Search Results (1,428)

Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, cellular context and biased coupling to G-protein αq (Gαq), G-protein α12/13 (Gα12/13) and β-arrestin. PAR-2 is best understood not as a simple inflammatory receptor but as a proteolytic rheostat that converts diverse coagulation, inflammatory, microbial and stromal protease inputs into distinct oncogenic programmes. Colorectal cancer and pancreatic ductal adenocarcinoma provide complementary models: in colorectal cancer, PAR-2 links mucosal inflammation and coagulation to proliferation, metastatic competence and resistance to epidermal growth factor receptor (EGFR)-targeted therapy, whereas in pancreatic cancer, it is embedded in a tissue-factor-rich desmoplastic microenvironment that promotes invasion, immune exclusion and chemoresistance. Therapeutic strategies suggested by this framework include direct and biased PAR-2 modulators, upstream protease and factor Xa (FXa) inhibition, statin repurposing and activated-fragment biomarkers such as the PAR-2 activation neoepitope (PRO-PAR2). These strategies must be applied under biomarker guidance, since PAR-2 blockade may benefit inflammation-dominant tumours yet prove counterproductive where PAR-2 sustains antitumour immunity. Full article

Background/Objectives: Triple negative breast cancer remains the most difficult breast cancer to treat as there are no specific targeted therapies. The tumor stroma is recognized as essential for the development of solid tumors. Cancer associated myofibroblasts are known to play a major role in the construction of a tumor microenvironment conducive to tumor progression. Therefore, we established a co-culture system to identify potential molecular targets controlling myofibroblast conversion. Methods: Co-cultures of MDA-MB-468 triple negative breast cancer cells and skin fibroblasts were either mixed prior to seeding or seeded individually on opposite sides of a culture dish and incubated in complete medium. Inhibitors were preincubated with cells for 1 h. Inflammatory cytokines were measured by ELISA. Proteins were analyzed using the Wes-Protein Simple System. Immunostaining was visualized using a Hamamatsu Photonics Nanozoomer. Statistical analysis was done by student’s t-test and one-way ANOVA. Results: The data indicate that co-culturing the cells promotes myofibroblast differentiation and cytokine release and this requires direct contact between the two cell types. Both myofibroblast conversion and cytokine release were prevented by inhibitors of TLR5, TGF-β and EDA-fibronectin. Conclusions: Data suggest that the TLR5 receptor on the MDA-MB-468 cells binds to EDA-fibronectin expressed by fibroblasts thus inducing inflammatory cytokine expression. Expression of EDA fibronectin is regulated through TGF-β whose synthesis is induced by TLR5 signaling in the tumor cells. The data are consistent with a model in which TLR5-mediated crosstalk between the cancer cells and the stromal fibroblasts creates a tissue microenvironment conducive to tumor growth and metastasis. Full article

Conventional histopathological diagnostics rely on morphological assessment of stained tissue sections, requiring extensive sample preparation and subjective expert interpretation. Mid-infrared (MIR) imaging offers a complementary approach by providing spatially resolved, label-free access to the intrinsic biochemical composition of tissue without exogenous contrast agents. This work introduces a preprocessing and analysis pipeline for multiphotometric MIR data, applied to formalin-fixed, paraffin-embedded tissue sections from two patients with histopathologically confirmed head and neck squamous cell carcinoma. Combining differential scattering correction, sub-pixel channel registration, and automated tissue segmentation with unsupervised K-Means clustering, the pipeline achieves label-free discrimination of biochemically distinct tissue compartments. K-Means clustering identified four distinct clusters, of which three corresponded to tissue compartments with protein-to-lipid ratios tentatively consistent with epithelial, tumor-associated, and stromal compartments. The resulting cluster maps showed partial spatial correspondence with mIF reference stainings targeting epithelial and stromal markers, supporting the potential of this approach for label-free tissue characterization in digital pathology. Full article

The expansion of neoadjuvant immune checkpoint blockade, chemoimmunotherapy, and targeted therapies in oncogene-driven tumors is reshaping the management of resectable non-small cell lung cancer (NSCLC). Major pathologic response (MPR) and pathologic complete response (pCR), defined respectively as 10% or less residual viable tumor (RVT) within the primary tumor bed and the complete absence of viable tumor in both the resected primary tumor and sampled regional lymph nodes, have become widely adopted early efficacy endpoints. Both are consistently associated with favorable survival outcomes at the patient level, although their validity as trial-level surrogates for long-term outcomes remains incompletely established. Accurate pathologic response assessment requires rigorous standardization of gross specimen handling, tumor bed sampling, and microscopic quantification of viable tumor, necrosis, and stroma. International recommendations have improved methodological harmonization, and reproducibility studies have demonstrated good interobserver agreement when standardized protocols are applied. Increasing evidence also indicates that RVT behaves as a continuous prognostic variable and that integration of primary-tumor and nodal response may improve postoperative risk stratification. Beyond quantification of RVT alone, additional histologic characteristics of the residual tumor, together with stromal and immune therapy-related features, may provide complementary prognostic information. Digital pathology and artificial intelligence may support more reproducible quantitative assessment, whereas circulating tumor DNA-based molecular residual disease evaluation may capture systemic risk not represented by the resection specimen. These emerging approaches remain investigational and require prospective validation. This review critically examines the methodological standardization, biological interpretation, and prognostic validation of pathologic response in resectable NSCLC, and discusses future strategies integrating histopathologic, digital, and molecular variables into post-neoadjuvant risk assessment. Full article

Gaseous air pollution is a major environmental risk factor for atherosclerosis, yet the specific molecular networks linking Gaseous air pollution to atherosclerosis are not fully characterized. This study aimed to elucidate how gaseous pollutants drive atherosclerosis using a multi-level framework integrating network toxicology, nine machine-learning algorithms, bulk and single-cell/spatial transcriptomics, molecular docking, clinical tissue/serum validation, and in vitro pollutant-exposure assays. A conserved RXRA–MMP9–TNF axis was identified as a core molecular network linking pollutant exposure to atherosclerosis. Single-cell and spatial transcriptomics showed broad expression of RXRA (Retinoid X Receptor Alpha) in vascular stromal and endothelial cells and its association with xenobiotic and lipid metabolism, whereas MMP9 (Matrix Metallopeptidase 9) and TNF (Tumor Necrosis Factor) were enriched in macrophages, T cells, and mast cells within plaques, correlating with immune cell infiltration. Multiple pollutants displayed high binding affinity to these proteins. Clinical samples showed upregulation of these targets in atherosclerotic tissue and serum. Toluene exposure in THP-1-derived macrophages significantly increased RXRA, MMP9, and TNF mRNA and protein levels. These findings highlight an immune–metabolic interplay centered on the RXRA–MMP9–TNF axis in Gaseous air pollution-driven atherosclerosis, supporting these molecules as candidate biomarkers for environmental health strategies. Full article

Bisphosphonates (BPs) are cornerstone therapeutic agents for the management of metabolic bone disorders and skeletal complications associated with malignant tumors. However, their long-term administration is accompanied by the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). In recent years, the pathogenesis of BRONJ has remained a major focus at the intersection of osteoimmunology and oral medicine. This review systematically summarizes the latest advances in the understanding of BRONJ pathogenesis, including the direct disruption of osteoclast differentiation and bone remodeling coupling by bisphosphonates, the systemic reprogramming of immune cell subsets and inflammatory signaling pathways, the multifaceted suppression of angiogenesis and the endothelial–stromal–immune axis, and the toxic impairment of oral soft tissue repair capacity. Building upon these mechanistic insights, we further discuss the modifying and synergistic effects of local oral risk factors, microbial dysbiosis, systemic comorbidities, and genetic susceptibility on the initiation and progression of BRONJ. Furthermore, emerging therapeutic strategies targeting these pathogenic mechanisms are highlighted, including restoration of small GTPase prenylation through modulation of metabolic pathways, reconstruction of T-cell subset homeostasis via immunomodulatory approaches, enhancement of local vascularization through pro-angiogenic interventions, and preservation of soft tissue barrier integrity. Collectively, this review provides a comprehensive and multidimensional overview of the pathological landscape of BRONJ and offers a theoretical framework for clinical risk stratification and the development of personalized prevention and treatment strategies. Full article

Fibrosis emerges when normally self-limiting tissue repair fails to resolve and overlapping phases of injury, stromal activation, extracellular matrix (ECM) deposition and remodelling become sustained. MicroRNAs (miRNAs) shape this transition by coordinating signalling, cell-state and matrix programmes. Functionally, pro-fibrotic fibro-miRs amplify fibrogenic pathways, whereas anti-fibrotic miRNAs restrain fibroblast activation and ECM production; the miR-29 family is a principal member of the latter group. This review examines miR-29 family organisation, the regulation of miR-29b by transforming growth factor-β (TGF-β)/Smad and additional transcriptional and inflammatory inputs, and the molecular targets through which miR-29b controls collagen synthesis, processing and crosslinking. Direct canonical targets are distinguished from experimentally supported, predicted and indirect pathway components. Evidence is evaluated across fibroblasts and myofibroblasts, epithelial and endothelial cells, and pulmonary, hepatic, renal, cardiac, dermal and ocular fibrosis models. Therapeutic translation is considered in relation to miR-29b mimics and agomirs, local and tissue-targeted delivery, pharmacokinetics, dose control, off-target repression, immune activation and long-term safety. Overall, miR-29b remains a credible network-level anti-fibrotic candidate, but successful translation requires cell- and disease-specific target validation, selective delivery and preservation of physiological wound repair. Full article

Corneal fibrosis is a major cause of visual impairment worldwide and is characterized by persistent stromal scarring that disrupts corneal transparency. Although transforming growth factor-β (TGF-β)-mediated myofibroblast differentiation is well established, the mechanisms that sustain myofibroblast survival and persistence remain poorly understood. In this study, we investigated the role of the insulin-like growth factor (IGF) signaling axis in corneal myofibroblast survival and evaluated the therapeutic potential of linsitinib, a dual IGF-1 receptor (IGF-1R)/insulin receptor (INSR) inhibitor. Primary corneal myofibroblasts were exposed to pro-apoptotic conditions and treated with IGF ligands in the presence or absence of linsitinib. The effects of IGF pathway inhibition were further examined in a mouse model of corneal fibrosis. IGF-1 and IGF-2 promoted myofibroblast survival under pro-apoptotic conditions, whereas pharmacologic inhibition of IGF-1R/INSR signaling with linsitinib blocked these pro-survival effects. In vivo, linsitinib treatment reduced myofibroblast persistence and attenuated corneal fibrosis. These findings identify the IGF axis as a critical regulator of corneal myofibroblast survival and suggest that persistent fibrosis is maintained, in part, by IGF-dependent resistance to apoptosis. Targeting survival pathways rather than myofibroblast differentiation may represent a novel therapeutic strategy for the treatment of corneal fibrosis. Full article

Follicular-cell-derived thyroid cancers that progress from differentiated tumors to poorly differentiated or anaplastic states commonly lose thyroid lineage identity, radioiodine avidity, and favorable clinical behavior. Genetic and signaling alterations within tumor cells explain part of this transition, but they do not fully account for the coexistence of different differentiation states within the same molecular subtype or even within the same lesion. Increasing functional evidence indicates that dedifferentiation is maintained by reciprocal interactions between malignant cells and the immune, stromal, metabolic, and inflammatory microenvironment. Cancer-associated fibroblast glycolysis and lactate release, IL-6/CXCL8-driven inflammatory signaling, hypoxia, transforming growth factor-beta signaling, and tumor-associated macrophage feedback can suppress thyroid lineage programs while promoting plasticity, invasion, and treatment resistance. Here, we synthesize mechanistic studies supported by genetic perturbation, co-culture, pharmacologic blockade, iodine-uptake assays, animal models, or patient-level radioiodine endpoints. We distinguish functional dedifferentiation from epithelial–mesenchymal transition, stemness, and lymph-node metastasis, and discuss therapeutic strategies that combine tumor-cell redifferentiation with targeting of microenvironmental feedback to restore durable radioiodine sensitivity. Full article

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are usually driven by activating mutations in KIT or PDGFRA. Although these alterations define the core molecular biology of GISTs and guide targeted therapy, they do not fully explain the variability observed in tumor behavior, recurrence risk, or response to tyrosine kinase inhibitors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been increasingly studied as regulators of gene expression in GISTs. Recent evidence suggests that these molecules may influence KIT-centered signaling, autophagy, apoptosis, invasion, angiogenesis, and drug resistance. However, the strength of evidence differs considerably across individual ncRNAs, ranging from bioinformatic associations to functional validation in cell lines and in vivo models. This review summarizes current knowledge on ncRNA-mediated regulation in GIST biology, with emphasis on tumor progression, therapeutic resistance, and possible clinical relevance. Rather than treating ncRNAs as isolated biomarkers, they function as part of broader regulatory networks that interact with oncogenic signaling and epigenetic mechanisms. Although several ncRNAs appear promising as prognostic or predictive candidates, further validation in independent clinical cohorts is required before their integration into routine risk stratification or treatment decision-making. Full article

Endometriosis is a chronic, oestrogen-responsive inflammatory disease characterised by endometrial-like tissue outside the uterine cavity. Because retrograde menstruation is common, lesion establishment probably requires cellular competence and a permissive ectopic microenvironment. This hypothesis-driven narrative review evaluates fascin (FSCN1) as a candidate cytoskeletal effector and considers antecedent eutopic priming versus induction after ectopic adhesion. Functional evidence was integrated with a targeted public-data screen. Donor-level reanalysis of GSE179640 found no conclusive overall eutopic case–control difference and predominantly non-epithelial expression. Exploratory analysis of GSE203191 suggested higher FSCN1 expression within a HSPA6+ stromal subcluster in diagnosed cases, without a comparable epithelial signal or detectable increase in subcluster abundance. This small post hoc analysis remains hypothesis-generating. FSCN1 was absent from the published HECA stromal/macrophage differential-expression lists and was not prioritised by the 2023 endometriosis GWAS. The current evidence therefore argues against uniform epithelial or whole-eutopic overexpression but permits a lineage-restricted stromal state. Fascin participates in autophagy- and miR-145-sensitive invasion networks, although these pathways are pleiotropic. Validation requires cycle- and lineage-resolved tissue mapping, compositional controls, matched lesions, and direct FSCN1 perturbation. Fascin should currently be regarded as a candidate multi-marker component and preclinical target, not a validated biomarker or systemic therapeutic target. Full article

Colorectal cancer progression and therapeutic response are determined not only by tumor-intrinsic programs but also by neural, stromal, and immune components of the tumor microenvironment. However, biologically interpretable transcriptomic scores that jointly capture neural/stromal remodeling and immune activation remain limited. We developed a neuro-immune score (NIS), defined as the neural/stromal module score minus the immune activation module score. NIS was constructed using the combined TCGA-COAD/READ colorectal cancer cohort and externally evaluated in independent Gene Expression Omnibus (GEO) datasets. Single-cell RNA sequencing, focused ligand–receptor analysis, and spatial transcriptomics were further integrated to characterize the cellular origins, spatial organization, and potential mechanisms underlying NIS-associated biology. A high NIS (NIS-high) was associated with adverse prognosis in bulk transcriptomic cohorts. External validation demonstrated that a high NIS was significantly associated with worse disease-free survival/relapse-free survival (DFS/RFS) in GSE39582 and worse overall survival in GSE17536. A multi-cohort meta-analysis further supported a consistent association between NIS-high and poor clinical outcomes. Single-cell analysis localized the NIS-high signal mainly to glial-like cells, fibroblasts, pericytes, endothelial cells, and malignant epithelial cells, whereas CD8+ T cells and natural killer cells exhibited low NIS. Focused ligand–receptor analysis suggested that NIS-high cellular compartments may communicate with immune and tumor compartments through MIF-CD74/CXCR4, SPP1-CD44, extracellular matrix (ECM)–integrin, TGF-β, and immune checkpoint-related axes. Spatial transcriptomics further demonstrated that NIS-high regions were enriched in stromal, neural/glial-like, vascular/pericyte, and tumor–stromal niches, whereas NIS-low regions were associated with immune-activated and cytotoxic T/NK cell-rich areas. NIS captures a spatially organized state of the colorectal cancer microenvironment characterized by neural/stromal remodeling, activation of ECM and vascular/pericyte niches, and relatively reduced or spatially segregated immune activation. NIS may serve as a biologically interpretable microenvironment stratification score associated with adverse outcomes. It also provides a framework for future studies targeting stromal remodeling, myeloid-mediated immune regulation, neural-associated signaling, and antitumor immunity. Full article

Differentiating active ulcerative colitis (UC) from Crohn’s disease (CD) is one of the unmet needs addressed by biomarkers in inflammatory bowel disease (IBD). The immune landscapes of UC and CD differ, justifying the search for discriminatory markers and novel therapy targets among their mediators. Herein, 27 systemic cytokines were measured using flow cytometry-based methodology in 138 IBD patients, with an additional 21 being determined in 67 of the patients. Their discriminatory power was assessed individually and as exploratory multivariable signatures generated using logistic regression, hierarchical clustering, and principal component analysis. Eotaxin-1, macrophage inflammatory protein (MIP)-1β, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) showed fair discriminatory potential, while multivariable models performed better. Interleukin (IL)-1β, IL-4, and MIP-1α were strongly associated with CD, whereas IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), MIP-1β, and TRAIL were associated with UC. Active UC was characterized by mediators linked to eosinophil-, mastocyte-, and neutrophil-driven inflammation and tissue repair (eotaxin-1, IL-5, growth-regulated oncogene (GRO), MIP-1β, stem cell factor (SCF), GM-CSF, IL-1 receptor antagonist, TRAIL, stem cell growth factor (SCGF)-β, and cutaneous T cell-attracting chemokine (CTACK)), whereas active CD was associated with Th1/Th17 immunity, myeloid activation, fibrosis, angiogenesis, and neuroimmune remodeling (IL-1β, IL-12p70, IL-15, ‘regulated on activation, normal T-cell expressed and secreted’ (RANTES), MIP-1α, stromal cell-derived factor (SDF)-1α, nerve growth factor β (β-NGF), and leukemia inhibitory factor (LIF)). In conclusion, integrated circulating immune signatures identify several understudied cytokines as potential contributors to disease-specific pathways and show potential in distinguishing active UC from CD warranting further mechanistic studies and independent validation in larger cohorts. Full article

Laryngeal dysplasia (LD) is the principal precursor of laryngeal squamous cell carcinoma (LSCC), but reliable biomarkers predicting malignant transformation remain unavailable. This study investigated programmed death-ligand 1 (PD-L1) expression and immune microenvironment remodeling during laryngeal carcinogenesis. Immunohistochemical analysis of PD-L1, CD4, CD8, CD68, and CD163 was performed in 36 benign lesions, 41 LDs, and 102 LSCCs. PD-L1 expression was assessed using the combined positive score (CPS) and tumor proportion score (TPS), while immune cell infiltration was quantified in the intraepithelial and stromal compartments and across the entire tissue specimen. PD-L1 expression and infiltration of all investigated immune cell populations increased progressively from benign lesions through dysplasia to invasive carcinoma. High-grade dysplasia exhibited significantly greater CD4 infiltration in all compartments and increased stromal CD8 and CD163 infiltration than low-grade dysplasia. PD-L1 expression positively correlated with intraepithelial CD163 and stromal CD8 infiltration. Although no biomarker independently distinguished progressive from non-progressive dysplasia, overall CD4, intraepithelial and overall CD68, and stromal CD163 were associated with progression risk. Immune microenvironment remodeling begins during the dysplastic stage of laryngeal carcinogenesis. These findings may improve risk stratification of laryngeal dysplasia and support the development of immunopreventive and immune-targeted therapeutic strategies. Full article

Strobilurin fungicides are among the most widely used agrochemicals worldwide. Dimoxystrobin has been shown to induce hepatic injury in adult zebrafish; however, whether this damage also involves early extracellular matrix remodelling and hepatobiliary remodelling remains unknown. Here, we investigated early remodelling of the extracellular matrix, focusing on initial collagen deposition and glycosaminoglycan redistribution after a short-term exposure (96 h) to two environmentally relevant concentrations of dimoxystrobin (6.56 and 13.13 µg/L) on the liver of Danio rerio using an integrated histological, histochemical, and semi-quantitative approach. The results showed a progressive dose-dependent alteration of hepatic architecture, accompanied by a significant increase in bile pigment-like deposits and collagen deposition. Exposure also induced a significant increase in the deposition of acidic glycosaminoglycans and a severe depletion of glycogen-dependent Periodic Acid–Schiff positivity components, accompanied by an increase in amylase-resistant Periodic Acid–Schiff reactive components. Overall, these findings indicate that dimoxystrobin-induced hepatotoxicity extends beyond parenchymal degeneration to encompass coordinated stromal and hepatobiliary remodelling. The present study also indicates that the periductal microenvironment may represent a sensitive target of dimoxystrobin toxicity and supports the use of histochemical and semi-quantitative analyses as sensitive tools for detecting sublethal pesticide-induced early extracellular matrix remodelling in fish liver. Full article