This literature review explores the complex interaction between p53 and microRNAs(miRNAs)in the occurrence and progression of breast cancer(BC),the most common and lethal tumor type among women.BC is a multifactorial ...This literature review explores the complex interaction between p53 and microRNAs(miRNAs)in the occurrence and progression of breast cancer(BC),the most common and lethal tumor type among women.BC is a multifactorial disease resulting from a combination of genetic and epigenetic alterations in cell DNA,influencing proliferation,differentiation,and migration.TP53 gene,which codifies p53 protein,is a known tumor suppressor,and it plays an important role in cell maintenance as DNA repair,cell proliferation control,and apoptosis activation.TP53 expression can be modulated by several miRNAs,as miR-30c,miR-34a,and the miR-200 family,inhibiting p53 production and silencing its tumor suppressor effects.On the other hand,p53 protein can modulate several miRNAs expression,as miR-146a,miR-192,and the miR-200 family,by acting as a transcription factor or by modulating miRNA processing,interfering with BC aggressiveness and progression.Understanding the role of p53 and miRNAs in BC may aid in identifying new biomarkers and developing new targeted therapies for patient treatment.展开更多
AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetu...AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.展开更多
Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are ...Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are stand-ard care for the patients with these mutations.In this study,we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro.Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was per-formed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital(HNCH cohort).The mutational landscape of HNCH patients was compared with TCGA patients.Logistic regression analysis was used to determine the factors associated with presence of these mutations.Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs.Results A total of 574 single nucleotide variants(SNVs),270 indels,88 amplifications,and 87 rearrangements were identified in this study,with EGFR and KRAS being the most frequently mutated genes.Females,mostly life-long non-smokers,had significantly higher EGFR mutation rates than males.Males,primarily smokers,more frequently had KRAS mutations.HNCH patients in general had a higher mutation count than TCGA patients(1.09 vs 0.93 mutations per patient(m/p)),in consistent with its higher proportion of patients with advanced disease.Rare EGFR compound mutations identified in this study,including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873,conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo.Conclusion This NGS-based 8-gene test efficiently identified over 70%of Chinese treatment-naive LUAD patients who are targetable for TKIs.Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.展开更多
文摘This literature review explores the complex interaction between p53 and microRNAs(miRNAs)in the occurrence and progression of breast cancer(BC),the most common and lethal tumor type among women.BC is a multifactorial disease resulting from a combination of genetic and epigenetic alterations in cell DNA,influencing proliferation,differentiation,and migration.TP53 gene,which codifies p53 protein,is a known tumor suppressor,and it plays an important role in cell maintenance as DNA repair,cell proliferation control,and apoptosis activation.TP53 expression can be modulated by several miRNAs,as miR-30c,miR-34a,and the miR-200 family,inhibiting p53 production and silencing its tumor suppressor effects.On the other hand,p53 protein can modulate several miRNAs expression,as miR-146a,miR-192,and the miR-200 family,by acting as a transcription factor or by modulating miRNA processing,interfering with BC aggressiveness and progression.Understanding the role of p53 and miRNAs in BC may aid in identifying new biomarkers and developing new targeted therapies for patient treatment.
基金the Fondazione Veronesi that granted Daniela Vivenza and Martino Monteverde with PostDoctoral Fellowship Veronesithe Fondazione Cassa Risparmio of Cuneo for partially supporting the study
文摘AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.
基金J.Li was supported by Henan Young Researcher training program(HNSWJW-2020007)supported by the Department of Science and Technology of Henan Province(212102310675,201300310400).
文摘Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are stand-ard care for the patients with these mutations.In this study,we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro.Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was per-formed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital(HNCH cohort).The mutational landscape of HNCH patients was compared with TCGA patients.Logistic regression analysis was used to determine the factors associated with presence of these mutations.Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs.Results A total of 574 single nucleotide variants(SNVs),270 indels,88 amplifications,and 87 rearrangements were identified in this study,with EGFR and KRAS being the most frequently mutated genes.Females,mostly life-long non-smokers,had significantly higher EGFR mutation rates than males.Males,primarily smokers,more frequently had KRAS mutations.HNCH patients in general had a higher mutation count than TCGA patients(1.09 vs 0.93 mutations per patient(m/p)),in consistent with its higher proportion of patients with advanced disease.Rare EGFR compound mutations identified in this study,including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873,conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo.Conclusion This NGS-based 8-gene test efficiently identified over 70%of Chinese treatment-naive LUAD patients who are targetable for TKIs.Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.
