Search Results (752)

Millions of new cancer cases and deaths worldwide annually demonstrate the pressing need for predictive preclinical models that go beyond standard two-dimensional (2D) cultures and animal systems. Recent developments in three-dimensional (3D) organoid technology have yielded a powerful platform for generating patient-specific mini-organ models that faithfully recapitulate primary tumors at the genetic, phenotypic, and architectural levels. Organoids retain functional fidelity by preserving key stem cell signaling pathways, including Wnt, Notch, and Hippo, making them robust platforms for disease modeling and high-throughput drug screening. This review describes representative organoid systems, ranging from patient-derived organoids (PDOs) to induced pluripotent stem cell (iPSC)-derived organoids, that serve as disease-specific “avatars” for personalized therapeutics. Predictive accuracy rates greater than 90% have been shown in clinical studies, providing evidence for the relevance of organoids in functional precision medicine. In addition to drug discovery, the extended use of organoids in regenerative oncology can provide a unique regulatory mechanism by selectively targeting CSCs and enhancing tissue repair after cytotoxic treatments. Recent advances in organoid-on-a-chip platforms, 3D bioprinting, and artificial intelligence (AI) address critical challenges involving vascularization, immune system integration, and scalability. With the advent of standardized, GMP-compliant platforms and recent regulatory initiatives, such as the FDA Modernization Act 2.0, organoids are well-positioned to support next-generation cancer research and therapy. This review aims to bridge the gap between stem cell-derived organoids (SCDOs), providing a fully humanized platform for preclinical cancer modeling and their clinical application, and to discuss their potential to advance ethically guided, personalized cancer therapeutics with improved predictive and translational power. Full article

Background: Glucocorticoids (GCs) are a key pathogenic factor in steroid-induced avascular necrosis of the femoral head (SANFH). GCs can directly damage bone microvascular endothelial cells (BMECs), leading to impaired intraosseous blood supply. Recent studies suggest the Hippo signaling pathway may be involved in the pathogenesis of SANFH; however, its role in vascular endothelial repair and angiogenesis remains unclear. This study aims to investigate the therapeutic effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on SANFH, with a particular focus on their protective or reparative mechanisms on BMECs. Methods: In vivo, a SANFH mouse model is established and divided into NC, MPS, and hUC-MSCs groups, followed by Micro-CT imagin, hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) (n = 8 per group). In vitro, BMECs are divided into NC, dexamethasone (Dex), hUC-MSCs, and Fer-1 groups to analyze cellular biological behaviors. Target protein expression is assessed using Western blotting and immunofluorescence microscopy. Ferroptosis-related markers are detected via biochemical assays. Mitochondrial ultrastructural changes are observed using transmission electron microscopy. Results: In vivo, the MPS group exhibited significant bone cavitation, sparse trabeculae, and disrupted trabecular architecture in the femoral head. The hUC-MSCs group showed marked improvement in bone microstructure, HE staining showed a significant decrease in the empty lacunae rate in the femoral head, and IHC results revealed markedly increased expression of cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF). In vitro, Dex stimulation suppressed BMECs proliferation. In Dex-treated cells, levels of intracellular reactive oxygen species (ROS), lipid peroxides, ferrous ion (Fe²⁺), malondialdehyde (MDA), acyl-CoA synthetase long chain family member 4 (ACSL4) and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) were all increased, while expression of glutathione (GSH) and glutathione Peroxidase 4 (GPX4) was reduced. Transmission electron microscopy revealed plasma membrane rupture and reduction or loss of mitochondrial cristae. Furthermore, Dex promoted Hippo-mediated phosphorylation of Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ), upregulated NOX4 expression, and suppressed CD31 and VEGF expression. Following hUC-MSCs treatment, BMECs demonstrated enhanced proliferation, migration, and tube-forming capacity. Cellular GSH and GPX4 levels increased, antioxidant capacity was restored, peroxide accumulation decreased, and cells were protected from ferroptosis-effects comparable to those in the Fer-1 group. Additionally, hUC-MSCs inhibited YAP/TAZ phosphorylation and promoted elevated expression of CD31 and VEGF. Conclusions: These findings suggest that hUC-MSCs may attenuate Dex-induced ferroptosis in BMECs, enhance BMEC migration and angiogenesis, and improve femoral head microstructure in SANFH through modulation of the Hippo-YAP/TAZ signaling pathway. This study provides novel insights into the therapeutic potential of hUC-MSCs for SANFH. Full article

Pathological cardiac hypertrophy is a critical factor leading to cardiomyopathy and ultimately heart failure. While several signaling pathways controlling cardiac hypertrophy have been identified, the molecular mechanisms underlying their precise regulation remain incompletely understood. Strip1, a structural component of STRIPAK complexes, has been implicated in various cellular functions; however, its role in cardiomyocytes is uncharacterized. Here we identify Strip1 as a potent anti-hypertrophic factor, controlling cell size and the hypertrophic gene program in neonatal rat ventricular cardiomyocytes (NRVCMs). STRIP1 expression was found to be significantly reduced in human dilated and ischemic cardiomyopathies (DCM/ICM), as well as in murine stress model induced by transverse aortic constriction (TAC). In a knockdown model with morpholino-driven STRIP1 reduction in zebrafish in vivo, impaired cardiac function and heart failure–like features were observed. Interestingly, Strip1 localized to the nucleolus in NRVCMs, suggesting a putative nuclear/epigenetic role in cardiomyocytes. Furthermore, our data support association of Strip1 with cardiac STRIPAK complex, modulating kinase activities, including MST1/MST2 and MST4. Mechanistically, Strip1 appears to influence prohypertrophic signaling, including Hippo- and Calcineurin/NFAT-related pathways, which may contribute to pathological cardiac remodeling. Collectively, these findings establish Strip1 as an important modulator of cardiomyocyte hypertrophy and a potential therapeutic target for cardiomyopathy and heart failure. Full article

Vaccinia-Related Kinase 3 (VRK3) is increasingly recognized as a crucial signaling modulator in both normal and pathological processes. This kinase was long thought of as a catalytically inactive pseudokinase, until recently it was established to phosphorylate Barrier to Autointegration Factor (BAF) proteins through its extracatalytic domain. VRK3 regulates diverse cellular pathways through scaffold interactions and context-dependent phosphorylation. This review is centered around the phosphoregulatory network that modulates VRK3 phosphorylation with implications in its abundance and function. A large-scale phosphoproteomic data integration was performed by combining phosphoproteomics profiling and differential phosphorylation from 115 mass spectrometry studies, identifying 32 high-confidence phosphorylation sites on VRK3. Notably, VRK3 (S59), (S82), and (S83) were predominantly observed highlighting plausible functional significance. These phosphorylation sites share 33 potential upstream kinases, and multiple interactor proteins, which in combination are known to regulate ERK, Hippo, and GPCR pathways. These insights advance the understanding of phosphorylation control by kinases and highlight opportunities to target VRK3-associated networks for therapeutic intervention in diseases such as glioma and liver cancer. Full article

Skeletal muscle myogenesis is a crucial factor influencing meat production in livestock. MicroRNAs (miRNAs) play a significant role in skeletal muscle myogenesis. The objective of this study was to identify key miRNAs involved in the process of goat skeletal muscle satellite cell (MuSC) differentiation into myotubes. We performed miRNA expression profiling analysis during the proliferation phase (cultured in growth medium, GM) and the differentiation phase (cultured in differentiation medium for 1 day and 5 days, classified as DM1 and DM5, respectively) of goat skeletal muscle satellite cells (MuSCs). A total of 1846 miRNAs were identified in MuSC samples, of which 677 differentially expressed miRNAs (DEmiRNAs) were screened through pairwise comparisons across three groups (GM vs. DM1, GM vs. DM5, and DM1 vs. DM5), and the results were further confirmed by a quantitative real-time PCR assay. Time-series expression profiling facilitated the categorization of the DEmiRNAs into eight distinct clusters, one of which demonstrated a significantly downregulated expression pattern (p < 0.05). Functional enrichment analysis revealed that the target genes of DEmiRNAs are involved in several pathways that are critical for myogenesis, including Hippo, TGF-β, MAPK and cell adhesion molecules. Interaction network analysis identified 19 miRNAs and 56 mRNAs associated with muscle cell development. Notably, novel-m0047-5p emerged as a key regulator, exhibiting strong negative correlations (r = −0.88 to −0.89, q < 0.01) with muscle-related target genes FOSB, CPT1B, and MYOZ2. These findings elucidate miRNA-mediated regulatory networks in goat myogenesis and provide candidate molecular targets for genetic improvement of meat production traits. Full article

The liver possesses a remarkable regenerative capacity following injury, a process fundamentally orchestrated by the dynamic extracellular matrix (ECM). Far beyond a passive scaffold, the liver matrisome functions as an integrative mechano-biochemical circuit. It comprises a core structural network together with regulatory non-core components that collectively establish a dynamic niche. This niche stores and releases mitogenic cues, transmits mechanical forces, and coordinates multicellular crosstalk. Through receptors like integrins and mechanosensitive channels, ECM-derived signals converge on key pathways, including Hippo-YAP/TAZ and Wnt/β-catenin, to drive hepatocyte proliferation and tissue restructuring. The balance between matrix stabilization and remodeling dictates the outcome, guiding physiological regeneration versus fibrotic progression. Consequently, the ECM emerges as a central therapeutic target and a blueprint for engineering strategies aimed at restoring liver function. Strategies to recalibrate its composition, mechanics, and remodeling, from pharmacological inhibitors to bioengineered decellularized ECM scaffolds, hold significant potential for steering liver repair and combating chronic liver disease. Full article

Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in homologous recombination (HR) but show limited and heterogeneous efficacy in non-small-cell lung cancer (NSCLC), where canonical HR deficiency is uncommon. Identifying alternative molecular determinants that modulate PARP inhibitor sensitivity therefore remains an important objective. In this study, we examined the role of the NDR/Hippo-associated cofactor human MOB2 (hMOB2) in shaping PARP inhibitor responses in lung cancer cells. hMOB2 was depleted by siRNA in A549 and H1299 cell lines, and cell viability, long-term survival, DNA damage, and apoptosis were assessed using WST-1 assays, clonogenic assays, Western blotting, immunofluorescence, comet assays, and caspase-3 activity assays. p53 dependency was evaluated using p53-null H1299 cells and p53 reconstitution via retroviral transduction. hMOB2 depletion sensitized A549 cells to olaparib and rucaparib, resulting in a marked reduction in long-term clonogenic survival. This effect was associated with enhanced p53 phosphorylation, persistent γH2AX accumulation, increased DNA strand breaks, and caspase-3-dependent apoptosis, while hMOB2 loss alone was not intrinsically cytotoxic. Sensitization required functional p53, as it was absent in p53-null cells but restored upon p53 re-expression. These findings suggest that hMOB2 contributes to PARP inhibitor responses in lung cancer cells and underscore the complexity of PARP inhibitor sensitivity beyond classical HR deficiency. Full article

Background/Objectives: Hepatoblastoma, the most common pediatric primary liver cancer, is no longer regarded as a conventional malignancy but rather as a tumor emerging from disrupted hepatic developmental processes. Although improvements in chemotherapy, surgical techniques, and liver transplantation have markedly enhanced survival, therapeutic decision-making is still primarily guided by anatomical criteria and insufficiently reflects the biological heterogeneity that contributes to variable treatment response and disease recurrence. This narrative review integrates recent advances in molecular biology, tumor stemness, microenvironmental interactions, and translational research models in pediatric hepatoblastoma. We critically examine how developmental signaling pathways, cellular plasticity, and immune–vascular context shape tumor behavior and therapeutic vulnerability, with a focus on emerging targeted, anti-angiogenic, immune, and epigenetic strategies. Results: Hepatoblastoma is characterized by aberrant activation of key developmental pathways, including Wnt/β-catenin, Hippo–YAP, IGF, and mTOR signaling, which cooperate to sustain proliferation, stem-like phenotypes, and treatment resistance. Tumor heterogeneity is further reinforced by cancer stem cell populations and a predominantly immune-cold microenvironment. While innovative therapeutic approaches show promise, their clinical impact has been limited by biological complexity and insufficient integration into current treatment algorithms. Liquid biopsy biomarkers, advanced translational models, and multi-omics approaches offer new opportunities for biologically informed risk stratification and therapy adaptation. Conclusions: Future progress in pediatric hepatoblastoma will require a paradigm shift from purely clinicopathological management toward an integrated molecular and surgical framework. Incorporating biological stratification into therapeutic decision-making may enable personalized treatment, rational therapy de-escalation, and improved outcomes for high-risk disease. This review highlights the foundations and future directions for precision medicine in hepatoblastoma. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Emerging evidence shows that mechanotransduction, driven by matrix stiffness and mechanical signaling, promotes TNBC invasion and metastasis. As breast cancer progresses, expansion of fibroblasts and tumor-reactive stroma increases extracellular matrix deposition, generating matrix tension and enhancing mechanotransduction, which promotes cell proliferation, invasion, and metastatic potential through altered gene expression patterns. To investigate the molecular mechanisms underlying these changes, human TNBC cells were subjected to constant or oscillatory strain, followed by comprehensive transcriptomic analysis. Results revealed pronounced differential expression of genes involved in cell migration, adhesion, and transforming growth factor-β (TGFβ) signaling, with RT-PCR validation confirming SKI Like Proto Oncogene (SKIL) as the most strongly upregulated gene. Analysis of The Cancer Genome Atlas (TCGA) datasets indicated that SKIL is highly expressed in multiple breast cancer subtypes. Cross-sectional comparison of oscillatory strain-induced genes with TCGA data revealed coordinated upregulation of TGFβ, SKIL, and other genes associated with invasive phenotypes, immune suppression, and drug resistance, highlighting the vital role of TGFβ signaling. Transcription factor enrichment analysis further identified regulators linked to oncogenic pathways, including TGFβ effectors and Hippo signaling, supporting a mechanotransduction-driven transcriptional program in breast cancer. Full article

The relationship between time and eternity is a central theme in Augustine’s thought and has often been interpreted, under Neoplatonic influence, through the paradigm of image and model. This article contributes to recent reassessments of Augustine’s doctrine of time by arguing that interpreting time as image does not adequately reflect his conceptual distinctions and his original thought. It proposes instead that time should be understood primarily as a sign, and more specifically as a vestige of eternity because time exhibits the defining features of a vestige, directing the soul from the temporal order toward the eternal and highlighting the salvific dimension of time within Augustine’s eschatology. Full article

Cardiac fibrosis represents a final common pathway in a wide range of cardiac disorders, leading to structural remodeling, diastolic dysfunction, and heart failure. From a pathologist’s viewpoint, fibrotic remodeling displays distinctive morphologic patterns such as interstitial, perivascular, and replacement fibrosis, which mirror specific cellular and molecular mechanisms. Central to this process is the activation of cardiac fibroblasts into myofibroblasts, driven by profibrotic signaling cascades such as transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog proteins (SMAD), Wingless/Integrated signaling pathway (Wnt)/βeta-catenin, and Hippo-Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathways. Neurohumoral mediators, including angiotensin II and aldosterone, further amplify extracellular matrix synthesis and tissue stiffness. Epigenetic modulators and non-coding RNAs (n-c RNAs) orchestrate transcriptional programs that perpetuate fibroblast activation. Histopathological correlates of these molecular events, collagen deposition, alpha-smooth muscle actin (α-SMA) expression, and extracellular matrix (ECM) cross-linking, can be demonstrated through immunohistochemistry and digital morphometry. This review integrates molecular signaling and morphologic evidence to delineate the mechanisms of cardiac fibrosis, emphasizing the pathologist’s role as a link between molecular insight and diagnostic interpretation. Understanding these intertwined processes provides the foundation for novel antifibrotic therapies targeting key molecular nodes of fibroblast activation and matrix remodeling. Full article

The Vehicle Routing Problems with Time Windows (VRPTW) has remained a classic and continuously studied problem since its introduction. With the rapid growth of cold chain product distribution demands, VRP research has become increasingly important for guiding real-world scheduling decisions. However, most studies focus on further subdividing new scenarios and constraints, often overlooking fundamental real-world applications. This includes the impact of unknown road conditions on costs, rough cost modeling, and poor algorithm adaptability to high-dimensional cold chain constraints. To address these three issues, this paper proposes the Spatio-temporal dependency and road network distribution-based traffic forecasting model (STD-RND) to provide region-level traffic scheduling information. The model also constructs cost functions to quantify cargo spoilage, refrigeration, and carbon emissions. Finally, we introduce an Improved Hippo Optimization with Traffic Forecasting (IHTF) that incorporates traffic prediction to enhance the solution quality of the VRPTW in cold chain scenarios. To strengthen optimization performance and prevent premature convergence to local optima, we integrate several enhanced strategies, including chaotic mapping, dynamic Cauchy mutation, and an escape mechanism. Through a series of experiments on the Solomon dataset and simulation datasets based on real road networks, we demonstrate that the proposed algorithm shows consistent superiority and effectiveness. Full article

This study examines the influence of the bishop’s and canons’ knowledge on the design of the presbytery’s keystones in Tortosa Cathedral, which has been governed by the Beati Augustini rule since 1155. The iconography representing the Coronation of the Virgin (1439) constitutes a recurring theme in medieval architecture and is closely linked to references found in manuscript illumination starting from the late 12th century. The presence of thirty-two works by Augustine of Hippo in the Cathedral’s Chapter Archives allows for a comparative methodology between the iconographic analysis of the Coronation of the Virgin and the study of the liturgical space through Terrestrial Laser Scanning (TLS). It is concluded that the metrology of the keystone is established based on the symbolic numbers 10 and 100 from the De Civitate Dei codices, and the number 150 from Augustine of Hippo’s De Supra Psalterium. Alongside this Augustinian foundation, both the iconography and the act of setting the keystone are enriched by the numerous codices related to the Summa Aurea by Jacobus de Voragine. Full article

Background/Objectives: Peritoneal mesothelioma is a rare malignancy characterized by limited therapeutic options and a poor prognosis. Genomic characterization can enhance the understanding of the molecular mechanisms that lead to this disease and can contribute to improved survival outcomes through therapeutic targets. Methods: Analysis was performed using a dataset from the AACR GENIE database (v17.0-public) comprising 204 samples from 192 patients. Data were analyzed to identify patterns in genomic alterations and clinical demographics. Within the GENIE cohort, histologic subtype information was incomplete and inconsistently reported across contributing institutions. Hence, histological subtype genomic analysis was not viable. Results: The most common somatic mutation was found in the BAP1 gene (25.98%). Other common mutations were found in the NF2 (15.19%), TP53 (9.3%) and SETD2 (8.3%) genes. Several pathways were found as potential treatment targets including the chromatin remodeling, Hippo, and p53 signaling pathways. Given the size of our dataset, we were unable to draw significant conclusions about certain demographics. Conclusions: This study presents data that can help draw conclusions on common mutations, mutual exclusivity patterns, and demographics at risk for peritoneal mesothelioma. Genomic analysis of peritoneal mesothelioma may inform possible intervention targets for therapeutic treatment. Full article

Objective: Abdominal aortic aneurysm (AAA) epidemiology differs significantly between the sexes; the biological factors behind this are mostly unknown. MicroRNAs (miRNAs) are short RNA molecules providing post-transcriptional regulation of protein synthesis. Several miRNAs have been associated with the development and growth of AAA, but only in men. We investigated whether the associations between some selected miRNAs and aortic size differ by sex and the possible target pathways for such differences. Methods: A cross-sectional study included subjects with AAA (30–58 mm) and normal aortas. Clinical data were collected through questionnaires. Abdominal aortic diameters were measured using ultrasound. The levels of 17 miRNAs were measured in plasma. The association between miRNA levels, aortic diameter, and sex were analysed using multivariable linear regression. Results: A total of 242 subjects were included, with 85 women and 157 men. In the group with aortic diameters below 30 mm were 122 men (15–29 mm) and 50 women (13–29 mm). There were 35 men (30–54 mm) and 35 women (30–58 mm) with AAA. The associations between six miRNAs and aortic diameter were influenced by sex: miR-125 (p = 0.013), miR-128–1 (p = 0.017), miR-24 (p = 0.013), miR-26a (p = 0.022), miR-93 (p = 0.0015), and miR-194 (p = 0.013). Bioinformatic analysis indicated Hippo and TGF-beta as the two signalling pathways most likely affected by these differences. Conclusions: This exploratory study found sex differences in the associations between miRNA levels and aortic diameter, involving signalling pathways that control organ size and maintain tissue homeostasis by regulating cell proliferation, survival, and differentiation. Full article