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AKT2^(S1.8)/CCTα^(S31./31./323)-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 782-796页

作者： Jie Chen Lingyuan Zhang Yuheng Zhu Di Zhao Jing Zhang Yanmeng Zhu Jingyuan Pang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan Key Laboratory of Carcinogenesis and Translational research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina Peking University International cancer {1. Peking University100191 BeijingChina research Unit of Molecular {1. research Chinese Academy of Medical SciencesBeijingChina Soochow University cancer {1. Suzhou 215000China institute of {1. research Shenzhen Bay LaboratoryShenzhen 518107China

Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic *** study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser1.8 and pCCTαSer31./31./323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)***,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in ***,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer31./31./323 sites and eventually enhancing stromal PC *** activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK *** of clinical samples demonstrated that stromal pAKT2 Ser1.8 and pCCTαSer31./31./323 are related to the tumor malignancy and reduced patient ***-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC *** conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

关键词： CAFs metabolism resistance

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Magnetic resonance imaging-based lymph node radiomics for predicting the metastasis of evaluable lymph nodes in rectal cancer

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1849-1860页

作者： Yong-Xia Ye Liu Yang Zheng Kang Mei-Qin Wang Xiao-Dong Xie Ke-Xin Lou Jun Bao Mei Du Zhe-Xuan Li Department of Radiology The Affiliated Cancer Hospital of Nanjing Medical University&Jiangsu Cancer Hospital&Jiangsu Institute of Cancer ResearchNanjing 210011Jiangsu ProvinceChina Department of Colorectal Surgery Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing 210000Jiangsu ProvinceChina1 Department of Pathology The Affiliated Cancer Hospital of Nanjing Medical University&Jiangsu Cancer Hospital&Jiangsu Institute of Cancer ResearchNanjing 210011Jiangsu ProvinceChina Colorectal Center The Affiliated Cancer Hospital of Nanjing Medical University&Jiangsu Cancer Hospital&Jiangsu Institute of Cancer ResearchNanjing 210011Jiangsu ProvinceChina

BACKGROUND Lymph node(LN)staging in rectal cancer(RC)affects treatment decisions and patient *** radiologists,the traditional preoperative assessment of LN metastasis(LNM)using magnetic resonance imaging(MRI)poses a *** To explore the value of a nomogram model that combines Conventional MRI and radiomics features from the LNs of RC in assessing the preoperative metastasis of evaluable *** In this retrospective study,270 LNs(1.8 nonmetastatic,1.2 metastatic)were randomly split into training(n=1.9)and validation sets(n=81..LNs were classified based on pathology-MRI *** MRI features[size,shape,margin,T2-weighted imaging(T2WI)appearance,and CE-T1.weighted imaging(T1.I)enhancement]were *** radiomics models used 3D features from T1.I and T2WI ***,a nomogram model combining conventional MRI and radiomics features was *** model used univariate analysis and multivariable logistic *** employed the receiver operating characteristic curve,with DeLong test for comparing diagnostic *** performance was assessed using calibration and decision curve *** The nomogram model outperformed conventional MRI and single radiomics models in evaluating *** the training set,the nomogram model achieved an area under the curve(AUC)of 0.92,which was significantly higher than the AUCs of 0.82(P1.and 0.89(P1.of the conventional MRI and radiomics models,*** the validation set,the nomogram model achieved an AUC of 0.91.significantly surpassing 0.80(P1.and 0.86(P1.,*** The nomogram model showed the best performance in predicting metastasis of evaluable LNs.

关键词： Radiomics Lymph node metastasis Rectal cancer Magnetic resonance imaging

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Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma:a real-world study

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cancer Biology & Medicine 2024年第9期21卷 799-812页

作者： Yuxiao Liu Xiaofan Guo Peijun Xu Yuning Song Jing Huang Xingyun Chen Wenbo Zhu Jihui Hao Song Gao Department of Pancreatic cancer Tianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin's Clinical Research Center for CancerTianjin 300060China

Objective:Little progress has been made in recent years using first-line chemotherapy,including gemcitabine combined with nab-paclitaxel,FOLFIRINOX,and NALIRIFOX,for advanced pancreatic adenocarcinoma(APC).In addition,the optimal second-line chemotherapy regimen has not been *** study aimed to compare the effectiveness of different types of second-line chemotherapy for ***:Patients with APC who received first-line treatment from January 2008 to January 2021.were considered eligible for this retrospective *** primary and secondary endpoints were overall survival(OS)and progression-free survival(PFS),***:Four hundred and thirty-seven and 61. patients were treated with 5-fluorouracil-and gemcitabine-based chemotherapy as first-line treatment,*** and clinical features,except age and liver metastasis,were comparable between the two groups(P1.244,95%CI=1.090–1.41.;P1..The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care,respectively(HR=0.766,95%CI=0.677–0.867;P1..The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination ***:A 5-fluorouracil-or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

关键词： Second-line chemotherapy advanced pancreatic adenocarcinoma 5-fluorouracil gemcitabine real-world study

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Targeting lncRNA1. 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 {1. Beijing 100191China institute of {1. research Shenzhen Bay LaboratoryShenzhen 518132China

Chemoresistance is a significant barrier to effective cancer *** mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting ***,we report a novel function of lncRNA1. in the inhibition of ROS generation and the progression of *** analyzing the serum levels of lncRNA1. in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 1. NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 1.8 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 lncRNA1. exhibited a poor response to platinum-based *** expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of ***1. binds to HBB and promotes HBB accumulation by inhibiting ***1. 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 ***,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA1. targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in ***,lncRNA1. is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA1. intervention can substantially enhance anti-tumor efficacy.

关键词： chemoresistance lncRNARNA interference ROs chemosensitizer

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Gastric cancer secreted miR 21.-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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Oncology research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI Medical Oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell *** is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis ***,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported *** exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been ***,we show that exosomes secreted by gastric cancer cells carry miR-21..3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of *** conclusion,inhibition of miR-21.-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome Tyrosine kinase inhibitor Gastrointestinal tumors miRNA

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Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma

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National Science Review 2024年第5期11卷 170-185页

作者： Yong Zhou Shanlan Mo Heyang Cui Ruifang Sun Weimin Zhang Xiaofei Zhuang Enwei Xu Hongyi Li Yikun Cheng Yongsheng Meng Meilin Liu Ting Yan Huijuan Liu Ling Zhang Bin Yang Yanfeng Xi Shubin Wang Xiaolong Cheng Shuai Cheng Li Zhihua Liu Qimin Zhan Zheng Hu Yongping Cui cancer {1. Department of Pathology Peking University Shenzhen Hospital Shenzhen Peking University-the Hong Kong University of Science and Technology(PKU-HKUST) Medical Center Institute of Cancer ResearchShenzhen Bay Laboratory Key Laboratory of Cellular Physiology of the Ministry of Education Department of Pathology Shanxi Medical University City University of Hong Kong Shenzhen research {1. CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of Sciences Department of Surgery Faculty of Medicine The Chinese University of Hong Kong Department of Tumor Biobank Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Key Laboratory of Carcinogenesis and Translational research(Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute research Unit of Molecular {1. research Chinese Academy of Medical Sciences Department of Thoracic Surgery Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Department of Pathology Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University College of Letters & Science University of California Berkeley State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Esophageal squamous cell carcinoma（ESCC） is a poor-prognostic cancer type with extensive intra-and inter-patient heterogeneity in both genomic variations and tumor microenvironment（TME）. However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 1.3 patients. We identified a novel tumor suppressor PREX2,accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the ***, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted ***, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

关键词： squamous cell carcinoma heterogeneity multi-omics evolution tumor microenvironment

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A retrospective analysis of mature T-and NK-cell lymphomas

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cancer Biology & Medicine 2024年第3期21卷 223-229页

作者： Junlei Jia Xiaohui Wang Zheng Song Shen Meng Yue Fei Jingwei Yu Xia Liu Xue Han Lanfang Li Lihua Qiu Zhengzi Qian Shiyong Zhou Wenchen Gong Bin Meng Xiubao Ren Xianhuo Wang Huilai Zhang National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine and Department of LymphomaTianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinThe Sino-US Center for Lymphoma and Leukemia ResearchTianjin 300060China Department of Radiation Oncology Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinan 250117China Department of Pathology Department of Immunology/Biotherapy Tianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin 300060China

Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1.per 1.0,000 people, according... 详细信息

关键词： lymphoma neoplasms killer

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The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells

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research 2024年第2期2023卷 373-387页

作者： Di Wu Yi Sun cancer {1.(Key Laboratory of cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China cancer Center of Zhejiang University Hangzhou 310029China Zhejang Provincial Clinical research Center for {1. Zhejang ProvinceChina Key Laboratory of Molecular Biology in Medical Sciences Zhejang ProvinceChina research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

Neddylation is necessary for activation of Cullin-RING ligases(CRLs),which degrade various immune regulatory *** recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T(T_(reg))cells had no obvious phenotype,the same depletion of either Ube2m or Rbx1.caused inflammation disorders with different *** these E2s or E3s compensate each other in functional regulations of T_(reg)cells is,however,previously *** this report,we generated Foxp3^(Cre);Ube2m^(fl/fl);Ube2f^(fl/fl)or Foxp3^(Cre);Rbx1.(fl/fl);Sag^(fl/fl)double-null mice by simultaneous deletion of both neddylation E2s or E3s in T_(reg)cells,***,Ube2m&Ube2f double-null mice developed much severe autoimmune phenotypes than did Ube2m-null mice,indicating that Ube2m markedly compensates Ube2f in T_(reg)*** minor worsened autoimmune phenotypes seen at the very early stage in Rbx1.Sag double-null than Rbx1.null mice is likely due to already severe phenotypes of the later,indicating a minor compensation of Rbx1.for *** RNA profiling-based analyses revealed that up-and down-regulations of few signaling pathways in T_(reg)cells are associated with the severity of autoimmune ***,severer inflammation phenotypes seen in mice with double E3-null than with double E2-null T_(reg)cells indicate a neddylation-independent mechanism of 2 E3s,also known to serve as the RING component of CRLs in regulation of T_(reg)cell fitness.

关键词： Foxp3 inflammation markedly

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Comparative study between three carbonaceous nanoblades and nanodarts for antimicrobial applications

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Journal of Environmental Sciences 2024年第2期136卷 594-605页

作者： Mohamed S.Selim Ahmed M.Azzam Mohamed A.Shenashen Shimaa A.Higazy Bayaumy B.Mostafa Sherif A.El-Safty National institute for Materials Science(NIMS) 1-2-1 SengenTsukuba-ShiIbaraki-Ken 305-0047Japan Petroleum Application Department Egyptian Petroleum Research InstituteNasr City 11727Egypt Department of Environmental research Theodor Bilharz Research InstituteGizaEgypt

The design of nanostructured materials occupies a privileged position in the development and management of affordable and effective technology in the antibacterial ***,we discuss the antimicrobial properties of three carbonaceous nanoblades and nanodarts materials of graphene oxide(GO),reduced graphene oxide(RGO),and single-wall carbon nanotubes(SWCNTs)that have a mechano-bactericidal effect,and the ability to piercing or slicing bacterial *** demonstrate the significance of size,morphology and composition on the antibacterial activity mechanism,the designed nanomaterials have been *** minimum inhibitory concentration(MIC),standard agar well diffusion,and transmission electron microscopy were utilized to evaluate the antibacterial activity of GO,RGO,and *** on the evidence obtained,the three carbonaceous materials exhibit activity against all microbial strains tested by completely encapsulating bacterial cells and causing morphological disruption by degrading the microbial cell membrane in the order of RGO>GO>*** of the external cell wall structure and outer membrane proteins,the synthesized carbonaceous nanomaterials exhibited higher antibacterial activity against Gram-positive bacterial strains than Gram-negative and fungal *** had the lowest MIC values(0.062,0.1.5,and 0.25 mg/mL against ***,***,and ***,respectively),as well as minimum fungal concentrations(0.5 mg/mL for both *** and ***).At 1. hr,the cell viability values against tested microbial strains were completely *** lysis and death occurred as a result of severe membrane damage caused by microorganisms perched on RGO *** work gives an insight into the design of effective graphene-based antimicrobial materials for water treatment and remediation.

关键词： Antimicrobial properties Nanoblades Mechano-bactericidal effect RGO nanosheets Gram-positive bacteria Cell viability

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Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1.and PHGDH

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4001-4013页

作者： Ziqi Huang Kun Zhang Yurui Jiang Mengmeng Wang Mei Li Yuda Guo Ruolin Gao Ning Li Chenyang Wang Jia Chen Jiefu Wang Ning Liu Xiang Liu Shuangwei Liu Mingming Wei Cheng Yang Guang Yang The State Key Laboratory of Medicinal Chemical Biology College of Life SciencesCollege of PharmacyNankai UniversityTianjin 300071China Tianjin Medical University cancer {1. and Hospital National Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China

cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and ***,targeting CSCs has emerged as a promising avenue for cancer ***,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem ***,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are *** this study,the novel“molecular glue”LXH-3-71.was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in ***,LXH-3-71.was observed to form a dynamic chimera,between PHGDH and the DDB1.CRL E3 *** insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH ***,compound LXH-3-71.was leveraged as a novel ligand for the DDB1.CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

关键词： Molecular glue Targeted protein degradation PHGDH cancer stem cells PROTACs

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