Search Results (11,291)

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract (GIT). This study aims to report the experience in the surgical treatment of GIST patients, evaluate the prognostic factors and discuss some controversial issues regarding the significance of microscopically margin-negative resection in GIST patients and the importance of tumor rupture during intraoperative surgical manipulation. Methods: Fifty-four GIST patients with primary disease without metastasis were admitted and treated during the past 15 years. Patients initially presenting with metastatic lesions and those who underwent adjuvant systemic therapy prior to surgical treatment were excluded from the study. Results: The median patient follow-up was 84 weeks. The 5-year overall survival was 34.34% and disease-free survival (DFS) was 35.37%. The median DFS was 244 weeks. In multivariate analysis, survival was affected by a high mitotic rate, resection margin status and the tumor rupture occurrence. Tumor size and tumor location did not show an impact. Conclusions: Surgical resection remains the mainstay of GIST treatment. Mitotic rate, resection margin status, and the occurrence of tumor rupture were predicators for DFS in patients presenting with primary disease. Recurrence of disease after resection was predominantly intra-abdominal and involved the original tumor size and the liver. Full article

Endometriosis is characterized by enhanced cellular proliferation, migration, and resistance to apoptosis, contributing to lesion persistence and progression. Targeting cellular plasticity and mesenchymal-associated functions may therefore represent a promising therapeutic strategy. Here, we investigated the effects of Pelargonium graveolens essential oil (PGEO) on proliferation, apoptosis, migration, cytoskeletal organization, transcriptional regulation, and metabolic alterations in human endometriotic 12Z cells. PGEO treatment suppressed proliferative capacity in a concentration-dependent manner and significantly impaired cell migration, accompanied by reduced β-tubulin expression and decreased levels of mesenchymal-associated markers CD73 and CD105. Increased GRP78 expression together with ultrastructural alterations, including cytoplasmic vacuolization and mitochondrial and endoplasmic reticulum changes, indicated activation of cellular stress responses. Although transcriptional analysis revealed increased CCND1 and PIK3CA mRNA levels, these changes did not parallel the observed suppression of proliferation, suggesting compensatory regulatory responses. Untargeted metabolomic profiling revealed alterations in energy metabolism characterized by increased levels of glycolysis-related metabolites, reduced levels of several amino acids including glutamine and histidine, and changes in lipid-associated metabolites. Collectively, these findings demonstrate that PGEO suppresses proliferative and migratory behavior in endometriotic cells while modulating cytoskeletal, transcriptional, and metabolic pathways, highlighting its potential as a candidate for further investigation in endometriosis-targeted therapeutic strategies. Full article

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular characterization and tumor biology have driven the development of antibody-based therapies targeting immune checkpoints, angiogenesis, and oncogenic signaling pathways critical for tumor growth and progression. Among these agents, Ramucirumab, Atezolizumab, and Amivantamab have demonstrated significant clinical efficacy in selected NSCLC populations. This review summarizes the mechanisms of action, pivotal clinical trials, and current clinical evidence supporting the use of ramucirumab, atezolizumab, and amivantamab in the management of advanced NSCLC. Relevant literature was identified through searches of PubMed, clinical trial registries, and recent international conference proceedings, with an emphasis on therapeutic efficacy, safety profiles, and rational combination strategies. Ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has shown a survival benefit when combined with docetaxel in patients with previously treated advanced NSCLC. Atezolizumab, a programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI), has become a cornerstone of NSCLC treatment across multiple disease stages, both as monotherapy and in combination with chemotherapy. Amivantamab, a bispecific antibody targeting both epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET), has demonstrated robust and durable clinical activity in patients with EGFR exon 20 insertion–mutated NSCLC. Collectively, these agents highlight the expanding role of antibody-based therapies in NSCLC and underscore the importance of biomarker-driven patient selection and treatment personalization. Ongoing research into resistance mechanisms, predictive biomarkers, and combination approaches is expected to further refine the integration of antibody-based strategies in precision oncology for NSCLC. Full article

Bone regeneration requires tight coordination between mesenchymal stem cells (MSCs), immune signaling, and extracellular matrix remodeling. Yet, how atypical immune receptors contribute to this process remains unclear. Here, we identify Toll-like receptor 10 (TLR10) as a key regulator of osteogenic differentiation in human adipose-derived MSCs. Herein, ASC/TERT1 MSCs were engineered to overexpress or silence TLR10 using lentiviral vectors, and osteogenic differentiation (0–14 days) was assessed by metabolic assays—RT-qPCR of COL1A2, ALPL and BGLAP—Alizarin Red S staining, and quantitative mass spectrometry. Enhancing TLR10 expression promoted osteogenic gene programs, extracellular matrix organization, metabolic adaptation, and robust matrix mineralization, whereas TLR10 suppression maintained proliferative states and impaired osteoblast maturation. Proteomic analyses revealed that TLR10 selectively activates osteogenic, ECM-remodeling, and vitamin D-responsive pathways, while restraining programs antagonistic to differentiation. Notably, active vitamin D induced TLR10 expression and partially restored osteogenesis in TLR10-deficient cells, indicating that TLR10 is associated with vitamin D-driven bone formation. Together, beyond its established role in innate immunity, TLR10 emerges as a vitamin D-responsive regulator of mesenchymal stem cell osteogenesis, highlighting a potential therapeutic axis to enhance bone regeneration and osteogenic outcomes. Full article

Breast cancer is classified into distinct molecular subtypes, including Luminal A, Luminal B, HER2-enriched, Basal-like, and Claudin-low. While traditional studies mostly use 2D cell cultures, 3D models better mimic in vivo tumor conditions. In this study, we generated and characterized 3D spheroids from breast cancer cell lines representing different molecular subtypes. Morphologically, spheroids were either compact (MCF-7/AZ, T47D, BT474, MDA-IBC-3, BT-20, SUM149PT) or loosely adhered (MDA-MB-468, SK-BR-3, MDA-MB-231), while retaining key parental subtype biomarkers. Cell viability decreased with increasing spheroid size, but apoptotic cCasp3 staining was restricted to Basal-like spheroids. Compact spheroids expressed E- and/or P-cadherin, indicating epithelial or epithelial–mesenchymal transition (EMT) hybrid traits, while loose spheroids showed vimentin expression linked to a mesenchymal phenotype. Overall, EMT status, rather than molecular subtype, primarily determined spheroid morphology. In conclusion, EMT-associated features, rather than intrinsic molecular subtype, may contribute to 3D spheroid architecture of breast cancer cell lines. Full article

Background and Objectives: Low back pain (LBP) is a leading cause of disability worldwide and is frequently associated with intervertebral disc degeneration (IVDD). Current therapeutic strategies are primarily symptomatic and do not restore native disc biology, largely due to the avascular nature of the intervertebral disc and the hostile inflammatory and mechanical microenvironment that characterizes degeneration. The aim of this study is to provide an updated and clinically oriented overview of the pathophysiology of IVDD and to evaluate the current evidence on mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP)-based therapies. Materials and Methods: A focused narrative literature review was performed to evaluate current evidence on MSC- and PRP-based therapies for intervertebral disc degeneration (IVDD). The search was conducted in PubMed. Only studies in English were considered eligible. Results: Mesenchymal stem cells (MSCs) demonstrated regenerative and immunomodulatory effects primarily through paracrine mechanisms, enhancing extracellular matrix synthesis and reducing inflammation and apoptosis. MSC-derived extracellular vesicles emerged as a promising cell-free alternative, potentially overcoming limitations related to cell survival and safety. Platelet-rich plasma (PRP) showed anabolic and anti-inflammatory properties, promoting disc cell proliferation and matrix production, particularly in early-stage degeneration. Clinical studies, including randomized trials, reported significant improvements in pain and function for both MSC and PRP therapies, with favourable safety profiles. However, heterogeneity in treatment protocols and limited long-term data remain significant limitations. Orthobiologic therapies represent a minimally invasive option for patients with discogenic low back pain refractory to conservative treatment. Patient selection is crucial and should consider degeneration stage, disc viability, and clinical presentation. PRP is primarily indicated in early-stage degeneration (Pfirrmann II–III), whereas MSC-based therapies may be considered in selected patients with more advanced but still viable discs. Based on current evidence, a stepwise approach is proposed, progressing from conservative management to PRP, MSCs, and ultimately surgery. Orthobiologics should be integrated within a multimodal strategy including rehabilitation. Conclusions: MSCs and PRP represent a promising and, eventually, complementary orthobiologic therapies for IVDD. PRP is primarily effective in early degenerative stages as a biologic stimulator, whereas MSCs may provide regenerative benefits in more advanced but still viable discs. Further studies are necessary to standardize protocols and confirm long-term efficacy and safety. Full article

Background: This study investigates the role of N6-methyladenosine (m6A) regulators in osteoporosis (OP) and their interplay with the immune microenvironment, aiming to identify potential m6A-related biomarkers for OP risk assessment and treatment. Methods: Transcriptomic data from GEO datasets were analyzed for differential expression of 22 m6A regulators and immune infiltration patterns. Consensus clustering and m6Ascore grouping defined molecular subtypes, while machine learning algorithms identified potential biomarkers, leading to the construction and validation of a nomogram. Experimental validation involved peripheral blood monocytes (PBMCs) transcriptome sequencing and Western blot of bone tissue. Results: FTO, HNRNPC, and METTL4 were upregulated, while CBLL1 and YTHDF2 were downregulated in OP, with two distinct m6A modification patterns and immune phenotypes identified. METTL4, HIRA, MATN4, and YTHDF2 were selected as potential biomarkers, and the nomogram demonstrated favorable predictive performance in training and external datasets. Single-cell RNA sequencing confirmed the cellular distribution of these biomarkers. HIRA heterogeneity in Marrow Mesenchymal Stem Cells (BMSCs) was associated with distinct cell–cell communication patterns. Transcriptome sequencing confirmed HIRA RNA downregulation in OP PBMCs, and Western blot verified decreased HIRA protein in OP bone tissue. Conclusions: This study establishes a potential m6A-related biomarker signature for OP and provides multi-level experimental evidence that HIRA is a consistently downregulated biomarker, linking epigenetic modification to immune dysregulation in osteoporosis. Full article

Diabetes mellitus affects an estimated 589 million adults globally, and cutaneous manifestations occur in up to 70% of affected individuals during the course of the disease. The objective of this narrative review is to examine the intersection of diabetes mellitus, skin aging, cosmetic dermatologic procedures, and regenerative therapies, with an emphasis on evidence-based best practices and clinical considerations. While the impaired wound healing associated with diabetes has been extensively studied, the aesthetic implications of diabetic skin disease remain comparatively underexplored. Individuals with diabetes frequently exhibit features of accelerated cutaneous aging, including premature wrinkling, dyschromia, xerosis, alopecia, and other cosmetically significant dermatoses that may negatively impact quality of life. In parallel, the demand for aesthetic dermatologic procedures among patients with diabetes has increased substantially; however, evidence-based recommendations guiding the safe and effective use of cosmetic interventions in this population remain limited. Diabetic skin demonstrates accelerated biological aging driven by complex pathophysiological mechanisms, including the accumulation of advanced glycation end products, chronic low-grade inflammation, oxidative stress, microvascular dysfunction, and neuropathy. These processes partially overlap with chronological aging and photoaging but are mechanistically distinct and may influence tissue repair, inflammatory responses, and the safety profile of commonly performed aesthetic procedures such as chemical peels, laser resurfacing, dermal fillers, neuromodulators, and microneedling. Emerging regenerative approaches, including platelet-rich plasma, platelet lysate, and mesenchymal stromal cell-derived products such as exosomes and secretomes, have attracted increasing attention as biologically targeted strategies for cutaneous rejuvenation. Nevertheless, clinical evidence specifically addressing aesthetic interventions in diabetic populations remains limited. A diabetes-informed approach to aesthetic dermatology that considers metabolic status, procedure selection, and post-procedural monitoring is therefore essential to optimize safety and therapeutic outcomes. Full article

Dysregulation of microRNA expression in breast cancer (BC) has been associated with molecular disturbances involved in cancer initiation, progression and metastasis. Specific microRNAs also act as endocrine modulators in BC, thereby influencing the biological behavior of the tumor and drug responses. Our objective was to employ bioinformatics tools to identify and characterize microRNAs acting as candidate players involved in epithelial–mesenchymal transition, migration, invasion, and/or hormonal regulation in BC. We systematically integrated microRNA profiling data from three different studies on BC cell lines with different invasive capabilities and from another study on lymph node metastases and matching primary BC, resulting in five microRNA hits—DE-microRNAs miR-146a-5p, miR-222-3p, miR-205-5p, miR-141-3p and miR-200c-3p. This set of microRNAs was evaluated for clinical significance in BC and subjected to target prediction, microRNA–mRNA network construction, functional enrichment analysis and quantification in BC cell lines by qPCR. An upregulated DE-microRNA, miR-222-3p, displayed distinctive pro-metastatic features, supported by its clinical relevance, as well as by the results of the functional enrichment analysis of its target genes. Downregulation of the members of the miR-200 family and miR-205-5p were significantly associated with negative clinical features, while their targets were enriched with genes that were relevant to cancer aggressiveness. These results are in line with the presumed functional relevance of the selected DE-microRNAs in BC. Full article

Cervical cancer (CC) is a complex, multistep process involving various viral, molecular, cellular, endogenous, and environmental events that transform normal cervical epithelium into a malignant tumor through a cascade of events. The contribution of high-risk human papillomavirus (HPV) to cancer is significant but involves many additional mechanisms such as oxidative stress (OS), arrested apoptosis of non-functional intraepithelial neoplastic cells, senescence-associated secretory phenotype (SASP), and the final epithelial–mesenchymal transition (EMT) of cervical epithelial neoplasia (CIN) cells. While high-risk HPV oncoproteins E6 and E7 are widely recognized as the primary triggers of CC, the critical role of E6 in degrading the p53 regulatory protein, thereby inhibiting the apoptosis of reactive oxygen species (ROS)-damaged neoplastic cells, is frequently underappreciated in the gynecological literature. Arrested apoptosis of non-functional neoplastic intraepithelial cells is a key event in cervical carcinogenesis and the biological basis of CIN progression via SASP senescence and ultimately EMT. While recent reviews touched upon each of the reviewed aspects, this review aims to provide a general understanding of all links in this complex molecular-biological chain, from HPV infection, oxidative stress, arrested apoptosis, SASP, and EMT. Beyond providing an encompassing primer for clinical researchers, we additionally review potential oxidative stress-related markers for shifting the classic diagnostic and therapeutic paradigms of CIN and cervical cancer. Full article

In rheumatoid arthritis (RA), activated synovial tissue-derived mesenchymal stem cells (MSC) acquire a pathogenic phenotype and produce pro-inflammatory cytokines, chemokines, metalloproteinases, pro-osteoclastic and pro-angiogenic factors. The acquisition of this aggressive phenotype might be due to modified expression of micro-RNAs. We aimed to clarify the role of specific micro-RNAs (miR-146a-5p, miR-221-3p, miR-34a-3p, miR-150, miR-203a-3p and miR-155-3p) in an in vitro model of RA. Methods: Micro-RNA expression was determined in RA patient plasma and in commercial human synovial tissue-derived MSC-like cells stimulated with a panel of pro-inflammatory mediators (poly I:C, TNF-α, IL-1β, IFN-γ) to mimic the rheumatoid arthritis pathogenic setting. Next, unstimulated cells or TNF-α stimulated cells were transfected with miR-146a-5p mimic or miR-221-3p mimic. Protein and/or mRNA expressions of chemokines, cytokines, VEGF, MMPs and RANKL were determined by ELISA or qRT-PCR. MiR-34a-3p, miR-146a-5p, miR-150, miR-221-3p and miR-203a-5p were upregulated in RA patient plasma versus healthy controls. Moreover, synovial tissue-derived MSC-like cells expressed miR-146a-5p and miR-221-3p in response to pro-inflammatory mediators. Overexpression of miR-146a-5p increased CCL2 and CXCL8 expression and miR-221-3p increased IL-1β and IL-6 expression in synovial tissue-derived MSC-like cells stimulated with TNF-α. Conclusion: Overexpression of miR-146a-5p and miR-221-3p might favour inflammation and participate in rheumatoid arthritis pathogenesis. Full article

Purpose: Cannabidiol (CBD) is a primary bioactive, non-intoxicating cannabinoid found in the cannabis plant. Studies have shown that CBD causes anticancer activity by inhibiting the expression of growth factors and inducing apoptosis, leading to cell cycle arrest. In this study, we aimed to determine how CBD influences the expression of genes that affect cancer pathways in doxorubicin-sensitive (MCF-7) and doxorubicin-resistant (MCF-7/Adr) breast cancer cells. Materials and Methods: IC₅₀ concentrations of CBD in MCF-7 and MCF-7/Adr cell lines were determined by the MTT cell cytotoxicity assay. RNA isolation and subsequent cDNA synthesis were performed for qPCR experiments with the determined IC₅₀ values. The effects of CBD on the cell cycle and apoptosis were studied using flow cytometry. IC₅₀ values of CBD were determined in MCF-7 and MCF-7/Adr breast cancer cell lines at eight different concentrations and at three different incubation periods (24 h, 48 h, and 72 h) with different doses. RT-qPCR was used to investigate the molecular mechanisms underlying the expression of genes involved in cancer pathway analysis. Results: Treatment with CBD at concentrations of 17.57 μM (MCF-7) and 11.41 μM (MCF-7/Adr) for 48 h decreased colony formation, induced apoptosis, and inhibited cell invasion in both cell lines. In addition, we observed significant alterations of angiogenesis, apoptosis, cell cycle, cellular senescence, DNA damage and repair, epithelial-to-mesenchymal transition, hypoxia, metabolism, telomeres, and telomerase in both cell lines. Conclusions: Our research indicates that CBD could be an effective natural bioactive compound for breast cancer treatment, inhibiting tumor cell proliferation and inducing apoptosis. Full article

Bovine mastitis is a common inflammatory disease that can progress to mammary fibrosis, thereby impairing udder health, milk yield, and milk quality. This study investigated the protective effects of palmatine on lipopolysaccharide (LPS)-induced epithelial–mesenchymal transition (EMT) in bovine mammary epithelial cells and mammary fibrosis in mice, as well as the underlying mechanisms. In vitro, palmatine markedly reversed LPS-induced EMT by increasing E-cadherin expression and decreasing N-cadherin and α-SMA expression. In vivo, palmatine alleviated inflammatory cell infiltration and collagen deposition in mammary tissue and reduced the expression of TGF-β1, p-Smad2, p-Smad3, p-p65, TNF-α, IL-1β, and IL-6. These findings suggest that palmatine alleviates LPS-induced mammary fibrosis, possibly through inhibition of the NF-κB/TGF-β1/Smad signaling pathway, and may represent a potential therapeutic strategy for the prevention and treatment of mammary fibrosis. Full article

Periodontal disease represents a major global health burden, beginning with gingivitis and progressing to periodontitis, which causes connective tissue breakdown, alveolar bone resorption, and eventual tooth loss. Beyond local pathology, periodontitis is a chronic inflammatory condition with systemic associations, including cardiovascular disease, diabetes, and metabolic disorders. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have emerged as promising candidates for periodontal regeneration. This review aimed to map the current evidence on MSC-derived EVs (MSC-EVs) in periodontal regeneration, focusing on their mechanisms of action, therapeutic potential, and translational challenges. A comprehensive literature search was conducted across a major biomedical database (PubMed) to identify preclinical and clinical studies investigating MSC-EVs in the context of periodontitis. Data were charted on EV cargo composition, biological functions, regenerative outcomes, and reported limitations. Evidence indicates that MSC-EVs encapsulate bioactive molecules—including antimicrobial peptides, proteins, lipids, and microRNAs—that modulate immune responses, suppress pro-inflammatory signaling, and promote angiogenesis and tissue repair. In periodontal models, MSC-EVs attenuate osteoclast activity, enhance fibroblast proliferation, and stimulate extracellular matrix remodeling, supporting regeneration of periodontal ligament and alveolar bone. Exosome-based approaches demonstrate advantages such as reduced immunogenicity, improved safety, and feasibility for storage and standardization. However, most findings remain preclinical, with limited human data available. To bridge the translational gap, well-designed clinical trials are needed to confirm efficacy and safety while addressing regulatory challenges, GMP standards, and outcome measures. Harnessing their regenerative capacity while mitigating side effects may guide precision-targeted therapies, and continued mechanistic studies with standardized production will be key to advancing MSC-EVs into clinical practice. Full article