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Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway

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Science China(Life Sciences) 2024年第4期67卷 663-679页

作者： Yanfang Liu Yan Wang Bing Liu Wenzhong Liu Yuanyuan Ma Yiren Cao Shi Yan Panpan Zhang Lixin Zhou Qimin Zhan Nan Wu key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Department of Thoracic Surgery IIPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Department of Thoracic Oncology IIPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of carcinogenesis and Translational Research(ministry of Education) Department of PathologyPeking University Cancer Hospital and InstituteBeijing 100142China Peking University International Cancer Institute Beijing 100191China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen 518132China

Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.

关键词： chemoresistance lncRNARNA interference ROs chemosensitizer

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Value of multiple models of diffusion-weighted imaging to predict hepatic lymph node metastases in colorectal liver metastases patients

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World Journal of Gastroenterology 2024年第4期30卷 308-317页

作者： Hai-Bin Zhu Bo Zhao Xiao-Ting Li Xiao-Yan Zhang Qian Yao Ying-Shi Sun key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Department of RadiologyPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Department of PathologyPeking University Cancer Hospital and InstituteBeijing 100142China

BACKGROUND About 10%-31% of colorectal liver metastases(CRLM)patients would concomitantly show hepatic lymph node metastases(LNM),which was considered as sign of poor biological behavior and a relative contraindication for liver resection.Up to now,there’s still lack of reliable preoperative methods to assess the status of hepatic lymph nodes in patients with CRLM,except for pathology examination of lymph node after resection.AIM To compare the ability of mono-exponential,bi-exponential,and stretchedexponential diffusion-weighted imaging(DWI)models in distinguishing between benign and malignant hepatic lymph nodes in patients with CRLM who received neoadjuvant chemotherapy prior to surgery.METHODS In this retrospective study,97 CRLM patients with pathologically confirmed hepatic lymph node status underwent magnetic resonance imaging,including DWI with ten b values before and after chemotherapy.Various parameters,such as the apparent diffusion coefficient from the mono-exponential model,and the true diffusion coefficient,the pseudo-diffusion coefficient,and the perfusion fraction derived from the intravoxel incoherent motion model,along with distributed diffusion coefficient(DDC)andαfrom the stretched-exponential model(SEM),were measured.The parameters before and after chemotherapy were compared between positive and negative hepatic lymph node groups.A nomogram was constructed to predict the hepatic lymph node status.The reliability and agreement of the measurements were assessed using the coefficient of variation and intraclass correlation coefficient.RESULTS Multivariate analysis revealed that the pre-treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes.A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients,with an area under the curve of 0.873.Furthermore,parameters from SEM showed substantial repeatability.CONCLUSION The dev

关键词： Colorectal cancer Individualized treatment Diffusion magnetic resonance imaging Intravoxel incoherent motion Liver

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Advances in MET tyrosine kinase inhibitors in gastric cancer

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Cancer Biology & Medicine 2024年第6期21卷 484-498页

作者： Yifan Zhang Lin Shen Zhi Peng key laboratory of carcinogenesis and Translational Research (ministry of Education) Department of Gastrointestinal Oncology Peking University Cancer Hospital & Institute State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Department of Gastrointestinal Oncology Peking University Cancer Hospital & Institute

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

关键词： Gastric cancer MET alterations MET testing MET tyrosine kinase inhibitors savolitinib

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Early Growth Response Gene-1 Deficiency Interrupts TGFβ1 Signaling Activation and Aggravates Neurodegeneration in Experimental Autoimmune Encephalomyelitis Mice

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Neuroscience Bulletin 2024年第3期40卷 283-292页

作者： Yunyi Lan Xinyan Han Fei Huang Hailian Shi Hui Wu Liu Yang Zhibi Hu Xiaojun Wu Shanghai key laboratory of Compound chinese Medicines The Ministry of Education Key Laboratory for Standardization of Chinese MedicinesThe State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghai201203China Central laboratory Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai200021China

Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and neurogenesis.However,its mechanism in neuronal survival and degeneration is still poorly understood.This study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)mice.Egr-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE mice.Consistently,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y cells.Our results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.

关键词： Early growth response protein 1 Transforming growth factor-beta 1 Multiple sclerosis Experimental autoimmune encephalomyelitis Neurodegeneration

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circRNAs deregulation in exosomes derived from BEAS-2B cells is associated with vascular stiffness induced by PM_(2.5)

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Journal of Environmental Sciences 2024年第3期137卷 527-539页

作者： Qingping Liu Yaling Zhang Bin Han Mengruo Wang Huaifang Hu Jie Ning Wentao Hu Meiyu Chen Yaxian Pang Yuanyuan Chen Lei Bao Yujie Niu Rong Zhang Department of Toxicology Hebei Medical UniversityShijiazhuang 050017China State key laboratory of Environment health(Incubation) Key Laboratory of Environment and HealthMinistry of EducationKey Laboratory of Environment and Health(Wuhan)Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China China CDC key laboratory of Environment and Population health National Institute of Environmental HealthChinese Center for Disease Control and PreventionBeijing 100021China Occupational health and Environmental health Hebei Medical UniversityShijiazhuang 050017China Hebei key laboratory of Environment and Human health Hebei Medical UniversityShijiazhuang 050017China

As an environmental pollutant,ambient fine particulate matter (PM_(2.5)) was linked to cardiovascular diseases.The molecular mechanisms underlying PM_(2.5)-induced extrapulmonary disease has not been elucidated clearly.In this study the ambient PM_(2.5)exposure mice model we established was to explore adverse effects of vessel and potential mechanisms.Long-term PM_(2.5)exposure caused reduced lung function and vascular stiffness in mice.And chronic PM_(2.5)induced migration and epithelial-mesenchymal transition (EMT) phenotype in BEAS-2B cells.After PM_(2.5)treatment,the circRNAs and mRNAs levels of exosomes released by BEAS-2B cells were detected by competing endogenous RNA (ceRNA) array,which contained 1664 differentially expressed circRNAs (DE-circRNAs) and 308 differentially expressed m RNAs (DE-mRNAs).By bioinformatics analysis on host genes of DE-circRNAs,vascular diseases and some pathways related to vascular diseases including focal adhesion,tight junction and adherens junction were enriched.Then,ceRNA network was constructed,and DE-mRNAs in ceRNA network were conducted functional enrichment analysis by Ingenuity Pathway Analysis,which indicated that hsa_circ_0012627,hsa_circ_0053261and hsa_circ_0052810 were related to vascular endothelial dysfunction.Furthermore,it was verified experimentally that Exo^(PM2.5)could induce endothelial dysfunction by increased endothelial permeability and decreased relaxation in vitro.In present study,we investigated in-depth knowledge into the molecule events related to PM_(2.5) toxicity and pathogenesis of vascular diseases.

关键词： Fine particulate matter Vascular stiffness Exosome ceRNA microarray Endothelial dysfunction

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Helicobacter pylori and immunotherapy for gastrointestinal cancer

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The Innovation 2024年第2期5卷 51-60页

作者： Keren Jia Yang Chen Yi Xie Xicheng Wang Yajie Hu Yu Sun Yanshuo Cao Liyan Zhang Yakun Wang Zhenghang Wang Zhihao Lu Jian Li Xiaotian Zhang Lin Shen key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China key laboratory of carcinogenesis and Translational Research(ministry of Education/Beijing) Department of PathologyPeking University Cancer Hospital&InstituteBeijing 100142China

Helicobacter pylori infection is associated with the risk of gastrointestinal(GI)cancers;however,its impact on immunotherapy for GI cancers remains uncertain.In this study,we included 10,122 patients who underwent ^(13)C-urea breath tests.Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer(GC)who were treated with anti-PD-1/PD-L1 therapy,H.pylori–positive patients exhibited significantly longer immune-related progression-free survival(irPFS)compared with H.pylori–negative patients(6.97 months versus 5.03 months,p<0.001,hazard ratio[HR]0.76,95%confidence interval[CI]0.62–0.95,p=0.015).Moreover,the H.pylori–positive group demonstrated a trend of 4 months longer median immune-related overall survival(irOS)than the H.pylori–negative group.H.pylori–positive GC displayed higher densities of PD-L1+cells and nonexhausted CD8+T cells,indicative of a“hot”tumor microenvironment.Transcriptomic analysis revealed that H.pylori–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC.However,H.pylori–positive patients with DNA mismatch repair–deficient(dMMR)/microsatellite instability–high(MSI-H)colorectal adenocarcinoma and esophageal squamous cell carcinoma(ESCC)had shorter irPFS compared with H.pylori–negative patients(16.13 months versus not reached,p=0.042,HR 2.26,95%CI 1.13–4.50,p=0.021 and 5.57 months versus 6.97 months,p=0.029,HR 1.59,95%CI 1.14–2.23,p=0.006,respectively).The difference in irOS between H.pylori–positive and–negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients.We also identified a trend of shorter irPFS and irOS in H.pylori–positive liver cancer and pancreatic cancer patients.In summary,our findings supported that H.pylori infection is a beneficial factor for GC immunotherapy by shaping hot tumor microenvironments.However,in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients,H.pylori adversely affects the efficacy of immunotherapy.

关键词： immunotherapy gastrointestinal pylori

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Ferroptosis:a critical mechanism of N^(6)-methyladenosine modification involved in carcinogenesis and tumor progression

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Science China(Life Sciences) 2024年第6期67卷 1119-1132页

作者： Qingqing Wei Changning Xue Mengna Li Jianxia Wei Lemei Zheng Shipeng Chen Yumei Duan Hongyu Deng Faqing Tang Wei Xiong Ming Zhou NHC key laboratory of carcinogenesis Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China Cancer Research Institute and School of Basic Medical Sciences Central South UniversityChangsha 410078China The key laboratory of carcinogenesis and Cancer Invasion of the chinese ministry of Education Central South UniversityChangsha 410078China Hunan key laboratory of Oncotarget Gene Hunan Key Laboratory of Cancer MetabolismHunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

关键词： ferroptosis m6A modification RNA methylation m^(6)A regulator tumor progression

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Total-factor energy efficiency of ten major global energy-consuming countries

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Journal of Environmental Sciences 2024年第3期137卷 41-52页

作者： Xuan Wang Yonglong Lu Chunci Chen Xiaojie Yi Haotian Cui State key laboratory of Urban and Regional Ecology Research Centre for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China State key laboratory of Marine Environmental Science and key laboratory of the ministry of Education for Coastal Wetland Ecosystems College of the Environment and EcologyXiamen UniversityFujian 361102China University of chinese Academy of Sciences Beijing 100049China

Improving energy efficiency is regarded as a key path to tackling global warming and achieving the Sustainable Development Goals(SDGs).In 2020,the energy consumption of the world's ten major energy-consuming countries accounted for 66.8%of the global total.This paper applied data envelopment analysis(DEA)to calculate these ten major energyconsuming countries'total-factor energy efficiency(TFEE)at national and sectoral levels from 2001-2020,and explored the infuencing factors of total-factor energy efficiency with the Tobit regression model.The results showed significant difference in the ten countries'energy efficiency.The United States and Germany topped the list for total-factor energy efficiency,while China and India were at the bottom.Meanwhile,the energy efficiency of the industrial subsector has increased significantly over the past two decades,while that of the other subsectors has been relatively fat.The industrial structure upgrading,per capita GDP,energy consumption structure,and foreign direct investment had significant impacts on energy efficiency with national heterogeneity.Energy consumption structure and GDP per capita were determinative factors of energy efficiency.

关键词： Total-factor energy efficiency SBM-UN model Major energy-consuming country Carbon emission reduction

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OcBSA:An NGS-based bulk segregant analysis tool for outcross populations

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Molecular Plant 2024年第4期17卷 648-657页

作者： Lingkui Zhang Yanfeng Duan Zewei Zhang Lei Zhang Shumin Chen Chengcheng Cai Shaoguang Duan Kang Zhang Guangcun Li Feng Cheng State key laboratory of Vegetable Biobreeding Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of the Ministry of Agriculture and Rural AffairsKey Laboratory of Biology and Genetic Improvement of Tuber and Root Crop of Ministry of Agriculture and Rural AffairsSino-Dutch Joint Laboratory of Horticultural GenomicsInstitute of Vegetables and FlowersChinese Academy of Agricultural SciencesBeijing 100081China

Constructing inbred lines for self-incompatible species and species with long generation times is challenging,making the use of F1 outcross/segregating populations the main strategy for genetic studies of such species.However,there is a lack of dedicated algorithms/tools for rapid quantitative trait locus(QTL)mapping using the F1 populations.To this end,we have designed and developed an algorithm/tool called OcBSA specifically for QTL mapping of F1 populations.OcBSA transforms the four-haplotype inheritance problem from the two heterozygous diploid parents of the F1 population into the two-haplotype inheritance problem common in current genetic studies by removing the two haplotypes from the heterozygous parent that do not contribute to phenotype segregation in the F1 population.Testing of OcBSA on 1800 simulated F1 populations demonstrated its advantages over other currently available tools in terms of sensitivity and accuracy.In addition,the broad applicability of OcBSA was validated by QTL mapping using seven reported F1 populations of apple,pear,peach,citrus,grape,tea,and rice.We also used OcBSA to map the QTL for flower color in a newly constructed F1 population of potato generated in this study.The OcBSA mapping result was verified by the insertion or deletion markers to be consistent with a previously reported locus harboring the ANTHOCYANIN 2 gene,which regulates potato flower color.Taken together,these results highlight the power and broad utility of OcBSA for QTL mapping using F1 populations and thus a great potential for functional gene mining in outcrossing species.For ease of use,we have developed both Windows and Linux versions of OcBSA,which are freely available at:https://***/Bioinformaticslab/OcBSA.

关键词： outcross BSA self-incompatible F1 population QTL mapping potato

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Nitrogen deposition mediates more stochastic processes in structuring plant community than soil microbial community in the Eurasian steppe

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Science China(Life Sciences) 2024年第4期67卷 778-788页

作者： Wei Yang Shuhan Zhang Ang Li Junjie Yang Shuang Pang Zonghao Hu Zhiping Wang Xingguo Han Ximei Zhang key laboratory of Dryland Agriculture Ministry of AgricultureInstitute of Environment and Sustainable Development in AgricultureChinese Academy of Agricultural SciencesBeijing 100081China State key laboratory of Vegetation and Environmental Change Institute of BotanyChinese Academy of SciencesBeijing 100093China

Anthropogenic environmental changes may affect community assembly through mediating both deterministic(e.g.,competitive exclusion and environmental filtering)and stochastic processes(e.g.,birth/death and dispersal/colonization).It is traditionally thought that environmental changes have a larger mediation effect on stochastic processes in structuring soil microbial community than aboveground plant community;however,this hypothesis remains largely untested.Here we report an unexpected pattern that nitrogen(N)deposition has a larger mediation effect on stochastic processes in structuring plant community than soil microbial community(those<2 mm in diameter,including archaea,bacteria,fungi,and protists)in the Eurasian steppe.We performed a ten-year nitrogen deposition experiment in a semiarid grassland ecosystem in Inner Mongolia,manipulating nine rates(0–50 g N m^(-2)per year)at two frequencies(nitrogen added twice or 12 times per year)under two grassland management strategies(fencing or mowing).We separated the compositional variation of plant and soil microbial communities caused by each treatment into the deterministic and stochastic components with a recently-developed method.As nitrogen addition rate increased,the relative importance of stochastic component of plant community first increased and then decreased,while that of soil microbial community first decreased and then increased.On the whole,the relative importance of stochastic component was significantly larger in plant community(0.552±0.035;mean±standard error)than in microbial community(0.427±0.035).Consistently,the proportion of compositional variation explained by the deterministic soil and community indices was smaller for plant community(0.172–0.186)than microbial community(0.240–0.767).Meanwhile,as nitrogen addition rate increased,the linkage between plant and microbial community composition first became weaker and then became stronger.The larger stochasticity in plant community relative to microbial community assembly suggested that more stochasti

关键词： deterministic process environmental change grassland restoration nitrogen deposition stochastic process

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