Search Results (45,643)

The liver’s regenerative capacity is essential for resection and transplantation, but chronic liver diseases compromise this ability. Conventional preoperative tests poorly predict regeneration in diseased livers, necessitating new intraoperative tools. Optical coherence tomography (OCT) provides real-time high-resolution “optical biopsy” and functional tissue assessment, making it a promising method for evaluating liver regenerative potential. The aim of this study was to identify characteristic criteria derived from MM OCT that could be used intraoperatively to detect the presence and type of pathology, and to assess the reduction in liver regenerative potential in patients. In this study, we used intraoperative multimodal OCT (MM OCT)—combining attenuation mapping and elastography—for real-time, label-free assessment of changes in liver structure, and stiffness during regeneration. MM OCT also provides higher resolution and specificity than conventional clinical imaging. In a rat model, we induced steatosis by high-fat diet and fibrosis by CCl₄ injections, then induced regeneration by 70% partial hepatectomy (PH). MM OCT monitoring was performed on day 0 (pre-PH), day 3, and day 7 (post-PH). Pathologies and regeneration were verified by biochemical blood tests, histological analysis, and real time-PCR for steatosis- and fibrosis-specific genes. As a result, attenuation coefficient and Young’s modulus obtained by MM OCT enable real-time assessment of liver tissue changes in steatosis and fibrosis, which vary with regeneration stage. Steatosis showed uniformly high attenuation and low stiffness before and after resection. Fibrosis exhibited heterogeneous attenuation and marked stiffness fluctuations—high pre-resection values dropped at day 3 and rose again by day 7. Attenuation coefficient detects lipid droplets in hepatocytes and identifies high-density hepatocyte zones near collagen septa, distinguishing them from densely packed unaltered cells. Thus, MM OCT identifies pathology type, lipid infiltration and collagen presence—features that serve as indicators of impaired liver regenerative capacity. Full article

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined. Materials and Methods: A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction. Results: A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations. Conclusions: FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver. Full article

The pathogenesis of knee osteoarthritis (KOA) involves bone homeostasis imbalance induced by inflammation, metabolism, age, mechanical stress, joint injury and other factors. Recently, Type H vessels (CD31^hiEMCN^hi endothelial cells) have emerged as a specialized endothelial cell subset that couples angiogenesis with osteogenesis. Type H angiogenesis in the diaphysis was found to be beneficial for maintaining bone homeostasis, while the abnormal proliferation of type H vessels in subchondral bone can lead to chondrocyte hypertrophy and osteophyte formation. However, the mechanism by which the abnormal proliferation of type H vessels induces KOA has not been elucidated in detail. In this review, we summarize the latest evidence on the role of type H endothelial cell function in the pathogenesis and progression of osteoarthritis (OA). We review the role of type H angiogenesis at different sites in the development and progression of OA and focus on the potential mechanisms that regulate type H angiogenesis in OA and the potential therapeutic value and significance of targeting type H angiogenesis in promoting bone regeneration and maintaining bone homeostasis. Finally, we discuss key obstacles and future directions for studying type H vessel regulation in KOA, offering an endothelial cell-based framework for understanding bone homeostasis and improving OA. Full article

Triply periodic minimal surfaces (TPMSs) are increasingly used in thermal management systems due to their high surface area and interconnected porous architecture. However, how TPMS geometry influences fire growth remains poorly understood. Herein, Gyroid, Diamond, and Schwarz-P PLA structures were fabricated through additive manufacturing, and their fire behavior was characterized via cone calorimetry. Univariate experiments demonstrate that flame propagation is primarily governed by cell structure, rather than porosity or specific surface area. The orthogonal array L₉(3³), covering three factors of wall thickness, cell size and cell type (Gyroid, Diamond, and Schwarz-P), indicates that their effects on the flame growth index (FGI) rank as: cell size > unit cell > thickness. Meanwhile, a multivariate regression model was developed to predict the FGI of TPMS porous PLA, exhibiting high prediction accuracy (R² = 0.95) and low residual standard deviation. These results provide quantitative insights into the correlation between TPMS geometric features and fire growth, which facilitates the design of safer porous structures for thermal management applications. Full article

Ruminants are unique among living mammals in possessing paired bony cranial appendages in the form of horns, pronghorns, antlers, or ossicones. This review summarizes current knowledge on the structure, development, function, and evolution of these appendages and integrates recent findings from genomics, transcriptomics, and single-cell analyses. Two competing hypotheses have been proposed to explain their origin. According to the independent-origin hypothesis, horns, pronghorns, antlers, and ossicones evolved separately in different pecoran lineages, possibly through repeated recruitment of similar developmental capacities of the frontal region of the skull. According to the common-origin hypothesis, these appendages derive from a single ancestral osseous cranial structure that was subsequently modified in different lineages. Comparative anatomy and developmental data reveal major differences among the four types of appendages, including dermally ossifying horn cores in bovids, annually regenerated antlers arising from frontal bone pedicles in cervids, deciduous keratin sheaths in pronghorns, and skin-covered ossicones in giraffids. The fossil record does not currently resolve these hypotheses, because the main appendage types are first documented within a relatively short early Miocene interval and transitional forms remain unknown. In contrast, molecular and cellular studies identify shared developmental pathways, cranial neural crest-derived progenitors, and conserved regulatory genes, including RXFP2, ALX1, SOX9, and components of Wnt signaling, which are consistent with a shared developmental module. We conclude that the homology of pecoran cranial appendages remains unresolved and that further paleontological, developmental, and comparative molecular studies are required to determine whether these structures share a common evolutionary origin or instead represent convergent recruitment of similar developmental programs. Full article

Background and Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease of the nasal and paranasal sinus mucosa, associated with significant impairment in quality of life, frequent postoperative recurrence, and repeated need for systemic glucocorticosteroid therapy. Despite the availability of biologics targeting IL-4/IL-13, IL-5, and IgE, a subset of patients shows incomplete or insufficient clinical response. In this context, upstream targeting of epithelial alarmins, particularly thymic stromal lymphopoietin (TSLP), has emerged as a potential therapeutic strategy. To critically review current evidence on the role of TSLP in CRSwNP and to evaluate available data on the mechanism of action, clinical efficacy, and therapeutic potential of tezepelumab in severe and recurrent disease. Materials and Methods: A narrative review was conducted using PubMed, Scopus, and Web of Science. Studies published between 2016 and 2026 were included, comprising experimental research, phase II–III clinical trials, systematic reviews, and international guidelines. Results: TSLP functions as an epithelial alarmin that initiates and amplifies type 2 inflammation via dendritic cell activation, Th2 polarization, and activation of type 2 innate lymphoid cells (ILC2). Data suggests that tezepelumab, a monoclonal antibody targeting TSLP, may reduce inflammation and regulate the immune system. Evidence from asthma populations and relevant CRSwNP subgroups indicates potential improvements in nasal polyp score, congestion, olfactory function and quality of life. It is our understanding that the safety profile appears comparable to placebo, with no new safety concerns having been identified in long-term studies. Conclusions: Tezepelumab is a promising biologic that targets inflammation in CRSwNP. It may benefit severe, recurrent, treatment-resistant disease by modulating immune pathways. However, evidence is indirect and limited, and more trials are needed to define its efficacy, identify biomarkers, and clarify its role in treatment algorithms. Full article

Most cancers are fatal and remain challenging to cure due to changes in tumorigenesis and therapeutic resistance. Despite significant advancements in cancer therapy, a substantial proportion of malignancies exhibit resistance to conventional therapies, driven primarily by cancer plasticity and the emergence of multidrug resistance. Recent cancer treatments include cytotoxic chemotherapy, molecular targeted therapy, and immune checkpoint inhibitors. A major hallmark of cancer cells is their ability to develop sophisticated evasion mechanisms that bypass programmed cell death when exposed to anti-cancer drugs. In addition, malignant cells evade the efficacy of anti-cancer drugs by altering cell proliferation, survival, and metastasis. To suppress oncogenic characteristics, necroptosis-based therapies have attracted substantial attention, as they can inhibit tumorigenesis and improve treatment outcomes across many cancer types. Furthermore, an increasing body of research focuses on suppressing tumorigenesis by targeting receptors that are overexpressed in cancer cells. In this review, we elucidate how tumorigenesis is inhibited by regulating the epidermal growth factor receptor (EGFR)–tumor necrosis factor receptor (TNFR) signaling pathway in necroptosis. By delineating the underlying mechanisms of these receptors, we propose that the induction of necroptosis via EGFR and TNFR represents an innovative paradigm for targeted therapy, offering a strategy to enhance clinical outcomes in treatment-resistant cancers. Full article

Tay-Sachs disease is a rare genetic disorder characterized by the accumulation of GM2 ganglioside in neuronal lysosomes due to deficient β-hexosaminidase A (HexA) activity. Progressive GM2 storage leads to severe neurodegeneration, including developmental delay, motor weakness, seizures, ataxia, and early death, typically by five years of age. Previous studies have elucidated several neuronal mechanisms, including apoptosis, endoplasmic reticulum stress, neuroinflammation, and demyelination, these investigations have focused almost exclusively on neurons. However, other components of the central nervous system, particularly astroglia, may play a critical role in disease pathophysiology as suggested by studies in related lysosomal storage disorders. To address this gap, we generated an astrocyte-like model deficient in HexA by targeted knockdown of the HEXA gene in U87MG astrocytoma cells. The resulting cell line recapitulates key pathological features, including lysosomal accumulation, increased neutral lipid content, reduced mitochondrial mass, and elevated reactive oxygen species production. Transcriptomic analysis revealed significant alterations in pathways associated with neuronal degeneration, synaptic organization, mitochondrial dysfunction, and ganglioside metabolism. In summary, this model reproduces some classical cellular alterations reported in Tay-Sachs disease and could potentially provide novel insight into astrocyte involvement in its pathophysiology. These findings support the relevance of non-neuronal cells in disease pathophysiology and establish this system as a valuable platform for screening potential novel mechanisms and therapeutic approaches. Furthermore, this approach highlights the importance of integrating cell type specific models to better understand disease heterogeneity and providing insights into the progressive neurodegeneration of Tay-Sachs disease, positioning this model as a valuable tool for studying its underlying pathophysiology. Full article

Background: Lung infections represent a major cause of morbidity and mortality in patients with cystic fibrosis (CF) and are predominantly associated with chronic infection by Pseudomonas aeruginosa. The clinical management of CF lung disease is increasingly compromised by the emergence of multidrug-resistant strains, biofilm formation, and the expression of multiple virulence determinants. Antimicrobial peptides (AMPs), evolutionarily conserved effectors of innate immunity, have emerged as promising therapeutic candidates due to their ability to exert both bactericidal and anti-virulence activities. In this study, we investigated the antimicrobial and mechanistic effects of Ranalexin-1G, an AMP derived from the skin secretion of Rana grylio, against P. aeruginosa, for which its antibacterial activity has not previously been reported in the literature. Methods: Antibacterial activity was determined against the reference strain and three clinical isolates of P. aeruginosa by broth microdilution assays, time-kill kinetics and anti-biofilm assays, while peptide-mediated modulation of virulence was evaluated through transcriptional analysis of key virulence-associated genes by RT-PCR. The impact of Ranalexin-1G on host–pathogen interactions was further assessed using bacterial invasion assays in human bronchial epithelial cells (BEAS-2B). Results: Ranalexin-1G exerted a rapid bactericidal effect within 6 h at non-cytotoxic concentrations and displayed modest anti-biofilm effects, with greater efficacy in inhibiting biofilm formation. Mechanistically, peptide treatment resulted in a reduction in the expression of selected genes involved in biofilm formation and virulence, including those associated with alginate biosynthesis and type III secretion system-mediated cytotoxicity. Consistently, Ranalexin-1G markedly impaired bacterial invasion of epithelial cells, indicating interference with early host–pathogen interaction processes. Notably, the peptide displayed robust antimicrobial activity against multidrug-resistant P. aeruginosa clinical isolates from CF patients. Conclusions: Collectively, these findings suggest that Ranalexin-1G acts through a dual mechanism involving direct bactericidal activity and modulation of selected virulence pathways, supporting further investigation of its potential as an anti-virulence and host-directed approach for the treatment of chronic P. aeruginosa infections in cystic fibrosis. Full article

Background: The neutrophil-to-lymphocyte ratio (NLR) has been the focus of extensive research in recent years as an inexpensive inflammatory biomarker with prognostic value in oncology, but its relationship with tumor grade across solid malignancies remains uncertain. Methods: This systematic review evaluated original clinical studies reporting the association between peripheral blood NLR and histological tumor grade in solid tumors. PubMed and Web of Science were searched using Boolean strategies, and eligible full-text studies were synthesized qualitatively because of heterogeneity in tumor type, grading system, NLR threshold, and statistical reporting. Results: The qualitative synthesis included 13 retrospective primary studies comprising 5394 patients. Eight studies reported statistically significant associations between higher NLR and higher tumor grade or poorer differentiation, most consistently in bladder cancer and in single studies of prostate cancer, soft tissue sarcoma, renal cell carcinoma, pancreatic cancer, breast cancer, and colorectal cancer with synchronous liver metastases. Four studies reported no statistically significant grade-related association, mainly in heterogeneous breast cancer and ovarian cancer cohorts, whereas a small colorectal adenocarcinoma cohort study showed a non-significant positive trend. Conclusions: The available evidence suggests a possible relationship between systemic inflammation and tumor grade in selected malignancies, but the evidence remains preliminary, tumor-specific, retrospective, and vulnerable to confounding. NLR should not be interpreted as a surrogate for histological grade. Full article

Background/Objectives: NF1 encodes neurofibromin, a RAS-GTPase-activating protein (GAP), and heterozygous loss-of-function variants cause neurofibromatosis type 1. Missense variants outside the GAP-related domain (GRD) are difficult to classify because supporting functional evidence is limited. NF1 c.6394T>C (p.Ser2132Pro) is currently listed in ClinVar as a variant of uncertain significance. We examined its functional consequences and evaluated whether the resulting evidence supports a likely pathogenic interpretation under the ACMG/AMP framework. Methods: We evaluated p.Ser2132Pro using population databases, evolutionary conservation, calibrated in silico predictors, and structural mapping onto the full-length cryo-EM model of neurofibromin. The variant was then introduced at the endogenous NF1 locus in HEK293T and A375 cells by prime editing, and we measured neurofibromin abundance, transcript levels, RAS-GTP dynamics, and MAPK pathway reactivation after PLX4032 treatment. Evidence was integrated under the ACMG/AMP framework. Results: p.Ser2132Pro was absent from population databases, affected a highly conserved residue buried within the C-terminal HEAT domain, and received concordant deleterious predictions from calibrated in silico tools. At the endogenous locus, p.Ser2132Pro reduced neurofibromin abundance by 88–95% in both cell models while NF1 transcript levels were only modestly reduced, impaired RAS-GTP signal termination, doubled steady-state RAS-GTP in A375 cells, and produced 5-fold higher ERK phosphorylation than the non-targeting control under PLX4032 treatment. Conclusions: These findings support a cellular loss-of-function effect of p.Ser2132Pro characterized primarily by reduced neurofibromin abundance with impaired neurofibromin-dependent RAS regulation. Under a conservative ACMG/AMP interpretation, the combined evidence supports a Likely Pathogenic interpretation of NF1 c.6394T>C (p.Ser2132Pro). Full article

Sodium–glucose co-transporter 2 (SGLT2) inhibitors confer cardioprotection in patients with and without diabetes; however, whether SGLT2 is expressed in cardiac tissue and how these drugs act locally in the heart remains unclear. We investigated SGLT2 expression and the effects of empagliflozin in human iPSC-derived cardiac cells exposed to diabetogenic conditions. SGLT2 expression and the effects of empagliflozin were assessed in iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts under acute diabetogenic conditions using protein expression and metabolic activity assays, and in a multicellular 3D cardiac microtissue model using metabolic activity and contraction analyses. SGLT2 was detected in all three iPSC-derived cardiac cell types with nuclear and perinuclear localisation; no membrane-bound expression was observed. Endothelial cell SGLT2 expression was elevated under diabetogenic conditions. Diabetogenic stress reduced metabolic activity in both cardiomyocytes and endothelial cells; empagliflozin partially rescued endothelial cell metabolic activity but had no effect in cardiomyocytes. Empagliflozin reversed diabetogenic stress-induced cardiac fibroblast activation. 3D cardiac microtissues under diabetogenic conditions exhibited prolonged relaxation time, reduced beat rate variability, and reduced metabolic activity. Empagliflozin maintained metabolic activity at levels comparable to those of the control but did not rescue relaxation time or beat rate variability. The responsiveness of non-myocytes (endothelial cells and cardiac fibroblasts) to empagliflozin, in the absence of any effect on cardiomyocytes, suggests that non-myocyte-mediated mechanisms may contribute to the clinically observed cardioprotection of SGLT2 inhibitors. Full article

Accumulating data indicate a role for the dysregulation of the cell cycle, autophagy and apoptosis in diabetic kidney disease. We aimed to evaluate the mediators of the PI3K/Akt and MAPK/ERK signaling pathways in the kidney of db/db mice, a model of type 2 diabetes, treated by the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and metformin. Eight-week-old male db/db mice were randomly assigned to treatment by these agents or vehicle for 8 weeks. Age-matched db/+ mice acted as controls. AMPKα1 and PI3Kp110β were evaluated in the renal cortex and medulla by Western Blot. Phosphorylated forms of principal molecules involved in the PI3K/Akt and MAPK/ERK pathways were assessed by multiplex analysis. Db/db mice had decreased PI3Kp110β, increased phospho-PTEN, HSP27 and MEK1 in the renal cortex and medulla, BAD in the renal cortex and decreased phospho-rpS6 in the renal medulla. Empagliflozin prevented the changes in the levels of cortical PI3Kp110β, phospho-MEK1, and medullar phospho-PTEN. Linagliptin restored PI3Kp110β levels. Both agents further decreased medullar phospho-rpS6. Metformin upregulated cortical AMPKα1, medullar PI3Kp110β, phospho-GSK-3α/β and MEK1, and increased phospho-HSP27 in the renal cortex and medulla. The data may provide further explanation of the mechanism underlying the development of diabetic kidney disease, as well as the renal protective effect of anti-diabetic agents. Full article

Introduction: Sevoflurane may exert cytotoxic effects in some cell types, but its impact on human cardiomyocytes and the potential protective role of remifentanil remain unclear. This study aimed to investigate whether remifentanil mitigates sevoflurane-induced apoptotic damage in human cardiomyocytes, with an exploratory focus on TRPA1 calcium channels. Materials and Methods: Human cardiomyocyte cells were exposed to sevoflurane (5.1% for 6 h) and/or remifentanil (2.5 µM for 30 min), with or without the TRPA1 antagonist AP18. Apoptosis, intracellular reactive oxygen species (ROS), mitochondrial depolarisation, caspase-3 and -9 activities, and cytosolic calcium levels were measured. Results: Sevoflurane exposure was associated with increased apoptosis, ROS production, mitochondrial depolarisation, caspase-3 and -9 activities, and intracellular calcium levels compared with the control group. Remifentanil pretreatment appeared to reduce these sevoflurane-related changes. In several parameters, the addition of AP18 partially reversed the effects of remifentanil, suggesting that TRPA1 channels may contribute to these effects. However, findings were not entirely consistent across all measured variables. Conclusions: Remifentanil effectively mitigates sevoflurane-induced apoptotic damage in human cardiomyocytes, likely by modulating oxidative stress and preserving mitochondrial function. The partial reversal by AP18 suggests that TRPA1 channels may contribute to these protective effects, though additional mechanisms are likely involved. Further mechanistic and translational studies are warranted to elucidate the precise signalling pathways and clinical relevance of these observations. Full article

Background/Objectives: Diabetes mellitus is associated with sensorineural hearing loss, but the cochlear molecular alterations related to this complication remain unclear. This pilot study aimed to characterize auditory function and region-specific transcriptomic changes in the diabetic cochlea. Methods: A streptozotocin-induced type 1 diabetic mouse model was established. Auditory function was assessed by auditory brainstem response (ABR) testing. Next-generation RNA sequencing was performed on micro-dissected cochlear regions, including the modiolus, lateral wall, and organ of Corti, followed by differential expression and gene ontology analyses. Results: STZ-induced diabetic mice showed elevated ABR thresholds compared with control mice. RNA sequencing revealed region-specific transcriptomic alterations across cochlear regions, with the lateral wall showing the greatest changes. Cross-region analysis identified a shared transcriptional signature consisting of 32 upregulated and 2 downregulated genes across the modiolus, lateral wall, and organ of Corti. Gene Ontology analysis showed enrichment of immune-related, inflammatory, metabolic stress-associated, and membrane-associated signaling. Conclusions: STZ-induced diabetes was associated with ABR threshold elevation and shared as well as region-specific cochlear transcriptomic alterations in this mouse model. These findings provide a region-specific cochlear transcriptomic resource for diabetes-associated auditory dysfunction and support future studies using larger cohorts, independent molecular validation, histological assessment, and cell-type-resolved approaches. Full article