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Identification of a dihydroorotate dehydrogenase inhibitor thatinhibits cancer cell growth by proteomic profiling

肿瘤学研究(英文) 2023年第6期31卷 833-844页

作者： MAKOTO KAWATANI HARUMI AONO SAYOKO HIRANUMA takeshi shimizu MAKOTO MUROI TOSHIHIKO NOGAWA TOMOKAZU OHISHI SHUN-ICHI OHBA MANABU KAWADA KANAMI YAMAZAKI SHINGO DAN NAOSHI DOHMAE HIROYUKI OSADA Biomolecular Characterization Unit Technology Platform DivisionRIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Chemical Resource Development Unit Technology Platform DivisionRIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Chemical Biology Research Group RIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Molecular Structure Characterization Unit Technology Platform DivisionRIKEN Center for Sustainable Resource Science(CSRS)Saitama351-0198Japan Institute of Microbial Chemistry(BIKAKEN) NumazuMicrobial Chemistry Research FoundationShizuoka410-0301Japan Division of Molecular Pharmacology Cancer Chemotherapy CenterJapan Foundation for Cancer ResearchTokyo135-8550Japan Department of Pharmaceutical Sciences University of ShizuokaShizuoka422-8526Japan

Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune *** study presents the identification of a potent DHODH inhibitor by proteomic ***-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer *** profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic ***,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic *** results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell ***,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.

关键词： Anticancer agents Differentiating agents Drug target identification

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Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?

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World Journal of Gastroenterology 2024年第10期30卷 1368-1376页

作者： Nobukazu Agatsuma Takahiro Utsumi Yoshitaka Nishikawa Takahiro Horimatsu takeshi Seta Yukitaka Yamashita Yukari Tanaka Takahiro Inoue Yuki Nakanishi Takahiro shimizu Mikako Ohno Akane Fukushima Takeo Nakayama Hiroshi Seno Department of Gastroenterology and Hepatology Kyoto University Graduate School of MedicineKyoto 606-8507Japan Department of Gastroenterology and Hepatology Japanese Red Cross Wakayama Medical CenterWakayama 640-8558Japan Department of Health Informatics Kyoto University School of Public HealthKyoto 606-8501Japan Institute for Advancement of Clinical and Translational Science(iACT) Kyoto University HospitalKyoto 606-8507Japan Medical Support Section Medical Affairs DivisionKyoto University HospitalKyoto 606-8507Japan

BACKGROUND Colorectal cancer(CRC)is a global health concern,with advanced-stage diagnoses contributing to poor *** efficacy of CRC screening has been well-established;nevertheless,a significant proportion of patients remain unscreened,with>70%of cases diagnosed outside *** identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources,the association between the diagnostic routes and identification of these subgroups has been less *** the Japanese cancer registry,the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related *** To clarify the stage at CRC diagnosis based on diagnostic *** We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two *** diagnostic routes were primarily classified into three groups:Cancer screening,follow-up,and *** early-stage was defined as Stages 0 or *** and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups,referencing the follow-up *** adjusted covariates were age,sex,and tumor *** Of the 2083 patients,715(34.4%),1064(51.1%),and 304(14.6%)belonged to the follow-up,symptomatic,and cancer screening groups,*** the 2083 patients,CRCs diagnosed at an early stage were 57.3%(410 of 715),23.9%(254 of 1064),and 59.5%(181 of 304)in the follow-up,symptomatic,and cancer screening groups,*** symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group[P<0.001,adjusted odds ratio(aOR),0.23;95%confidence interval(95%CI):0.19-0.29].The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening gro

关键词： Colorectal neoplasms Cancer registry Diagnostic route Cancer screening Stage at diagnosis

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Prognostic factors in heart failure patients with cardiac cachexia

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Journal of Geriatric Cardiology 2020年第1期17卷 26-34页

作者： Yu Sato Akiomi Yoshihisa Yusuke Kimishima Tetsuro Yokokawa Satoshi Abe takeshi shimizu Tomofumi Misaka Shinya Yamada Takamasa Sato Takashi Kaneshiro Masayoshi Oikawa Atsushi Kobayashi Takayoshi Yamaki Hiroyuki Kunii Yasuchika Takeishi Department of Cardiovascular Medicine Fukushima Medical UniversityFukushimaJapan Department of Advanced Cardiac Therapeutics Fukushima Medical UniversityFukushimaJapan

Objective To clarify whether cardiac cachexia(CC)alters the prognostic impact of other general risk factors in patients with heart failure(HF).Methods This was an observational *** was defined as the combination of a body mass index of5 mg/L;hemoglobin<12 g/dL;and/or albumin<3.2 g/d *** divided 1608 hospitalized HF patients into a CC group(n=176,10.9%)and a non-CC group(n=1432,89.1%).The primary endpoints were cardiac event and all-cause *** The presence of CC showed significant interactions with other risk factors including cancer,estimated glomerular filtration rate(eGFR),and sodium in predicting these *** Cox proportional analysis revealed that use of a blockers[hazard ratio(HR)=1.900,95%confidence interval(CI):1.045–3.455,P=0.035]and eGFR(HR=0.989,95%CI:0.980–0.998,P=0.018)were independent predictors of cardiac event in the CC group,while age(HR=1.020,95%CI:1.002–1.039,P=0.029)and hemoglobin(HR=0.844,95%CI:0.734–0.970,P=0.017)were independent predictors of all-cause *** survival classification and regression tree analysis showed the optimal cut-off points for cardiac event(eGFR:59.9 m L/min per 1.73 m^2)and all-cause death(age,83 years old;hemoglobin,10.1 g/dL)in the CC *** In predicting prognosis,CC showed interactions with several risk *** function,age,and hemoglobin were pivotal markers in HF patients with CC.

关键词： Body mass index Cachexia Heart failure Mortality Prognosis

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True left-sided gallbladder with variations of bile duct and cholecystic vein

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World Journal of Gastroenterology 2015年第21期21卷 6754-6758页

作者： Hiromichi Ishii Akinori Noguchi Mie Onishi Koji Takao Takahiro Maruyama Hiroaki Taiyoh Yasunobu Araki takeshi shimizu Hiroyuki Izumi Naoki Tani Masahide Yamaguchi Tetsuro Yamane Department of Surgery Matsushita Memorial Hospital

A left-sided gallbladder without a right-sided round ligament,which is called a true left-sided gallbladder,is extremely rare.A 71-year-old woman was referred to our hospital due to a gallbladder *** tomography(CT) revealed not only a gallbladder polyp but also the gallbladder located to the left of the round ligament connected to the left umbilical *** portography revealed that the main portal vein diverged into the right posterior portal vein and the common trunk of the left portal vein and right anterior portal *** cholangiography revealed that the infraportal bile duct of segment 2 joined the common bile *** cholecystectomy was performed for a gallbladder polyp,and the intraoperative finding showed that the cholecystic veins joined the round ligament.A true left-sided gallbladder is closely associated with several anomalies; therefore,surgeons encountering a true left-sided gallbladder should be aware of the potential for these anomalies.

关键词： True left-sided gallbladder Infraportal bileduct of segment 2 Anomaly of the cholecystic vein Anomaly of the portal vein Laparoscopic cholecystectomy

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Helicobacter pylori eradication treatment for primary gastric diffuse large B-cell lymphoma:A single-center analysis

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世界临床病例杂志 2023年第27期11卷 6424-6430页

作者： Makoto Saito Akio Mori Sayaka Kajikawa Emi Yokoyama Minoru Kanaya Koh Izumiyama Masanobu Morioka takeshi Kondo Zen-Ichi Tanei Ai shimizu Blood Disorders Center Aiiku HospitalSapporo 064-0804HokkaidoJapan Department of Cancer Pathology Faculty of MedicineHokkaido UniversitySapporo 060-8638HokkaidoJapan Department of Surgical Pathology Hokkaido University HospitalSapporo 060-8648HokkaidoJapan

BACKGROUND Unlike the already established effect of Helicobacter pylori(***)eradication on gastric mucosa-associated lymphoid tissue(MALT)lymphoma,its therapeutic effect on primary gastric diffuse large B-cell lymphoma(DLBCL)is still *** To clarify the efficacy of *** eradication treatment for primary gastric *** We reported on 3 new cases,and added them to 3 previously reported *** analyzed the usefulness of *** eradication treatment for gastric DLBCL for a total of 6 cases at our *** Of the 6 patients(27-90 years old,3 males and 3 females),all 3 patients with single lesions(one transformed from MALT lymphoma)achieved complete remission(CR)after *** *** the 2 newly reported cases,CR was maintained for more than 6 years with eradication treatment *** contrast,none of the 3 patients with 2 lesions achieved *** 1 newly reported case,endoscopic CR was achieved in one lesion,while stable disease was obtained in the other *** patients with progressive disease responded to standard chemo therapy±radiation and remained in CR for more than 6 *** We believe it is worthwhile to attempt *** eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden.

关键词： Primary gastric diffuse large B-cell lymphoma Treatment Helicobacter pylori Eradication

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Gallbladder Burkitt's lymphoma mimicking gallbladder cancer:A case report

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World Journal of Gastroenterology 2022年第6期28卷 675-682页

作者： Kiyotaka Hosoda Akira shimizu Koji Kubota Tsuyoshi Notake Hikaru Hayashi Koya Yasukawa Kentaro Umemura Atsushi Kamachi Takamune Goto Hidenori Tomida Shiori Yamazaki Yuri Narusawa Naoko Asano takeshi Uehara Yuji Soejima Division of Gastroenterological Hepato-Biliary-PancreaticTransplantation and Pediatric SurgeryDepartment of SurgeryShinshu University School of MedicineMatsumoto 390-8621Japan Department of Laboratory Medicine Shinshu University School of MedicineMatsumoto 390-8621Japan

BACKGROUND Malignant lymphoma is a rare form of gallbladder *** of these malignancies are diffuse large B-cell lymphomas or mucosa-associated lymphoid tissue-type lymphomas;however,Burkitt’s lymphoma of the gallbladder is extremely rare,and only two previous reports are available in the ***,we report a rare case of Burkitt’s lymphoma of the gallbladder mimicking gallbladder *** SUMMARY An 83-year-old man with no abdominal complaints was found to have a gallbladder tumor and periportal lymph node enlargement on computed tomography(CT)performed for hypertension *** laboratory data revealed slightly elevated serum levels of carcinoembryonic antigen and soluble interleukin 2 *** examinations revealed two irregular and contrastenhanced masses extending into the gallbladder lumen,but these did not infiltrate the ***,a periportal lymph node had enlarged to 30 *** on these findings,we diagnosed the patient as having gallbladder adenocarcinoma with lymph node metastasis,which was treated using bile duct resection with gallbladder bed resection and periportal lymph node ***,the patient was finally diagnosed as having Burkitt’s *** the surgical margin was pathologically negative,recurrence was noted at the hepatic radical margin and superior pancreaticoduodenal lymph nodes on positron emission tomography/CT soon after ***,he was referred to a hematologist and started receiving treatment with reduced-dose cyclophosphamide,doxorubicin,vincristine,and *** Burkitt’s lymphoma can occur in the *** can be useful in cases with findings suggestive of gallbladder malignant lymphoma.

关键词： Gallbladder Malignant lymphoma Burkitt’s lymphoma Gallbladder cancer Lymphadenopathy Case report

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Anoctamin 5 regulates the cell cycle and affects prognosis in gastric cancer

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World Journal of Gastroenterology 2022年第32期28卷 4649-4667页

作者： Tomoyuki Fukami Atsushi Shiozaki Toshiyuki Kosuga Michihiro Kudou Hiroki shimizu Takuma Ohashi Tomohiro Arita Hirotaka Konishi Shuhei Komatsu takeshi Kubota Hitoshi Fujiwara Kazuma Okamoto Mitsuo Kishimoto Yukiko Morinaga Eiichi Konishi Eigo Otsuji Division of Digestive Surgery Department of SurgeryKyoto Prefectural University of MedicineKyoto 602-8566Japan Department of Pathology Kyoto City HospitalKyoto 604-8845Japan Department of Pathology Kyoto Prefectural University of MedicineKyoto 602-8566Japan

BACKGROUND Anoctamin 5(ANO5)/transmembrane protein 16E belongs to the ANO/transmembrane protein 16 anion channel *** comprise a family of plasma membrane proteins that mediate ion transport and phospholipid scrambling and regulate other membrane proteins in numerous cell *** studies have elucidated the roles and mechanisms of ANO5 activation in various cancer ***,it remains unclear whether ANO5 acts as a plasma membrane chloride channel,and its expression and functions in gastric cancer(GC)have not been *** To examine the role of ANO5 in the regulation of tumor progression and clinicopathological significance of its expression in *** Knockdown experiments using ANO5 small interfering RNA were conducted in human GC cell lines,and changes in cell proliferation,cell cycle progression,apoptosis,and cellular movement were *** gene expression profiles of GC cells were investigated following ANO5 silencing by microarray *** staining of ANO5 was performed on 195 primary tumor samples obtained from patients with GC who underwent curative gastrectomy between 2011 and 2013 at our *** Reverse transcription-quantitative polymerase chain reaction(PCR)and western blotting demonstrated high ANO5 mRNA and protein expression,respectively,in NUGC4 and MKN45 *** these cells,ANO5 silencing inhibited cell proliferation and induced *** addition,the knockdown of ANO5 inhibited G1-S phase progression,invasion,and *** results of the microarray analysis revealed changes in the expression levels of several cyclin-associated genes,such as CDKN1A,CDK2/4/6,CCNE2,and E2F1,in ANO5-depleted NUGC4 *** expression of these genes was verified using reverse transcription-quantitative *** staining revealed that high ANO5 expression levels were associated with a poor *** analysis identified high ANO5 expression as an independent prognostic fa

关键词： Anoctamin 5 Gastric cancer Cell cycle G1/S checkpoint Cell proliferation

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Cell-free synthesis of stable isotope-labeled internal standards for targeted quantitative proteomics

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Synthetic and Systems Biotechnology 2018年第2期3卷 97-104页

作者： Ryohei Narumi Keiko Masuda takeshi Tomonaga Jun Adachi Hiroki RUeda Yoshihiro shimizu Laboratory of Proteome Research National Institutes of Biomedical InnovationHealth and Nutrition7-6-8Satio-AsagiIbarakiOsaka 567-0085Japan Laboratory for Single Cell Mass Spectrometry RIKEN Quantitative Biology Center(QBiC)6-2-3FuruedaiSuitaOsaka 565-0874Japan Department of Systems Pharmacology Graduate School of MedicineThe University of Tokyo7-3-1 HongoBunkyo-kuTokyo 113-0033Japan Laboratory for Synthetic Biology RIKEN Quantitative Biology Center(QBiC)6-2-3FuruedaiSuitaOsaka 565-0874Japan Laboratory for Cell-Free Protein Synthesis RIKEN Quantitative Biology Center(QBiC)6-2-3FuruedaiSuitaOsaka 565-0874Japan

High-sensitivity mass spectrometry approaches using selected reaction monitoring(SRM)or multiple reaction monitoring(MRM)methods are powerful tools for targeted quantitative proteomics-based investigation of dynamics in specific biological *** high-sensitivity detection of lowabundance proteins and their quantification using this technique employ stable isotope-labeled peptide internal ***,there are various ways for preparing standards,including chemical peptide synthesis,cellular protein expression,and cell-free protein or peptide ***-free protein synthesis(CFPS)or in vitro translation(IVT)systems in particular provide high-throughput and low-cost preparation methods,and various cell types and reconstituted forms are now commercially ***,we review the use of such systems for precise and reliable protein quantification.

关键词： Absolute quantification Mass spectrometry Cell-free protein synthesis system In vitro translation Targeted quantitative proteomics PURE system

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Evaluation of small bowel blood flow in healthy subjects receiving low-dose aspirin

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World Journal of Gastroenterology 2011年第2期17卷 226-230页

作者： Urara Nishida Mototsugu Kato Mutsumi Nishida Go Kamada takeshi Yoshida Shouko Ono Yuichi shimizu Masahiro Asaka Department of Gastroenterology Hokkaido University Graduate School of Medicine Division of Endoscopy Hokkaido University Hospital Department of Clinical Laboratory and Transfusion Hokkaido University Hospital

AIM:To investigate the relationship between low-dose aspirin-induced small bowel mucosal damage and blood flow,and the effect of rebamipide. METHODS:Ten healthy volunteers were enrolled in this *** subjects were divided into two groups:a placebo group given low-dose aspirin plus placebo and a rebamipide group given low-dose aspirin plus rebamipide for a period of 14 *** endoscopy and contrast-enhanced ultrasonography were performed before and after administration of *** under the curves and peak value of time-intensity curve were calculated. RESULTS:Absolute differences in areas under the curves were-1102.5(95%CI:-1980.3 to-224.7,P=0.0194) in the placebo group and-152.7(95%CI:-1604.2 to 641.6,P=0.8172) in the rebamipide group. Peak values of time intensity curves were-148.0(95% CI:-269.4 to-26.2,P=0.0225) in the placebo group and 28.3(95%CI:-269.0 to 325.6,P=0.8343) in the rebamipide *** endoscopy showed mucosal breaks only in the placebo group. CONCLUSION:Short-term administration of low-dose aspirin is associated with small bowel injuries and blood flow.

关键词：阿司匹林血液流动低剂量小肠健康强度曲线评价药物管理

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An Integrated Approach for Decision Support through Multi-objective Optimization with Application to an Ill-posed Design Problem

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Computer Technology and Application 2011年第11期2卷 912-925页

作者： Yoshiaki shimizu Yasumasa Kato takeshi Kariyahara Mechanical Engineering Toyohashi University of Technology Toyohashi 441-8580 Japan

In the current scenario of global competition and short product life cycles, customer-defined satisfaction has attracted interest in artifact design. Accordingly, intelligent decision-making through multi-objective optimization has been proposed as an efficient method for human-centered manufacturing. However, previous vast researches on optimization have been mainly focused on optimization theory and optimization techniques and paid little interests on the process of problem formulation itself. In this paper, therefore, the authors present a total framework for supporting multi-objective decision making. Then, the authors try to solve the formulated multi-objective optimization problem that involves both qualitative and quantitative performance measures as a general consequence from the above procedure. Taking especially quality as a qualitative measure, the authors gave a new idea to evaluate the quality quantitatively. Additionally, to facilitate the portability of the proposed method in multidisciplinary decision-making environments, the authors implement the proposal algorithm in an Excel spreadsheet and validate the effectiveness of the approach through a case study.

关键词：多目标优化问题设计问题决策支持 Excel电子表格应用产品生命周期评估质量以人为中心

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