Search Results (1,353)

Background: Tumour glycosylation regulates immune modulation and progression, but whether the CRC sialylome—the complete repertoire of sialylated glycans—defines a biologically distinct subtype remains unclear. We investigated how the “sugar code” shapes CRC biology, immunity, and therapeutic response. Methods: Transcriptomic data from three CRC cohorts (TCGA, Sidra-LUMC, and CPTAC-2; n = 988) were batch-corrected and integrated. Single-sample gene set enrichment analysis (ssGSEA) quantified sialyltransferase expression, sialic acid metabolism, EMT, MDR mechanisms, immune phenotypes, and Siglec-associated transcriptional signatures. GSEA, gene ontology enrichment analysis (GOEA), and drug ontology enrichment analysis (DOEA) characterised pathways and identified drug response-associated transcriptional signatures. Results: High sialylome activity defined a genomically stable but clinically advanced CRC subset enriched for left-sided tumours, mucinous histology, MSI, and BRAF mutations. At the transcriptional level, Sialyl-High tumours were associated with a mesenchymal, stromal-remodelling programme accompanied by reduced proliferative activity. They demonstrated enrichment of vesicular trafficking-related pathways alongside reduced representation of canonical efflux-associated programmes. Critically, the sialylome was associated with Siglec-related immune signatures, with sialylated glycan-related gene expression correlating with Siglec receptor expression (CD33 and SIGLEC7/9/10), consistent with an immune-inflamed yet structurally excluded microenvironment. DOEA identified selective enrichment of drug-response signatures related to sialic acid metabolism inhibitors (oseltamivir and Neu5Ac) and glycocalyx-disrupting agents (ginsenosides and soyasaponins). Conclusions: The CRC sialylome is associated with tumour phenotypic variation, including immune-excluded states linked to Siglec-associated transcriptional signatures and patterns consistent with non-canonical drug resistance programmes. These findings position the “sugar code” as a central organising principle in CRC and identify glycan-directed therapies as a promising strategy for the targeting of this aggressive subtype. Full article

Background: Responses to atezolizumab plus bevacizumab (Atezo+Bev) in hepatocellular carcinoma (HCC) are heterogeneous, and response determinants remain unclear. We investigated whether spatial proximity between PD-L1(+) tumor-associated macrophages (TAMs) and CD8(+) T cells represents an immune niche associated with Atezo+Bev responsiveness. Methods: Multiplex immunohistochemistry was performed on biopsies from patients treated with Atezo+Bev (n = 23) or lenvatinib (n = 20). An interaction variable was defined via nearest-neighbor analysis as CD8(+) T cells within 25 µm of PD-L1(+) TAMs, normalized to cell counts. Associations with tumor shrinkage and progression-free survival (PFS) were examined. CD8(+) T cell phenotypes were evaluated via GZMB and TIM3. Transcriptomic profiling of resected HCCs (n = 8) was conducted using next-generation sequencing and gene set enrichment analysis (GSEA). Results: In a patient with responsive and non-responsive lesions, the responsive lesion showed closer PD-L1(+) TAM-CD8(+) T cell proximity. In cohort analyses, the interaction variable was associated with tumor shrinkage and prolonged PFS in the Atezo+Bev group, whereas PD-L1(+) TAM or CD8(+) T cell density alone was not predictive. This association was absent in the lenvatinib cohort. High-interaction tumors showed increased GZMB(+) and TIM3(+) CD8(+) T cells. Transcriptomic analysis revealed the upregulation of inflammatory, cytotoxic, chemotactic, and immunoregulatory genes, with enrichment of the chemokine, IFN-gamma, and IL-10 signaling pathways. Conclusions: Spatial proximity between PD-L1(+) TAMs and CD8(+) T cells defines an immune niche characterized by coexisting immune activation and regulatory programs and is strongly associated with Atezo+Bev responsiveness in HCC. Quantification of this spatial interaction may serve as a biopsy-based biomarker for immunotherapy stratification. Full article

Background/Objectives: Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. Methods: This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. Results: SHP-1 protein levels were significantly lower in highly invasive cell lines (p < 0.001) and muscle-invasive tumors (p < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial–mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression (p < 0.001) and negatively correlated with N-cadherin (p < 0.01) and Vimentin (p < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration (p < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios (p < 0.05). Conclusions: Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer. Full article

Fucosylation, the enzymatic addition of fucose residues to glycans, modulates receptor signalling and cellular identity in the intestinal epithelium. Its role as an integrative determinant of cancer cell fate in colorectal cancer (CRC) remains undefined. Transcriptomic and clinicopathological data from 976 CRC patients across three independent cohorts (TCGA-CRC, CPTAC2-CRC, Sidra-LUMC) were analysed. A curated fucosylation gene set was used to calculate tumour fucosylation scores. Associations with histogenetic status, genomic features, microenvironmental phenotypes, drug resistance programmes, and survival were evaluated using gene set enrichment analysis, multivariable Cox regression, and integrated molecular subtyping. High-fucosylation tumours exhibited elevated epithelial differentiation, MSI-H/BRAF-mutant enrichment, oxidative phosphorylation dominance, the complete absence of EMT and invasion programmes, and favourable prognosis (HR = 0.633, 95% CI: 0.470–0.853, p = 0.003). Low-fucosylation tumours demonstrated mesenchymal phenotypes, TP53 mutations, chromosomal instability, comprehensive multi-family RTK signalling, immune-excluded microenvironments, and poor outcomes. Distinct multidrug resistance programmes emerged: drug efflux in low-fucosylation tumours versus xenobiotic sensing, target bypass, and drug sequestration in high-fucosylation tumours. Tumour fucosylation status defines two fundamentally distinct CRC cell states with mutually exclusive engagement of invasion programmes, metabolic pathways, immune phenotypes, and resistance mechanisms. Fucosylation represents an independent prognostic biomarker and integrative determinant of cancer cell fate, with significant implications for risk stratification and personalised therapeutic strategies. Full article

Background: High-grade serous ovarian carcinoma (HG-SOC) remains the most lethal gynecological malignancy, largely due to intrinsic or acquired resistance to platinum-based chemotherapy. Although large-scale sequencing studies have delineated the genomic landscape of HG-SOC, clinically actionable biomarkers predictive of platinum response and outcome are still lacking. This study aimed to identify genomic alterations associated with platinum sensitivity, resistance, or refractoriness, and to assess their prognostic relevance. Methods: Tumor DNA from 24 HG-SOC patients with optimal cytoreductive resection, classified as platinum-sensitive (n = 9), platinum-resistant (n = 8), or platinum-refractory (n = 7) underwent targeted next-generation sequencing of 409 cancer-associated genes. Somatic variants were filtered and classified for oncogenicity using established criteria incorporating predicted functional impact, REVEL scores, and population allele frequencies. Associations between mutational profiles, platinum response, and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Key findings were validated in the TCGA ovarian serous carcinoma (TCGA-OV) dataset using survival analyses. Results: A total of 1367 protein-altering somatic variants across 301 genes were identified. While TP53 mutations were ubiquitous, platinum-resistant and platinum-refractory tumors showed enrichment of pathogenic alterations affecting DNA repair, transcriptional regulation, epigenetic modification, and oncogenic signaling, including FANCA, ATF1, MAF, NCOA2, PIK3CA, and TET1. Mutations in these genes were associated with reduced overall survival in exploratory analyses (median 2.5–9 months vs. 27.5–45 months). Multivariate analysis identified FANCA and ATF1 as potential independent predictors in exploratory modeling. In the TCGA-OV cohort, patients harboring pathogenic variants in a multi-gene panel derived from this study (excluding BRCA1/2) exhibited significantly worse survival compared with both BRCA1/2-mutated cases and the overall cohort. Conclusions: This exploratory study identifies a set of genomic alterations converging on transcriptional and epigenetic regulation, DNA repair, and oncogenic signaling that are associated with platinum resistance and adverse prognosis in HG-SOC. Independent validation in TCGA supports the potential clinical relevance of this mutational signature. These findings warrant further validation in larger prospective cohorts and functional studies to clarify their role as biomarkers of aggressive disease and therapeutic vulnerability. Full article

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Although epigenetic dysregulation is a hallmark of HCC, rational combinatorial targeting strategies remain incompletely defined. Here, we identify cooperative oncogenic functions of the chromatin modifiers enhancer of zeste homolog 2 (EZH2) and lysine-specific demethylase 1 (LSD1) in HCC. Analysis of the TCGA-LIHC cohort revealed that co-elevated EZH2 and LSD1 expressions are significantly associated with reduced overall survival. Gene set enrichment analysis demonstrated enrichment of Sonic Hedgehog (SHH) signaling and stress-responsive transcriptional programs in tumors with high EZH2/LSD1 expression. Functionally, dual pharmacological inhibition of EZH2 (GSK126) and LSD1 (SP2509) suppressed HCC cell proliferation, induced G1-phase arrest, and enhanced apoptosis, as evidenced by increased caspase-3/7 activity and decreased pro-caspase levels. Dual inhibition also impaired migration, invasion, tumor sphere formation, and stemness-associated gene expression. Mechanistically, co-targeting disrupted SHH signaling through the suppression of GLI1 expression. Chromatin immunoprecipitation revealed reduced EZH2, LSD1, and STAT3 occupancy at the GLI1 promoter following dual inhibition, leading to the repression of GLI1 and its downstream targets. Collectively, these findings demonstrate that EZH2 and LSD1 cooperatively sustain GLI1-dependent SHH signaling in HCC, and that dual epigenetic inhibition represents a mechanistically defined therapeutic strategy. Full article

Background: Neuroinflammation is recognized as a key contributor to Parkinson’s disease (PD), but the relationships between inflammatory signaling, immune-state alterations, and cell-type-specific transcriptional programs remain unclear. Methods: Public transcriptomic datasets, including GSE20141 (discovery cohort) and the substantia nigra subset of GSE114517 (external validation cohort), were analyzed. Genes identified by exploratory differential-expression screening in the discovery cohort were intersected with predefined inflammation- and chemokine-related gene sets to define a candidate space for downstream prioritization. Protein–protein interaction, Gene Ontology, KEGG, and immune-signature analyses were performed, followed by machine learning-based feature prioritization using Elastic Net, support vector machine-recursive feature elimination, and random forest. Prioritized candidates were further evaluated by cross-platform validation, single-nucleus transcriptomic mapping, and a hypothesis-generating in silico perturbation analysis in PD astrocytes. Results: Seventeen genes were retained at the intersection of PD-related differentially expressed genes and inflammation-/chemokine-associated gene sets. These candidates formed a response module enriched in mitochondrial organization, oxidative phosphorylation, and mitophagy pathways. Immune-signature analysis suggested an altered transcriptome-derived immune landscape in PD, with changes in NK cell-related signatures and significant correlations between immune-state scores and the candidate genes. Machine learning-based prioritization yielded five shared candidates, of which only CCL2 and PAK6 showed same-direction support with nominal significance in the external validation cohort. Single-nucleus transcriptomic analysis localized CCL2 predominantly to astrocytes, whereas PAK6 was more strongly associated with neuronal populations, particularly OTX2-positive ventral midbrain neurons. In silico perturbation analysis further predicted that CCL2 suppression in PD astrocytes may be associated with translational- and ribosome-related regulatory programs. Conclusions: CCL2 and PAK6 emerged as prioritized candidate biomarkers associated with PD-related inflammatory and chemokine-linked transcriptional alterations in the substantia nigra. More broadly, this study provides a multi-layered framework for candidate prioritization, cross-platform validation, and cell-type-level contextualization in PD neuroinflammation. Because the study is computational and the perturbation analysis is predictive, orthogonal experimental validation will be required to determine whether CCL2 and PAK6 are biomarkers of disease-associated transcriptional states, functional contributors to PD pathogenesis, or both. Full article

Background: Cellular senescence is a key regulatory mechanism in tumor initiation and progression, influencing cancer development through modulation of the cell cycle, the immune microenvironment, and inflammatory responses. However, the molecular characteristics and potential clinical value of senescence-related genes in lung adenocarcinoma (LUAD) have not been systematically elucidated. This study aimed to comprehensively characterize the expression patterns, molecular subtypes, and prognostic significance of cellular senescence-related genes in LUAD, and to identify key regulatory determinants. Methods: Transcriptomic data of cellular senescence-related genes were obtained from The Cancer Genome Atlas (TCGA) cohort, and integrated analyses were performed to characterize their mutational landscape, copy number variations, and differential expression profiles. Senescence-related molecular subtypes were established using consensus clustering, followed by gene set variation analysis (GSVA) for pathway enrichment and immune infiltration analyses. A prognostic risk model was subsequently constructed using LASSO-penalized Cox regression, and its predictive performance was systematically evaluated. Candidate key regulators were further prioritized through bioinformatic screening, identifying FOLR1 as a hub gene. The biological function of FOLR1 was validated by qRT–PCR, Western blotting, assessment in clinical specimens, and a subcutaneous xenograft tumor model in mice. Results: Cellular senescence-related genes in LUAD exhibited a high frequency of somatic mutations and copy number alterations, accompanied by marked transcriptional dysregulation. Based on the expression profiles of these genes, LUAD patients could be stratified into three distinct molecular subtypes with significantly different clinical outcomes. These subtypes displayed pronounced heterogeneity in pathway enrichment patterns and immune cell infiltration. The subsequently developed prognostic signature demonstrated robust predictive performance in both the training and validation cohorts. Functional assays showed that FOLR1 was significantly downregulated in LUAD tissues and cell lines; FOLR1 knockdown promoted tumor cell proliferation, whereas restoration of its expression or pharmacological intervention markedly suppressed tumor progression. Consistently, in vivo xenograft experiments further corroborated the tumor-suppressive role of FOLR1 in lung adenocarcinoma. Conclusions: This study systematically delineated the molecular landscape of cellular senescence-related genes in LUAD and elucidated their associations with the tumor immune microenvironment and patient prognosis. Moreover, FOLR1 was identified as a potential tumor suppressor and therapeutic target. These findings provide a theoretical basis for senescence-informed molecular stratification and the development of precision treatment strategies in lung adenocarcinoma. Full article

Background/Objectives: SARS-CoV-2 is the causative agent of COVID-19, an infectious viral respiratory disease with human-to-human transmission. Current molecular understanding of how hosts respond to infection by respiratory viral pathogens in general and to SARS-CoV-2 in particular is still a research field under development. The activation levels of various host pathways are dependent on several variables, including the host tissue compartment. Methods: In this work, Illumina RNA sequencing was performed to assess the transcriptional host response to SARS-CoV-2 infection using COVID-19 PCR testing nasopharyngeal (NP) swab remnants from twenty infected and nine non-infected individuals. Results: Differential gene expression (DGE) analysis identified 182 overexpressed genes, with strong enrichment in innate immune and viral response genes. This included a significant induction of IFIH1/MDA5, a pattern recognition receptor (PRR) gene participating in the initial sensing of viral RNAs and subsequent cascade activation of interferon (IFN) and IFN-stimulated genes (ISGs). Interestingly, we observed different levels of concordance with previous similar studies and a significant induction of RIG1 and TLR3, two PRR genes encoding proteins that function to upregulate IFN and ISGs, but which are not normally identified as differentially expressed genes (DEGs). Finally, the overexpression of MX1, a well-characterized biomarker of viral infection; IFIT1, one of the top upregulated genes; and OAS1, OAS2 and OAS3, genes with a molecular function, 2-5-oligoadenylate synthase activity, identified as enriched in the DGE analyses, was confirmed by RT-qPCR. Conclusions: This study provides insights into upper respiratory tract responses to SARS-CoV-2 infections and identifies a set of differentially expressed genes (DEGs) with potential as candidates for further investigations as viral infection biomarkers. Full article

Background and Objectives: Gastric cancer remains a leading cause of cancer-related mortality worldwide and develops through complex interactions between environmental factors, microbial dysbiosis, and host molecular pathways. Although Helicobacter pylori infection is a well-established risk factor, emerging evidence suggests that broader alterations in the gastric microbiome may also contribute to carcinogenesis. However, the associations between gastric cancer-associated microbial taxa and host gene expression profiles remain insufficiently characterized. This study aimed to identify host gene signatures associated with gastric cancer-related microbial taxa through a descriptive analysis integrating microbiome-derived taxa with transcriptome data. Materials and Methods: Microbial taxa associated with gastric cancer were systematically retrieved from the Disbiome database. Taxon set enrichment analysis (TSEA) was performed using the MicrobiomeAnalyst platform to identify host genes associated with gastric cancer-associated taxa. Importantly, TSEA relies on healthy reference data from the Human Microbiome Project and does not establish gastric cancer-specific interactions or causal relationships. Gene expression levels were subsequently evaluated using The Cancer Genome Atlas (TCGA) PanCancer stomach adenocarcinoma (STAD) dataset by comparing tumor and matched normal gastric tissues. Gene interaction network and transcription factor (TF) enrichment analyses were conducted to explore predicted regulatory relationships. Results: Among 64 microbial taxa associated with gastric cancer, 43 were reported as elevated. After removing overlapping taxa across studies, 37 elevated and 21 reduced taxa were retained for analysis. TSEA identified 11 host genes associated with gastric cancer-related microbial taxa. Transcriptomic analysis demonstrated significant downregulation of DPP6 and DLG2, while KDM4D, USP34, and VDR were significantly upregulated in gastric cancer tissues compared with normal controls. Network and TF enrichment analyses revealed predicted co-expression and co-localization patterns among these genes, suggesting their potential involvement in immune-related processes, epigenetic regulation, and cellular organization. Conclusions: This descriptive study identifies distinct host gene expression signatures associated with gastric cancer-associated microbial dysbiosis. This study is purely associative and hypothesis-generating; no causal or mechanistic inferences are made. TSEA used healthy reference data and therefore does not reflect gastric cancer-specific host–microbe interactions. The findings provide a basis for future hypothesis-driven research but require validation in independent cohorts. Full article

Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic PCa and to identify key microenvironmental signaling pathways involved in tumor survival and chemoresistance. Methods: Bulk RNA sequencing was performed on 49 non-metastatic and 28 bone-metastatic PCa specimens. Differential expression analysis was integrated with weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis, and immune/stromal deconvolution. Key findings were validated using in vitro functional assays, including Transwell co-culture models, small interfering RNA (siRNA)-mediated gene silencing, cell viability, apoptosis, and docetaxel resistance analyses. Results: Transcriptomic profiling identified 574 differentially expressed genes. Bone-metastatic tumors were enriched in ribosome-related and translational pathways, whereas non-metastatic tumors displayed immune-associated signatures, including natural killer (NK) cell-mediated cytotoxicity and cytokine signaling. WGCNA revealed immune-related gene modules preferentially enriched in non-metastatic disease. Immune deconvolution demonstrated significantly higher infiltration of NK cells and endothelial cells in non-metastatic tumors. Chemokine-receptor analysis highlighted upregulation of the CXCL10-CXCR3 axis in non-metastatic PCa. In vitro, PCa cells expressed CXCR3, while endothelial cells markedly increased CXCL10 expression upon co-culture. Functional assays showed that endothelial-derived CXCL10 promoted PCa cell survival, suppressed apoptosis, and conferred resistance to docetaxel via CXCR3-dependent signaling; these effects were reversed by CXCL10 or CXCR3 knockdown. Conclusions: These findings uncover a context-dependent endothelial-immune chemokine network distinguishing non-metastatic from bone-metastatic PCa and identify the CXCL10-CXCR3 axis as a critical mediator of tumor survival and chemoresistance, suggesting a potential therapeutic vulnerability in advanced prostate cancer. Full article

The purpose of this project was to define gene expression changes associated with the acquisition and loss of resilience to diabetic retinopathy (RDR) in individual retinal cell types. A non-immune form of type 1 diabetes mellitus (DM) was induced by injecting male C57Bl6J mice with streptozotocin. Single-cell RNA sequencing was performed on retinas from mice that experienced DM for 5 or 15 days, along with retinas from age-matched, non-DM mice. The resulting data sets were analyzed to identify DM-associated differentially expressed genes and pathway enrichments after each duration of DM. We observed that acquisition of RDR, previously shown to arise after 5 days of DM was linked to altered expression of genes in a subset of retinal cells, mainly Müller cells. Pathway analysis indicated enhancement of numerous modes of protection, including reinforced neurovascular and structural homeostasis through phagocytosis, integrin signaling, and interferon-mediated defense. After 15 days of DM, when we previously showed that RDR is waning this pro-protection surge in gene expression subsided. We conclude that a duration of DM that is too short to cause diabetic retinopathy (DR) nonetheless evoked a profound change in the gene expression profile within a subset of retinal cell types. The nature and timing of this molecular shift indicated that it was not the preamble to DM-related damage that eventually develops. Rather, DM engaged numerous defense programs within Müller cells. The temporal alignment between RDR and activation of Müller cell-based defense provides a molecular foundation for the retina’s transient ability to remain healthy in the face of DM. Full article

With increasing environmental pollution and a high incidence of respiratory infections, pulmonary nodules (PN) are being detected more frequently. Although most are benign, they are often accompanied by chronic inflammation and localized fibrosis, which may predispose patients to progression toward idiopathic pulmonary fibrosis (IPF). However, the biological relationship between benign pulmonary nodules (BPNs) and IPF remains poorly understood. Therefore, this study aims to investigate the shared molecular mechanisms and identify potential biomarkers linking BPN and IPF, with the goal of elucidating the pathogenic transition from BPN to IPF. In this study, microarray data from GEO datasets were systematically analyzed to explore shared molecular mechanisms, immune infiltration characteristics, and potential early intervention strategies linking BPN and IPF. Differential expression analysis, protein–protein interaction (PPI) networks, weighted gene co-expression network analysis (WGCNA), and integrative machine learning approaches identified MME and ANKRD23 as key hub genes associated with the transition from BPN to IPF. Both genes demonstrated strong diagnostic performance, with Area Under the Curve (AUC) values exceeding 0.7, and were significantly correlated with immune cell infiltration, particularly effector memory CD8⁺ T cells. Functional enrichment and gene set enrichment analyses indicated that these genes were mainly involved in immune-related processes in BPN, while in IPF, ANKRD23 was linked to cytoskeletal organization and genomic stability, and MME was enriched in profibrotic pathways such as TGF-β signaling. The diagnostic value of these biomarkers was further validated in a bleomycin-induced IPF mouse model using quantitative polymerase chain reaction (qPCR). In addition, drug–gene interaction prediction and molecular docking analyses highlighted several naturally derived compounds with favorable binding affinity and anti-inflammatory properties, among which folic acid, curcumin, and arbutin emerged as promising candidates for safe early intervention. Collectively, these findings identify MME and ANKRD23 as potential biomarkers for early identification of BPN patients at risk of developing IPF and provide a theoretical basis for early diagnosis and targeted preventive strategies. Full article

Tumor-associated Tie2-expressing monocytes/macrophages (TEMs) have been implicated in promoting angiogenesis and metastasis in colorectal cancer (CRC), yet the molecular mechanisms linking TEMs infiltration to tumor metastasis and progression remain incompletely defined. This study investigated the distribution of TEMs in CRC and their association with gene expression profiles, microvessel density (MVD), and clinical outcomes. Immunohistochemistry on 30 formalin-fixed paraffin-embedded (FFPE) primary CRC samples revealed that TEMs, which characteristically express tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2) receptor and CD14, preferentially localize to perivascular regions and are associated with higher histological grade, tumor size, lymph node metastasis, and increased MVD. However, Tie2⁻/CD14⁺ macrophages and CD68⁺ tumor-associated macrophages (TAMs) showed uniform stromal distribution. Gene set enrichment analysis (GSEA) of in silico transcriptomic datasets of metastatic CRC (mCRC) identified enrichment of pathways related to cell–cell recognition, calcium signaling, transcription regulation, and metalloexopeptidase activity in Tie2⁺/CD14⁺ tumors. Subsequent qRT-PCR validation on FFPE primary CRC samples confirmed significant upregulation of C-C chemokine receptor 7 (CCR7), platelet-derived growth factor A (PDGFRA), CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), and carboxypeptidase E (CPE) in TEMs⁺ regions. Notably, angiopoietin1 (Ang1), but not angiopoietin2 (Ang2), was significantly elevated in TEMs⁺ primary tumors. Kaplan–Meier analysis on 1336 CRC patients indicated that high expression of CITED2, CPE, and Ang2 is associated with reduced overall survival. Collectively, these findings suggest that TEM infiltration is linked to transcriptional regulation, biological processes, and enzymatic programs in CRC, potentially contributing to tumor progression and poor prognosis, and highlight CCR7, PDGFRA, CITED2, CPE, and Ang1 as candidate biomarkers for further mechanistic exploration. Full article

Background: Glioblastoma exhibits profound intratumoral heterogeneity, with anatomically distinct tumor zones characterized by divergent molecular programs that drive therapy resistance. Whether magnetic resonance imaging (MRI)-derived radiomic features can capture these regional transcriptomic differences remains unknown. We aimed to determine whether subcompartment-level radiomic features associate with transcriptomic pathway enrichment scores derived from biologically approximate tumor zones. Methods: We matched 28 patients (mean age 58.5 years; 13/28 MGMT methylated) across the IvyGAP RNA-seq atlas and the IVYGAP-RADIOMICS datasets. Single-sample GSEA (ssGSEA) pathway scores were computed for 24 gene sets. Radiomic features (3920 per subcompartment) were reduced to 597. Nested leave-one-patient-out cross-validation (LOPO-CV) with Elastic Net served as the primary predictive analysis; linear mixed-effects models (LMM) provided exploratory associational analysis. Analyses used a biologically motivated but spatially non-co-registered zone-to-subcompartment mapping; all reported associations are zone-approximate. Results: Twenty-one of 24 pathways showed no predictive signal (R²_cv ≤ 0). Inflammatory Response (R²_cv = 0.185, 95% CI [0.071, 0.355], p = 0.008) was the only pathway supported by both the nested CV (FDR = 0.096) and the exploratory LMM (FDR = 0.024, ΔR² = 0.214 beyond subcompartment effects) analyses; the LMM association was robust to clinical covariate adjustment (likelihood ratio test p = 0.004). Angiogenesis (R²_cv = 0.209, 95% CI [0.028, 0.353], p = 0.006) reached nested CV significance (FDR = 0.096) but was not corroborated by the LMM (FDR = 0.445); it is therefore reported as a tentative single-framework signal requiring independent validation. T2-derived texture features were selected in 100% of folds for both pathways. Conclusions: Inflammatory Response is the only pathway supported by both analytical frameworks; Angiogenesis is a tentative nested-CV-only signal pending independent validation. The absence of signal for 21 of 24 pathways should not be interpreted as evidence of biological inaccessibility: at N = 28 (vs. N ≈ 240 required by Riley criteria), severe underpowering, attenuation from the non-spatial zone-to-subcompartment mapping, and methodological constraints each independently suffice to suppress real associations. Five of the 24 gene sets (the IvyGAP zone modules) are non-independent from the outcome data and cannot be interpreted as discovery. All reported associations are zone-approximate and may partly reflect macro-compartment (between-subcompartment) effects; validation in larger cohorts with spatially precise co-registration is essential. Full article