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Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1690-1705页

作者： Yan Fu Keyu Shen Hao Wang Shun Wang Xufeng Wang Le Zhu Yan Zheng Tiantian Zou Hongfei Ci Qiongzhu Dong Lun-Xiu Qin Hepatobiliary surgery Department of General SurgeryHuashan Hospital&Cancer Metastasis InstituteFudan University200040 ShanghaiChina Center of Interventional Radiology and Vascular surgery Department of RadiologyZhongda HospitalMedical SchoolSoutheast University87 Dingjiaqiao Road210009 NanjingChina institutes of Biomedical Sciences Fudan University200032 ShanghaiChina Key Laboratory of Whole-period Monitoring and Precise Intervention of digestive Cancer Shanghai Municipal Health CommissionMinhang HospitalFudan UniversityShanghaiChina

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor *** cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated *** the dysregulated nervous systems might represent a novel strategy for cancer ***,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely *** staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC ***93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC *** all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.

关键词： GSK3β metastasis Alpha

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis

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Chinese Journal of Cancer Research 2024年第3期36卷 282-297页

作者： Yifei Wang Yidan Ma Lei He Jun Du Xiaoguang Li Peng Jiao Xiaonan Wu Xiaomao Xu Wei Zhou Li Yang Jing Di Changbin Zhu Liming Xu Tianlin Sun Lin Li Dongge Liu Zheng Wang department of Pathology department of Minimally Invasive tumor Therapies Center department of Thoracic surgery department of Oncology department of Respiratory and Critical Care Medicine Beijing HospitalNational Center of GerontologyInstitute of Geriatric MedicineChinese Academy of Medical SciencesBeijing 100730China Amoy Diagnostics Co. Ltd.Xiamen 361027China

Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully *** study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical ***:A total of 355 treatment-naïve NSCLC patients were retrospectively *** status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered ***,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were ***:Of the patients,25.1%(89/355)were *** to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(Ptumor proliferation and immunosuppression ***-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T ***-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy ***:Unique genomic and transcriptional characteristics were found in HRD-positive *** prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive *** study highlights potential actionable alterations in HRD

关键词： Non-small cell lung cancer homologous recombination deficiency genetic alterations transcriptional analysis tumor microenvironment prognosis

Human pangenome:far-reaching implications in precision medicine

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Frontiers of Medicine 2024年第2期18卷 403-409页

作者： Yingyan Yu Hongzhuan Chen department of General surgery of Ruijin Hospital Shanghai Institute of Digestive Surgeryand Shanghai Key Laboratory for Gastric NeoplasmsShanghai Jiao Tong University School of MedicineShanghai200025China Shuguang Lab for Future Health Shanghai Frontier Science Center of TCM Chemical BiologyShanghai University of Traditional Chinese MedicineShanghai201203China

*** May 11,2023,the internationally renowned journal Nature announced that a first draft of the human pangenome reference has been constructed[1].This research was carried out by the Human Pangenome Reference Consortium(HPRC).One month later,on June 14,2023,a pangenome reference of 36 Chinese populations was published on journal Nature[2],which was performed by Chinese Pangenome Consortium(CPC).As the scientists pointed out that since the Human Genome Project(HGP)published the human reference genome,it provided a reference blueprint for genomic ***,the limitations of the human reference genome have gradually emerged,and it is difficult to reflect the genome diversity of the"human"species.

关键词： Human journal limitations

Close relationship between mediators of inflammation and pancreatic cancer:Our experience

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World Journal of Gastroenterology 2024年第23期30卷 2927-2930页

作者： Francesca Vescio Michele Ammendola Giuseppe Currò Silvia Curcio department General Surgery UnitUniversity“Magna Graecia”Medical SchoolUniversity Hospital“R.Dulbecco”Catanzaro 88100Italy Science of Health department Digestive Surgery UnitUniversity“Magna Graecia”Medical SchoolUniversity Hospital“R.Dulbecco”Catanzaro 88100Italy

In this editorial,we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic *** of the pancreas remains one of the deadliest cancer *** highest incidence and mortality rates of pancreatic cancer are found in developed *** of pancreatic cancer incidence and mortality vary considerably worldwide.A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this *** tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this *** this editorial,we highlight the foundational studies that have driven our understanding of these *** our experimental center,we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic *** focused on the role of mast cells(MCs).MCs contain pro-angiogenic factors,including tryptase,that are associated with increased angiogenesis in various *** this editorial,we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal *** assessment includes the density of c-Kit receptor-positive MCs,the density of tryptase-positive MCs,the area of tryptasepositive MCs,and angiogenesis in terms of microvascularization density.

关键词： Mast cells C-Kit receptor Tryptase Angiogenesis Microvascular density Endothelial area Pancreatic tumor tissue Adjacent normal tissue

Endoscopic-ultrasound-guided biliary drainage with placement of electrocautery-enhanced lumen-apposing metal stent for palliation of malignant biliary obstruction:Updated meta-analysis

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World Journal of Gastrointestinal surgery 2024年第3期16卷 907-920页

作者： Zu-Xiang Peng Fang-Fang Chen Wen Tang Xu Zeng Hong-Juan Du Ru-Xian Pi Hong-Ming Liu Xiao-Xiao Lu department of Hepatobiliary surgery Daping HospitalArmy Medical UniversityChongqing 400042China department of Oncology Chongqing General HospitalChongqing UniversityChongqing 401147China department of Gastroenterology and Hepatobiliary surgery People’s Hospital of Fenggang CountyGuizhou 564200Guizhou ProvinceChina Hepatobiliary and Pancreatic tumor Center Chongqing University Cancer HospitalChongqing 400030China

BACKGROUND Endoscopic ultrasound-guided biliary drainage using electrocautery-enhanced(ECE)delivery of lumen-apposing metal stent(LAMS)is gradually being re-cognized as a viable palliative technique for malignant biliary obstruction after endoscopic retrograde cholangiopancreatography(ERCP)***,most of the studies that have assessed its efficacy and safety were small and *** meta-analyses of six or fewer studies that were published 2 years ago were therefore underpowered to yield convincing *** To update the efficacy and safety of ECE-LAMS for treatment of biliary ob-struction after ERCP *** We searched PubMed,EMBASE,and Scopus databases from the inception of the ECE technique to May 13,*** outcome measure was pooled technical success rate,and secondary outcomes were pooled rates of clinical success,re-intervention,and adverse ***-analysis was performed using a random-effects model following Freeman-Tukey double-arcsine transformation in R soft-ware(version 4.1.3).RESULTS Fourteen eligible studies involving 620 participants were ultimately *** pooled rate of technical success was 96.7%,and clinical success was 91.0%.Adverse events were reported in 17.5%of *** reinter-vention rate was 7.3%.Subgroup analyses showed results were generally *** ECE-LAMS has favorable success with acceptable adverse events in relieving biliary obstruction when ERCP is *** consistency of results across most subgroups suggested that this is a generalizable approach.

关键词： Biliary obstruction Biliary drainage Electrocautery-enhanced lumen-apposing metal stents Endoscopic ultrasound Endoscopic retrograde cholangiopancreatography failure

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

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Chinese Journal of Cancer Research 2024年第1期36卷 55-65页

作者： Yaping Yang Liang Jin Yudong Li Nanyan Rao Chang Gong Shunrong Li Jiannan Wu Jinghua Zhao Linxiaoxiao Ding Fengxia Gan Jun Zhang Ruifa Feng Zhenzhen Liu Qiang Liu Breast tumor Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene RegulationGuangzhou 510120China department of Thyroid and Breast surgery Shenzhen Qianhai Shekou Free Trade Zone HospitalShenzhen 518000China Breast and Thyroid surgery Guilin Medical College Second Affiliated HospitalGuilin 541199China department of Breast Disease Henan Breast Cancer Centerthe Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhou 450008China

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity ***: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety

关键词： Breast cancer HER2-positive breast cancer dual HER2 blockade neoadjuvant therapy sequential therapy

Paeoniflorin,the Main Monomer Component of Paeonia lactiflora,Exhibits Anti-inflammatory Properties in Osteoarthritis Synovial Inflammation

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Chinese Journal of Integrative Medicine 2024年第5期30卷 433-442页

作者： CHEN Pu ZHOU Jun RUAN An-min MA Yu-feng WANG Qing-fu department of Orthopaedic surgery Beijing University of Chinese Medicine Third Affiliated HospitalBeijing 100029China department of Orthopaedic surgery Guangdong Provincial Hospital of Chinese MedicineGuangzhou 510120China department of Orthopaedic surgery Beijing Longfu HospitalBeijing 100010China

Objective:To explore the mechanism of paeoniflorin(PF)on osteoarthritis(OA)synovial inflammation from network pharmacology to experimental ***:Targets of OA were constructed by detecting the database of network database platforms(Therapeutic Target database,Drug Bank and Gene Cards),and the targets of PF were constructed by Pub Chem and Herbal Ingredients'Targets *** Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis of these co-targeted genes were conducted via Database for Annotation,Visualization,and Integrated Discovery(DAVID)database,and protein-protein interaction(PPI)networks were conducted via the search tool for the retrieval of interacting genes(STRING)*** counting kit-8(CCK-8)assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes(FLS),quantitative real-time polymerase chain reaction(q PCR),enzyme-linked immunosorbent assay(ELISA)and Western blot were used to verify the potential mechanism of PF in synovial ***:Twenty-six co-targeted genes were *** enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm,and the biological processes mainly involved'cellular response to hypoxia''lipopolysaccharide(LPS)-mediated signaling pathway'and'positive regulation of gene expression'.KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with'hypoxia-inducible factor-1(HIF-1)signaling pathway'and'tumornecrosis factor(TNF)signaling pathway'.The PPI network showed that the top 3 hub genes were TP53,TNF,and *** docking results showed that PF was well docking with ***-8 showed no potential toxicity of 10,20 and 50μmol/L PF on human OA *** PF significantly decreased the expression levels of interleukin-1β,interleukin-6,TNF-αmatrix metalloproteinase 13(MMP13),and a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5)and TNF

关键词： paeoniflorin osteoarthritis synovial inflammation tumor necrosis factor-α network pharmacology Paeonia lactiflora

Hepatocellular carcinoma:An analysis of the expression status of stress granules and their prognostic value

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2571-2591页

作者： Qing-Shuai Ren Qiu Sun Shu-Qin Cheng Li-Ming Du Ping-Xuan Guo department of Cardiovascular surgery North China University of Science and Technology Affiliated HospitalTangshan 063000Hebei ProvinceChina department of Hepatobiliary Kailuan General HospitalTangshan 063000Hebei ProvinceChina department of Gastroenterology and Hepatology Tianjin Medical University General HospitalTianjin Institute of Digestive DiseasesTianjin Key Laboratory of Digestive DiseasesTianjin 300000China department of Traditional Chinese Medicine Kailuan General HospitalTangshan 063000Hebei ProvinceChina department of Anesthesiology Kailuan General HospitalNorth China University of Science and TechnologyTangshan 063000Hebei ProvinceChina

BACKGROUND Hepatocellular carcinoma(HCC)is a global popular malignant tumor,which is difficult to cure,and the current treatment is *** To analyze the impacts of stress granule(SG)genes on overall survival(OS),survival time,and prognosis in *** The combined The Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC),GSE25097,and GSE36376 datasets were utilized to obtain genetic and clinical *** hub gene numbers and corresponding coefficients were determined using the Least absolute shrinkage and selection operator model approach,and genes for constructing risk scores and corresponding correlation coefficients were calculated according to multivariate Cox regression,*** prognostic model’s receiver operating characteristic(ROC)curve was produced and plotted utilizing the time ROC software *** models were constructed to predict the outcomes at 1,3,and 5-year OS prognostications with good prediction *** We identified seven SG genes(DDX1,DKC1,BICC1,HNRNPUL1,CNOT6,DYRK3,CCDC124)having a prognostic significance and developed a risk score *** findings of Kaplan-Meier analysis indicated that the group with a high risk exhibited significantly reduced OS in comparison with those of the low-risk group(P<0.001).The nomogram model’s findings indicate a significant enhancement in the accuracy of OS prediction for individuals with HCC in the TCGA-HCC *** Ontology and Gene Set Enrichment Analysis suggested that these SGs might be involved in the cell cycle,RNA editing,and other biological *** Based on the impact of SG genes on HCC prognosis,in the future,it will be used as a biomarker as well as a unique therapeutic target for the identification and treatment of HCC.

关键词： Stress granule genes Hepatocellular carcinoma Gastrointestinal neoplasms Bioinformatics prognosis Prognostic value

Cellular zinc metabolism and zinc signaling:from biological functions to diseases and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 401-441页

作者： Bonan Chen Peiyao Yu Wai Nok Chan Fuda Xie Yigan Zhang Li Liang Kam Tong Leung Kwok Wai Lo Jun Yu Gary M.K.Tse Wei Kang Ka Fai To department of Anatomical and Cellular Pathology State Key Laboratory of Translational OncologyPrince of Wales HospitalThe Chinese University of Hong KongHong KongChina State Key Laboratory of digestive Disease Institute of Digestive DiseaseThe Chinese University of Hong KongHong KongChina CUHK-Shenzhen Research Institute The Chinese University of Hong KongShenzhenChina department of Pathology Nanfang Hospital and Basic Medical CollegeSouthern Medical UniversityGuangdong Province Key Laboratory of Molecular Tumor PathologyGuangzhouChina Institute of Biomedical Research Taihe HospitalHubei University of MedicineShiyanChina department of Pediatrics The Chinese University of Hong KongHong KongChina department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina

Zinc metabolism at the cellular level is critical for many biological processes in the body.A key observation is the disruption of cellular homeostasis,often coinciding with disease *** an essential factor in maintaining cellular equilibrium,cellular zinc has been increasingly spotlighted in the context of disease *** research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells,despite its low tissue *** has led to a growing body of literature investigating zinc’s cellular metabolism,particularly the functions of zinc transporters and storage mechanisms during cancer *** transportation is under the control of two major transporter families:SLC30(ZnT)for the excretion of zinc and SLC39(ZIP)for the zinc ***,the storage of this essential element is predominantly mediated by metallothioneins(MTs).This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression,with a special focus on *** also compile a summary of clinical trials involving zinc *** the main localization of zinc transporters at the cell membrane,the potential for targeted therapies,including small molecules and monoclonal antibodies,offers promising avenues for future exploration.

关键词： metabolism invasion involvement