Your browser does not allow saving data (e.g. private mode): bookmarks will be lost when the tab closes.
Search PubMed
Keywords, author, journal, years — results from PubMed, abstracts with Russian translation, bookmarks in your browser.
Found: 4 949
Page 485 of 495-
Expression of Bruton's Tyrosine Kinase Reflects Immune Cells Infiltration and Cell Proliferation in Breast Cancer.
BACKGROUND: Bruton's tyrosine kinase (BTK) is a downstream mediator in B-cell receptor (BCR) signaling and is essential for B-cell differentiation and proliferation. BTK inhibitors are approved and in clinical use for hematological cancers such as lymphoma and leukemia, with testing underway in solid tumors. Because BTK is expressed in myeloid-derived suppressor cells (MDSCs) known to worsen breast cancer (BC) outcomes, we investigated the clinical relevance of BTK expression in multiple BC subtypes as a predictor of progression and/or response to treatment. METHODS: We performed an integrative transcriptomic analysis of tumor BTK expression across three large BC cohorts (The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and Sweden Cancerome Analysis Network-Breast (SCAN-B); total n = 5,240), 10 neoadjuvant chemotherapy (NAC) datasets, and the I-SPY2 neoadjuvant immunotherapy trial cohort. Gene set enrichment analysis (GSEA) and xCell deconvolution were used to evaluate associations with cell proliferation, immune infiltration, and tumor microenvironment (TME) composition while single-cell sequencing datasets (SCP1039, SCP1106) were used to identify BTK-expressing cell populations. Survival analyses were performed using Kaplan-Meier and log-rank tests. RESULTS: BTK levels were the highest in triple-negative BC (TNBC) among the subtypes and unexpectedly drove stronger proliferation gene set enrichment in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) tumors (e.g., MITOTIC_SPINDLE, G2M_CHECKPOINT). However, BTK expression did not correlate with American Joint Committee on Cancer (AJCC) stage or overall, disease-free, or disease-specific survival across cohorts or molecular subtypes. Notably, BTK-high tumors showed robust enrichment of immune pathways (interferon gamma (IFN-γ) response, interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α (TNF-α) signaling) and exhibited elevated tumor-infiltrating leukocyte and lymphocyte fractions, increased cytolytic activity, and greater abundance of myeloid and lymphoid cell populations. BTK expression was not consistently associated with NAC response as only one of 10 datasets (GSE25066) showed a weak association within ER+ and HER2-positive subtypes. Similarly, BTK levels did not predict response in I-SPY2 patients receiving durvalumab plus olaparib, despite strong correlations with programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) expression. Single-cell analysis localized BTK transcripts primarily to myeloid and B cells. CONCLUSION: BTK expression in BC reflects a proliferative and immune-active TME, particularly in TNBC and HER2-positive subtypes, but lacks prognostic or predictive value for NAC or PD-L1-based immunotherapy response.
-
Systems pharmacology: a combination strategy for improving efficacy of PD-1/PD-L1 blockade.
Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.
-
Spatially Resolved Molecular Subtyping Uncovers Tumor Progression and Immune Evasion Mechanisms in High-grade Serous Ovarian Cancer.
UNLABELLED: High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by profound intratumoral heterogeneity and immune evasion. Although previous research has identified 4 molecular subtypes of HGSOC, defining their spatial distribution across anatomic sites could help identify functional mediators of progression and immune evasion. In this study, we performed single-cell and spatial transcriptomic sequencing on 66 anatomically paired samples across 5 sites from 8 patients and conducted an integrated analysis on the generated datasets. Five distinct gene programs (GP) with specific spatial distributions and functional roles were identified: GP1 (differentiated-invasive), GP2 (differentiated-proliferative), GP3 (immunoreactive), GP4 (mesenchymal), and GP5 (proliferative). Interestingly, molecular subtypes exhibited dynamic spatial transitions that promote HGSOC progression. The differentiated-proliferative subtype dominated tumor cores, whereas the differentiated-invasive subtype localized to the invasive front driven by SDC4-expressing epithelial cells (c40) that were functionally validated to promote migration/invasion. Concurrently, immune evasion operated through distinct mechanisms. Differentiated-invasive and immunoreactive subtype co-localization established immunosuppression via the TNFα-SAA1/2-APOE signaling axis that recruits immunosuppressive myeloid cells across primary and metastatic sites, whereas fibroblast-derived collagen barriers were constructed at the interfaces between mesenchymal and immunoreactive subtypes in omental metastases along with dysregulated chemokines to exclude immune infiltration. This spatially resolved atlas directly links subtype spatial transitions to tumor progression and subtype co-localization to immune evasion, providing a mechanistic framework for targeting spatially organized tumor-immune interactions in HGSOC. SIGNIFICANCE: Spatially resolved transcriptomic analysis reveals tumor subtype transitions and niche-specific immune evasion mechanisms in ovarian cancer.
-
A novel iTreg-related signature for prognostic prediction in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Most patients are diagnosed at an advanced stage, therefore it is crucial to identify novel prognostic biomarkers for LUAD. As important regulatory cells, inducible regulatory T cells (iTregs) play a vital role in immune suppression and are important for the maintenance of immune homeostasis. This study explored the prognostic value and therapeutic effects of iTreg-related genes in LUAD. Data for LUAD patients, including immune infiltration data, RNA sequencing data, and clinical features, were acquired from The Cancer Genome Atlas, Gene Expression Omnibus, and Tumor Immune Single-cell Hub 2 databases. Immune-related subgroups with different infiltration patterns and iTreg-related genes were identified through univariate and multivariate Cox regression analyses and weighted correlation network analysis. Functional enrichment analyses were performed to explore the underlying mechanisms of iTreg-related genes. A prognostic risk signature was constructed using Cox regression analysis with the least absolute shrinkage and selection operator penalty. The ESTIMATE algorithm was applied to determine the immune status of LUAD patients. We applied the constructed signature to predict chemosensitivity and performed single-cell RNA sequencing analysis. The infiltration of iTregs was identified as an independent factor for predicting patient outcomes. We constructed a prognostic signature based on seven iTreg-related genes (GIMAP5, SLA, MS4A7, ZNF366, POU2AF1, MRPL12, and COL5A1), which was applied to subdivide patients into high- and low-risk subgroups. Our results revealed that patients in the iTreg-related low-risk subgroup had a better prognosis and possibly greater sensitivity to traditional chemotherapy. Our study provides a novel iTreg-related signature to elucidate the mechanisms underlying LUAD prognosis and promote individualized chemotherapy treatment.
-
Uncovering the regulatory landscape of early human B cell lymphopoiesis and its implications in the pathogenesis of B-ALL.
Dysregulation of early B cell lymphopoiesis-the process guiding cellular immunity development-can lead to malignancy, making it crucial to understand its regulatory mechanisms. We generated a multiomics resource comprising paired chromatin accessibility and gene expression profiles across eight human B cell precursor populations, providing a detailed characterization of early human B cell development. Integrative analysis revealed highly cell type-specific regulatory elements and enabled the reconstruction of the gene regulatory network governing differentiation. We identified putative candidate regulons, such as ELK3, enriched in pro-B cells and potentially involved in cell cycle progression. Regulons from bulk data were projected onto single-cell data, validating their activity and refining the regulatory landscape. This resource enabled identification of active regulatory programs and transformation-associated states in B cell acute lymphoblastic leukemia. The publicly available atlas provides a valuable resource for understanding B cell development and disease, supporting future efforts to decode regulatory programs in immunity and hematologic malignancies.
-
Cross-Species Transcriptomic and Metabolomic Analysis Reveals Conserved and Divergent Fatty Acid Metabolic Regulatory Strategies During Mammalian Oocyte Maturation.
Mammalian oocyte maturation is a metabolically demanding process relying on lipid metabolism that supplies energy, structural substrates, and signaling mediators. However, a comprehensive cross-species understanding of the dynamic requirement for lipids during this process remains elusive, hindering the optimization of assisted reproductive technologies. Utilizing an integrated single-cell transcriptomic and targeted lipidomic approach, we mapped the metabolic landscape of bovine oocyte maturation. Our analysis uncovered a global transcriptional downregulation, with 3259 genes suppressed during the transition from the germinal vesicle (GV) to the metaphase II (MII) stage. This was particularly apparent in lipid catabolism pathways (e.g., for ACAA1), while mitochondrial energy production genes (ATP6) were upregulated. Lipidomics indicated a selective depletion of saturated fatty acids (SFAs; e.g., C16:0, C18:0) in MII oocytes, while monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs) were preferentially retained. Integrated network analysis specified hexadecanoic acid (C16:0) as a central metabolic hub, which rewires its interactions from biosynthetic genes (FASN, ELOVL6) in GV oocytes to degradative enzymes (ACADVL, HADH) in MII oocytes. Expanding to a cross-species transcriptomic atlas, we identified a core set of 59 lipid metabolism genes conserved across bovine, mouse, and human oocytes. Despite this conservation, we discovered stark species-specific regulatory strategies: bovine and human oocytes significantly downregulated fatty acid degradation and elongation post-maturation, whereas murine oocytes maintain pathway activity, upregulating key regulators like Acsl3. Our work unveils an evolutionarily conserved core lipid metabolic program in mammalian oocytes that is adaptively tuned to meet species-specific physiological demands. Bovine and human oocytes prioritize catabolic flexibility, using SFAs for energy, while mouse oocytes maintain their anabolic capacity for membrane biosynthesis. These findings provide a transformative resource for the field, offering biomarkers for oocyte quality and a rationale for enhancing species-tailored lipid formulations to develop in vitro maturation systems and amend reproductive outcomes in both agriculture and medicine.
-
A comprehensive evaluation of spontaneous pelvic organ prolapse in rhesus macaques as an ideal model for the study of human pelvic organ prolapse.
Pelvic organ prolapse (POP) seriously affects a woman's quality of life, and the treatment complications are severe. Although new surgical treatments are being developed, the host tissue responses and safety need to be evaluated in preclinical trials. However, there is a lack of suitable animal models, as most quadrupeds exhibit different structural and pathological changes. In this study, 72 elderly rhesus macaques (Macaca mulatta) were physically examined, and the incidence of spontaneous POP was similar to that in humans. The vaginal wall from five control monkeys and four monkeys with POP were selected for further analysis. Verhoeff-van Gieson staining showed that elastin content decreased significantly in monkeys with POP compared with control samples. Immunohistological staining revealed that the smooth muscle bundles in monkey POP appeared disorganized, and the number of large muscle bundles decreased significantly. The collagen I/III ratio in monkey POP also significantly decreased, as revealed by Sirius Red staining. These histological and biochemical changes in monkeys with POP were similar to those in humans with POP. Moreover, we generated a single-cell transcriptomic atlas of the prolapsed monkey vagina. Cross-species analysis between humans and monkeys revealed a comparable cellular composition. Notably, a differential gene expression analysis determined that dysregulation of the extracellular matrix and an immune disorder were the conserved molecular mechanisms. The interplay between fibroblasts and macrophages contributed to human and monkey POP. Overall, this study represents a comprehensive evaluation of spontaneous POP in rhesus macaques and demonstrates that monkeys are a suitable animal model for POP research.
-
Gap junction protein beta 5 interacts with Gαi3 to promote Akt activation and cervical cancer cell growth.
Identifying novel therapeutic targets for cervical cancer is crucial for improving patient outcomes and reducing the global burden of this disease. Gap junction protein beta 5 (GJB5) is a member of the connexin family of proteins involved in cell-to-cell communication. This study investigated GJB5's expression and functional significance in cervical cancer. Analysis of The Cancer Genome Atlas (TCGA) data demonstrated significantly increased GJB5 mRNA expression in cervical cancer tissues compared to normal cervical epithelium. Moreover, high GJB5 expression correlated with reduced overall survival and other adverse clinical outcomes. Single-cell RNA sequencing corroborated GJB5 overexpression within the malignant tumor cell population. The downregulation of GJB5 through shRNA or CRISPR/Cas9 gene knockout techniques significantly impaired the viability, proliferation, and migratory capacity of cervical cancer cells, while concurrently inducing apoptotic processes. Conversely, the forced overexpression of GJB5 resulted in enhanced malignant behaviors. Investigations into the underlying mechanisms revealed that GJB5 is integral to the activation of the Akt-mTOR (mammalian target of rapamycin) signaling pathway. GJB5 knockdown or knockout led to diminished phosphorylation of Akt and S6 kinase, whereas GJB5 overexpression correlated with increased Akt-mTOR signaling in primary human cervical cancer cells. Additionally, we identified a novel interaction between GJB5 and the Gαi3 (G alpha inhibitory protein 3), underscoring the crucial role of GJB5 in mediating Akt activation via Gαi3. In vivo studies utilizing xenograft models provided further evidence for the oncogenic function of GJB5. The knockdown of GJB5 resulted in a marked reduction in the growth of cervical cancer xenografts. Observations of proliferation arrest, inactivation of the Akt-mTOR pathway, and the induction of apoptosis were noted in GJB5-depleted cervical cancer xenograft tissues. Collectively, these findings underscore GJB5 as a key oncogenic driver in cervical cancer and indicate that targeting GJB5 could be a promising therapeutic approach for this disease.
-
TCL1A-expressing B cells are critical for tertiary lymphoid structure formation and the prognosis of oral squamous cell carcinoma.
BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant tumor with a poor prognosis. Traditional treatments have limited effectiveness. Regulation of the immune response represents a promising new approach for OSCC treatment. B cells are among the most abundant immune cells in OSCC. However, the role of B cells in OSCC treatment has not been fully elucidated. METHODS: Single-cell RNA sequencing analysis of 13 tissues and 8 adjacent normal tissues from OSCC patients was performed to explore differences in B-cell gene expression between OSCC tissues and normal tissues. We further investigated the relationship between differentially expressed genes and the immune response to OSCC. We utilized tissue microarray data for 146 OSCC clinical samples and RNA sequencing data of 359 OSCC samples from The Cancer Genome Atlas (TCGA) to investigate the role of T-cell leukemia 1 A (TCL1A) in OSCC prognosis. Multiplex immunohistochemistry (mIHC) was employed to investigate the spatial distribution of TCL1A in OSCC tissues. We then investigated the effect of TCL1A on B-cell proliferation and trogocytosis. Finally, lentiviral transduction was performed to induce TCL1A overexpression in B lymphoblastoid cell lines (BLCLs) to verify the function of TCL1A. RESULTS: Our findings revealed that TCL1A was predominantly expressed in B cells and was associated with a better prognosis in OSCC patients. Additionally, we found that TCL1A-expressing B cells are located at the periphery of lymphatic follicles and are associated with tertiary lymphoid structures (TLS) formation in OSCC. Mechanistically, upregulation of TCL1A promoted the trogocytosis of B cells on dendritic cells by mediating the upregulation of CR2, thereby improving antigen-presenting ability. Moreover, the upregulation of TCL1A expression promoted the proliferation of B cells. CONCLUSION: This study revealed the role of B-cell TCL1A expression in TLS formation and its effect on OSCC prognosis. These findings highlight TCL1A as a novel target for OSCC immunotherapy.
-
Metal ion transporter SLC39A14-mediated ferroptosis and glycosylation modulate the tumor immune microenvironment: pan-cancer multi-omics exploration of therapeutic potential.
BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in cancer progression and therapeutic resistance. Concurrently, glycosylation, as a key post-translational modification, plays a critical role in regulating cell signaling, immune evasion, and metastasis. Although both processes are independently implicated in tumor biology, the intersection between ferroptosis and glycosylation remains largely unexplored. METHODS: We performed a comprehensive pan-cancer multi-omics analysis, integrating bulk transcriptomics, epigenomics, and single-cell RNA sequencing datasets. Ferroptosis and glycosylation-related genes were curated from The Molecular Signatures Database (MSigDB), leading to the identification of the metal ion transporter, SLC39A14 (solute carrier family 39 member 14), as a key intersecting gene. A ferroptosis-related gene signature was constructed using machine learning and Cox regression models, followed by survival analyses, immune microenvironment profiling, and a pathway enrichment analysis across The Cancer Genome Atlas (TCGA) cohort. RESULTS: SLC39A14 was found to be significantly upregulated across multiple tumor types and associated with a poor prognosis, immune-stromal infiltration, and ferroptosis resistance. Among all cancer types analyzed, glioblastoma multiforme (GBM) and kidney renal cell carcinoma (KIRC) exhibited the significantly prognostic associations and the most pronounced differential expression of SLC39A14. Single-cell analysis revealed that SLC39A14 expression was enriched between stromal and immune populations, hypoxic perivascular niches, confirming its microenvironment-specific functions. These findings were corroborated by DNA methylation data showing promoter hypomethylation of SLC39A14 in tumors compared to normal tissues. Functionally, SLC39A14 was highly enriched in pathways related to angiogenesis, the epithelial-to-mesenchymal transition, cytokine signaling, and oxidative stress adaptation including vascular endothelial growth factor (VEGF) and cell metabolism-related signaling. A nomogram integrating SLC39A14 expression with clinical parameters improved overall survival predictions. CONCLUSIONS: In this study, we identified SLC39A14 as a dual regulator at the interface of ferroptosis and glycosylation, with significant impacts on tumor microenvironmental remodeling and therapeutic resistance. By leveraging multi-omics and single-cell transcriptomic data, we establish SLC39A14 as a promising prognostic biomarker and therapeutic target, particularly in brain and kidney cancers where ferroptosis modulation could offer novel clinical strategies.