Aims:The aim of this study is to develop a prognostic model for hepatocellular carcinoma(HCC)using stemness-related genes(SRGs),while also pinpointing and validating pivotal genes associated with this process.Methods:...Aims:The aim of this study is to develop a prognostic model for hepatocellular carcinoma(HCC)using stemness-related genes(SRGs),while also pinpointing and validating pivotal genes associated with this process.Methods:Utilizing the TCGA and ICGC database,a prognostic stemness-related scores(SRS)for HCC through a combination of WGCNA and machine learning.Bioinformatics analysis evaluated tumor immune infiltration characteristics and drug sensitivity in different SRS subgroups,identifying the key gene TOMM40L.qRT-PCR and IHC were employed to detect the expression level of TOMM40 L.Kaplan-Meier survival analysis assessed the prognostic value of TOMM40L in HCC.In vitro cell experiments explored the influence of TOMM40L on HCC cell progression and stemness.Results:The prognostic model SRS for HCC was developed and validated,incorporating four SRGs:EIF2B4,CDCA8,TCOF1,and TOMM40L.Distinct variations in tumor immune infiltration profiles and drug sensitivity were noted across different SRS subgroups.Elevated TOMM40L levels are notably detected in malignant tissues in contrast to adjacent tissues,with heightened TOMM40L expression correlating with unfavorable prognostic outcomes.In addition,knockdown of TOMM40L significantly inhibited cell progression and stemness.Conclusion:The newly constructed SRS model is a potential biomarker for assessing HCC prognosis,and the key gene TOMM40L exhibits oncogenic properties.展开更多
Background:Hepatocellular carcinoma(HCC)is a major cause of cancer-related deaths.The Nod-like receptor(NLR)family is involved in innate immunity and tumor progression,but its role inHCC remains unclear.This study aim...Background:Hepatocellular carcinoma(HCC)is a major cause of cancer-related deaths.The Nod-like receptor(NLR)family is involved in innate immunity and tumor progression,but its role inHCC remains unclear.This study aimed to evaluate the prognostic value and biological function of NLR genes in HCC.Methods:Transcriptomic and clinical data from The Cancer Genome Atlas were analyzed using nonnegative matrix factorization(NMF)to classify HCC into molecular subtypes.Differentially expressed genes were used to build an NLR-based prognostic model(NLR_score)through univariate Cox,least absolute shrinkage and selection operator(LASSO),andmultivariate Cox regression.Predictive performance and correlation with chemotherapy sensitivity were assessed.NLR family pyrin domain containing 5(NLRP5)was identified as a key oncogene and validated via in vitro assays,including cell counting kit-8(CCK-8),colony formation,transwell,and flow cytometry in vivo xenograft models.Results:The two NMFdefined subtypes showed distinct survival outcomes.The NLR_score reliably predicted prognosis and was associated with sensitivity to six chemotherapeutic drugs.NLRP5 knockdown suppressed HCC cell proliferation,migration,and invasion in vitro and reduced tumor growth in vivo.Mechanistically,NLRP5 modulated the p53 signaling pathway,influencing cell cycle and apoptosis.Conclusion:This study developed an NLR-based prognosticmodel that effectively stratifies HCC patients by survival risk.NLRP5 was identified as a novel oncogene promoting HCC progression via the p53 pathway,suggesting its potential as a therapeutic target.展开更多
Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity,expanding antibacterial spectra,and reducing required dosages.Previously,compound 15 was identified as a potential adjuvant for Poly...Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity,expanding antibacterial spectra,and reducing required dosages.Previously,compound 15 was identified as a potential adjuvant for Polymyxin B(PB)against multidrug-resistant(MDR)Pseudomonas aeruginosa DK2;however,its clinical utility was hindered by high cytotoxicity,uncertain in vivo efficacy,and an unclear synergetic mechanism.To address these challenges,we synthesized and evaluated a series of novel benzamide derivatives,with A22 emerging as a particularly promising candidate.A22 demonstrated potent synergistic activity to PB,minimal cytotoxicity,improved water solubility,and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains.In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22.Moreover,A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2.Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production,reducing ATP levels,increasing NOX activity,and inhibiting biofilm formation,leading to bacterial death.These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants,offering a robust approach to combating MDR Gram-negative bacterial infections.展开更多
基金supported by the National Natural Science Foundation of China(No.82370608)Natural Science Foundation of Anhui Province(No.2208085MH204)+5 种基金Natural Science Foundation of Education Department of Anhui Province(No.2022AH040160)Anhui Provincial Special Fund for Clinical Medical Research Transformation(No.202304295107020040)Suzhou Health Commission“Suzhou Health Young Talent”National Mentor Training Program(No.Qngg2023046)Kunshan Social Development Science and Technology Special Fund(No.KS1719)New Coronavirus Pneumonia Research Project of Kunshan First People’s Hospital(First Batch,No.XGF202018)Kunshan First People’s Hospital Medical and Health Science and Technology Innovation Special Project(No.KETDCX202424).
文摘Aims:The aim of this study is to develop a prognostic model for hepatocellular carcinoma(HCC)using stemness-related genes(SRGs),while also pinpointing and validating pivotal genes associated with this process.Methods:Utilizing the TCGA and ICGC database,a prognostic stemness-related scores(SRS)for HCC through a combination of WGCNA and machine learning.Bioinformatics analysis evaluated tumor immune infiltration characteristics and drug sensitivity in different SRS subgroups,identifying the key gene TOMM40L.qRT-PCR and IHC were employed to detect the expression level of TOMM40 L.Kaplan-Meier survival analysis assessed the prognostic value of TOMM40L in HCC.In vitro cell experiments explored the influence of TOMM40L on HCC cell progression and stemness.Results:The prognostic model SRS for HCC was developed and validated,incorporating four SRGs:EIF2B4,CDCA8,TCOF1,and TOMM40L.Distinct variations in tumor immune infiltration profiles and drug sensitivity were noted across different SRS subgroups.Elevated TOMM40L levels are notably detected in malignant tissues in contrast to adjacent tissues,with heightened TOMM40L expression correlating with unfavorable prognostic outcomes.In addition,knockdown of TOMM40L significantly inhibited cell progression and stemness.Conclusion:The newly constructed SRS model is a potential biomarker for assessing HCC prognosis,and the key gene TOMM40L exhibits oncogenic properties.
基金supported by the National Natural Science Foundation of China(Nos.81973983,82270015,82100017,82302577,82304209,82370016)Anhui Province Scientific Research Planning Project(2023AH010083,2023AH053282)+4 种基金the Joint Construction Project of Clinical Medicine University and Hospital(No.2021lcxk006)the Anhui Provincial Natural Science Foundation(Nos.2208085MH264,2308085QH284,2308085MH243)the China Primary Health Care Foundation(No.MTP2022A015)the Project Supported by Anhui Medical University(2021xkj138,2021xkj067)Anhui Provincial Health Research Project(AHWJ2022b076).
文摘Background:Hepatocellular carcinoma(HCC)is a major cause of cancer-related deaths.The Nod-like receptor(NLR)family is involved in innate immunity and tumor progression,but its role inHCC remains unclear.This study aimed to evaluate the prognostic value and biological function of NLR genes in HCC.Methods:Transcriptomic and clinical data from The Cancer Genome Atlas were analyzed using nonnegative matrix factorization(NMF)to classify HCC into molecular subtypes.Differentially expressed genes were used to build an NLR-based prognostic model(NLR_score)through univariate Cox,least absolute shrinkage and selection operator(LASSO),andmultivariate Cox regression.Predictive performance and correlation with chemotherapy sensitivity were assessed.NLR family pyrin domain containing 5(NLRP5)was identified as a key oncogene and validated via in vitro assays,including cell counting kit-8(CCK-8),colony formation,transwell,and flow cytometry in vivo xenograft models.Results:The two NMFdefined subtypes showed distinct survival outcomes.The NLR_score reliably predicted prognosis and was associated with sensitivity to six chemotherapeutic drugs.NLRP5 knockdown suppressed HCC cell proliferation,migration,and invasion in vitro and reduced tumor growth in vivo.Mechanistically,NLRP5 modulated the p53 signaling pathway,influencing cell cycle and apoptosis.Conclusion:This study developed an NLR-based prognosticmodel that effectively stratifies HCC patients by survival risk.NLRP5 was identified as a novel oncogene promoting HCC progression via the p53 pathway,suggesting its potential as a therapeutic target.
基金supported by the National Natural Science Foundation of China(No.22107023 and 32300033)the Natural Science Foundation of Hainan(No.222QN220,China)the Scientific Research Foundation of Hainan University(No.KYQD(ZR)-22010 and KYQD(ZR)-23006,China).
文摘Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity,expanding antibacterial spectra,and reducing required dosages.Previously,compound 15 was identified as a potential adjuvant for Polymyxin B(PB)against multidrug-resistant(MDR)Pseudomonas aeruginosa DK2;however,its clinical utility was hindered by high cytotoxicity,uncertain in vivo efficacy,and an unclear synergetic mechanism.To address these challenges,we synthesized and evaluated a series of novel benzamide derivatives,with A22 emerging as a particularly promising candidate.A22 demonstrated potent synergistic activity to PB,minimal cytotoxicity,improved water solubility,and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains.In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22.Moreover,A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2.Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production,reducing ATP levels,increasing NOX activity,and inhibiting biofilm formation,leading to bacterial death.These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants,offering a robust approach to combating MDR Gram-negative bacterial infections.
