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The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan

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Cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan clinical research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of Pathology and clinical laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National Cancer Center research Institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： Cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

The prognostic value of collateral circulation in coronary chronic total occlusion underwent percutaneous coronary intervention

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Journal of Geriatric Cardiology 2024年第2期21卷 232-241页

作者： Xiao-Ying HU Wei-Xian YANG Chang-Dong GUAN Li-Hua XIE Ke-Fei DOU Yong-Jian WU Jin-Qing YUAN Jie QIAN Yue-Jin YANG Shu-Bin QIAO Lei SONG Department of Cardiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina National clinical research Center for Cardiovascular Diseases BeijingChina Catheterization laboratories Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

BACKGROUND The prognostic value of coronary collateral circulation(CC)in patients undergoing chronic total occlusion(CTO)percutaneous coronary intervention(PCI)is *** purpose of the study was to assess the prognostic value of current two CC grading systems and their association with long-term outcomes in patients with CTO underwent *** We consecutively enrolled patients with single-vessel CTO underwent PCI between January 2010 and *** patients were categorized into well-developed or poor-developed collaterals group according to angiographic Werner's CC(grade 2 *** 0–1)or Rentrop(grade 3 *** 0–2)grading *** primary endpoint was 5-year cardiac *** Of 2452 enrolled patients,the overall technical success rate was 74.1%.Well-developed collaterals were present in686 patients(28.0%)defined by Werner's CC grade 2,and in 1145 patients(46.7%)by Rentrop grade *** to Werner's CC grading system,patients with well-developed collaterals had a lower rate of 5-year cardiac death compared with those with poordeveloped collaterals(1.6%vs.3.3%,P=0.02),those with suboptimal recanalization was associated with higher rate of 5-year cardiac death compared with optimal recanalization(4.7%vs.0.8%,P=0.01)and failure patients(4.7%vs.1.6%,P=0.12).However,the similar effect was not shown in Rentrop grading *** In patients with the single-vessel CTO underwent PCI,well-developed collaterals by Werner's CC definition were associated with lower rate of 5-year cardiac ***'s CC grading system had a greater prognostic value than Rentrop grading system in patients with CTO underwent PCI.

关键词： coronary collateral occlusion

Genomic medicine in clinical practice:national genomic medicine program in Japan

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Cancer Biology & Medicine 2024年第1期21卷 4-9页

Cancer statistics in Japan Cancer is the most common cause of death in Japan based on Statistics 2021~*** statistics were first gathered,infectious diseases,such as tuberculosis,and cerebrovascular disease have been the main causes of death in *** surpassed cerebrovascular disease as the main cause of death in 1981,and the number of cancer deaths has *** 38,000 people died of cancer in *** National Cancer Center(NCC)reported that the 5-year survival rate for patients with cancer was improving(62%for males and 66.9%for females)in a population-based cancer registry.

关键词： Cancer cancer death

Drug repurposing for cancer therapy

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1981-2013页

作者： Ying Xia Ming Sun Hai Huang Wei-Lin Jin Center for clinical laboratories The Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004PR China The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine Guiyang 550001PR China School of clinical Laboratory Science Guizhou Medical UniversityGuiyang 550004PR China Division of Gastroenterology and Hepatology Department of Medicine andDepartment of OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21287USA Institute of Cancer Neuroscience Medical Frontier Innovation Research CenterThe First Hospital of Lanzhou UniversityThe First Clinical Medical College of Lanzhou UniversityLanzhou 730000PR China

Cancer,a complex and multifactorial disease,presents a significant challenge to global *** significant advances in surgical,radiotherapeutic and immunological approaches,which have improved cancer treatment outcomes,drug therapy continues to serve as a key therapeutic ***,the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects,and thus there remains a critical need to develop novel cancer *** promising strategy that has received widespread attention in recent years is drug repurposing:the identification of new applications for existing,clinically approved *** repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective,proven to be safe,and can significantly expedite the drug development process due to their already established safety *** light of this,the present review offers a comprehensive overview of the various methods employed in drug repurposing,specifically focusing on the repurposing of drugs to treat *** describe the antitumor properties of candidate drugs,and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor *** addition,we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug *** also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy *** conclude,we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

关键词： drugs integrating spite

The role of inflammasomes in human diseases and their potential as therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 479-508页

作者： Jing Yao Keenan Sterling Zhe Wang Yun Zhang Weihong Song The National clinical research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053China Townsend Family laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Key Laboratory of Neurodegenerative Diseases Ministry of EducationBeijingP.R.China Zhejiang clinical research Center for Mental Disorders Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and The Affiliated Kangning HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325000China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiang 325000China

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune *** inflammasome complex has three major components:an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein *** formation typically occurs in response to infectious agents or cellular *** active inflammasome then triggers caspase-1 activation,followed by the secretion of pro-inflammatory cytokines and pyroptotic cell *** inflammasome activation and activity contribute to the development of diabetes,cancer,and several cardiovascular and neurodegenerative *** a result,recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation,as well as the potential of targeting inflammasomes to treat various *** clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting ***,understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic *** this article,we provide a summary of the biological and pathological roles of inflammasomes in health and *** also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

关键词： inflam therapeutic potential

Targeting ferroptosis and ferritinophagy:new targets for cardiovascular diseases

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 1-22页

作者： Yi LUAN Yang YANG Ying LUAN Hui LIU Han XING Jinyan PEI Hengdao LIU Bo QIN Kaidi REN clinical Systems Biology research laboratories Translational Medicine Centerthe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China State Key Laboratory for Artificial Microstructures and Mesoscopic Physics School of PhysicsPeking UniversityBeijing100871China School of Laboratory Medicine Xinxiang Medical UniversityXinxiang453003China Quality Management Department Henan No.3 Provincial People’s HospitalZhengzhou450052China Department of Cardiology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China Center for Translational Medicine the First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China Department of Pharmacy the First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China Henan Key Laboratory of Precision clinical Pharmacy Zhengzhou UniversityZhengzhou450052China Henan Engineering research Center for Application&Translation of Precision clinical Pharmacy Zhengzhou UniversityZhengzhou450052China

Cardiovascular diseases(CVDs)are a leading factor driving mortality ***,an essential trace mineral,is important in numerous biological processes,and its role in CVDs has raised broad discussion for ***-mediated cell death,namely ferroptosis,has attracted much attention due to its critical role in cardiomyocyte damage and ***,ferritinophagy is the upstream mechanism that induces ferroptosis,and is closely related to *** review aims to delineate the processes and mechanisms of ferroptosis and ferritinophagy,and the regulatory pathways and molecular targets involved in ferritinophagy,and to determine their roles in ***,we discuss the possibility of targeting ferritinophagy-induced ferroptosis modulators for treating ***,this review offers some new insights into the pathology of CVDs and identifies possible therapeutic targets.

关键词： Cardiovascular disease Iron Ferroptosis Ferritinophagy Therapeutic target

Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2505-2519页

作者： Xiafei Wei Yuzheng Zhou Xiaotong Shen Lujie Fan Donglan Liu Xiang Gao Jian Zhou Yezi Wu Yunfei Li Wei Feng Zheng Zhang Institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSouthern University of Science and TechnologyShenzhen 518112China Guangzhou Laboratory Guangzhou Medical UniversityGuangzhou 511495China State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China

The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long *** its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug *** this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell *** significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP *** induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower *** condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP *** results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.

关键词： SARS-CoV-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy-lysosome Drug target

Diagnostic performance of intravascular ultrasound-based fractional flow reserve in evaluating of intermediate left main stenosis

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Journal of Geriatric Cardiology 2024年第1期21卷 34-43页

作者： Yong-Gang SUI Cheng YANG Chang-Dong GUAN Yan-Lu XU Na-Qiong WU Wei-Xian YANG Yong-Jian WU Ke-Fei DOU Yue-Jin YANG Shu-Bin QIAO Wei YU Bo XU Sheng-Xian TU Jie QIAN Department of Cardiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Catheterization laboratories Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Biomedical Instrument Institute School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghaiChina National clinical research Center for Cardiovascular Diseases BeijingChina

BACKGROUND The recently introduced ultrasonic flow ratio(UFR),is a novel fast computational method to derive fractional flow reserve(FFR)from intravascular ultrasound(IVUS)*** the present study,we evaluate the diagnostic performance of UFR in patients with intermediate left main(LM)*** This is a prospective,single center study enrolling consecutive patients with presence of intermediated LM lesions(diameter stenosis of 30%-80%by visual estimation)underwent IVUS and FFR *** independent core laboratory assessed offline UFR and IVUS-derived minimal lumen area(MLA)in a blinded *** Both UFR and FFR were successfully achieved in 41 LM patients(mean age,62.0±9.9 years,46.3%diabetes).An acceptable correlation between UFR and FFR was identified(r=0.688,P50%(AUC=0.66,P<0.001)and numerically higher than IVUS-derived MLA(AUC=0.82;P=0.09).Patient level diagnostic accuracy,sensitivity and specificity for UFR to identify FFR≤0.80 was 82.9%(95%CI:70.2-95.7),93.1%(95%CI:82.2-100.0),58.3%(95%CI:26.3-90.4),*** In patients with intermediate LM diseases,UFR was proved to be associated with acceptable correlation and high accuracy with pressure wire-based FFR as standard *** present study supports the use of UFR for functional evaluation of intermediate LM stenosis.

关键词： stenosis flow fractional

miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2024年第2期14卷 635-652页

作者： Man Luo Yayan Pang Junjie Li Lilin Yi Bin Wu Qiuyun Tian Yan He Maoju Wang Lei Xia Guiqiong He Weihong Song Yehong Du Zhifang Dong Pediatric research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China Department of Anatomy Basic Medical CollegeChongqing Medical UniversityChongqing 400016China Townsend Family laboratories Department of PsychiatryThe University of British ColumbiaVancouver BC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceZhejiang Clinical Research Center for Mental DisordersSchool of Mental Health and the Affiliated Kangning HospitalWenzhou Medical UniversityWenzhou 325000China Institute for Brain Science and Disease of Chongqing Medical University Chongqing 400016China

Alzheimer ’s disease(AD) is a leading cause of dementia in the ***-activated protein kinase phosphatase 1(MKP-1) plays a neuroprotective role in ***,the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively ***(miRNAs) regulate gene expression at the post-transcriptional level,thereby repressing mRNA ***,we reported that the microRNA-429-3p(miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model *** further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3’-untranslated region(3’ UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ *** importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase(ERK1/2)-mediated GluAl hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluAl-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

关键词： Alzheimer's disease MKP-1 miR-429-3p AMPAreceptor Learning and memory Long-term potentiation