目的:通过双向两样本MR方法探讨皮肌炎(Dermatomyositis, DM)、免疫细胞与肺癌(Lung cancer, LC)之间的因果关系,验证免疫细胞在其中起到的中介作用。方法:使用双向双样本孟德尔随机化(Mendelian Randomization, MR)法分析DM与LC及其各...目的:通过双向两样本MR方法探讨皮肌炎(Dermatomyositis, DM)、免疫细胞与肺癌(Lung cancer, LC)之间的因果关系,验证免疫细胞在其中起到的中介作用。方法:使用双向双样本孟德尔随机化(Mendelian Randomization, MR)法分析DM与LC及其各种亚型的因果关系,通过两步法MR探讨免疫细胞在DM与LC及各种亚型之间是否起到中介作用。使用MR-Egger截距法和MR-PRESSO法检查有无水平多效性,Cochran’s Q检查有无异质性。结果:根据MR分析结果,DM会增加患小细胞肺癌(Small cell lung cancer, SCLC)和肺腺癌(Lung adenocarcinoma, LUAD)的风险。38种免疫细胞表型与LC密切相关。其中,效应记忆CD8+ T细胞在CD8+ T细胞中所占的百分比、静息CD4调节性T细胞上CD25的表达水平、IgD− CD38+ B细胞的绝对计数、效应记忆CD8+ T细胞在T细胞中所占的百分比,以及CD33+ HLA-DR+ CD14低表达细胞上CD45的表达水平,都参与介导了DM与LUAD以及小细胞肺癌SCLC之间的因果关系。结论:我们的研究结果表明,DM患者并发LUAD和SCLC发生风险将显著增加。此外,我们发现五种免疫细胞性状(效应记忆CD8+ T细胞在CD8+ T细胞中所占的百分比、静息CD4调节性T细胞上CD25的表达水平、IgD− CD38+ B细胞的绝对计数、效应记忆CD8+ T细胞在T细胞中所占的百分比,以及CD33+ HLA-DR+ CD14低表达细胞上CD45的表达水平)在DM患者并发LC中的发病过程中起到重要作用。针对这些免疫细胞性状的深入研究将进一步明确DM导致LC风险升高的病理生理机制。Objective: To explore the causal relationships among dermatomyositis (DM), immune cells, and lung cancer (LC) through the bidirectional two-sample Mendelian randomization (MR) method, and to verify the mediating role of immune cells in this process. Methods: The bidirectional two-sample Mendelian randomization (MR) method was used to analyze the causal relationships between DM and LC as well as its various subtypes. The two-step MR method was applied to explore whether immune cells played a mediating role between DM and LC and its various subtypes. The MR-Egger intercept method and the MR-PRESSO method were used to check for horizontal pleiotropy, and Cochran’s Q test was used to check for heterogeneity. Results: According to the results of the MR analysis, DM increases the risk of developing small cell lung cancer (SCLC) and lung adenocarcinoma (LUAD). 38 immune cell characteristics were closely related to LC. Among them, the percentage of effector memory CD8+ T cells in CD8+ T cells, the expression level of CD25 on resting CD4 regulatory T cells, the absolute count of IgD− CD38+ B cells, the percentage of effector memory CD8+ T cells in T cells, and the expression level of CD45 on CD33+ HLA-DR+ CD14 low-expression cells all participated in mediating the causal relationships between DM and LUAD as well as SCLC. Conclusion: Our research results indicate that the risk of developing LUAD and SCLC in patients with DM will increase significantly. In addition, we found that five immune cell traits (the percentage of effector memory CD8+ T cells in CD8+ T cells, the expression level of CD25 on resting CD4 regulatory T cells, the absolute count of IgD− CD38+ B cells, the percentage of effector memory CD8+ T cells in T cells, and the expression level of CD45 on CD33+ HLA-DR+ CD14 low-expression cells) play an important role in the pathogenesis of LC in patients with DM. In-depth research on these immune cell traits will further clarify the pathophysiological mechanism by which DM leads to an increased risk of LC.展开更多
Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limite...Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.展开更多
Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damag...Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum agents.Alteration in this repair mechanism may affect patients’survival.Materials and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to 2020.mRNA expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor samples.Results:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls.Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.展开更多
Objective:This study aimed at exploring the effects of the epigenetic regulator,chidamide,on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer(SCLC),particularly the roles in macroph...Objective:This study aimed at exploring the effects of the epigenetic regulator,chidamide,on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer(SCLC),particularly the roles in macrophage polarization and angiogenesis.The therapeutic efficacy of combining chidamide with the anti-angiogenic agent,anlotinib,for refractory SCLC was also evaluated.Methods:RNA sequencing and functional validation were performed to assess chidamide’s effects on macrophages.Signal transducer and activator of transcription 4(STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR.The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.Results:Chidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype.Mechanistically,chidamide upregulated CCL2 via STAT4 transcriptional activation,thereby reshaping the tumor immune microenvironment(TIME).Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.Conclusions:Chidamide reshaped the SCLC TIME by activating STAT4/CCL2,thus driving M1 macrophage polarization and enhancing anti-tumor immunity.Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.展开更多
Background:Small cell lung cancer(SCLC)is characterized by its aggressive nature and high propensity for brain metastases.This study investigates the clinical efficacy and safety profile of Anlotinib in combination wi...Background:Small cell lung cancer(SCLC)is characterized by its aggressive nature and high propensity for brain metastases.This study investigates the clinical efficacy and safety profile of Anlotinib in combination with Stereotactic Radiotherapy(SRT)for treating brain metastases in patients with small cell lung cancer(SCLC).Methods:This research included 98 SCLC brain metastasis patients treated at Chengde Central Hospital from October 2020 to January 2024.The patients were categorized into a combined treatment group(CTG)(n=45)and a Simple SRT group(SSG)(n=53).The CTG(58 lesions)received Anlotinib with brain SRS,while the SSG(67 lesions)underwent only brain SRS.We compared the rates of intracranial hypertension relief,intracranial lesion treatment efficacy,radiation-induced brain necrosis,intracranial progression-free survival,and overall survival between the groups.Additionally,Anlotinib usage and adverse reactions in the CTG were documented.Results:Intracranial hypertension relief was significantly higher in the CTG at 80.0%(36/45)compared to 11.3%(6/53)in the SSG(p<0.001).Radiation-induced brain necrosis occurred in 3.4%(2/58)of the CTG,markedly less than the 20.9%(14/67)in the SSG,indicating a significant difference(χ^(2)=8.479,p=0.004).Effective intracranial lesion treatment rates were 86.7%(39/45)in the CTG and 62.3%(33/53)in the SSG,with a notable difference(χ^(2)=7.951,p=0.047).The median intracranial progression-free survival was 7.8 months in the CTG vs.4.8 months in the SSG(p<0.0001).Median overall survival times were 11.3 months for the CTG and 7.8 months for the SSG(p=0.3506).The duration of Anlotinib treatment in the CTG was 6(6,18)weeks.Adverse reactions included Grade I hypertension in three patients and Grade I hand-foot skin reactions in two patients,with a drug-related adverse reaction rate of 11.1%(5/45).Conclusion:Anlotinib combined with SRT significantly alleviates brain edema,reduces the incidence of radiation-induced brain necrosis,enhances intracranial progression-free survival,and demonstrates a low adverse reaction rate.展开更多
Introduction Small cell lung cancer(SCLC)is a highly aggressive malignancy with limited treatment options.Despite advances in immunotherapy,response rates remain low,and the efficacy of current molecular subtyping1,2 ...Introduction Small cell lung cancer(SCLC)is a highly aggressive malignancy with limited treatment options.Despite advances in immunotherapy,response rates remain low,and the efficacy of current molecular subtyping1,2 is insufficient to predict therapeutic outcomes3,4.A recently identified vulnerability in SCLC involves the dysregulation of nuclear-cytoplasmic transport,particularly through exportin 1(XPO1)5-7.展开更多
文摘目的:通过双向两样本MR方法探讨皮肌炎(Dermatomyositis, DM)、免疫细胞与肺癌(Lung cancer, LC)之间的因果关系,验证免疫细胞在其中起到的中介作用。方法:使用双向双样本孟德尔随机化(Mendelian Randomization, MR)法分析DM与LC及其各种亚型的因果关系,通过两步法MR探讨免疫细胞在DM与LC及各种亚型之间是否起到中介作用。使用MR-Egger截距法和MR-PRESSO法检查有无水平多效性,Cochran’s Q检查有无异质性。结果:根据MR分析结果,DM会增加患小细胞肺癌(Small cell lung cancer, SCLC)和肺腺癌(Lung adenocarcinoma, LUAD)的风险。38种免疫细胞表型与LC密切相关。其中,效应记忆CD8+ T细胞在CD8+ T细胞中所占的百分比、静息CD4调节性T细胞上CD25的表达水平、IgD− CD38+ B细胞的绝对计数、效应记忆CD8+ T细胞在T细胞中所占的百分比,以及CD33+ HLA-DR+ CD14低表达细胞上CD45的表达水平,都参与介导了DM与LUAD以及小细胞肺癌SCLC之间的因果关系。结论:我们的研究结果表明,DM患者并发LUAD和SCLC发生风险将显著增加。此外,我们发现五种免疫细胞性状(效应记忆CD8+ T细胞在CD8+ T细胞中所占的百分比、静息CD4调节性T细胞上CD25的表达水平、IgD− CD38+ B细胞的绝对计数、效应记忆CD8+ T细胞在T细胞中所占的百分比,以及CD33+ HLA-DR+ CD14低表达细胞上CD45的表达水平)在DM患者并发LC中的发病过程中起到重要作用。针对这些免疫细胞性状的深入研究将进一步明确DM导致LC风险升高的病理生理机制。Objective: To explore the causal relationships among dermatomyositis (DM), immune cells, and lung cancer (LC) through the bidirectional two-sample Mendelian randomization (MR) method, and to verify the mediating role of immune cells in this process. Methods: The bidirectional two-sample Mendelian randomization (MR) method was used to analyze the causal relationships between DM and LC as well as its various subtypes. The two-step MR method was applied to explore whether immune cells played a mediating role between DM and LC and its various subtypes. The MR-Egger intercept method and the MR-PRESSO method were used to check for horizontal pleiotropy, and Cochran’s Q test was used to check for heterogeneity. Results: According to the results of the MR analysis, DM increases the risk of developing small cell lung cancer (SCLC) and lung adenocarcinoma (LUAD). 38 immune cell characteristics were closely related to LC. Among them, the percentage of effector memory CD8+ T cells in CD8+ T cells, the expression level of CD25 on resting CD4 regulatory T cells, the absolute count of IgD− CD38+ B cells, the percentage of effector memory CD8+ T cells in T cells, and the expression level of CD45 on CD33+ HLA-DR+ CD14 low-expression cells all participated in mediating the causal relationships between DM and LUAD as well as SCLC. Conclusion: Our research results indicate that the risk of developing LUAD and SCLC in patients with DM will increase significantly. In addition, we found that five immune cell traits (the percentage of effector memory CD8+ T cells in CD8+ T cells, the expression level of CD25 on resting CD4 regulatory T cells, the absolute count of IgD− CD38+ B cells, the percentage of effector memory CD8+ T cells in T cells, and the expression level of CD45 on CD33+ HLA-DR+ CD14 low-expression cells) play an important role in the pathogenesis of LC in patients with DM. In-depth research on these immune cell traits will further clarify the pathophysiological mechanism by which DM leads to an increased risk of LC.
基金supported by grants from the Dongguan Science and Technology of Social Development Program(No.20231800940192)the Talent Development Foundation of the First Dongguan Affiliated Hospital of Guangdong Medical University(No.PU2023002).
文摘Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.
文摘Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum agents.Alteration in this repair mechanism may affect patients’survival.Materials and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to 2020.mRNA expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor samples.Results:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls.Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.
基金supported in part by grants from National Natural Science Foundation of China(Grant Nos.82172635,82272686,and 82203628)the Natural Science Foundation of Tianjin(Grant Nos.23JCZDJC00200 and 21JCYBJC01000)the Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-010A).
文摘Objective:This study aimed at exploring the effects of the epigenetic regulator,chidamide,on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer(SCLC),particularly the roles in macrophage polarization and angiogenesis.The therapeutic efficacy of combining chidamide with the anti-angiogenic agent,anlotinib,for refractory SCLC was also evaluated.Methods:RNA sequencing and functional validation were performed to assess chidamide’s effects on macrophages.Signal transducer and activator of transcription 4(STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR.The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.Results:Chidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype.Mechanistically,chidamide upregulated CCL2 via STAT4 transcriptional activation,thereby reshaping the tumor immune microenvironment(TIME).Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.Conclusions:Chidamide reshaped the SCLC TIME by activating STAT4/CCL2,thus driving M1 macrophage polarization and enhancing anti-tumor immunity.Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.
基金supported by the Science and Technology Program of Chengde(Project Number:202301A016).
文摘Background:Small cell lung cancer(SCLC)is characterized by its aggressive nature and high propensity for brain metastases.This study investigates the clinical efficacy and safety profile of Anlotinib in combination with Stereotactic Radiotherapy(SRT)for treating brain metastases in patients with small cell lung cancer(SCLC).Methods:This research included 98 SCLC brain metastasis patients treated at Chengde Central Hospital from October 2020 to January 2024.The patients were categorized into a combined treatment group(CTG)(n=45)and a Simple SRT group(SSG)(n=53).The CTG(58 lesions)received Anlotinib with brain SRS,while the SSG(67 lesions)underwent only brain SRS.We compared the rates of intracranial hypertension relief,intracranial lesion treatment efficacy,radiation-induced brain necrosis,intracranial progression-free survival,and overall survival between the groups.Additionally,Anlotinib usage and adverse reactions in the CTG were documented.Results:Intracranial hypertension relief was significantly higher in the CTG at 80.0%(36/45)compared to 11.3%(6/53)in the SSG(p<0.001).Radiation-induced brain necrosis occurred in 3.4%(2/58)of the CTG,markedly less than the 20.9%(14/67)in the SSG,indicating a significant difference(χ^(2)=8.479,p=0.004).Effective intracranial lesion treatment rates were 86.7%(39/45)in the CTG and 62.3%(33/53)in the SSG,with a notable difference(χ^(2)=7.951,p=0.047).The median intracranial progression-free survival was 7.8 months in the CTG vs.4.8 months in the SSG(p<0.0001).Median overall survival times were 11.3 months for the CTG and 7.8 months for the SSG(p=0.3506).The duration of Anlotinib treatment in the CTG was 6(6,18)weeks.Adverse reactions included Grade I hypertension in three patients and Grade I hand-foot skin reactions in two patients,with a drug-related adverse reaction rate of 11.1%(5/45).Conclusion:Anlotinib combined with SRT significantly alleviates brain edema,reduces the incidence of radiation-induced brain necrosis,enhances intracranial progression-free survival,and demonstrates a low adverse reaction rate.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82172635,82272686,and 82203628)Natural Science Foundation of Tianjin(Grant No.23JCZDJC00200)Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-010A).
文摘Introduction Small cell lung cancer(SCLC)is a highly aggressive malignancy with limited treatment options.Despite advances in immunotherapy,response rates remain low,and the efficacy of current molecular subtyping1,2 is insufficient to predict therapeutic outcomes3,4.A recently identified vulnerability in SCLC involves the dysregulation of nuclear-cytoplasmic transport,particularly through exportin 1(XPO1)5-7.
