Search Results (1,466)

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Bone immunity represents a dynamic interface where skeletal homeostasis intersects with systemic immune regulation. We synthesize emerging paradigms by contrasting two functionally distinct microenvironments: the marrow cavity, a hematopoietic and immune cell reservoir, and cancellous bone, a metabolically active hub orchestrating osteoimmune interactions. The marrow cavity not only generates innate and adaptive immune cells but also preserves long-term immune memory through stromal-derived chemokines and survival factors, while cancellous bone regulates bone remodeling via macrophage-osteoclast crosstalk and cytokine gradients. Breakthroughs in lymphatic vasculature identification challenge traditional views, revealing cortical and lymphatic networks in cancellous bone that mediate immune surveillance and pathological processes such as cancer metastasis. Central to bone immunity is the neuro–immune–endocrine axis, where sympathetic and parasympathetic signaling bidirectionally modulate osteoclastogenesis and macrophage polarization. Gut microbiota-derived metabolites, including short-chain fatty acids and polyamines, reshape bone immunity through epigenetic and receptor-mediated pathways, bridging systemic metabolism with local immune responses. In disease contexts, dysregulated immune dynamics drive osteoporosis via RANKL/IL-17 hyperactivity and promote leukemic evasion through microenvironmental immunosuppression. We further propose the “brain–gut–bone axis” as a systemic regulatory framework, wherein vagus nerve-mediated gut signaling enhances osteogenic pathways, while leptin and adipokine circuits link marrow adiposity to inflammatory bone loss. These insights redefine bone as a multidimensional immunometabolic organ, integrating neural, endocrine, and microbial inputs to maintain homeostasis. By elucidating the mechanisms of immune-driven bone pathologies, this work highlights therapeutic opportunities through biomaterial-mediated immunomodulation and microbiota-targeted interventions, paving the way for next-generation treatments in osteoimmune disorders. Full article

Peritoneal carcinomatosis (PC) and malignant pleural effusions (MPE) are two common complications of cancers metastatic to the respective body cavities. A PC diagnosis indicates metastasis to the tissue lining the abdominal cavity and is most common in patients with gastrointestinal and gynecological cancers. It is often accompanied by ascites, an accumulation of serous fluid in the abdomen. MPE presents as the accumulation of fluid in the space between the lungs and chest wall. It is a common terminal event in patients diagnosed with breast cancer, lung cancer, lymphoma, and mesothelial cancers, and less commonly, in a wide variety of other epithelial cancers. Due to the aggressive nature of cavitary tumors, the outcome of current treatments for both PC and MPE remains bleak. Although PC and MPE are characteristically affected by different sets of primary tumors (lung/breast/mesothelioma for MPE and gynecologic/gastrointestinal for PC), their environments share common cytokines and cellular components. Owing to the unique cytokine and chemokine content, this environment promotes aggressive tumor behavior and paradoxically both recruits and suppresses central memory and effector memory T cells. The cellular and secretomic complexity of the cavitary tumor environment renders most currently available therapeutics ineffective but also invites approaches that leverage the robust T-cell infiltrate while addressing the causes of local suppression of anti-tumor immunity. Interactions between the heterogeneous components of the tumor environment are an area of active research. We highlight the roles of the immune cell infiltrate, stromal cells, and tumor cells, and the soluble products that they secrete into their environment. A more comprehensive understanding of the cavitary tumor environment can be expected to lead to better immunotherapeutic approaches to these devastating conditions. Full article

The ovary is among the earliest organs to undergo age-related degeneration, limiting the reproductive potential of elite horses and constraining the growth of the equine industry. Follicular development during estrus is a key determinant of fertility, yet the molecular mechanisms underlying its decline, particularly at the level of specific ovarian cell types, remain poorly understood in equids. Here, we constructed a single-cell transcriptomic atlas to investigate ovarian changes in Kazakh horses. Using single-cell RNA sequencing (scRNA-seq), we profiled 112,861 cells from follicle-containing and follicle-absent ovaries, identifying nine distinct ovarian cell types and their subtypes, each with distinct gene expression signatures. Functional enrichment analyses revealed cell type-specific engagement in biological pathways, including ECM–receptor interaction, PI3K-Akt signaling, and oxytocin signaling. Gene expression patterns indicated tightly regulated processes of ovarian activation and cell differentiation. Notably, stromal cells exhibited high expression of ROBO2, LOC111770199, and TMTC2, while smooth muscle cells (SMCs) were marked by elevated levels of CCL5, KLRD1, and NKG7. Moreover, cell–cell interaction analyses revealed robust signaling interactions among SMCs, endothelial cells, neurons, and proliferating (cycling) cells. Together, these findings provide a comprehensive single-cell transcriptomic map of normal and abnormal ovarian states during estrus in Kazakh horses, offering novel insights into the cellular mechanisms of follicular development and identifying potential diagnostic biomarkers and therapeutic targets for ovarian quiescence in equids. Full article

Virus-associated hepatocellular carcinoma (HCC) remains a major global health burden despite effective antiviral therapies. Chronic infection with hepatitis B (HBV), hepatitis C (HCV), and hepatitis D (HDV) promotes malignant transformation through overlapping pathways of fibrosis, immune dysregulation, and microenvironmental remodeling. YKL-40, a glycoprotein secreted by hepatic stellate cells, hepatocytes under stress, macrophages, and endothelial cells, has emerged as a marker that reflects stromal activation rather than direct hepatocyte injury. Its expression is reinforced by profibrotic and angiogenic circuits, and circulating concentrations correlate with advanced fibrosis, residual risk after viral suppression, and oncologic outcomes. This review synthesizes current evidence on YKL-40 across HBV, HCV, and HDV cohorts, with emphasis on its role in bridging molecular mechanisms to clinical applications. We examine its utility in non-invasive fibrosis assessment, longitudinal monitoring after antiviral therapy, and prognostic modeling in HCC. Particular attention is given to its potential in the liver transplant pathway, where YKL-40 may refine eligibility beyond morphology, inform bridging therapy response, and predict post-transplant recurrence or graft fibrosis. Remaining challenges include its lack of disease specificity, assay variability, and limited multicenter validation. Future integration of YKL-40 into multimarker, algorithm-based frameworks could enable risk-adaptive strategies that align surveillance and transplant decisions with the evolving biology of virus-associated liver disease. Full article

Background: Breast cancer remains a predominant malignancy among females globally, and the tumor microenvironment (TME) exerts a pivotal role in its progression. Despite notable advancements in diagnostic and therapeutic modalities, resistance to conventional therapies persists as a critical hurdle, underscoring the necessity of exploring TME-related prognostic biomarkers. Methods: To elucidate the role of the TME in breast cancer progression and identify potential prognostic biomarkers, we analyzed RNA-seq data from 1081 breast cancer cases and 99 normal controls to assess tumor-infiltrating immune cells (TICs) and stromal components. Differential gene expression analysis identified genes correlated with ImmuneScore and StromalScore. A protein–protein interaction (PPI) network was constructed, followed by univariate Cox regression to pinpoint survival-associated genes. JCHAIN, significantly linked to survival outcomes, was selected for further investigation. Gene Set Enrichment Analysis (GSEA) and TIC correlation analyses were performed to explore its associations with immune pathways. Additionally, immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) were performed on 61 clinical samples. Results: High ImmuneScore was associated with improved survival. Joining chain of multimeric IgA and IgM (JCHAIN) expression was notably reduced in tumor tissues, with low expression correlating with poorer prognosis. GSEA highlighted immune-related pathways enriched in high JCHAIN expression groups. TIC analysis revealed positive correlations with CD8+ T cells and M1 macrophages. IHC and mIF validations further confirmed decreased JCHAIN protein expression in tumor tissues, and higher JCHAIN expression was associated with increased M1 macrophage density. Conclusions: JCHAIN serves as a promising prognostic biomarker in breast cancer, reflecting immune activity within the TME, providing valuable insights into immune-stromal interactions and the therapeutic potential of JCHAIN. Full article

A growing interest is focused on the efficient production of deinoxanthin (DEIX) and its use as a bioactive antioxidant. Here, we produced DEIX from Deinococcus radiodurans and examined how DEIX regulates hydrogen peroxide (H₂O₂)-mediated oxidative behaviors in mouse-derived bone marrow (BM) stromal cells and BM monocytes. We also evaluated whether oral supplementation with DEIX has radioprotective potential against total body irradiation (TBI)-mediated impairments in growth, organs, survival, and hematopoietic development using a mouse model. The direct addition of DEIX recovered H₂O₂-mediated oxidative disorders in the proliferation and the balance between osteoblast and osteoclast activity of the BM-derived cells in a dose-dependent manner. We found that recovery was closely associated with the DEIX’s potencies to remove cellular reactive oxygen species and to restore the expression of key molecules that tightly control bone homeostasis. Long-term oral supplementation with DEIX (25 mg/kg body weight, once per day for 42 consecutive days) protected mice against sub-lethal TBI (5 Gy)-mediated decreases in organ and body weights and lifespan. Supplemental DEIX also inhibited TBI-mediated structural damage in organs and restored endogenous antioxidant defense systems in the liver of TBI-exposed mice. Moreover, supplemental DEIX recovered a dysregulated hematopoietic process in TBI-exposed mice. Collectively, our results introduce an efficient method to produce DEIX and demonstrate its potency to recover oxidative cellular complication in H₂O₂-exposed BM-derived cells. Overall, our findings suggest that DEIX is a great antioxidative molecule to prevent or protect TBI-mediated systemic damages. Full article

Collagens make up the main components of the extracellular matrix (ECM), and, in cancer, are often aberrantly secreted by both tumor cells and stromal cells in the tumor microenvironment (TME). Collagen prolyl 4-hydroxylase (C-P4H), an enzyme that hydroxylates proline into 4-hydroxyproline at the Y position of the collagen -X-Y-Gly- triplet motif, is essential for the stability of the mature collagen trimer and collagen secretion. In this review, we summarize the research on the structure and function of C-P4H, the regulation of C-P4H enzyme activity, and the role of overexpression of its α-subunit, P4HA1, in promoting cancer progression as well as its potential as a prognostic marker and therapeutic target. Overexpression of P4HA1 is displayed in almost all solid cancers, including breast, colorectal, and lung cancer, and is associated with cancer progression, worse response to therapy, and poorer patient survival. Characterization of P4HA1 overexpression has demonstrated links to key hallmarks of cancer, not only in the canonical collagen deposition role, but also in non-canonical functions, such as cell stemness, hypoxic response, glucose metabolism, angiogenesis, and modulation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. P4HA1 is thus an attractive target for developing novel targeted therapies to improve treatment response in many cancer types. Full article

The secretome of mesenchymal stromal cells (MSCs) can efficiently stimulate regeneration and therefore is a tempting remedy for “cell-free cellular therapy”. However, the usage of primary MSC cultures as secretome producers for translation studies has obvious obstacles, including the rapid aging of MSC cultures, the need for a large number of verified donors, and donor-to-donor variability of secretome content. MSCs immortalization makes it possible to overcome those limitations and to obtain secretome-producing cultures with a prolonged lifetime. However, the efficacy and safety of such secretomes are critical issues that limit their usage as therapeutic agents. In this study, we tested in large detail how the immortalization of MSC cultures affects the content, biological activity and safety of their secretome. MSCs immortalization via the overexpression of human TERT gene does not significantly alter the qualitative and quantitative composition of their secretome or its activity according to the results of proteomic analysis, ELISA, qPCR and functional tests in vitro. Moreover, we have demonstrated that the secretome of immortalized MSCs does not contain detectable amounts of telomerase and does not possess any transforming activity. Altogether, our data suggest that immortalized MSC cultures may become a reliable source for obtaining standardized active secretome in large-scale quantities for clinical use. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with a severe stromal reaction mediated by pancreatic stellate cells (PSCs), leading to increased resistance to chemotherapy and radiotherapy. Following a repurposing concept, this preclinical study investigates the potential of approved drugs, known to be modulators of cellular copper transport, in combination with cisplatin for therapeutic approaches in PDAC. Two major strategies were pursued: (i) inhibiting copper transporters ATP7A and B with tranilast (TR) and omeprazole (OM) to block the cellular copper and, potentially, also cisplatin efflux, and (ii) using the chelator elesclomol (ES) to elevate intracellular copper and cisplatin levels. Human cell lines PanC-1 (PDAC), HPaSteC (PSC), and their co-culture, as well as the hepatocellular carcinoma cell line HepG2 as a reference model, were used. In addition to an analysis of the expression of copper transport proteins, the dynamics of cellular copper uptake and transport were monitored using a [⁶⁴Cu]CuCl₂ radiotracer approach. In vitro, all drugs enhanced cellular copper uptake and/or reduced copper efflux. Moreover, all drugs contributed to the enhanced cellular anticancer activity of cisplatin, with ES being the most effective compound. The results suggest that the targeted modulation of copper transport mechanisms may offer novel adjuvant approaches for the treatment of PDAC. Full article

Background/Objectives: Macrophages with the M2 phenotype are an immune population with great relevance for tumor development. We have previously demonstrated that mesenchymal stromal cells (MSCs) from cervical cancer (CeCa-MSCs) enhance the immunomodulatory activity of CeCa cells on T lymphocytes; however, the effect of these cells on the ability of tumor cells to polarize macrophages had not been evaluated to date. Methods: To address this, we set out to analyze the effect of normal cervix (NCx) and CeCa-MSCs interacting with CeCa tumor cells (TCs) to polarize macrophages in a coculture system. Results: Our results show that macrophages from TC/NCx-MSC cocultures decreased CD163 expression. In turn, we observed that macrophages from TC/CeCa-MSC cocultures, in contrast to those in the presence of TCs/NCx-MSCs, increased the intracellular production of IDO, IL-4, and IL-10; decreased T lymphocyte proliferation; and increased the presence of soluble IL-10. Interestingly, coculture in the presence of TCs/NCx-MSCs decreased the capacity of macrophages to generate regulatory T lymphocyte populations, as well as their phagocytic capacity, and increased IL-6 secretion, unlike the coculture of macrophages in the presence of TCs/CeCa-MSCs. Our results show that TCs/CeCa-MSCs in cocultures, unlike TCs/NCx-MSCs, have a greater capacity to polarize macrophages to an M2 phenotype and that such macrophages have a greater immunosuppressive potential. Conclusions: This in vitro study suggests that intracellular communication between MSCs and tumor cells in CeCa may promote tumor growth through the polarization of macrophages with increased immunosuppressive activity. Full article

The ultrastructural organization of different cell types involved in homeostatic growth in the cerebellum of juvenile chum salmon (Oncorhynchus keta) was investigated using transmission and scanning electron microscopy. The organization of astrocytes, oligodendrocytes, dark cells, adult-type glial and non-glial progenitors, stellate neurons, and eurydendroid cells (EDCs) in the molecular and granular layers and granular eminences was characterized. The organization of dendritic bouquets of Purkinje cells and climbing fibers was studied for the first time at the ultrastructural level, and the ultrastructural features of mossy fibers and the rosettes they form were characterized. Scanning electron microscopy (SEM) revealed the presence of single and paired adult-type neural stem/progenitor cells (aNSPCs) on the cerebellar surface and stromal clusters of aNSPCs outside the dorsal matrix zone (DMZ). Immunohistochemical (IHC) verification of proliferating cell nuclear antigen (PCNA) revealed five types of proliferating cells in the cerebellum of juvenile chum salmon: neuroepithelial cells (NECs), glial aNSPCs, and non-glial aNSPCs. A glial fibrillary acidic protein-positive (GFAP) complex consisting of radial glial fibers and aNSPCs was detected in the DMZ. At the same time, a complex of GFAP+ cerebellar afferents, consisting of differentiating mossy and climbing fibers, was found to develop in the cerebellum of juvenile chum salmon. Nestin+ non-glial aNSPCs and small nestin+ resident cells were detected in the dorsal, lateral, and basal areas, as well as in the granular layer (GrL) and granular eminences (GrEm). These cell types may contribute to the homeostatic growth of the cerebellum by acting as both active participants (PCNA+) and resident (silent) aNSPCs. Studying vimentin-positive systems in the cerebellum revealed a widespread presence of proliferating glial aNSPCs that actively contribute to homeostatic growth, as well as small resident immunopositive cells throughout the cerebellum of juvenile chum salmon. Immunolocalization of the neuronal RNA-binding protein marker (HuCD) was detected in numerous molecular layer (ML) cells at the early stages of neuronal differentiation in the dorsal and lateral regions of the cerebellum of juvenile chum salmon. HuCD + EDCs were detected for the first time in the dorsal (DZ) and basal (BZ) zones, forming broad axonal arborization. Immunolabeling of HuCD in combination with transmission electron microscopy (TEM) allowed EDCs to be characterized in the cerebellum of juvenile chum salmon for the first time. Full article

Background: Phosphaturic mesenchymal tumours secreting fibroblast growth factor 23 (hereinafter referred to as FGF23+ PMT) are rare neoplasms that can cause hypophosphataemic osteomalacia, owing to excessive FGF23 production. Mast cells (MCs) play a key role in tumour biology by modulating proliferative activity of atypical cells, resistance to innate and acquired immunity, angiogenesis, and metastatic behaviour. However, MCs associated with FGF23+ PMT have not previously been investigated. This study, to our knowledge, is the first to characterise features of the tumour microenvironment through spatial phenotyping of the immune and stromal landscape, together with histotopographic mapping of intercellular MC interactions with other subcellular populations in FGF23+ PMT. Methods: Histochemical staining (haematoxylin and eosin, toluidine blue, Giemsa solution, picro-Mallory protocol, silver impregnation), as well as monoplex and multiplex immunohistochemical staining with spatial phenotyping, were performed to detect atypical FGF23-secreting cells, immune cells (CD3, CD4, CD8, CD14, CD20, CD38, CD68, or CD163), stromal components (CD31, α-SMA, or vimentin), and specific MC proteases (tryptase, chymase, or carboxypeptidase A3). Bioinformatics analysis using artificial intelligence technologies was applied for spatial profiling of MC interactions with tumour, immunocompetent, and stromal cells in the tumour microenvironment. Results: Bioinformatic analysis of the entire tumour histological section, comprising over 70,000 cells stained using monoplex and multiplex immunohistochemical protocols, enabled identification of more than half of the cell population. The most abundant were CD14+ (30.7%), CD163+ (23.2%), and CD31+ (17.9%) cells. Tumour-associated MCs accounted for 0.7% of the total pool of immunopositive cells and included both mucosal and connective tissue subpopulations, predominantly of the tryptase + chymase-CPA3-specific protease phenotype. This pattern reflected combined multidirectional morphogenetic processes in the patient’s FGF23+ PMT. More than 50% of MCs were colocalized with neighbouring cells of the tumour microenvironment within 20 μm, most frequently with monocytes (CD14+CD68+), M2 macrophages (CD68+CD163+), and endothelial cells (CD31+). In contrast, colocalization with atypical FGF23-secreting cells was rare, indicating minimal direct effects on tumour cell activity. Interaction with T lymphocytes, including CD8+, was also infrequent, excluding their activation and the development of antitumour effects. Mapping of MC histotopography validated the hypothesis of their inductive role in monocyte differentiation into M2 macrophages and probable polarisation of macrophages from M1 into M2, thereby contributing to slow tumour growth. MCs were further involved in extracellular matrix remodelling and participated in the formation of pro-osteogenic niches within the FGF23+ PMT microenvironment, leading to pathological osteoid development. Conclusions: This study demonstrated active MC participation in the evolution of the FGF23+ PMT microenvironment. The findings may be applied in translational medicine to develop novel algorithms for personalised therapy in patients with FGF23-secreting tumours, offering an alternative when surgical removal of the tumour is not feasible. Full article

Background/Objectives: In children, gastroesophageal reflux disease (GERD) may lead to epithelial barrier dysfunction and the release of thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), interleukin-33 (IL-33) and periostin, known as alarmins. These cytokines are associated with type 2 inflammation and may contribute to respiratory and allergic conditions. The main purpose of this study is to evaluate serum concentrations of TSLP, IL-25, IL-33, and periostin in children with and without GERD and to assess their relationships with bronchial hyperresponsiveness (BHR) and sensitization to inhaled allergens. Methods: The study included 93 children aged 7–17 years. GERD was diagnosed based on 24-h esophageal pH impedance monitoring. Serum levels of TSLP, IL-25, IL-33, and periostin were measured using enzyme-linked immunosorbent assay (ELISA). It should be noted that the assay used does not distinguish between TSLP isoforms, which represents a limitation of the study. BHR was assessed via a methacholine challenge test, and allergen sensitization was determined using skin prick tests and allergen-specific immunoglobulin E (asIgE). Results: Serum TSLP levels were significantly higher in children with GERD compared to those without, whereas IL-25, IL-33 and periostin did not differ notably between groups. Periostin was associated with the degree of sensitization to inhalant allergens, but no significant links were found between cytokine levels and bronchial hyperresponsiveness. Conclusions: Significantly higher TSLP levels were noted in children with GERD than in those without. Hence, TSLP may have a potential role as a biomarker of epithelial immune activation in pediatric GERD. In addition, periostin was associated with sensitization to inhalant allergens, although it did not differentiate between children with and without GERD. Full article

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, has emerged as a critical stromal factor that contributes to tumor progression in various malignancies, including skin cancers. Beyond its classical role in inhibiting plasminogen activators, PAI-1 exerts pleiotropic effects within the tumor microenvironment, promoting immunosuppression, angiogenesis, and extracellular matrix remodeling. This review highlights the tumor-promoting functions of PAI-1 in melanoma, cutaneous squamous cell carcinoma, cutaneous angiosarcoma and cutaneous T-cell lymphoma, with a particular focus on its modulation of tumor-associated macrophages, cancer-associated fibroblasts, and endothelial cells. We also discuss recent preclinical and clinical studies targeting PAI-1, including TM5614, a novel oral PAI-1 inhibitor currently under investigation in phase II /III trials. By summarizing the multifaceted roles of PAI-1 and its impact on the immune and stromal landscape of skin malignancies, this review provides a rationale for PAI-1 as a promising therapeutic target and calls for further clinical validation of PAI-1–directed therapies. Full article