Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 4 942
Страница 348 из 495-
Pan-cancer analysis of NADPH oxidase 4 identifying its prognostic and immunotherapy predictive value and in vitro experimental verification in glioblastoma.
BACKGROUND: NADPH oxidase 4 (NOX4) plays an important role in metabolic reprogramming, epithelial-mesenchymal transition (EMT), and other cellular processes by strictly regulating intracellular ROS generation. However, there is a lack of analysis on the role of NOX4 in the tumor immune microenvironment and predictive value for prognosis and immunotherapy response in various tumor types. METHODS: This study used data from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Tumor Immune Single-cell Hub (TISCH), Genotype-Tissue Expression (GTEx), cBioPortal, Tumor Immune Estimation Resource (TIMER 2.0), and ROC Plotter databases to analyze the expression, prognosis, biological function, immune cell infiltration, and genetic and epigenetic changes of NOX4 in various tumor types. Meanwhile, in vitro experiments were conducted to verify the role of NOX4 in the migration, invasion, proliferation, and apoptosis of glioblastoma (GBM). RESULTS: The findings indicated that NOX4 is upregulated in various types of cancer, accompanied by gene amplification, mutation, and deletion. The high expression of NOX4 is associated with poor prognosis in various cancers. Functional enrichment analysis showed that NOX4 is mainly enriched in immune and cancer progression pathways, such as angiogenesis, EMT, interferon response, inflammatory response. Immune cell infiltration analysis showed that high expression of NOX4 is associated with increased infiltration of cancer-associated fibroblasts (CAF) and macrophages. In vitro experiments showed that silencing NOX4 inhibits the proliferation, migration, and invasion of GBM and increases cell apoptosis. CONCLUSION: NOX4 can serve as a prognostic and immunotherapy response biomarker for various cancers and targeting NOX4 may be a feasible anti-tumor therapy and may have synergistic anti-tumor effects combined with immunotherapy.
-
The Myeloid Biomarker MS4A6A Drives an Immunosuppressive Microenvironment in Glioblastoma via Activation of the PGE2 Signaling Axis.
Glioblastoma (GBM) remains one of the most lethal brain tumors, characterized by extensive immune evasion and a macrophage-dominated tumor microenvironment (TME). However, the molecular determinants governing tumor-associated macrophage (TAM) states and their immunoregulatory functions remain poorly understood. We integrated bulk- and single-cell transcriptomic datasets (TCGA, CGGA, Ivy GAP, and Brain Immune Atlas) to systematically characterize the expression, prognostic relevance, and immune contexture of the myeloid biomarker membrane-spanning 4-domain A6A, MS4A6A, in GBM. Differential expression, survival, and pathway enrichment analyses were performed. Single-cell mapping and CellChat modeling delineated MS4A6A-associated TAM subpopulations, intercellular communication networks, and ligand-receptor signaling dynamics. Spatial transcriptomic validation and pharmacogenomic modeling were conducted to assess anatomic enrichment and therapeutic vulnerabilities. High MS4A6A expression predicted unfavorable survival and correlated with increased stromal and immune infiltration. Single-cell analyses localized MS4A6A predominantly to TAMs, especially Regulatory- and Ribo-TAM states enriched for antigen presentation, T-cell regulation, and ribosomal biogenesis pathways. CellChat analysis revealed that MS4A6A-high TAMs exhibited markedly enhanced communication with CD4+ T cells and Tregs through upregulated PGE2-PTGER2/PTGER4, PECAM1-CD38, and THBS1-CD36 signaling axes, implicating MS4A6A in prostaglandin-driven immune suppression. Spatial profiling confirmed preferential localization of MS4A6A within perivascular and angiogenic niches. Pharmacogenomic prediction indicated that MS4A6A-high tumors were more sensitive to ERK, mTOR, and CDK4/6 inhibition. MS4A6A defines a macrophage-centered, immunosuppressive ecosystem in GBM, mediated by the activation of the PGE2 signaling axis. These findings position MS4A6A both as a prognostic biomarker and as a potential therapeutic node linking myeloid reprogramming to actionable pathway vulnerabilities in glioblastoma.
-
A Novel Intercellular Communication-Associated Gene Signature for Prognostic Prediction and Clinical Value in Patients With Lung Adenocarcinoma.
BACKGROUND: Lung cancer remains the leading cause of cancer death globally, with lung adenocarcinoma (LUAD) being its most prevalent subtype. This study aimed to identify the key intercellular communication-associated genes (ICAGs) in LUAD. METHODS: Eight publicly available datasets were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The prognosis-related ICAGs were identified and a risk score was developed by using survival analysis. Machine learning models were trained to predict LUAD recurrence based on the selected ICAGs and clinical information. Comprehensive analyses on ICAGs and tumor microenvironment were performed. A single-cell RNA-sequencing dataset was assessed to further elucidate aberrant changes in intercellular communication. RESULTS: Eight ICAGs with prognostic potential were identified in the present study, and a risk score was derived accordingly. The best machine-learning model to predict relapse was developed based on clinical information and the expression levels of these eight ICAGs. This model achieved a remarkable area under receiver operator characteristic curves of 0.841. Patients were divided into high- and low-risk groups according to their risk scores. DNA replication and cell cycle were significantly enriched by the differentially expressed genes between the high- and the low-risk groups. Infiltrating immune cells, immune functions were significantly related to ICAGs expressions and risk scores. Additionally, the changes of intercellular communication were modeled by analyzing the single-cell sequencing dataset. CONCLUSION: The present study identified eight key ICAGs in LUAD, which could contribute to patient stratification and act as novel therapeutic targets.
-
Single cell transcriptomic analysis reveals molecular mechanisms of chemoresistance and immune microenvironment remodeling in ovarian cancer.
BACKGROUND: Chemotherapy resistance remains a major clinical challenge in ovarian cancer treatment, limiting therapeutic efficacy and patient survival. Understanding the molecular mechanisms underlying chemoresistance at the single-cell level is crucial for developing targeted therapeutic strategies. METHODS: We performed comprehensive single-cell RNA sequencing analysis on primary and chemoresistant ovarian cancer samples to characterize cellular heterogeneity and identify resistance-associated molecular signatures. Cell type identification, differential gene expression analysis, functional enrichment analysis, and immune microenvironment characterization were conducted to elucidate chemoresistance mechanisms. Computational predictions were validated by RT-qPCR analysis of four key resistance genes (BIRC5, ABCB1A, ABCG2, BCL2) in SKOV3 and SKOV3-CDDP cell lines. RESULTS: Our analysis identified nine distinct cell populations within the ovarian cancer microenvironment, revealing extensive transcriptional reprogramming in chemoresistant tumors. Key chemoresistance genes including Abcb1a, Abcg2, Bcl2, Birc5, Nek2, Inhba, Irs1, and Prc1 showed differential expression patterns across cell types. Epithelial cells and proliferating cells exhibited elevated expression of multiple resistance markers, particularly Birc5. Functional analysis revealed enrichment of ribosome biogenesis, protein synthesis machinery, and amoeboid-type cell migration pathways in resistant cells. Macrophage polarization states were significantly altered, and immune checkpoint molecules showed coordinated upregulation, indicating comprehensive immune microenvironment reprogramming. RT-PCR validation confirmed single-cell predictions with significant upregulation in resistant cells: BIRC5 (4.2-fold, p < 0.001), ABCB1A (3.8-fold, p < 0.001), ABCG2 (2.9-fold, p < 0.01), and BCL2 (2.1-fold, p < 0.05). CONCLUSIONS: This study provides a comprehensive single-cell atlas of chemoresistance in ovarian cancer, revealing cell type-specific resistance mechanisms and immune evasion strategies. The identified molecular signatures offer potential therapeutic targets for overcoming chemotherapy resistance and improving patient outcomes.
-
Comprehensive analysis of KLF2 as a prognostic biomarker associated with fibrosis and immune infiltration in advanced hepatocellular carcinoma.
PURPOSE: Most Hepatocellular carcinoma (HCC) patients are in advanced or metastatic stage at the time of diagnosis. Prognosis for advanced HCC patients is dismal. This study was based on our previous microarray results, and aimed to explore the promising diagnostic and prognostic markers for advanced HCC by focusing on the important function of KLF2. METHODS: The Cancer Genome Atlas (TCGA), Cancer Genome Consortium database (ICGC), and the Gene Expression Comprehensive Database (GEO) provided the raw data of this study research. The cBioPortal platform, CeDR Atlas platform, and the Human Protein Atlas (HPA) website were applied to analyze the mutational landscape and single-cell sequencing data of KLF2. Basing on the results of single-cell sequencing analyses, we further explored the molecular mechanism of KLF2 regulation in the fibrosis and immune infiltration of HCC. RESULTS: Decreased KLF2 expression was discovered to be mainly regulated by hypermethylation, and indicated a poor prognosis of HCC. Single-cell level expression analyses revealed KLF2 was highly expressed in immune cells and fibroblasts. The function enrichment analysis of KLF2 targets indicated the crucial association between KLF2 and tumor matrix. 33-genes related with cancer associated fibroblasts (CAFs) were collected to identify the significant association of KLF2 with fibrosis. And SPP1 was validated as a promising prognostic and diagnostic marker for advanced HCC patients. CXCR6 CD8+ T cells were noted as a predominant proportion in the immune microenvironment, and T cell receptor CD3D was discovered to be a potential therapeutic biomarker for HCC immunotherapy. CONCLUSION: This study identified that KLF2 is an important factor promoting HCC progression by affecting the fibrosis and immune infiltration, highlighting its great potential as a novel prognostic biomarker for advanced HCC.
-
Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye.
Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here, we used high-throughput single-nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in six extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases-for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the data presented here complete a "Version 1" cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as the neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.
-
Single-Cell Atlas of the Peripheral Immune Response in Patients With Chronic Hepatitis B.
Cellular immune responses are crucial in determining outcomes of the hepatitis B virus (HBV) infection. Ineffective immune responses enable persistent HBV infection and contribute to progressive liver disease. Understanding the mechanisms underlying immunological HBV tolerance and restoring functional adaptive immune responses is essential for successful chronic hepatitis B (CHB) treatment. This study examined the dysregulated immune responses and immunopathological cell states associated with CHB using single-cell RNA sequencing of peripheral blood mononuclear cells to investigate immune cell composition and transcriptional differences between patients with CHB and healthy donors. Phenotypic alterations in the lymphoid and myeloid compartments were observed following HBV infection. T cell immune profiling in patients with CHB showed enrichment of exhausted CD8+ T cells, impaired cytotoxicity of effector CD8+ T cells, and increased regulatory T cell (Treg) suppressive activity. Immature neutrophils and a unique CD14+ monocyte subset (myeloid-derived suppressor cells) exhibited potent immunosuppressive abilities. A novel population of CD14+CD163+VSIG4+ M2-like macrophages with immunosuppressive and anti-inflammatory phenotypes was enriched in a patient with severe CHB and liver failure, indicating a potential contribution to dysfunctional immune responses. Our study demonstrated immune exhaustion and evasion in chronic HBV infection, elucidating its immunopathological features and suggesting new therapeutic strategies for immune-mediated disorders and unresolved chronic HBV infection.
-
Integrating single-cell and bulk RNA sequencing to develop a cancer-associated fibroblast-related signature for immune infiltration prediction and prognosis in lung adenocarcinoma.
BACKGROUND: An accumulating amount of studies are highlighting the impacts of cancer-associated fibroblasts (CAFs) on the initiation, metastasis, invasion, and immune evasion of lung cancer. However, it is still unclear how to tailor treatment regimens based on the transcriptomic characteristics of CAFs in the tumor microenvironment of patients with lung cancer. METHODS: Our study examined single-cell RNA-sequencing data from the Gene Expression Omnibus (GEO) database to identify expression profiles for CAF marker genes and constructed a prognostic signature of lung adenocarcinoma using these genes in The Cancer Genome Atlas (TCGA) database. The signature was validated in 3 independent GEO cohorts. Univariate and multivariate analyses were used to confirm the clinical significance of the signature. Next, multiple differential gene enrichment analysis methods were used to explore the biological pathways related to the signature. Six algorithms were used to assess the relative proportion of infiltrating immune cells, and the relationship between the signature and immunotherapy response of lung adenocarcinoma (LUAD) was explored based on the tumor immune dysfunction and exclusion (TIDE) algorithm. RESULTS: The signature related to CAFs in this study showed good accuracy and predictive capacity. In all clinical subgroups, the high-risk patients had a poor prognosis. The univariate and multivariate analyses confirmed that the signature was an independent prognostic marker. Moreover, the signature was closely associated with particular biological pathways related to cell cycle, DNA replication, carcinogenesis, and immune response. The 6 algorithms used to assess the relative proportion of infiltrating immune cells indicated that a lower infiltration of immune cells in the tumor microenvironment was associated with high-risk scores. Importantly, we found a negative correlation between TIDE, exclusion score, and risk score. CONCLUSIONS: Our study constructed a prognostic signature based on CAF marker genes useful for prognosis and immune infiltration estimation of lung adenocarcinoma. This tool could enhance therapy efficacy and allow individualized treatments.
-
Identification and validation of anoikis-related genes to clarify the prognosis and immune mechanisms of patients with low-grade glioma.
BACKGROUND: Low-grade glioma (LGG) has an extremely poor prognosis, and the mechanism leading to malignant development has not been determined. The aim of our study was to clarify the function and mechanism of anoikis and TIMP1 in the malignant progression of LGG. METHODS: We screened 7 anoikis-related genes from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to construct a prognostic-predicting model. The study assessed the clinical prognosis, pathological characteristics, and immune cell infiltration in both high- and low-risk groups. Additionally, the potential modulatory effects of TIMP1 on proliferation, migration, and anoikis in LGG were investigated both in vivo and in vitro. RESULTS: In this study, we identified seven critical genes, namely, PTGS2, CCND1, TIMP1, PDK4, LGALS3, CDKN1A, and CDKN2A. Kaplan‒Meier (K‒M) curves demonstrated a significant correlation between clinical features and overall survival (OS), and single-cell analysis and mutation examination emphasized the heterogeneity and pivotal role of hub gene expression imbalances in LGG development. Immune cell infiltration and microenvironment analysis further elucidated the relationships between key genes and immune cells. In addition, TIMP1 promoted the malignant progression of LGG in both in vitro and in vivo models. CONCLUSIONS: This study confirmed that TIMP1 promoted the malignant progression of LGG by inhibiting anoikis, providing insights into LGG pathogenesis and potential therapeutic targets.
-
Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis.
BACKGROUND: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell-based molecular alterations are largely unknown. OBJECTIVE: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. METHODS: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10× Genomics. RESULTS: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5+COL18A1+ subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3+ dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A+FCER1A+) and tissue-resident memory T cells (CD69+CD103+). The frequencies of type 2 (IL13+)/type 22 (IL22+) T cells were higher than those of type 1 (IFNG+) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. CONCLUSION: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.