Search Results (715)

Endothelial cells (ECs) play a critical role in physiological processes, including regulating blood fluidity, angiogenesis, and regulating the immune response. Integrins, which participate in sensing external stimuli and signal transduction, are crucial for the proper functioning of ECs. Like other cells, ECs undergo senescence, which is associated with their dysfunction and contributes to increased susceptibility to cardiovascular disease. However, the role of integrin-dependent pathways in endothelial senescence is poorly understood. Here, we identify integrin-linked kinase (ILK) as a crucial factor modulating endothelial function and senescence. Using two complementary models, replicative and stress-induced premature senescence, in endothelial cells of different origins, we show that the senescent endothelium shows phenotypic and functional dysfunction. Furthermore, we revealed that these modulations correlated with ILK downregulation. Functionally, ILK depletion in young ECs was sufficient to trigger a senescence-associated phenotype and manifested key features of endothelial dysfunction. In line with this, ILK restoration in senescent cells reduced selected senescence markers and improved endothelial function. Together, these findings show that ILK is not only correlated with endothelial ageing but also works as an active regulator of senescence-linked endothelial dysfunction. Thus, ILK, as a link between adhesion-dependent signalling and endothelial ageing, is a potential target for limiting age-associated vascular decline. Full article

Background/Objectives: This study evaluates the prognostic utility of placental insufficiency biomarkers in late-onset fetal growth restriction occurring after 32 weeks of gestation. These markers were assessed both independently and in conjunction with ultrasound and Doppler indices to predict adverse perinatal outcomes. Given the clinical integration of maternal angiogenic factor assessment, it is imperative to determine whether these markers—specifically the sFlt-1/PlGF ratio—can effectively mitigate fetal and neonatal morbidity and mortality. Methods: This review is registered with PROSPERO and encompasses the literature from the last decade. The present analysis incorporated prospective observational cohort studies. Four comprehensive databases were queried, resulting in the evaluation of fifty-one relevant records. Thirty-six full-text articles were assessed for eligibility, resulting in the inclusion of six relevant manuscripts. The total sample size was 14.499 patients. Detection rates for growth restricted fetuses demonstrated significant variability, ranging from 15% to 88.5%. Conclusions: The clinical utility of angiogenic biomarkers for the prediction of fetal growth restriction remains unresolved; moreover, the empirical evidence synthesized within this review exhibits a significant degree of heterogeneity. Full article

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy with a rising global incidence and limited therapeutic options. Vascular invasion (VI) is a hallmark of advanced disease, correlating with early recurrence and dismal prognosis, yet its tumor microenvironment (TME) drivers remain elusive. We analyzed single-cell RNA sequencing (scRNA-seq) data from 25 ICC samples to systematically characterize the cellular composition and molecular features related to VI. By integrating bulk RNA-seq data, spatial transcriptomics, and multiplex immunofluorescence, we identified a distinct subset of tumor-like cancer-associated fibroblasts (CAFs), termed tCAFs, enriched in VI-positive tumors. Functional enrichment analyses revealed that tCAFs were prominently associated with hypoxia and angiogenesis pathways, findings corroborated by the significant upregulation of tCAF markers (MME and NT5E) in ICC-derived CAFs under hypoxic conditions in vitro. Cell–cell communication analysis and spatial mapping uncovered that tCAFs might promote VI primarily through VEGF signaling interactions with endothelial cells. Integrative bioinformatics and RT-qPCR validation identified three key functional genes in tCAFs: SLC2A1, PTGS2, and PLOD2. In endothelial sprouting assays, pharmacological inhibition of SLC2A1 exerted a pronounced suppressive effect. Consistently, sprouting assays using ICC-derived CAFs with SLC2A1 knockdown confirmed that its downregulation significantly reduced endothelial sprouting capacity. Importantly, administration of the SLC2A1 inhibitor BAY-876 effectively suppressed tumor progression and intrahepatic metastasis in the orthotopic ICC mouse model. Our findings define a VI-associated cellular ecosystem and molecular landscape in ICC, unveiling a novel hypoxia–tCAFs–endothelial cells axis. Furthermore, we identify SLC2A1 as a clinically relevant therapeutic target, offering new insights into tumor VI. Full article

The invasive tumor front (ITF) of colorectal carcinoma (CRC) is a biologically active interface where epithelial dissociation, stromal activation, immune remodeling, and angiogenesis converge. This retrospective histopathological association study examined whether tumor budding combined with selected ITF microenvironmental markers could better characterize aggressive clinicopathological features of non-metastatic CRC. Fifty-two surgically resected primary CRCs were analyzed after exclusion of patients with distant metastatic disease at diagnosis or surgery. Tumor budding was scored according to ITBCC 2016 criteria. Immunohistochemistry evaluated stromal podoplanin (D2-40) expression, CD34-based microvessel density, the CD163/CD68 ratio, and CD117-positive mast cell density. An unweighted integrated ITF microenvironment score (0–4) was generated by summing high values for these four parameters. High histological grade, lymphovascular invasion, high tumor budding, and node-positive disease were significantly associated with multiple microenvironment-related alterations. The integrated ITF score was significantly higher in high-grade, lymphovascular invasion-positive, node-positive, and high-budding CRCs, suggesting cumulative stromal, immune, and vascular remodeling at the invasive front. These findings support the ITF as an integrated histopathological compartment in CRC progression. However, the score remains hypothesis-generating and requires validation in larger, independent, molecularly and outcome-annotated cohorts before prognostic or clinical use. Full article

Upper limb disorders, including carpal tunnel syndrome (CTS), are a common cause of pain, functional limitations, and reduced quality of life. Increasing attention has been directed toward the role of inflammatory and angiogenic mediators in the pathophysiology of CTS and their potential relationship with patient-reported functional outcomes. The aim of this study was to evaluate selected cytokines as potential markers of upper limb disability assessed using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. This cross-sectional study included 55 patients with idiopathic CTS referred for surgical treatment. Functional impairment was assessed using the DASH questionnaire, and concentrations of selected inflammatory and angiogenic mediators—IL-4, IL-6, MCP-1, TNF-α, VEGF, and fraktalkine—were measured in synovial tissue samples; these markers were selected based on their established roles in inflammation, angiogenesis, and nociceptive modulation relevant to CTS pathophysiology. VEGF was identified as a significant predictor of DASH category (p = 0.032), with higher concentrations associated with a lower likelihood of severe upper limb dysfunction. In contrast, higher TNF-α levels were associated with an increased risk of severe disability (p = 0.031). Other cytokines did not demonstrate significant associations with functional impairment. These findings suggest that selected inflammatory and angiogenic mediators were associated with the severity of functional disability in CTS and warrant investigation in prospective longitudinal studies to clarify their potential role alongside patient-reported outcome measures. Full article

Background: Vasculogenic mimicry (VM) is a tumor-driven vascularization strategy in which aggressive cancer cells form perfusable, endothelium-independent channels that support tumor growth, metastasis, and therapy resistance. VM is prevalent in triple-negative breast cancer (TNBC), but within this group of tumors, VM heterogeneity is underexplored. Likewise, VM competence and its relationship to classical endothelial angiogenesis (EA) remain incompletely understood. Methods: Here, as a proof of concept, we combine functional analysis of three molecularly distinct TNBC cell lines with a panel-wide DepMap transcriptomic survey to characterize VM heterogeneity. Results: Using an in vitro tube formation assay, we show that the VM-competent TNBC cell lines MDA-MB-231 and MDA-MB-231-4175 form robust 3D vessel-like networks in a matrigel matrix, whereas the VM-incompetent line MDA-MB-468 does not. As a control, we use an immortalized endothelial cell line, 3B-11, that forms classical EA vessel-like networks. Moreover, we visualize VM (Laminin-5⁺) and EA (CD31⁺) markers in vessel-like networks of VM-competent TNBC xenografts using immunohistochemical staining and show that while they are distinctly labeled, they can also coexist to form mosaic-like vessels. Then, we use DepMap-based transcription profiles and reveal that VM competence is associated with a distinct signature. Interestingly, VM and EA transcription profiles partially overlap, yet they also remain transcriptionally distinct, with inferred mechanistic divergence, with VM being more associated with cancer cell stemness (CSC), epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling programs and EA being more associated with vessel strength. In addition, VM-competent TNBC cells display migration patterns and transcriptomic features consistent with endothelial-like mechanosensitivity. Conclusions: Together, these findings indicate that VM is a distinct, heterogeneous, and therapy-relevant state in TNBC that complements classical angiogenesis. Finally, the mechanistic distinction between VM and EA programs made here will motivate future studies on dual-targeting strategies that inhibit both vascularization processes while also motivating future studies on VM for precision treatment in TNBC. Full article

Background/Objectives: This study aimed to investigate the effect of pancreatic ductal adenocarcinoma (PDAC) on the alterations in red blood cell aggregation related to angiogenesis and hypoxia markers. Methods: We studied 31 patients with confirmed PDAC. The aggregation of red blood cells (RBCs) was evaluated using a Laser-assisted Optical Rotational Cell Analyzer (LORCA). Serum vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) levels were measured using ELISA. We estimated the following parameters specific to the aggregation process: the aggregation index (AI), the aggregation half-time (t_1/2), and the threshold shear rate (γ_thr). Results: All measured RBC aggregation parameters among PDAC subjects differed from those in the controls. The AI (p < 0.05) and γ_thr (p < 0.005) were significantly higher in the PDAC group, whereas t_1/2 (p < 0.01) and AMP (p < 0.001) were significantly lower compared to the control group. The levels of VEGF (p < 0.0001) and HIF-1α (p < 0.0001) were significantly higher in the PDAC group than in the control group. There were significant correlations between RBC aggregation parameters and VEGF and HIF-1α. Multivariate analyses further identified t_1/2 (p < 0.01) and γ_thr (p < 0.05) as independent predictors for VEGF. For HIF-1α, t_1/2 (p < 0.05) was confirmed as an independent predictor. Conclusions: The results suggest, but do not demonstrate, a direct pathophysiological link between PDAC-associated hypoxia/angiogenesis and erythrocyte aggregation. Further studies are needed because the relationship linking PDAC to these aggregation indices is unclear. Full article

Background: Fracture healing requires a coordinated inflammatory response, and its dysregulation, as seen in polytrauma, can impair bone regeneration. Human mesenchymal stem cells (hMSCs) play a central role in fracture repair through osteogenic differentiation and also via their secretome, which regulates local inflammation, angiogenesis, and tissue regeneration. Interleukin-6 (IL-6), an early pro-inflammatory cytokine, contributes to fracture healing by promoting MSC recruitment and osteogenic differentiation, whereas bone morphogenetic protein-2 (BMP-2) is a key osteoinductive factor that drives bone formation. However, the combined effects of IL-6 and BMP-2 on the hMSC secretome remain poorly understood. Methods: We cultured hMSCs in osteogenic media supplemented with recombinant IL-6 (1–20 ng/mL) alone or combined with recombinant BMP-2 (1 ng/mL) on tissue culture plastic (TCP) and within gelatin methacryloyl (GelMA) hydrogels of low (~3 kPa), medium (~15 kPa), and high (~30 kPa) stiffness. Osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity and calcium deposition; cytokine profiling was performed using a multiplex antibody array. Results: When cultured on TCP, IL-6 suppressed ALP activity by day 21. Co-treatment with IL-6 and BMP-2 induced a dysregulated secretome with concurrent upregulation of pro-inflammatory markers (MIP-1α, TNF-α, and GM-CSF) and anti-inflammatory mediators (IL-10, TGF-β1, and VEGF). This hyperinflammatory response was attenuated when hMSCs were encapsulated in GelMA, with high-stiffness gels most effectively suppressing pro-inflammatory chemokines and medium-stiffness gels yielding the highest ALP activity. Conclusions: These findings suggest that mechanically tuned GelMA hydrogels modulate immune and osteogenic responses of hMSCs in vitro, warranting further investigation in the context of scaffold design for fracture care. Full article

Myocardial infarction (MI) triggers excessive oxidative stress, a detrimental immune response, and insufficient angiogenesis, which collectively impede effective cardiac repair. This study developed a multifunctional composite polysaccharide hydrogel, termed KgXd^gel, based on konjac glucomannan (KGM) and xanthan gum (XG) functionalized with gallic acid (GA) and dopamine (DA), respectively, to integrate reactive oxygen species (ROS) scavenging, macrophage polarization, and pro-angiogenic activities. In vitro assays demonstrated that the KgXd^gel hydrogel exhibited excellent cytocompatibility, effectively scavenged ROS, promoted the polarization of macrophages towards the reparative M2 phenotype, and enhanced the migration and tube formation of human umbilical vein endothelial cells. In a rat MI model, treatment with KgXd^gel significantly improved cardiac function (e.g., left ventricular ejection fraction, LVEF; left ventricular fractional shortening, LVFS), attenuated left ventricular dilation (LVIDs), and favorably modulated the post-infarction microenvironment. This was evidenced by the upregulation of the M2 marker CD163 and the angiogenic factor VEGF, alongside the downregulation of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and the M1 marker iNOS. These findings conclusively demonstrate that the KgXd^gel hydrogel synergistically promotes cardiac repair post-MI through its integrated antioxidant, immunomodulatory, and pro-angiogenic functions, presenting a promising multi-targeted therapeutic strategy. Full article

Background: Preoperative assessment of Head and Neck Squamous Cell Carcinoma (HNSCC) aggressiveness is often hindered by the sampling errors of incisional biopsies. While Contrast-Enhanced Computed Tomography (CECT) is the standard for staging, its potential to serve as a non-invasive complementary radiological tool of the entire tumor volume remains underutilized. Objective: To evaluate the predictive performance of preoperative CECT-derived tumor volume, densitometric values, and morphological features as predictors of histopathological grade and lymph node metastasis (pN) in HNSCC. The primary outcome was predicting lymph node metastasis (pN+), and the secondary outcome was predicting histopathological grade. Methods: This retrospective observational study analyzed 42 patients with SCC of the oral cavity, larynx, or maxilla. Quantitative (3D volume, Hounsfield Units [HU], HU Delta) and qualitative (margins, lobulations, necrosis) CT parameters were correlated with definitive histopathology. Diagnostic performance was assessed using Receiver Operating Characteristic (ROC) curve analysis and Spearman’s rank correlation. Results: High-grade tumors (G2/G3) demonstrated significantly larger median volumes (18.1 vs. 2.9 cm³, p = 0.006), lower contrast density (55 vs. 68 HU, p = 0.010), and reduced vascular wash-in (23 vs. 30 HU Delta, p = 0.008) compared to G1 lesions. ROC analysis identified a volume threshold of ≥9.43 cm³ for high-grade disease (AUC = 0.865; sensitivity 67.6%, specificity 100%). For regional metastasis (pN+), tumor volume was the only significant predictor (25.4 vs. 6.2 cm³, p = 0.036), with an optimal cut-off of ≥6.76 cm³ (AUC = 0.769; sensitivity 100%). Strong negative correlations were observed between contrast enhancement and internal necrosis (r = −0.812, p < 0.001). Conclusions: Preoperative CECT parameters show promise as non-invasive imaging surrogates of HNSCC aggressiveness. A paradoxical reduction in contrast enhancement characterizes high-grade biology, reflecting disorganized neo-angiogenesis and internal hypoxia. Integrating 3D volumetric analysis and morphological markers shows potential as a complementary exploratory tool that, pending future prospective validation, may support risk stratification and surgical planning alongside traditional histopathological assessment. Full article

Chronic wound management remains a significant clinical challenge, requiring adaptive therapeutic approaches to achieve wound closure that nonetheless frequently prove fruitless. Balancing the initial pro-inflammatory response with debris removal and tissue rebuilding remains elusive in most cases, leading to pain, drastic quality-of-life deterioration, and, eventually, amputation. Meanwhile, patient adherence is an overarching theme. Furthermore, non-surgical alternatives that effectively promote tissue rebuilding are essential for patients seeking to avoid further invasive procedures. We report a patient with a recalcitrant ulcer managed using human amniotic membrane dressing (hAM-pe) and a bovine collagen matrix (BCM) in spatially distinct areas as an intra-patient control. Methodology included clinical monitoring and ad hoc molecular and histological analyses to assess inflammatory markers and tissue architecture. Following 59 days of observation, the superior evolution of the hAM-pe-treated zone led to the clinical decision to extend hAM-pe treatment over the adjacent BCM area, resulting in total wound closure. The hAM-pe-treated site demonstrated accelerated closure and clinical resolution of inflammation without the presence of a granulomatous response. Molecular analysis revealed downregulated pro-inflammatory mediators (IL-1β, TNF-α, CXCL-10) and upregulated markers associated with angiogenesis (VEGF, CD34) and tissue repair (Arginase-1). In this case, the non-surgical hAM-pe treatment was associated with a favorable healing trajectory, characterized by superior inflammation resolution and enhanced tissue organization (collagen type I/III maturation). While these descriptive findings suggest the potential advantages of amniotic membrane dressings in promoting advanced tissue repair, they remain limited to this individual observation. Further research in larger cohorts is required to validate these mechanisms. Full article

Long-term survival after solid organ transplantation remains limited by chronic remodeling, fibrosis, vascular complications, and malignancy despite advances in immunosuppressive therapy. Current monitoring strategies primarily rely on functional and immunological parameters that often identify complications only after irreversible injury has occurred. There is a critical need for earlier, mechanistically informative biomarkers that can predict survival outcomes. Many platelet-associated growth factors (PDGF, TGF-β, VEGF, EGF, and IGF-1) are stored in platelet α-granules but can also originate from immune, endothelial, and stromal cells, regulate angiogenesis, extracellular matrix deposition, immune modulation, and tissue repair—processes central to graft adaptation and chronic injury. In this review, we propose the growth factor signaling network as a conceptual framework that potentially links platelet biology, ischemia-reperfusion injury, alloimmune responses, and chronic immunosuppression to sustained growth factor signaling and maladaptive graft remodeling. This framework should be interpreted as a biologically plausible integrative model rather than a fully validated mechanistic pathway in transplant recipients. Importantly, direct clinical evidence linking platelet activation markers (e.g., P-selectin, PF4, β-thromboglobulin) with circulating growth factor levels and long-term transplant outcomes remains limited, highlighting a critical gap in current biomarker research. Emerging clinical evidence suggests their potential prognostic relevance in transplant outcomes. Elevated TGF-β levels have been associated with increased risk of opportunistic infections, while early postoperative IGF-1 concentrations predict short-term survival. Increased VEGF-A levels correlate with primary graft dysfunction and cardiac allograft vasculopathy, while PDGF isoforms contribute to fibrotic and vascular progression across transplanted organs. However, their clinical applicability is limited by methodological variability and lack of large-scale validation. Rather than serving solely as markers of rejection, platelet-associated growth factors may reflect dynamic processes involved in transplant remodeling and mortality risk. Incorporating growth factor profiling into multiparametric survival prediction models may improve early risk stratification and support precision post-transplant management strategies. Full article

Background: Diabetic foot ulcers (DFUs) are difficult to heal because hyperglycemia-associated pathological exudation, excessive oxidative stress, chronic inflammation, and impaired cellular regeneration jointly maintain a nonhealing wound microenvironment. This study aimed to develop and evaluate a composite hydrogel containing Periplaneta americana (PA) extract and calamine as a Zn²⁺ source for dynamic modulation of the diabetic wound microenvironment and promotion of tissue repair. Methods: A PA composite hydrogel was prepared and assessed in vitro for reactive oxygen species (ROS)-scavenging activity and effects on fibroblast migration. Therapeutic efficacy was further evaluated in a streptozotocin (STZ)-induced diabetic full-thickness wound model in rats. Wound closure, histological remodeling, oxidative stress markers, inflammatory mediators, growth factors, angiogenesis, and AGEs-RAGE/NF-κB pathway-related changes were analyzed. Results: The composite hydrogel reduced excessive intracellular ROS and enhanced fibroblast migration in vitro compared with pathological-condition controls. In diabetic rats, topical treatment accelerated macroscopic wound closure and promoted more mature histological repair. Mechanistic analyses showed attenuation of the AGEs-RAGE/NF-κB signaling axis, accompanied by restoration of superoxide dismutase activity, reduction of malondialdehyde levels, and suppression of TNF-α-associated inflammatory responses. The improved wound microenvironment was associated with increased expression of platelet-derived growth factor and basic fibroblast growth factor, enhanced cellular proliferation, and increased neovascularization within the wound tissue. Conclusions: The PA composite hydrogel improved diabetic wound healing by concurrently alleviating oxidative and inflammatory barriers and enhancing regenerative signaling. These findings suggest that microenvironment-modulating PA composite hydrogel systems may represent a promising therapeutic strategy for refractory diabetic wounds. Full article

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8⁺ TILs exhibiting a progenitor stem-cell-like profile (CD39⁻ CD69⁻). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the “double-edged sword” nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome. Full article

Background: Hepatocellular carcinoma (HCC) shows a high rate of early recurrence after curative resection, indicating a critical contribution of tumor microenvironment-driven molecular mechanisms. Early recurrence of hepatocellular carcinoma is defined as recurrence within 6 months after curative resection, with a prevalence exceeding 30%. Hypoxia signaling and immune dysregulation have been implicated, yet their compartment-specific relevance remains unclear. Methods: This multicenter nested case–control study included 49 HCC patients to evaluate associations between hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), tumor-infiltrating lymphocytes (TILs), CD4⁺ T cells, CD8⁺ T cells, regulatory T cells (Tregs), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) and early recurrence after resection. TIL density was assessed using hematoxylin and eosin staining, while immunohistochemistry was performed to quantify intratumoral and peritumoral expression of the studied markers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance. Recurrence-free survival (RFS) was analyzed using the Kaplan–Meier, and independent predictors were identified using multivariate Cox proportional hazards regression. Results: Early recurrence occurred in 11 of 49 patients (22.4%) of Child–Pugh A patients. Recurrent tumors were characterized by elevated VEGF expression despite absent HIF-1α, alongside significant depletion of intratumoral TILs (HR 5.02; 95% CI 1.09–23.26), CD4⁺ (HR 7.68; 95% CI 1.66–35.60) and CD8⁺ cells (HR 6.68; 95% CI 1.77–25.23) and reduced peritumoral CD8⁺ infiltration (HR 4.20; 95% CI 1.11–15.91). Multivariable analysis identified low intratumoral CD4⁺ (HR 7.98; 95% CI 1.63–39.07) and reduced peritumoral CD8⁺ expression (HR 4.98; 95% CI 1.14–21.70) as independent predictors, whereas HIF-1α, VEGF, Treg, PD-1, and PD-L1 were not significantly associated. Conclusions: Early HCC recurrence shows HIF-1α-independent angiogenesis alongside spatial immune depletion, supporting integrated immune profiling over single angiogenic markers. Full article