Search Results (2,950)

Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article

Polycyclic aromatic hydrocarbons (PAHs) are widespread, persistent pollutants that can be sequestered within human adipose tissue due to their lipophilic nature. While this accumulation poses toxicological risks depending on dose and individual susceptibility, the specific morphological impact of chronic PAH storage on tissue architecture remains poorly defined. Here, we performed a histopathological and morphometric analysis on human subcutaneous adipose tissue samples characterized by high pyrene levels. We evaluated tissue organization, collagen distribution, the presence of inflammatory, neural, and vascular alterations and adipocyte morphometry to assess the structural response to PAH sequestration. Despite high pyrene concentrations, PAH-positive tissues maintained preserved overall architecture with normal collagen distribution, absence of lymphocytic infiltration, low macrophages, unaltered nerve fiber patterns, without evidence of vascular remodeling. Morphometry revealed smaller adipocyte area in PAH-positive samples, although not statistically significant. Our experimental data indicate that high PAH accumulation does not necessarily induce subcutaneous adipose tissue remodeling, suggesting that biochemical or metabolic alterations might occur even in the absence of evident histological changes. Further studies, with a broadened cohort, are needed to define the threshold at which PAHs’ presence translates into permanent tissue damage. Full article

Background/Objectives Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases involved in collagen cross-linking, has emerged as a key mediator of pathological extracellular matrix remodeling and tissue fibrosis. Dysregulated LOXL2 activity has been implicated in various fibrotic diseases; however, its role in fibrosis-driven chronic kidney injury, particularly in the context of calcineurin inhibitor-induced kidney toxicity, remains incompletely defined. Methods To investigate the contribution of LOXL2 inhibitor to cyclosporine A (CsA)-induced nephropathy, a well-established model of progressive tubulointerstitial fibrosis, male CD-1 mice were administered either saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. After 4 weeks of CsA exposure, CsA-treated mice were further divided into two groups and received either vehicle or a LOXL2 inhibitor (10 mg/kg/day, oral gavage) for an additional 4 weeks. Kidney function, albuminuria, histological fibrosis, inflammatory cell infiltration, and profibrotic gene expression were assessed. Results In a murine model of CsA-induced nephropathy, pharmacological inhibition of LOXL2 markedly improved kidney outcomes. LOXL2 inhibition significantly reduced albuminuria and ameliorated kidney dysfunction. In parallel, tubulointerstitial fibrosis was substantially attenuated, accompanied by reduced myofibroblast activation and extracellular matrix accumulation. These protective effects were associated with downregulation of profibrotic and inflammatory mediators and inhibition of TGF-β-related downstream signaling pathways activated by CsA. Conclusions The present preclinical findings suggest that Compound #765-mediated LOXL2 inhibition may offer a potential therapeutic benefit in CsA-induced fibrosis, though further validation is warranted. Full article

Eosinophilic chronic rhinosinusitis (eCRS) is an upper respiratory condition frequently associated with olfactory dysfunction (OD). Despite its high prevalence, the mechanisms underlying OD remain poorly understood. Several eCRS models have been described, but their olfactory phenotypes are poorly characterized. In this study, we compared two of the most frequently used mouse models of eCRS in order to standardize in vivo research on eCRS-related OD. Male and female mice were challenged with ovalbumin (OVA) combined with Staphylococcus aureus enterotoxin B (SEB) over a 13-week protocol or with OVA combined with Aspergillus oryzae protease (AP) for 6 or 12 weeks. Olfactory function was assessed using the buried food test and habituation/dishabituation test. After sacrifice, the integrity and inflammation of the olfactory epithelium were assessed on coronal skull sections by (immuno)histology, including sex as a biological variable. Both models exhibited impaired olfactory function, reduced olfactory epithelium surface area and thickness, and eosinophil infiltration of the olfactory mucosa. The OVA-AP model showed additional presence of neutrophils in the olfactory mucosa, suggesting a mixed inflammatory response. No functional or histological difference was detected between male and female mice, except for epithelial thickness in OVA-SEB control mice. Overall, both murine models are suitable for mechanistic studies of OD in eCRS, with the AP-12-week model displaying the most pronounced inflammation. Full article

Glioblastoma (GB) is the most aggressive primary central nervous system tumor in adults and the most common malignant primary brain tumor, representing approximately 50.9% of all malignant CNS tumors, with a median overall survival of approximately 14.6 months despite standard multimodal treatment, consisting of surgical resection, concurrent radiotherapy, and temozolomide (TMZ), followed by adjuvant TMZ (Stupp protocol). Tumor recurrence is inevitable and attributed to diffuse infiltration of neoplastic cells into the brain parenchyma, marked intratumoral heterogeneity, the presence of glioma stem cells, and the protection conferred by the BBB. Flavonoids are plant-derived polyphenolic compounds with more than 8000 identified. They have attracted growing interest as potential therapeutic agents because of their capacity to modulate multiple oncogenic signaling pathways and their favorable toxicity profile. Here we synthesize the preclinical evidence on the main flavonoids with documented activity in GB models, with emphasis on quercetin, apigenin, luteolin, and EGCG, while distinguishing glioblastoma-specific evidence from indirect findings derived from other experimental systems. We analyze their underlying molecular mechanisms, including induction of apoptosis through the intrinsic and extrinsic pathways, inhibition of cell proliferation and angiogenesis, suppression of migration and invasion, epigenetic modulation, and, particularly, the capacity to target the glioma stem cell population. We also examine the limited oral bioavailability and restricted penetration across the BBB, as these factors remain major barriers to translational development. We conclude with an analysis of emerging nanotechnological strategies, targeted delivery systems, and synergistic combinations with conventional chemotherapeutic agents, together with a cautious assessment of the current clinical evidence, which remains insufficient to support the use of flavonoids outside controlled clinical trials. Full article

Background: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. Methods: In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and 50 mg/L Cr(VI) (as potassium dichromate, K₂Cr₂O₇) via drinking water for four weeks to investigate splenic damage and the underlying molecular pathways. Spleen pathological injury was evaluated by hematoxylin and eosin (H&E) staining, and the distribution of T cells, B cells, and macrophages was assessed by immunohistochemistry. Antioxidant enzyme activities and antioxidant substance levels were determined using ELISA, and the relative mRNA expression of immune factor genes, antioxidant-related genes, and ferroptosis-related genes was quantified by quantitative real-time PCR (qRT-PCR). In addition, the distribution of iron in splenic tissue was detected by enhanced Prussian blue staining. Results: Our results demonstrate that high-dose Cr(VI) significantly inhibited body weight gain, induced lymphocyte atrophy, vacuolization, and widening of intercellular spaces in the splenic white pulp. Furthermore, Cr(VI) reduced T and B lymphocyte populations, promoted macrophage infiltration and inflammatory cytokine gene expression in a concentration-dependent manner, impaired total antioxidant capacity, and led to a decrease in glutathione (GSH) levels in the spleen. Additionally, Cr(VI) exposure increased iron accumulation, activated the ACSL4–NOX lipid peroxidation cascade, and downregulated GPX4 expression, ultimately triggering ferroptosis. Conclusions: These findings reveal that Cr(VI) causes splenic immune injury by disrupting oxidative homeostasis and inducing ferroptosis, providing novel insights for evaluating immunotoxicity and identifying metabolic targets under Cr(VI) pollution. Full article

A therapeutic antibody, CSL305, has been developed, which combines inhibition of the complement classical and lectin pathways via complement C2 binding with an ability to act as an antagonist of the neonatal Fc receptor (FcRn). CSL305 binds to human C2 (huC2) but shows no binding or activity against mouse C2 precluding its use in mouse models of disease to fully assess in vivo efficacy. To circumvent this, a mouse strain was developed that replaced the expression of mouse C2 with huC2 by homologous recombination. These mice (huC2 “knock-in”; KI) were shown to express huC2 protein and to have complement activity. Interestingly, male huC2-KI mice showed much stronger complement activity compared to female mice and were also sensitive to inhibition by CSL305. Two models of disease using male huC2-KI mice were then used to assess the in vivo efficacy of CSL305. The first was an attenuated passive anti-glomerular basement membrane (GBM) glomerulonephritis model involving complement activation as its primary mechanism of action. CSL305 showed dose-dependent inhibition of disease as measured by urine albumin, with reductions in kidney cellular infiltration and plasma C3 cleaved fragments C3b/C3c/iC3b also observed. The second model was a collagen autoantibody-induced arthritis (CAIA) mouse model. Here, CSL305 showed a significant and dose-dependent inhibition of clinical score in both prophylactic and therapeutic settings, mediated exclusively via its FcRn mechanism of action. Although the animal models used in this study were found to preclude the demonstration of a synergistic effect on both mechanisms, CSL305 does act in vivo as both a complement inhibitor and as a FcRn antagonist to ameliorate disease. Full article

Accurate assessment of vitreous inflammation is essential for the diagnosis, monitoring and management of uveitis. Traditionally, vitritis has been evaluated using subjective clinical grading systems based on vitreous haze and cellular infiltration, which are limited by interobserver variability and poor reproducibility, particularly in cases of mild or subclinical inflammation. In recent years, advances in ocular imaging have enabled the development of more objective, quantitative approaches. Ultra-widefield imaging, optical coherence tomography (OCT) and ultrasound-based techniques have provided new insights into structural alterations within the vitreous. In parallel, automated image analysis and artificial intelligence (AI)-based methods have improved the detection and quantification of inflammatory biomarkers, including vitreous hyperreflective foci and signal intensity-based metrics. Despite these advances, important limitations remain, including a restricted field of view, a lack of standardized segmentation algorithms and an incomplete representation of the entire vitreous cavity. No single modality currently provides a comprehensive and fully reproducible assessment of vitreous inflammation. This review summarizes current qualitative and quantitative methods for evaluating vitreous inflammation, highlighting their respective strengths and limitations. In addition, emerging diagnostic strategies, including multimodal imaging integration, AI-driven analysis and molecular biomarker profiling, are discussed as potential tools to improve accuracy, standardization and clinical applicability. The transition from subjective grading toward objective quantification of inflammatory burden represents a key step in advancing both clinical management and research in ocular inflammatory diseases. Full article

Cisplatin is a widely used platinum-based chemotherapeutic agent that often causes irreversible hair cell loss, leading to hearing impairment. To date, effective strategies for preventing cisplatin-induced ototoxicity remain limited. Corchorus olitorius L. (COL) is rich in bioactive phytochemicals with antioxidant and anti-inflammatory properties; however, the protective role of COL stem against cisplatin-induced hearing loss has not been explored. This study aimed to determine whether COL stem extract treatment could mitigate cisplatin-induced hair cell damage in the lateral line system of zebrafish. Herein, we use 7-day post-fertilization (dpf) transgenic zebrafish larvae as a high-throughput screening platform to assessed COL stem extract against cisplatin-induced hair cell injury. Endpoints included mechanotransduction (MET) function, reactive oxygen species (ROS) production, apoptotic and inflammatory responses, and locomotor behavior. Antioxidant capacity and acute toxicity were also evaluated. Pretreatment with COL stem extract preserved hair cell viability, restored MET function, reduced ROS accumulation, upregulated Nrf-2-dependent cytoprotective genes, suppressed apoptosis, and attenuated macrophage infiltration. The recovery of swimming behavior correlated with hair cell protection, confirming the phenotypic relevance. This study demonstrates, for the first time, that COL stem exerts potent otoprotective effects through antioxidative, anti-apoptotic, and anti-inflammatory mechanisms, contributes to maintain mechanosensory function and swimming behavior. The findings support COL stem as a promising candidate for otoprotection and validate zebrafish-based high-throughput screening for novel therapeutic discovery. Full article

Background: Hysteroscopic endometrial fundal incision (HEFI) is a novel addition to the standard IVF procedure. This study aimed to evaluate whether different depths of incision during HEFI could affect reproductive outcomes in oocyte recipients. Methods: A prospective analysis was conducted on women who underwent HEFI 1–2 months prior to embryo transfer with donor oocytes. Patients were categorized into three groups based on the depth of incision: U2a (superficial level) U2aa (intermediate level), and U2aaa (deep level). Pregnancy and live birth rates were assessed. Results: A total of 212 women without intrauterine pathology were included. Positive pregnancy rates were 78% in U2a, 76.9% in U2aa, and 77.1% in U2aaa (p = 0.95). Live birth rates were 58.5%, 57.1%, and 56.4%, respectively (p = 0.97). Early and late miscarriage rates and biochemical pregnancies showed no significant differences between the groups. Conclusions: Based on the results obtained, we could speculate that the depth of infiltration during HEFI does not significantly influence reproductive outcomes in oocyte recipients without intrauterine pathology. However, these findings should be interpreted with caution, given the limitations of the study, including its non-randomized design and differences among groups, such as variations in the number of embryos transferred and intraoperative group allocation. Therefore, further randomized clinical trials should be performed to more comprehensively understand the impact of incision depth on reproductive outcomes. Full article

Background: Deep infiltrating endometriosis (DIE), particularly when involving the bowel, significantly impairs health-related quality of life (HRQoL) and gastrointestinal function. This study aimed to evaluate the short- and mid-term impact of minimally invasive excision on these parameters in a large multicenter cohort. Methods: A retrospective observational study was conducted on 837 patients treated for endometriosis in two tertiary referral centers between 2018 and 2024. All patients underwent laparoscopic or robotic-assisted excision. Quality of life was assessed preoperatively and at 6 months (VAS: n = 69; SF-36: n = 100; GIQLI: n = 98) and 12 months (VAS: n = 30; SF-36: n = 46; GIQLI: n = 44) postoperatively, using validated patient-reported outcome measures (PROMs): the Visual Analog Scale (VAS) for pain, the Short Form-36 (SF-36) survey, and the Gastrointestinal Quality of Life Index (GIQLI). Results: The study population presented with predominantly advanced disease (Stage III–IV in 83.4% of cases), with 39.7% of patients undergoing segmental bowel resection. Postoperatively, a statistically significant reduction was observed in dysmenorrhea (VAS 7.6 vs. 5.0, p < 0.001) and chronic pelvic pain. The SF-36 scores improved significantly across all eight domains at 6 months, with the most dramatic recovery seen in Role Physical (p < 0.001) and Bodily Pain (p < 0.001). Regarding digestive function, the mean GIQLI score showed a progressive increase, reaching statistical significance at 12 months compared to baseline (112.6 vs. 106.6, p = 0.027), indicating superior long-term functional outcomes. Conclusions: Multidisciplinary minimally invasive surgery for deep infiltrating endometriosis was associated with significant and sustained improvements in quality of life among patients with available follow-up. Gastrointestinal quality of life, as measured by GIQLI, improved significantly at 12 months postoperatively, including in patients who underwent segmental bowel resection. Systematic use of PROMs is essential for accurate patient counseling and outcome monitoring. Full article

This study proposes a novel simulation-driven intelligent framework for the performance and reliability assessment of renewable energy-integrated pavement systems by unifying coupled multiphysics finite element modeling, structured dataset generation, and graph-based artificial intelligence within a single computational paradigm. The proposed pavement is formulated as a seven-layer multifunctional infrastructure system comprising the asphalt surface, intermediate binder, base layer, thermoelectric energy layer, piezoelectric insert zone, subbase, and subgrade soil, thereby enabling simultaneous consideration of structural load transfer, thermal gradient-driven energy harvesting, moisture-sensitive support behavior, and reliability-oriented performance interpretation. A three-dimensional thermo-hydro-mechanical Abaqus model was developed to simulate the concurrent effects of moving wheel load, solar heat flux, rainfall infiltration, and internal moisture diffusion, and it was subsequently used to construct an AI-ready dataset containing 6000 simulation cases and 68 variables spanning geometric, material, environmental, traffic, uncertainty, structural, thermal, hydraulic, renewable-energy, and probabilistic reliability descriptors. To preserve the physical hierarchy of the layered pavement within the learning process, a Layer-Coupled Reliability Graph Operator Network (LaRGO-Net) was proposed, in which pavement layers are represented as interacting graph nodes linked through adaptive interlayer coupling and optimized through multi-task, physics-aware, and coupling-consistent learning. Experimental evaluation across nine progressive configurations demonstrated a monotonic improvement from baseline dense and graph-convolution models to the full LaRGO-Net formulation. The final model achieved the best overall performance with mean RMSE = 0.040, mean MAE = 0.028, mean $R^2=0.994$, and reliability prediction accuracy characterized by F1 = 99.21 and AUC = 99.53. These results confirm that the proposed framework provides a highly accurate, physically interpretable, and reliability-aware surrogate for next-generation pavement systems capable of simultaneously supporting structural serviceability, renewable-energy functionality, and intelligent decision-making. Full article

Background/Objectives: Endodontic perforation repair requires biomaterials that balance sealing ability with minimal cellular injury. AH Plus (epoxy resin-based) remains widely used despite cytotoxicity concerns. CeraSeal (calcium silicate-based bioceramic) is a potentially more biocompatible alternative. However, comparative data on sealer-induced cytotoxicity and inflammatory responses remain limited. This study compared the cytotoxicity and inflammatory profiles of CeraSeal and AH Plus using in vitro and in vivo approaches. Methods: Human periodontal ligament stem cells (hPDLSCs) were exposed to sealer extracts (1:4 AH Plus, 1:8 CeraSeal) for 120 h. Cell death was assessed by MTT, Live/Dead, LDH release, and Annexin V/PI flow cytometry. Oxidative stress was quantified via ROS generation (DCFH-DA). In a rat furcation perforation model (n = 8 teeth/group), inflammatory markers (TNF-α, IL-1β, CD68), osteogenic activity (ALP), and osteoclasts (TRAP) were evaluated. Results: AH Plus was associated with significantly greater necrotic cell death (357.6 ± 47.6% LDH release vs. CeraSeal 128.8 ± 37.5%; p = 0.0079) and reduced hPDLSC viability at all time points (p < 0.0001). ROS generation was comparable between sealers (~32–35%, p > 0.05). In vivo, IL-1β was higher in AH Plus-treated tissues (52.25 vs. 24.88 cells/mm²; p = 0.0002), while TNF-α and CD68 were greater in CeraSeal (p ≤ 0.0011). ALP was higher in AH Plus (median 6.15 vs. 3.68; p = 0.0002), with no difference in TRAP-positive osteoclasts. Morphometric analysis showed superior cellular preservation with CeraSeal (p = 0.0079), while inflammatory infiltration was higher in CeraSeal (p = 0.0002). Conclusions: AH Plus was associated with a necrotic-inflammatory profile with elevated IL-1β and higher ALP expression. CeraSeal demonstrated better cellular preservation, lower LDH release, and a distinct inflammatory signature (higher TNF-α and CD68). These findings establish comparative response profiles for the two sealers and support CeraSeal as a potentially biocompatible alternative, though further mechanistic studies are warranted. Full article

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), includes clinically relevant intestinal inflammation; however, the mechanisms associated with tissue injury remain incompletely understood. ArtinM is an immunomodulatory lectin with known effects on innate and adaptive immunity, although its intestinal role during acute T. cruzi infection remains unclear. This study investigated whether ArtinM modulates the intestinal inflammatory response during acute experimental T. cruzi infection. In vivo, BALB/c mice were allocated to Saline control, T. cruzi + Saline, and T. cruzi + ArtinM groups. Intestinal inflammatory infiltrate and tissue concentrations of TNF-α, IFN-γ, IL-12p40, and IL-10 were quantified. Acute infection markedly increased TNF-α, IFN-γ, IL-12p40, and inflammatory infiltrate, whereas ArtinM significantly attenuated these responses. TNF-α, IFN-γ, and IL-12p40 remained associated with group after adjustment for infiltrate, whereas IL-10 reached statistical significance only in the adjusted model and was therefore interpreted cautiously. In parallel, an exploratory analysis of a public murine intestinal scRNA-seq dataset (GSE319934; GSM9529706 and GSM9529707), derived from a chronic infection setting, was performed to provide pathway-level context for inflammatory mediators assessed in vivo. This transcriptomic analysis indicated that related inflammatory, innate immune, chemotactic, and adhesion-associated genes were detectable in intestinal single-cell data from T. cruzi infection. However, because this dataset was not temporally matched to the acute model, it was not interpreted as a phase-matched comparator, mechanistic validation, or temporal extension of the experimental findings. Together, the results support that ArtinM treatment is associated with attenuation of acute intestinal inflammatory outcomes in experimental T. cruzi infection. Because local intestinal parasite burden was not measured, these findings should be interpreted as evidence of inflammatory modulation rather than as direct evidence of local antiparasitic activity. The public scRNA-seq analysis provides only exploratory contextual information for related inflammatory pathways. Full article

Background/Objectives: Despite the substantial clinical and socioeconomic burden of chronic low back pain (CLBP), objective diagnostic biomarkers remain limited. Structural alterations of the lumbosacral muscles, particularly muscle atrophy and fatty infiltration (FI), have been proposed as imaging correlates of chronic pain. This scoping review aimed to synthesize current evidence on these alterations in CLBP and characterize the imaging and segmentation methods used. Methods: The review was conducted in accordance with PRISMA-ScR guidelines and guided by the Population–Concept–Context framework. Population: adults with CLBP. Concept: MRI segmentation techniques are used to evaluate morphological soft-tissue changes. Context: clinical and research settings using MRI for CLBP evaluation. A comprehensive search of PubMed, Scopus, Embase, and Web of Science was performed for studies published between January 2014 and October 2024. Results: Twelve observational studies met the inclusion criteria. Degenerative alterations were consistently observed in CLBP and were not reported in control groups. Muscle atrophy was reported in ten studies (multifidus [MF]: 9; erector spinae [ES]: 7; psoas major [PM]: 2; paraspinal muscles [PPM]: 1; and increased FI in all studies (MF: 9; ES: 5; PM: 2; PPM: 2). Considerable heterogeneity between studies was noted. Conclusions: Lumbosacral muscles assessment may provide useful objective information for a more objective characterization of CLBP. Degenerative alterations were reported in all examined muscles except QL, with the MF most consistently affected. Changes in ES and PM may be specific for CLBP. The frequent co-occurrence of muscle atrophy and FI suggests that their combined evaluation may provide complementary information. Full article