背景与目的 肺腺癌易发生脑转移,患者预后极差。蛋白磷酸酶1调节亚基13样(protein phosphatase 1 regulatory subunit 13-like, PPP1R13L)基因编码的p53凋亡刺激蛋白家族抑制成员(inhibitor of apoptosis-stimulating protein of p53, i...背景与目的 肺腺癌易发生脑转移,患者预后极差。蛋白磷酸酶1调节亚基13样(protein phosphatase 1 regulatory subunit 13-like, PPP1R13L)基因编码的p53凋亡刺激蛋白家族抑制成员(inhibitor of apoptosis-stimulating protein of p53, iASPP)蛋白是p53通路的关键抑制因子,在多种肿瘤中促癌,但其在肺腺癌脑转移中的作用未知。本研究通过单细胞测序数据整合与临床样本分析,旨在分析肺腺癌脑转移患者的肿瘤微环境特征,并探讨PPP1R13L在脑转移组织中的表达情况及其临床意义。方法 收集2014年1月至2024年12月新疆医科大学附属肿瘤医院就诊的4例肺腺癌脑转移和2例少突胶质细胞瘤患者的脑组织进行单细胞测序,并结合公共数据库中4例肺腺癌样本和4例正常肺组织样本的单细胞测序数据解析肿瘤微环境;另收集此医院50例肺腺癌脑转移患者的临床资料及石蜡切片,采用免疫组化技术检测iASPP蛋白表达,分析其与临床特征及预后的关系。结果 相较于胶质瘤和肺腺癌组,肺腺癌脑转移组特异的上皮细胞主要富集于氧化磷酸化、细胞凋亡、缺氧和p53通路;PPP1R13L作为上调差异基因,在脑转移组特异上皮细胞亚群高表达;PPP1R13L阳性细胞与成纤维细胞交互作用显著,激活细胞-基质黏附相关通路,关键配体-受体对为I型胶原蛋白α1链-白细胞分化抗原44(collagen type I alpha 1 chain-cluster of differentiation 44, COL1A1-CD44)。临床数据分析显示,吸烟史(HR=2.543, 95%CI:1.159-5.583, P=0.020)和iASPP高表达(HR=3.351, 95%CI:1.310-8.575, P=0.012)为肺腺癌脑转移患者预后的独立危险因素。结论 本研究阐明了肺腺癌脑转移微环境中上皮细胞与成纤维细胞的相互作用,提示PPP1R13L可作为潜在预后标志物及治疗靶点,为肺腺癌脑转移的精准治疗提供依据。展开更多
In this work, we put forward a new and universal approach, i.e., cyanine ketone method, for fabricating meso–aryl heptamethine indocyanines, which is so simple that the treatment of the easy-to-get cyanine ketones wi...In this work, we put forward a new and universal approach, i.e., cyanine ketone method, for fabricating meso–aryl heptamethine indocyanines, which is so simple that the treatment of the easy-to-get cyanine ketones with various aromatic lithium(Ar Li), followed by acidification, could straightforwardly give rise to the products in one-pot way. Importantly, due to the strong nucleophilicity of Ar Li, a series of bulky hydrophilic aromatic groups can be facilely integrated into the meso–position of heptamethine indocyanines, not only effectively inhibiting the undesired dye self-aggregation but also largely improving the water-solubility. Using one of anti-aggregation meso–aryl heptamethine indocyanines, we fabricated a dye-antibody conjugate for in vivo imaging tumor in a mouse model and achieved a high tumor-tonormal tissue ratio. The work laid a chemical foundation for constructing various meso–aryl heptamethine indocyanines, facilitating the advanced imaging and therapeutic applications in future.展开更多
Background:This study was designed to investigate the feasibility of tumor-infiltrating immune cells with different phenotypic characteristics for predicting short-term clinical responses in patients with locally adva...Background:This study was designed to investigate the feasibility of tumor-infiltrating immune cells with different phenotypic characteristics for predicting short-term clinical responses in patients with locally advanced cervical cancer(LACC).Methods:Thirty-four patients who received concurrent chemoradiotherapy and twenty-one patients who merely underwent radiotherapy were enrolled in this study.We retrospectively analyzed the T cell markers(i.e.,CD3,CD4,CD8),memory markers(i.e.,CD45,CCR7),and differentiation markers(i.e.,CD27)in the peripheral blood and tumor tissues of patients with LACC before treatment based on flow cytometry.We also analyzed the relationship of T cell subsets between peripheral blood and tumor tissues,and their correlation with complete response or partial response.Results:The percentage of central memory CD8^(+)TCM(CD8^(+)CD45RA^(−)CD27^(+)CCR7^(+))cells in LACC patients was significantly lower than that of the control group.The percentage of CD8^(+)TN in the peripheral blood of LACC patients was significantly higher than that of tumor tissues.CD8^(+)TEM in the peripheral blood was significantly lower than that of tumor tissues.The percentage of CD8^(+)TN and CD8^(+)TCM in human papillomavirus(HPV)positive samples was significantly higher than that of HPV-negative samples.Similarly,the percentage of CD8^(+)TCM in tumor tissues was significantly higher in cancer tissue samples with lymph nodes compared with those without.Conclusion:A higher proportion of CD4^(+)TCM and a lower proportion of CD8^(+)TN in the tumor microenvironment of LACC may contribute to the therapy response prediction.展开更多
Background:Cervical squamous cell carcinoma(CESC),the most common subtype of cervical cancer,is primarily caused by the high-risk human papillomavirus(HPV)infection and genetic susceptibility.Single-cell RNA sequencin...Background:Cervical squamous cell carcinoma(CESC),the most common subtype of cervical cancer,is primarily caused by the high-risk human papillomavirus(HPV)infection and genetic susceptibility.Single-cell RNA sequencing(scRNA-seq)has been widely used in CESC research to uncover the diversity of cell types and states within tumor tissues,enabling a detailed study of the tumor microenvironment(TME).This technology allows precise mapping of HPV infection in cervical tissues,providing valuable insights into the initiation and progression of HPV-mediated malignant transformation.Methods:We performed the scRNA-seq to characterize gene expression in tumor tissues and paired adjacent para-cancerous tissues from four patients with early-stage CESC using the 10×Genomics platform.The HPV infection and its subtypes were identified using the scRNA data and viral sequence mapping,and trajectory analyses were performed using HPV+or HPV-cells.Interactions between different types of keratinized cells and their interactions with other cell types were identified,and pathways and specificity markers were screened for proliferating keratinized cells.The Cancer Genome Atlas(TCGA)dataset was used to verify the prognostic correlation between tumor-specific PI3+S100A7+keratinocyte infiltration and CESC,and the localization relationship between PI3+S100A7+keratinocytes and macrophages was verified by immunofluorescence staining.Results:Various types of keratinocytes and fibroblasts were the two cell types with the most significant differences in percentage between the tumor tissue samples and paired adjacent non-cancerous tissue samples in the early stages of CESC.We found that PI3+S100A7+keratinocytes were associated with early HPV-positive CESC,and PI3+S100A7+keratinocytes were more abundant in tumors than in adjacent normal tissues in the TCGA-CESC dataset.Analysis of clinical information revealed that the infiltration of PI3+S100A7+keratinocytes was notably higher in tumors with poor prognosis than in those with good prognosis.Additionally,multiplex immunofluorescence analysis showed a specific increase in PI3+S100A7+expression within tumor tissues,with PI3+S100A7+keratinocytes and CD163+macrophages being spatially very close to each other.In the analysis of cell-cell interactions,macrophages exhibited strong crosstalk with PI3+S100A7+proliferating keratinocytes in HPV-positive CESC tumors,mediated by tumor necrosis factor(TNF),CCL2,CXCL8,and IL10,highlighting the dynamic and tumor-specific enhancement of macrophage-keratinocyte interactions,which are associated with poor prognosis and immune modulation.Using CIBERSORTx,we discovered that patients with high infiltration of both PI3+S100A7+proliferating keratinocytes and macrophages had the shortest overall survival.In the analysis of cell-cell interactions,PI3+S100A7+proliferating keratinocytes and macrophages were found to be involved in highly active pathways that promote differentiation and structure formation,including cytokine receptor interactions,the Nuclear Factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway,and TNF signaling pathway regulation.Further subtyping of fibroblast populations identified four subtypes.The C1 group,characterized by its predominance in tumor tissues,is a subtype enriched with cancer-associated fibroblasts(CAFs),whereas the C3 group is primarily enriched in adjacent non-cancerous tissues and consists of undifferentiated cells.Moreover,the distinct molecular and cellular differences between HPV16-and HPV66-associated tumors were demonstrated,emphasizing the unique tumor-promoting mechanisms and microenvironmental influences driven by each HPV subtype.Conclusions:We discovered a heterogeneous population of keratinocytes between tumor and adjacent non-cancerous tissues caused by HPV infection and identified macrophages and specific CAFs that play a crucial role during the early stage in promoting the inflammatory response and remodeling the cancer-promoting TME.Our findings provide new insights into the transcriptional landscape of early-stage CESC to understand the mechanism of HPV-mediated malignant transformation in cervical cancer.展开更多
文摘背景与目的 肺腺癌易发生脑转移,患者预后极差。蛋白磷酸酶1调节亚基13样(protein phosphatase 1 regulatory subunit 13-like, PPP1R13L)基因编码的p53凋亡刺激蛋白家族抑制成员(inhibitor of apoptosis-stimulating protein of p53, iASPP)蛋白是p53通路的关键抑制因子,在多种肿瘤中促癌,但其在肺腺癌脑转移中的作用未知。本研究通过单细胞测序数据整合与临床样本分析,旨在分析肺腺癌脑转移患者的肿瘤微环境特征,并探讨PPP1R13L在脑转移组织中的表达情况及其临床意义。方法 收集2014年1月至2024年12月新疆医科大学附属肿瘤医院就诊的4例肺腺癌脑转移和2例少突胶质细胞瘤患者的脑组织进行单细胞测序,并结合公共数据库中4例肺腺癌样本和4例正常肺组织样本的单细胞测序数据解析肿瘤微环境;另收集此医院50例肺腺癌脑转移患者的临床资料及石蜡切片,采用免疫组化技术检测iASPP蛋白表达,分析其与临床特征及预后的关系。结果 相较于胶质瘤和肺腺癌组,肺腺癌脑转移组特异的上皮细胞主要富集于氧化磷酸化、细胞凋亡、缺氧和p53通路;PPP1R13L作为上调差异基因,在脑转移组特异上皮细胞亚群高表达;PPP1R13L阳性细胞与成纤维细胞交互作用显著,激活细胞-基质黏附相关通路,关键配体-受体对为I型胶原蛋白α1链-白细胞分化抗原44(collagen type I alpha 1 chain-cluster of differentiation 44, COL1A1-CD44)。临床数据分析显示,吸烟史(HR=2.543, 95%CI:1.159-5.583, P=0.020)和iASPP高表达(HR=3.351, 95%CI:1.310-8.575, P=0.012)为肺腺癌脑转移患者预后的独立危险因素。结论 本研究阐明了肺腺癌脑转移微环境中上皮细胞与成纤维细胞的相互作用,提示PPP1R13L可作为潜在预后标志物及治疗靶点,为肺腺癌脑转移的精准治疗提供依据。
基金supported by National Natural Science Foundation of China (Nos. 22277070, 22274091, 22007061)Youth Talent Support Program of Shanxi Province+1 种基金Program for the Top Young Academic Leaders of Higher Learning Institutions of ShanxiFundamental Research Program of Shanxi Province (No. 20210302123445)。
文摘In this work, we put forward a new and universal approach, i.e., cyanine ketone method, for fabricating meso–aryl heptamethine indocyanines, which is so simple that the treatment of the easy-to-get cyanine ketones with various aromatic lithium(Ar Li), followed by acidification, could straightforwardly give rise to the products in one-pot way. Importantly, due to the strong nucleophilicity of Ar Li, a series of bulky hydrophilic aromatic groups can be facilely integrated into the meso–position of heptamethine indocyanines, not only effectively inhibiting the undesired dye self-aggregation but also largely improving the water-solubility. Using one of anti-aggregation meso–aryl heptamethine indocyanines, we fabricated a dye-antibody conjugate for in vivo imaging tumor in a mouse model and achieved a high tumor-tonormal tissue ratio. The work laid a chemical foundation for constructing various meso–aryl heptamethine indocyanines, facilitating the advanced imaging and therapeutic applications in future.
基金the Project of the Central Government Guiding Local Science and Technology under Grant Number ZYYD2022B18the Institutional Ethics Committee of Affiliated Cancer Hospital of Xinjiang Medical University(No.K-2019001).
文摘Background:This study was designed to investigate the feasibility of tumor-infiltrating immune cells with different phenotypic characteristics for predicting short-term clinical responses in patients with locally advanced cervical cancer(LACC).Methods:Thirty-four patients who received concurrent chemoradiotherapy and twenty-one patients who merely underwent radiotherapy were enrolled in this study.We retrospectively analyzed the T cell markers(i.e.,CD3,CD4,CD8),memory markers(i.e.,CD45,CCR7),and differentiation markers(i.e.,CD27)in the peripheral blood and tumor tissues of patients with LACC before treatment based on flow cytometry.We also analyzed the relationship of T cell subsets between peripheral blood and tumor tissues,and their correlation with complete response or partial response.Results:The percentage of central memory CD8^(+)TCM(CD8^(+)CD45RA^(−)CD27^(+)CCR7^(+))cells in LACC patients was significantly lower than that of the control group.The percentage of CD8^(+)TN in the peripheral blood of LACC patients was significantly higher than that of tumor tissues.CD8^(+)TEM in the peripheral blood was significantly lower than that of tumor tissues.The percentage of CD8^(+)TN and CD8^(+)TCM in human papillomavirus(HPV)positive samples was significantly higher than that of HPV-negative samples.Similarly,the percentage of CD8^(+)TCM in tumor tissues was significantly higher in cancer tissue samples with lymph nodes compared with those without.Conclusion:A higher proportion of CD4^(+)TCM and a lower proportion of CD8^(+)TN in the tumor microenvironment of LACC may contribute to the therapy response prediction.
基金supported by grants from the Shanghai Cooperation Organization Science and Technology Partnership Program and the International Science and Technology Cooperation Program(No.2020E01056)the Tianshan Talent Program-Science and Technology Innovation Team(No.2023TSYCTD0015).
文摘Background:Cervical squamous cell carcinoma(CESC),the most common subtype of cervical cancer,is primarily caused by the high-risk human papillomavirus(HPV)infection and genetic susceptibility.Single-cell RNA sequencing(scRNA-seq)has been widely used in CESC research to uncover the diversity of cell types and states within tumor tissues,enabling a detailed study of the tumor microenvironment(TME).This technology allows precise mapping of HPV infection in cervical tissues,providing valuable insights into the initiation and progression of HPV-mediated malignant transformation.Methods:We performed the scRNA-seq to characterize gene expression in tumor tissues and paired adjacent para-cancerous tissues from four patients with early-stage CESC using the 10×Genomics platform.The HPV infection and its subtypes were identified using the scRNA data and viral sequence mapping,and trajectory analyses were performed using HPV+or HPV-cells.Interactions between different types of keratinized cells and their interactions with other cell types were identified,and pathways and specificity markers were screened for proliferating keratinized cells.The Cancer Genome Atlas(TCGA)dataset was used to verify the prognostic correlation between tumor-specific PI3+S100A7+keratinocyte infiltration and CESC,and the localization relationship between PI3+S100A7+keratinocytes and macrophages was verified by immunofluorescence staining.Results:Various types of keratinocytes and fibroblasts were the two cell types with the most significant differences in percentage between the tumor tissue samples and paired adjacent non-cancerous tissue samples in the early stages of CESC.We found that PI3+S100A7+keratinocytes were associated with early HPV-positive CESC,and PI3+S100A7+keratinocytes were more abundant in tumors than in adjacent normal tissues in the TCGA-CESC dataset.Analysis of clinical information revealed that the infiltration of PI3+S100A7+keratinocytes was notably higher in tumors with poor prognosis than in those with good prognosis.Additionally,multiplex immunofluorescence analysis showed a specific increase in PI3+S100A7+expression within tumor tissues,with PI3+S100A7+keratinocytes and CD163+macrophages being spatially very close to each other.In the analysis of cell-cell interactions,macrophages exhibited strong crosstalk with PI3+S100A7+proliferating keratinocytes in HPV-positive CESC tumors,mediated by tumor necrosis factor(TNF),CCL2,CXCL8,and IL10,highlighting the dynamic and tumor-specific enhancement of macrophage-keratinocyte interactions,which are associated with poor prognosis and immune modulation.Using CIBERSORTx,we discovered that patients with high infiltration of both PI3+S100A7+proliferating keratinocytes and macrophages had the shortest overall survival.In the analysis of cell-cell interactions,PI3+S100A7+proliferating keratinocytes and macrophages were found to be involved in highly active pathways that promote differentiation and structure formation,including cytokine receptor interactions,the Nuclear Factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway,and TNF signaling pathway regulation.Further subtyping of fibroblast populations identified four subtypes.The C1 group,characterized by its predominance in tumor tissues,is a subtype enriched with cancer-associated fibroblasts(CAFs),whereas the C3 group is primarily enriched in adjacent non-cancerous tissues and consists of undifferentiated cells.Moreover,the distinct molecular and cellular differences between HPV16-and HPV66-associated tumors were demonstrated,emphasizing the unique tumor-promoting mechanisms and microenvironmental influences driven by each HPV subtype.Conclusions:We discovered a heterogeneous population of keratinocytes between tumor and adjacent non-cancerous tissues caused by HPV infection and identified macrophages and specific CAFs that play a crucial role during the early stage in promoting the inflammatory response and remodeling the cancer-promoting TME.Our findings provide new insights into the transcriptional landscape of early-stage CESC to understand the mechanism of HPV-mediated malignant transformation in cervical cancer.
