Cardiotoxicity remains a major limitation of current anticancer therapies, highlighting the need for agents that combine antitumor efficacy with intrinsic cardiac safety. Phenotypic screening of a pyrimidine-based compound library identified compound 9v as a potent anti-prostate cancer candidate with dual biological functions. Compound 9v inhibited PC-3 cell proliferation with an IC₅₀ of 3.96 ± 0.18 μM, outperforming 5-fluorouracil, and markedly suppressed colony formation and migration while inducing apoptosis. Mechanistic studies showed that 9v activated the mitochondrial apoptotic pathway by increasing Bax, cleaved caspase-9, and cleaved caspase-3 levels while reducing Bcl-2 expression. Remarkably, 9v exerted bidirectional regulation of ROS homeostasis, promoting ROS accumulation in PC-3 cells but suppressing oxidative stress in H9C2 cardiomyocytes under H₂O₂ challenge. In addition, 9v exhibited weak cytotoxicity toward normal prostate stromal cells, no obvious acute toxicity in mice, and no detectable cardiotoxicity in vitro. Moreover, it exhibited protective effects against oxidative injury in cardiomyocytes, as demonstrated by increased cell viability and decreased LDH and cTnT release. Taken together, these results identify 9v as a promising lead compound with both anti-prostate cancer activity and cardioprotective potential in an in vitro oxidative stress model, providing a basis for the development of multifunctional anticancer agents with improved cardiovascular safety.

Nine previously undescribed prenylated xanthones, aspxanthones A-I (1-9), were isolated and characterized from the endophytic fungus Aspergillus sp. TJ507. Their structures were established through comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and DP4+ probability analysis. Compounds 1, 2, and 4 exhibited modest in vitro SIRT1 activating effects, with EC50 values ranging from 9.3 to 13.7 μM. The positive control resveratrol yielded an EC50 of 2.4 ± 0.4 μM under identical assay conditions. Molecular docking was conducted with resveratrol as a reference ligand, which revealed obvious differences in binding modes between resveratrol and the tested xanthones. To further clarify their dynamic binding behaviors, molecular dynamics simulations, free-energy landscape analysis, and MM/GBSA calculations were carried out on these active compounds. Among them, compound 4 displayed the most stable simulated binding profile and the most favorable estimated binding free energy among the three complexes, broadly consistent with the experimental activity ranking. In contrast, compound 2 exhibited higher conformational flexibility throughout the simulation, indicating a distinct binding mode. This study expands the chemical diversity of fungal-derived xanthones and provides valuable templates for the design and development of potential SIRT1 activators.

Colorectal cancer (CRC) remains poorly responsive to immune checkpoint blockade in a substantial proportion of patients, highlighting the need to identify druggable mechanisms that regulate tumor immune evasion. CD155, a ligand of the inhibitory receptor TIGIT, is highly expressed in CRC and contributes to impaired natural killer (NK) cell-mediated antitumor immunity. Lysine-specific demethylase 1 (LSD1/KDM1A) is a pharmacologically targetable epigenetic enzyme with emerging roles in tumor immunogenicity, but whether LSD1 inhibition modulates the CD155/TIGIT immune checkpoint axis in CRC remains unclear. In this study, we found that LSD1 and CD155 were highly expressed in CRC tissues and showed a significant positive correlation. Genetic depletion of LSD1 reduced CD155 expression at both the mRNA and protein levels in CRC cells. Importantly, pharmacological inhibition of LSD1 with two small-molecule inhibitors, CC-90011 and ORY-1001, markedly decreased CD155 expression and membrane abundance in multiple CRC cell lines. Mechanistically, LSD1 depletion or inhibition increased H3K4me2 enrichment at the CD155 promoter, suggesting that LSD1 activity is required for maintaining CD155 transcription in CRC cells. Functionally, LSD1 inhibition decreased CD155 expression and cell-surface abundance, resulting in reduced CD155/TIGIT interaction and enhanced NK cell-mediated cytotoxicity, accompanied by increased secretion of IFN-γ and TNF-α. In a CT26 syngeneic tumor model, LSD1 knockdown suppressed tumor growth and decreased CD155 expression in vivo. Collectively, these findings reveal that pharmacological inhibition of LSD1 attenuates CRC immune escape, at least in part, by epigenetically suppressing the CD155/TIGIT axis. This study provides a rationale for exploiting LSD1 inhibitors as immunomodulatory agents to enhance antitumor immunity in CRC.

The objective of this study was to verify the non-inferiority of ultra-low-dose computed tomography (ULD-CT) versus standard-dose CT (SD-CT) for esophageal foreign body (EFB) detection and to quantify dose-quality trade-offs. This prospective, randomized, blinded-reader study enrolled 180 patients (120 adults, 60 children) presenting with suspected EFB ingestion. Patients were randomized to ULD-CT (100 kV/50 mA, adaptive statistical iterative reconstruction-V 80% + deep learning image reconstruction) or SD-CT (120 kV/200 mA, filtered back projection + adaptive statistical iterative reconstruction-V 30%) groups. All patients underwent endoscopic or surgical reference-standard evaluation within 12 h of CT imaging, with 30-day follow-up for negative findings. The primary endpoint was the area under the curve (AUC); secondary endpoints included image quality metrics, radiation dose, and incidental findings. Both protocols achieved excellent diagnostic performance, with sensitivity/specificity of 97.8%/100% for ULD-CT and 98.9%/100% for SD-CT. The AUC was 0.985 for ULD-CT versus 0.991 for SD-CT (difference < non-inferiority margin). The effective dose was reduced by 63% with ULD-CT (P < 0.001). The signal-to-noise ratio decreased by 37% (P < 0.001), yet diagnostic acceptability (score ≥3) was maintained at 94.4% versus 97.8% (P = 0.070). Incidental findings were identified in 54 patients (30.0%), including 19 potentially actionable findings (10.6%) and 6 high-significance findings requiring urgent evaluation. Ultra-low-dose CT demonstrates non-inferior diagnostic accuracy compared with SD-CT for EFB detection while reducing radiation exposure by over 60%. These findings show potential for ULD-CT as a first-line modality for suspected EFBs pending multicenter validation.

Upper gastrointestinal symptoms, including dyspepsia, gastro-oesophageal reflux disease (GERD), and alarm symptoms, frequently prompt referral for upper gastrointestinal endoscopy (UGIE). However, inappropriate endoscopic prescriptions contribute to increased healthcare costs, prolonged waiting lists, and environmental burden. We aimed to evaluate the diagnostic yield of UGIE according to the age threshold and presenting symptoms in routine clinical practice. In this nationwide, multicentre, cross-sectional study, consecutive adult patients undergoing their first UGIE for upper gastrointestinal symptoms were enrolled across 18 Italian centres. During pre-endoscopy patients' interview, the main symptom was captured and accordingly used to categorize symptomatology as dyspepsia, reflux symptoms, or alarm symptoms. Endoscopic and histological findings, including Helicobacter pylori infection status, were prospectively collected. The association between clinical variables and endoscopic lesions was assessed using univariate and multivariate analyses. Overall, 762 patients were included (mean age 55.5 ± 15.4 years; 42.1% males). Dyspepsia was the indication for UGIE in 42.4% of cases, reflux symptoms in 35.4%, and alarm symptoms in 22.2%. At least one endoscopic lesion was detected in 33.5% of patients, with erosive oesophagitis being the most frequent finding (16.5%). Histologically confirmed neoplastic lesions were identified in 1% of cases. Patients aged ≥ 50 years showed a significantly higher prevalence of mucosal lesions compared with younger individuals (51% vs 29%; OR 2.54, 95% CI 1.84-3.53). At multivariate analysis, Helicobacter pylori infection and smoking habit were independently associated with all endoscopic lesions, whilst male sex and reflux symptoms with oesophageal lesions, and alarm symptoms with gastric and duodenal lesions. The diagnostic yield of UGIE is significantly higher in patients aged ≥ 50 years and in those presenting with alarm symptoms or additional risk factors. Conversely, younger patients with uncomplicated dyspepsia showed a low prevalence of clinically relevant lesions. Integrating age threshold, symptom profile, and selected risk factors into referral strategies may improve the appropriateness of UGIE prescriptions and support more sustainable use of endoscopic resources.

Fluorouracil plus cisplatin has historically served as the dominant platinum-fluoropyrimidine backbone for esophageal squamous cell carcinoma (ESCC). In the immunotherapy era, the key practical question is not whether oxaliplatin can universally replace cisplatin, but whether FOLFOX can provide a rational, patient-centered cisplatin-sparing backbone for selected patients receiving first-line chemoimmunotherapy. CheckMate 648 established nivolumab plus chemotherapy using fluorouracil plus cisplatin, whereas RATIONALE-306 demonstrated that oxaliplatin-containing backbones can be incorporated into successful global phase III immunochemotherapy. Recent Japanese retrospective data in cisplatin-unfit patients showed clinically meaningful activity of nivolumab plus FOLFOX, with reduced renal and hydration burden, outpatient feasibility, and treatment continuity representing potential practical advantages. Oxaliplatin-induced immunogenic cell death provides an additional mechanistic rationale, although this remains predominantly preclinical. Prospective evaluation is underway in Japan through the FLONTALE and OXA-REPLACE phase II trials. This review summarizes the clinical and biological rationale, current evidence, limitations, and future positioning of nivolumab plus FOLFOX. At present, it should be regarded as an emerging selective strategy rather than an established alternative to cisplatin-based chemoimmunotherapy.

Esophageal squamous cell carcinoma is the most common histological subtype of esophageal cancer, and novel therapeutic strategies, including immunotherapy, are increasingly needed to improve outcomes in advanced-stage disease. Identifying patients who may benefit from immunotherapy through individualized risk stratification and reliable prognostic biomarkers is therefore essential. This study aims to evaluate the association between tumor-infiltrating lymphocyte (TIL) subtypes (CD4+, CD8+, FOXP3+) and their ratios, with clinicopathological features, and tumor budding.The study included 75 patients diagnosed with esophageal squamous cell carcinoma who underwent esophagectomy without receiving preoperative neoadjuvant therapy. Sections best representing the tumor area and TILs were selected, and immunohistochemical staining for CD4, CD8, and FOXP3 was performed. Positive lymphocytes were counted in 10 high-power fields at the invasive front. TIL densities were categorized as low or high based on mean counts. Tumor budding was assessed and classified as low, intermediate, or high grade.According to our results, low CD4+ TIL levels were significantly associated with poor histological grade, deeper tumor invasion, advanced pathological stage, and low tumor budding. High FOXP3+ TIL expression was associated with invasion depth and lymph node metastasis, whereas superficial tumors showed no high FOXP3 expression. A low FOXP3+/CD4+ ratio was correlated with longer survival. CD8+ TIL density alone showed no significant prognostic impact.In conclusion, combined assessment of TIL subtypes and tumor budding may contribute to improved prognostic stratification and postoperative treatment planning in esophageal squamous cell carcinoma.

ObjectiveGastroesophageal reflux disease comprises heterogeneous phenotypes, and symptom severity does not always correlate with endoscopic findings. This retrospective observational study aimed to characterize serum proteomic alterations in gastroesophageal reflux disease and to explore whether nonerosive reflux disease and reflux esophagitis exhibit distinct circulating protein signatures.MethodsSeventy individuals were included, comprising 26 controls, 14 patients with nonerosive reflux disease, and 30 with reflux esophagitis. For exploratory group-level proteomic discovery, pooled serum samples from each group were analyzed using liquid chromatography-tandem mass spectrometry. Clinical characteristics, upper gastrointestinal endoscopy, high-resolution manometry, and 24-h pH-impedance monitoring were assessed as appropriate. Differentially expressed proteins were identified using a fold change threshold of 1.3 together with nominal statistical significance, followed by functional annotation and enrichment analyses.ResultsAge and sex were comparable among the groups. Nonerosive reflux disease and reflux esophagitis showed no significant differences in gastroesophageal reflux disease questionnaire score, disease duration, body mass index, or most reflux-monitoring parameters. However, patients with reflux esophagitis had more gas reflux episodes, lower distal contractile integral values, and a higher frequency of esophageal motility disorders, suggesting impaired motor function. Proteomic profiling identified 872 proteins, including 666 quantified proteins. Differential expression analysis identified 48 proteins in nonerosive reflux disease versus controls, 43 in reflux esophagitis versus controls, and 7 in nonerosive reflux disease versus reflux esophagitis. The exploratory nonerosive reflux disease-associated protein profile was mainly characterized by cytoskeletal remodeling, adhesion-related regulation, redox adaptation, and selective immune rearrangement, whereas the exploratory reflux esophagitis-associated profile showed features related to actin remodeling, injury-defense responses, and alterations in lipid homeostasis.ConclusionsNonerosive reflux disease and reflux esophagitis exhibited distinct but partially overlapping serum proteomic profiles in this exploratory pooled serum analysis. These preliminary findings suggest phenotype-related biological differences beyond reflux burden alone; however, they should be interpreted as hypothesis-generating and require validation in independent, individual-level cohorts.