES ARC Centre of Excellence in Ore Deposits University of TasmaniaTasmania7001Australia

The active Sagaing fault in Myanmar defines the boundary between the Indian Plate and the Eurasian Plate and causes seismic damage in the major cities of Myanmar. Small bodies of serpentinite occur along the fault. We for the first time investigated the highly sheared serpentinite bodies in the Sheinmagar area and Yega Inn area along the Sagaing fault. Extensively sheared/brecciated serpentinites and related rocks, such as talc and/or chlorite-bearing rocks contains small rock fragments of serpentinites. Serpentine texture and mineral chemistry indicate that the protolith of these serpentinites were mainly harzburgite with minor amounts of dunite, some of which are cut by gabbroic veins. No shape-preferred orientation of the antigorite is present, indicating that the serpentinization was occurred under relatively static conditions. Protolith and serpentine minerals are similar to those of the jadeitite-bearing serpentinites in the north of the Sagaing fault(the Jade Mine belt). Chemical variations of spinels in the studied area are within the compositional range of forearc peridotites and those in the mantle section of nearby ophiolites. After the formation of antigorite serpentinite under static conditions, these serpentinites were subsequently, but locally deformed, probably due to the activity of the Sagaing fault, resulting in the formation of serpentinite schist/brecciated rock. The presence of the less-deformed antigorite serpentinite in the sheared/brecciated zone indicates the strain localization mainly along the surrounding serpentine-talc(±chlorite) schistose rocks, which is probably formed by the reaction between serpentinite and country rocks. Further studies are needed to better understand whether the distribution of serpentinized peridotites cause variations in the activity of the Sagaing fault.

关键词： Sagaing fault serpentinite deformation ophiolite

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