Ningbo First Hospital

Allergic rhinitis (AR) is a prevalent chronic inflammatory disorder of the upper airways, driven by Th2-mediated immune dysregulation and compromised epithelial barrier function. Current therapies, such as intranasal corticosteroids, often exhibit limited efficacy and adverse effects upon prolonged use. Herein, we developed a novel dual-action nasal spray, termed Mefp, by combining mussel adhesive protein (MAP) and xylitol to simultaneously target epithelial barrier repair and inflammatory pathways. The Mefp formulation exhibited strong mucoadhesive properties, with nasal retention lasting up to 24h, facilitated by catechol-mediated adhesion of 3,4-dihydroxyphenylalanine (DOPA) residues in MAP. In vitro experiments using LPS-stimulated human nasal epithelial cells (HNEpCs) demonstrated that Mefp significantly restored tight junction proteins (ZO-1 and occludin), suppressed NF-κB activation, reduced oxidative stress, and attenuated the release of pro-inflammatory (TNF-α, IL-6) and Th2 cytokines (IL-4, IL-5, IL-13). In an ovalbumin-induced murine AR model, Mefp treatment markedly alleviated allergic symptoms, reduced eosinophil infiltration, decreased OVA-specific IgE levels, and enhanced antioxidant enzyme activities. Histological and immunofluorescence analyses confirmed the restoration of mucosal integrity and tight junction assembly. Notably, Mefp demonstrated comparable or superior efficacy to mometasone furoate (MF) in alleviating allergic symptoms and suppressing key inflammatory mediators, while showing a better safety profile regarding epithelial integrity in vitro. These findings indicate that Mefp effectively addresses both epithelial barrier dysfunction and type 2 inflammation, offering a promising and safe therapeutic strategy for AR.

The concurrent use of serotonergic antidepressants (SSRIs, SNRIs) and opioid analgesics is frequent in the perioperative setting. While this combination carries a known risk of serotonin syndrome, large-scale epidemiological evidence remains scarce. We performed a multinational pharmacovigilance study using data from the US FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) from Q1 2004 to Q2 2025. Disproportionality analyses, including Reporting Odds Ratio (ROR) with a multi-algorithm framework, were employed to quantify signals for serotonin syndrome and other adverse events. We further characterized clinical profiles and conducted gender-stratified and time-to-onset analyses. Opioids (e.g., tramadol, fentanyl, oxycodone) were consistently among the top drugs associated with serotonin syndrome reports. Concomitant SSRI/SNRI-opioid use showed exceptionally strong signals for serotonin syndrome (SSRI-opioid ROR 95.94, 95% CI 88.9-103.53; SNRI-opioid ROR 57.68, 95% CI 52.32-63.59). SSRI-opioid combinations were uniquely associated with cardiac disorders (ROR 1.87, 95% CI 1.77-1.98), whereas SNRI-opioid use was linked to drug withdrawal syndrome. Gender-stratified analysis indicated a higher reporting proportion for serotonin syndrome in males prescribed SSRI-opioids. Notably, up to 30% of adverse events occurred more than 300 days after therapy initiation, indicating a persistent risk. This study provides robust multinational evidence that concomitant serotonergic antidepressant and opioid use is strongly associated with a high risk of serotonin syndrome and distinct adverse event profiles. These findings highlight the urgent need for systematic preoperative medication review, tailored perioperative monitoring, and sustained clinical vigilance.

Background: The value of radical prostatectomy (RP) in large volume and unresectable locally advanced prostate cancer (LAPC) or oligometastatic prostate cancer (OMPC) is largely unknown. This retrospective study aims to evaluate the conversion efficacy and safety profile of preoperative androgen deprivation therapy combined with docetaxel (A + D) in patients with large-volume (≥60 mL) and initially unresectable LAPC or OMPC. Methods: Patients with LAPC or OMPC from three large tertiary medical centers (between April 2017 and October 2024) were included. Eligibility criteria included prostate volume ≥60 mL, unresectability, and an expected survival of more than 5 years, as confirmed by two senior urologists and one radiologist. All patients received preoperative A + D therapy (≥3 cycles), followed by reassessment for RP feasibility with multimodal therapy discussion. The primary endpoint was surgical conversion rate. Secondary endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), overall survival (OS), PSA response rate, adverse events, pathological response, perioperative complications, urinary continence, and sexual function. Results: Among 31 enrolled patients, the mean age was 67.71 ± 6.69 years, and 29 (93.55%) successfully underwent RP. The mean follow-up duration was 42.83 ± 23.58 months (up to October 2024). Median PSA-PFS was 49 months (95% CI: 24.20–73.79 months), and median OS was not reached. Hematologic toxicity was the most common adverse event during chemotherapy. After A + D therapy, median prostate tumor volume decreased from 67.50 mL to 25.81 mL, and median PSA declined from 168 to 0.49 ng/mL. After RP, 11 patients (37.93%) experienced a downgrade in Gleason score, and 14 patients (48.28%) experienced a downgrade in T-stage. Positive surgical margins were found in 11 patients (37.93%). Perioperative complications included blood transfusion (11.11%), rectal injury (3.70%), lymphorrhea (7.41%), and fever >38.5°C (3.70%). The 1-year urinary continence rate was 89.66%, while 100% of patients experienced sexual dysfunction. Conclusion: Preliminary data suggest that preoperative A + D therapy followed by RP may be integrated into multimodal management for large-volume, initially unresectable LAPC and OMPC, demonstrating promising conversion efficacy and clinical outcomes.

NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications on RNA to regulate mRNA stability. However, its roles in normal hematopoiesis and leukemogenesis remain poorly understood. Here, we show that NSUN2 is markedly upregulated in primary AML patient samples compared with normal hematopoietic cells. NSUN2 knockdown (KD) impaired AML cell proliferation, induced apoptosis, and reduced colony formation. Genetic ablation of Nsun2 in an MLL-AF9 (MA9)-transformed murine AML model substantially impaired leukemia stem cell (LSC) self-renewal and prolonged overall survival (OS), while sparing normal hematopoiesis, highlighting NSUN2 as a potential therapeutic target. Notably, wild-type NSUN2, but not catalytically inactive mutants, restored LSC function and leukemogenesis in NSUN2-deficient AML cells, indicating that these effects are m􀀀C-dependent. Mechanistically, NSUN2 stabilized FosB proto-oncogene (FOSB) mRNA via m􀀀C modification at nucleotide 3656 in the 3′-UTR, thereby upregulating FOSB expression. In turn, FOSB transcriptionally activated NSUN2, forming a feedforward regulatory loop. Furthermore, FOSB promoted expression of the anti-apoptotic regulator B-cell lymphoma-2-like protein 1 (BCL2L1) by directly binding to its promoter. In conclusion, these findings uncover a novel NSUN2-FOSB-BCL2L1 axis that drives AML leukemogenesis in an m5C-dependent manner, suggesting the therapeutic potential for targeting this pathway.

Sphingolipids, particularly ceramide (Cer) and sphingomyelin (SM), are critical for cellular homeostasis, serving as both essential membrane components and key signaling molecules. This review systematically classifies sphingolipid disorders by organ system, emphasizing chain-length-dependent effects such as the pro-inflammatory role of C16-Cer versus the protective functions of C24-Cer in disease. The review details sphingolipid involvement across seven major organ systems. In cardiovascular disease, SM(d18:1/16:1) contributes to atherosclerotic plaque instability, while Cer promotes NLRP3 inflammasome activation. In neurodegenerative diseases, an altered Cer/SM ratio disrupts lipid raft integrity and accelerates pathogenic protein aggregation. In oncology, cancer progression is facilitated through mechanisms like nSMase-mediated exosome release and CerS6-dependent metastasis. Translational applications are emerging, including Cer-based biomarkers with high diagnostic accuracy for early stroke and investigational aSMase inhibitors for atherosclerosis. Modulating sphingolipid metabolism presents a promising therapeutic strategy for precision medicine. However, challenges remain in deciphering tissue-specific regulatory networks and standardizing lipidomic methodologies.

Bladder cancer is one of the most prevalent malignancies of the urinary system and is associated with high morbidity and mortality. With advances in medical image analysis, deep learning has shown promise for automated bladder cancer classification using magnetic resonance imaging (MRI). However, clinical deployment remains challenging due to substantial inter-center distributional discrepancies and limited feature discriminability between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). To address these challenges, we propose a Domain-Adaptive Deep Contrastive Network (DADCNet) for MRI-based bladder cancer classification. The proposed framework jointly incorporates source- and target-domain samples during feature learning to obtain domain-invariant yet discriminative representations, thereby improving cross-center generalization. In addition, a deep contrastive learning strategy is introduced to enhance inter-class separability and intra-class compactness, leading to more robust classification. Experiments conducted on a multi-center bladder cancer MRI dataset demonstrate that DADCNet consistently outperforms existing convolutional neural network- and Transformer-based methods, achieving an accuracy of 0.955, an F1-score of 0.955, and an area under the curve of 0.991.

Alveolar epithelial cell pyroptosis exacerbates inflammation and tissue damage by releasing inflammatory mediators, thereby promoting the development of acute lung injury (ALI). However, the fundamental mechanism underlying alveolar epithelial cell pyroptosis in ALI has not yet been elucidated. Lipopolysaccharide (LPS) was used to simulate ALI invitro and invivo. Cell viability was measured using the MTT assay. The expression of these molecules was determined by Western blot, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence, and immunohistochemical assays. The level of pyroptosis was determined using flow cytometry. The interactions between the molecules were validated using co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays. Homeobox A5 (HOXA5) was expressed at low levels, whereas lysine acetyltransferase 2A (KAT2A) and NIMA-related kinase 7 (NEK7) were highly expressed in LPS-induced (type II alveolar epithelial) ATII cells and mice. HOXA5 overexpression suppressed pyroptosis in LPS-induced ATII cells and mice. Notably, KAT2A overexpression abolished the effects induced by HOXA5 overexpression in LPS-induced ATII cells. Mechanistically, HOXA5 inhibits KAT2A transcriptional activity by binding to the KAT2A promoter. KAT2A positively regulates NEK7 by promoting H3K9ac/H3K27ac enrichment in the NEK7 promoter. In conclusion, HOXA5 indirectly inhibits NEK7 expression by inhibiting KAT2A transcriptional activity, thereby suppressing pyroptosis in alveolar epithelial cells in ALI.