Antimicrobial resistance (AMR) seriously threatens the health of humans and animals. Antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) were enriched in the goose farms. However, the influence of goose farming exposure on the gut microbiota and ARGs of workers was unclear. In this study, metagenomic analysis was used to characterize gut microbiome structures, annotate bacterial taxa, and quantify the abundances of ARGs and MGEs in geese and human samples. Results showed that goose feces harbored more abundant ARGs and ARB than human feces. Significantly higher abundances of special ARGs (such as vanY, lsaE, AAC3-IId and ampC) were identified in workers compared to villagers. Compositions of gut bacteria were significantly different between workers and villagers, and some certain gut pathogens were abundant in the feces of workers, including Bacillus anthracis, Clostridium perfringens, and Escherichia coli O45:K1:H7. A total of 51 ARGs were pinpointed in the metagenome-assembled genomes (MAGs). Based on ARG-MGE associations and co-occurrence signals in MAGs, the potential for horizontal gene transfer (HGT) was inferred. With this transfer capacity and ubiquitous gut colonization, E. coli carrying 38 ARGs is proposed as a putative AMR indicator for the goose farm. This study demonstrates that goose farming had non-ignorable influences on the gut microbiome and antibiotic resistome of workers. More efforts should be made to control the ARGs and ARB in the goose farm.

Pet dogs provide well-documented physical and mental health benefits to humans through close interactions. However, the potential role of pet dogs as reservoirs of antibiotic resistance genes (ARGs) and the impact on shaping the gut microbiomes of their owners remains poorly characterized. The growing dual challenges of global antimicrobial resistance and widespread pet ownership underscore the importance of understanding human-animal resistome interactions crucial for One Health solutions. Consequently, this study conducted a metagenomic analysis of pet dogs, dog owners, and non-dog owners to investigate the effects of dogs on the microbiota composition, ARGs profiles, and mobile genetic elements (MGEs) of the human gut. The results indicated that pet dogs exhibited significantly higher gut abundance of both ARGs and ESKAPE pathogens (Enterococcus faecium and Acinetobacter baumannii) compared to humans. Moreover, the abundance of aminoglycoside resistance genes aac(6’)-Im and aac(6’)-Ie-aph(2’’)-Ia, tetracycline resistance genes tetO and tet40 were was significantly higher in dog owners than in non-dog owners. Enterobacteriaceae were identified as shared core ARG hosts in both dog and human guts. Collectively, our results indicate that cohabitation with pet dogs is associated with a shared gut resistome, reflecting correlated patterns of ARGs and resistant microbes. These findings emphasize the necessity of monitoring antibiotic resistance in companion animals, while maintaining the benefits of human-dog relationships.

Severe hand, foot, and mouth disease (HFMD) poses a risk of serious multi-organ complications in children. While renal dysfunction has been observed in some cases, detailed investigations on kidney injury and molecular mechanisms remain limited. Coxsackievirus A6 (CVA6) has emerged as a major pathogen responsible for HFMD. To reveal the underlying pathways of CVA6-associated renal injury, we enrolled 90 children diagnosed with CVA6 infection and 45 healthy children. The levels of uric acid (UA), creatinine (CREA) and UREA in the serum were measured. We found that serum levels of UA, CREA, and UREA were significantly elevated in CVA6-infected children compared to healthy children. Subsequently, a previously established mouse model of CVA6 infection was used to assess urinary retention, kidney inflammation, and histopathological changes. Consistent with the clinical findings, infected mice exhibited increased CREA, UREA, and UA levels, urinary retention, and renal inflammation. Electron microscopy revealed glomerular atrophy and basement membrane thickening in CVA6-infected mice, accompanied by reduced expression of VEGF, Occludin, and VE-cadherin. Furthermore, complement deposition was also observed in glomeruli and renal tubules. Finally, CVA6 infection significantly increased phospho-p38 levels in mouse kidneys. To investigate the role of the p38-MAPK signaling pathway in CVA6-induced renal injury, we treated the CVA6-infected mice with PD169316, a specific inhibitor of p38/MAPK signaling pathway, and observed that the kidney injury in the treated group was alleviated. Overall, our findings highlight a critical role for the p38 phosphorylation in CVA6-induced renal injury, and provide new insights into the management of severe HFMD-associated kidney complications.

OBJECTIVE:To perform genomic analysis on plasmid-mediated quinolone-resistance (PMQR) in Shigella. METHODS:We assembled a global collection of 8325 PMQR-positive Shigella isolates (1998-2025) and subjected them to comprehensive genomic analysis. RESULTS:Geographically, the isolates spanned 37 countries, with the majority sourced from the United States (47.02%) and the United Kingdom (32.28%). Eight distinct PMQR genes-aac(6')-Ib-cr, oqxAB, qepA, qnrA, qnrB, qnrD, qnrS, and qnrVC-were identified in the Shigella analysed. qnrS was the most predominant PMQR gene (62.05%), followed by qnrB (38.76%). One hundred and eight sequence types were identified among the PMQR-positive Shigella isolates, with ST152 predominating (59.51%). Notably, multiple antibiotic resistance genes (ARGs) were universal in PMQR-positive Shigella, with aph(6)-Id (5825 out of 8325), tet(B) (2398 out of 8325), and blaTEM-1 (2232 out of 8325) the most prevalent. PMQR-positive Shigella from developed countries displayed a significant decreasing trend in the abundance of ARGs and collection year and displayed the opposite trend in the abundance of virulence factors between developed and developing countries (P < .001). Correlation analysis demonstrated that mobile genetic elements constitute principal vectors for the spread of PMQR genes. The abundance of plasmid replicons positively correlated with the abundance of ARGs (P < .001), demonstrating the spread of plasmid-driven ARGs in PMQR-positive Shigella. In addition, high genetic similarity among geographically dispersed PMQR-positive Shigella isolates implies intercountry dissemination. CONCLUSIONS:These findings elucidate PMQR-positive Shigella genomic characteristics and transmission dynamics, necessitating global surveillance reinforcement against this antimicrobial resistance threat.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (M.tb), which poses a notable threat to human health. The present review aims to explore the application of humanized mice in the study of M.tb infections. Due to differences in immune responses between mice and humans, humanized mice with human immune systems have been developed as models to characterize human immune responses to M.tb. The present review searched for research on humanized mice and tuberculosis in Web of Science and PubMed using the keywords 'humanized', 'mice' or 'mouse' and 'tuberculosis', and summarized the findings. Humanized non‑obese diabetic (NOD).Cg‑Rag1tm1MoMIl2rgtm1Wjl and NOD.Cg‑PrkdcscidIl2rgtm1Wjl mice have the potential to accelerate the screening of vaccine candidates, therapeutic regimens and the 'bench to bedside' translation process. New therapies, such as IgG1 P1AM25 in humanized Fcγ receptor mice and phage DS6A in humanized NOD.Cg‑Prkdcscid Il2rgtm1Wjl Tg(cytomegalovirus‑interleukin‑3, granulocyte‑macrophage colony‑stimulating factor and KIT ligand)1Eav/MloySzJ mice, may have potential for treating tuberculosis. The humanized bone marrow‑liver‑thymus and human leukocyte antigens transgenic mouse models are effective tools for studying the co‑infection of M.tb and human immunodeficiency virus (HIV). The present review highlights the key role of humanized mouse models in advancing the understanding of M.tb infection, including host‑pathogen interactions, immune evasion mechanisms, vaccine development, therapeutic interventions and co‑infection with HIV. In conclusion, humanized mice provide a powerful platform for bridging the gap between preclinical research and clinical tuberculosis therapeutics.

BACKGROUND:Enterovirus 71 (EV71) is the main causative agent of severe hand, foot, and mouth disease (HFMD) in children. Dysregulation of microRNAs (miRNAs) has been associated with HFMD progression, but the underlying regulatory mechanisms remain incompletely characterized. METHODS:Rhabdomyosarcoma cells (RD) and human glioblastoma astrocytoma cells (U87-MG) were infected with EV71 at varying multiplicities of infection. In vivo, 5-day-old C57BL/6 mice, with C57 mice treated with STM2457 were intraperitoneally injected with a lethal dose of EV71. Molecular analyses included Western blotting, co-immunoprecipitation, and RNA immunoprecipitation. Clinical blood samples from HFMD patients were used for validation. RESULTS:In this study, we found that EV71 infection increased METTL3 expression and m6A methylation levels in the flanking regions of pri-miR-146a, promoting miR-146a maturation, which in turn suppresses TRAF6 and IRAK1 expression and inhibits IFN-I production, affecting the progression of EV71-induced HFMD. Co-immunoprecipitation and immunofluorescence assays demonstrated interaction between METTL3 and DGCR8, as well as nuclear co-localization of METTL3 with DGCR8. Furthermore, this regulatory mechanism was also confirmed through the intraperitoneal injection of STM2457 (a METTL3 inhibitor) to intervene in EV71 infection. Finally, detection conducted on clinical blood samples of HFMD demonstrated the specificity of IRAK1 in detecting severe HFMD. CONCLUSION:These findings will not only aid in understanding the mechanisms by which EV71 infection impacts the host immune system but also provide a scientific basis for identifying early diagnostic biomarkers and developing new therapeutic strategies.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with stage at diagnosis significantly influencing survival outcomes. This systematic review evaluates global variations in lung cancer stage distribution at diagnosis and examines the associations of socioeconomic factors and screening programs with these disparities. We conducted a systematic review following PRISMA guidelines, searching PubMed, Embase, and grey literature up to August 14, 2024, to identify population- or hospital-based cancer registry data on lung cancer staging. Data from 36 countries were analyzed, focusing on the proportion of distant metastatic cases. We assessed associations with Human Development Index (HDI) and Socio-Demographic Index (SDI) using case-number-weighted linear regression model and evaluated time trends in countries with and without screening programs. Subgroup analyses explored variations by sex, age, and tumor type. Among the 35 countries analyzed in the main study, the median proportion of lung cancer cases diagnosed with distant metastasis was 50.8

To estimate the prevalence of hepatitis vaccine hesitancy among Chinese university students and identify modifiable correlates to guide campus programs. We ran a multicampus cross-sectional survey (December 2023-February 2024) using a two-stage stratified cluster design across eastern, central, and western China. Hesitancy was measured with an 11 item hepatitis-adapted Vaccine Hesitancy Scale (α = 0.83). Multivariable logistic regression examined Health Belief Model constructs and convenience (travel/visit time). Among 2526 respondents, 51.8% met the prespecified hesitancy threshold. Seniors were more hesitant than juniors (aOR = 1.55, 95% CI: 1.25-1.91); students in the central region exceeded those in the east (1.30, 1.07-1.59). Off-campus residence (0.58, 0.41-0.83) and non-medical majors (0.68, 0.54-0.85) had lower odds. Higher perceived risk was also associated with lower hesitancy (0.66, 0.55-0.78). Ordering takeout showed a dose - response (e.g. 3-4/week vs never: 2.52, 1.67-3.82), whereas sharing tableware/drinkware was inversely associated (e.g., 3-4/week vs never: 0.38, 0.23-0.63). Time costs mattered: travel time >30 minutes was linked to higher hesitancy (1.43, 1.06-1.94), and unclear visit duration was also associated (1.40, 1.02-1.93). Hepatitis vaccine hesitancy is common among university students. Two modifiable levers - risk perception and service convenience - support highyield campus strategies.

8586 Background: IBI363 is a first-in-class, PD-1/IL-2 α-bias bispecific antibody fusion protein with great potential for immune-cold and immunotherapy (IO)-resistant tumors. Previously, IBI363 monotherapy demonstrated encouraging and durable efficacy in patients (pts) with IO-treated advanced NSCLC (2025 ASCO #8509). Here, we report a phase 1 study evaluating IBI363 plus platinum-based doublet-chemotherapy (PDC, pemetrexed/paclitaxel plus platinum) in 1L NSCLC. Methods: Previously untreated pts with advanced NSCLC, without sensitizing EGFR, ALK, or ROS1 alterations were enrolled. The safety lead-in evaluated IBI363 at 1.5 or 3 mg/kg Q3W plus PDC. In dose optimization (PD-L1 TPS < 50% required), pts were randomized 1:1:1 to 3 cohorts: 3-1.5 mg/kg (IBI363 3 mg/kg plus PDC in cycle 1, then 1.5 mg/kg Q3W plus PDC in subsequent cycles), 3 mg/kg (IBI363 3 mg/kg Q3W plus PDC) and 1.5 mg/kg (IBI363 1.5 mg/kg Q3W plus PDC). Stratification factors were squamous vs non-squamous, and PD-L1 TPS < 1% vs 1-49%. Primary endpoints were safety and efficacy assessed by investigators per RECIST v1.1. Secondary endpoints included pharmacokinetics (PK) and immunogenicity. Results: As of December 22, 2025, 80 pts were enrolled in safety lead-in (N = 11) and dose optimization (N = 69) with median follow-up (mFU) of 5.8 months (range: 0.9-9.5). Baseline characteristics (median age: 64 years, male: 88.8%, ECOG PS 1: 81.3%, stage IV: 72.5%, sqNSCLC: 66.3%) were balanced among 3-1.5 mg/kg (N = 23), 1.5 mg/kg (N = 28) and 3 mg/kg (N = 29) cohorts. Median treatment duration of IBI363 was 25.0 weeks (range: 4.0-41.1) while 65.0% pts with ongoing treatment, and 88.9% pts having completed ≥4 cycles of PDC. Grade≥3 (G3+) treatment-emergent adverse events (TEAEs) occurred in 81.3% pts including 65.2% for 3-1.5 mg/kg, 82.1% for 1.5 mg/kg and 93.1% for 3 mg/kg cohorts. Common TEAEs were anemia (any grades 78.8%, G3+ 18.8%), neutrophil count decrease (75.0%, G3+ 42.5%), white blood cell count decrease (63.8%, G3+ 20.0%), arthralgia (51.3%, G3+ 2.5%), and platelet count decrease (45.0%, G3+ 17.5%). IBI363-related AEs led to corresponding treatment discontinuation and death in 6.3% and 1.3% pts. In dose optimization, 65.2% pts had PD-L1 TPS < 1 and 34.8% had TPS 1-49%. Efficacy was evaluable in 62 pts with at least 1 tumor assessment. For 3-1.5 mg/kg cohort (N = 22), ORR was 86.4% (95% CI: 65.1-97.1, confirmed ORR [cORR]: 81.8%) and DCR was 100% (95% CI: 84.6-100). ORR was 85.7% for sqNSCLC (N = 14) and 87.5% for non-sqNSCLC (N = 8). For the 1.5 mg/kg (N = 19) and 3 mg/kg cohorts (N = 21), ORR was 57.9% (cORR: 42.1%) and 66.7% (cORR: 57.1%). PFS was immature (events 28.8%). Clinical PK data also supported an optimal benefit-risk profile based on efficacy and safety observed at 3-1.5 mg/kg. Conclusions: IBI363 plus PDC was well tolerated and showed encouraging efficacy in advanced NSCLC. Safety, efficacy, and PK data supported 3-1.5 mg/kg as the recommended dose. Clinical trial information: NCT06468098 .

OBJECTIVES:Shigella is the pathogen of bacterial dysentery. With the widespread use of antibiotics, the burden of antibiotic resistance in Shigella has become increasingly pronounced. METHODS:In this study, the cfa gene of ampicillin-resistant strain (Res) was knocked out and back-complemented strains were constructed. The susceptibility of Res and Δcfa strains to ampicillin was compared, and the molecular regulatory mechanisms of cfa gene on antibiotic resistance in Shigella were explored by screening the differentially expressed mRNAs, proteins, and metabolites of the two groups. In addition, we examined differences between the two groups in growth, biofilm formation, environmental stress (including temperature, pH, salt, oxidative stress, and carbon and nitrogen sources), and cytotoxicity. RESULTS:The sensitivity of Δcfa to ampicillin was increased 32-fold compared to the Res strain (64 µg/mL vs. 2 µg/mL). Compared to the Res strain, the Δcfa mutant exhibited a 16-fold increase in susceptibility to amoxicillin, penicillin and aztreonam, a 4-fold increase in susceptibility to cefotaxime, and a 2-fold increase in susceptibility to cefazolin, ceftazidime, ceftriaxone and tetracycline. The MICs of Δcfa-pcfa complemented strain was elevated to 4, 32, and 16 µg/mL for ampicillin, penicillin, and amoxicillin, respectively. The differential metabolites of the two groups were significantly enriched in the cysteine and methionine metabolic pathways (P < 0.05). Under no antibiotic stress, Δcfa grew faster than the Res strain and had greater biofilm formation capacity and environmental stress adaptation, but there was no significant difference in the virulence effect of the culture supernatant on Vero cell between the two groups. CONCLUSIONS:The cfa gene orchestrates sulfur metabolism and coordinates the cysteine-methionine biosynthetic pathway in bacteria. The cfa gene not only mediates penicillin antibiotics resistance mechanisms in Shigella sonnei but also modulates critical physiological processes.

Enterovirus A71 (EV-A71), a member of the genus Enterovirus within the family Picornaviridae , induces neuroinflammation; however, the underlying mechanisms remain incompletely understood. This study demonstrates that the C5a-C5aR1 axis plays a pivotal role in EV-A71-induced blood-brain barrier (BBB) disruption and neuroinflammation, primarily by regulating neutrophil migration. Using human brain specimens and a mouse model, we observed pronounced inflammatory cell infiltration in the brainstem and BBB disruption following EV-A71 infection. Immunofluorescence analysis revealed robust activation of the C5a-C5aR1 axis in fatal EV-A71 cases. Notably, C5aR1 knockout (KO) mice displayed reduced Evans blue extravasation and preserved tight junction protein expression after infection. Immunopathological examination of fatal human cases further confirmed perivascular neutrophil (CD177⁺) infiltration in the brainstem. Importantly, C5aR1 deficiency significantly attenuated neutrophil accumulation and neutrophil extracellular trap (NET) release. Given that peptidylarginine deiminase 4 (PAD4) is a key enzyme driving NET formation, we generated neutrophil-specific PAD4 knockout mice (PAD4 Ne-KO) by crossing S100A8-Cre and PAD4 fl/fl lines. As anticipated, neutrophil-specific PAD4 deletion or pharmacological NET blockade substantially ameliorated BBB injury and neuroinflammation following EV-A71 infection. Overall, our findings underscore a critical role for the C5a-C5aR1-neutrophil/NETs pathway in EV-A71 encephalitis pathogenesis and support its targeting as a therapeutic strategy for critically ill patients.

Treatment options are limited for patients with extensive-stage small cell lung cancer (ES-SCLC) after platinum-based therapy. This open-label, single-arm, multicenter phase 2 trial evaluates penpulimab plus anlotinib in 65 patients with first-line platinum-resistant ES-SCLC. The confirmed objective response rate by blinded independent central review is 41.5% (95% confidence interval [CI]: 29.2%-53.8%), and the disease control rate is 75.4% (95% CI: 64.6%-86.1%). Median progression-free survival and overall survival are 4.4 (95% CI: 3.5-5.3) and 10.5 (95% CI: 4.1-17.2) months, respectively. Grade ≥3 treatment-related adverse events occurred in 23.1% of patients, with no new safety signals. Exploratory circulating tumor DNA (ctDNA) analysis suggests that lower baseline maximum somatic allele frequency is associated with improved survival, and decreased T cell receptor clonal diversity is observed at disease progression. Penpulimab plus anlotinib shows promising antitumor activity with a manageable safety profile and may represent a potential second-line treatment option for platinum-resistant ES-SCLC. This study was registered at ClinicalTrials.gov (NCT05001971).

Methicillin-resistant Staphylococcus aureus (MRSA), a major global public health threat due to its broad resistance, urgently requires the development of new antibiotic alternatives. (‒)‒Epigallocatechin-3-gallate (EGCG) is considered a natural bioactive compound with anti-MRSA properties. The L-Lectin module of serine-rich adhesin for platelets (SraP) is considered an important target for blocking MRSA-infected hosts. This study aims to investigate the mechanism of action of EGCG against MRSA. Surface plasmon resonance (SPR), cell adhesion and invasion, biofilm formation, checkerboard assays, RNA sequencing (RNA-seq) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. The results showed that EGCG bound to SraP L Lectin with high affinity and effectively inhibited MRSA colonization. Additionally, EGCG significantly suppressed pyrimidine metabolism and downregulated related genes, thereby potentially inhibiting bacterial growth. It also markedly reduced the expression of multiple genes associated with β-lactam resistance and inhibited biofilm formation. A strong synergistic effect was observed between EGCG and the bactericidal agent ceftriaxone (CRO). When combined with 10 μg/mL EGCG, CRO required 75% less dosage and exhibited a prolonged antimicrobial effect. In conclusion, EGCG exerts anti-MRSA effects through multiple pathways and represents a promising candidate as an alternative therapeutic agent against MRSA infections.

Many factors affect bovine skeletal muscle development, among which noncoding RNAs are very important. While circular RNAs (circRNAs) play a central role in various physiological and pathological processes, their potential role in muscle development is poorly understood. Here, we identified several differentially expressed circRNAs in fetal and adult skeletal muscle tissue sequencing data. They included a circRNA originating from exon 24 circularization of the myosin heavy chain protein 8 gene (MYH8), circMYH8, which was significantly downregulated in the adult muscle tissue. We examined circMYH8’s role in skeletal muscle cell proliferation, apoptosis, and differentiation through its overexpression or inhibition. Specifically, we used luciferase reporter gene assays, western blots, real-time reverse transcription quantitative PCR, cell counting kit 8, and 5-ethynyl-2-deoxyuridine to explore circMYH8’s molecular sponge effect on bovine myoblast proliferation, apoptosis, and differentiation via competitively binding microRNA 221 to activate cyclin-dependent kinase inhibitor 1B. Then, we investigated circMYH8’s role in promoting muscle regeneration by injecting a circMYH8 overexpression plasmid into muscle-injured mice. The results suggest that circMYH8 inhibits bovine myoblast proliferation and facilitates cell apoptosis and differentiation acts through the miR-221/P27 axis. This study shows that circMYH8 is a potential myogenesis-related factor and provides new evidence for elucidating complex molecular mechanisms and a better understanding of the function of mammalian circular RNAs in muscle development.

Circular RNAs (circRNAs) have emerged as critical regulators of skeletal muscle development, yet the functions of many muscle-derived circRNAs remain uncharacterized. In this study, we identified a novel circRNA, circAIDA, formed by exons 2 to 6 of the AIDA gene, based on bovine muscle sequencing data. Mechanistically, we demonstrate that circAIDA acts as a molecular sponge for miR-29a, thereby relieving the repression of its downstream targets, AKT3 and CLCN2. Functionally, circAIDA promotes bovine myoblast proliferation while inhibiting apoptosis and differentiation in vitro. Furthermore, experiments in vivo suggested circAIDA could attenuate regeneration of skeletal muscle in mice. In brief, we discovered a novel circAIDA/miR-29a interaction that regulates bovine myogenesis, providing new insights into the molecular networks controlling skeletal muscle development.

Antimicrobial resistance (AMR) poses a critical threat to global public health in the 21st century. Escherichia coli (E. coli), as a major bacterial pathogen, is widely distributed in humans, animals, and the environment, is not only a common pathogen causing urinary tract infections, bacteremia, and infectious diarrhea, but also one of the main pathogens leading to the sharp increase of multi-drug resistant strains. Therefore, understanding the long-term changing patterns of drug resistance in E. coli and exploring the key driving factors of drug resistance development are of vital importance for curbing the spread of AMR. Here, we observed the patterns of antibiotic resistance genes (ARGs) in 3085 E. coli isolates collected over the past 70 years since 1948. Our results indicated that the count of ARGs in E. coli had gradually increased in recent decades (P < 0.001). In particular, we found that the human development index may have indirectly contributed to the rise in antibiotic resistance in E. coli isolates by promoting the use of antibiotics. Finally, generalized linear models combined with restricted cubic splines showed that global antibiotic consumption, mobile genetic elements, and climatic factors all affected the count of ARGs in E. coli isolates. Overall, this study monitored the long-term trend of ARGs in E. coli isolates, analyzed the potential influencing factors of ARGs in these isolates, and offered a theoretical framework for controlling the global risk of antibiotic resistance.

Thyroid cancer is the most common endocrine malignancy globally. While papillary thyroid carcinoma (PTC) typically exhibits favorable prognosis, a subset undergoes dedifferentiation into anaplastic thyroid carcinoma (ATC), an aggressive, treatment-refractory subtype with near-universal lethality. However, the molecular driver of this process remains elusive. In this study, we find that IGF2BP2 is upregulated in ATC and correlates with adverse prognosis. Pseudotime trajectory analysis tracks progressively escalating IGF2BP2 expression throughout dedifferentiation. Functionally, IGF2BP2 promotes proliferation, suppresses thyroid differentiation genes (TSHR, SLC26A4, SLC5A5, TPO, PAX8, FOXE1, and NKX2.1), and enhances cancer stemness. Mechanistically, integrated multi-omics analysis (RNA-seq, RIP-seq, and MeRIP-seq) reveals that IGF2BP2 binds m6A-modified STAT1 mRNA, accelerating its decay. STAT1 directly activates transcription of thyroid differentiation genes. Rescue experiments confirms that STAT1 mediates IGF2BP2-driven dedifferentiation. The IGF2BP2-m6A-STAT1 complex is a master regulator of thyroid cancer dedifferentiation, establishing a novel therapeutic target for redifferentiation therapy in advanced thyroid cancer.

Coxsackievirus A6 (CVA6) is a nonenveloped, single-stranded RNA virus linked to neurological complications. Emerging evidence suggests neutrophil pyroptosis drives inflammation. However, the role of neutrophil pyroptosis in CVA6 pathogenesis remains unexplored. Ten-day-old wild-type (WT), Caspase-1 KO, and GSDMD KO mice were infected with a lethal dose of CVA6. For in vivo and in vitro studies, we used the caspase-1 inhibitor belnacasan, disulfiram, and anti-Ly6G antibody. We also generated neutrophil-specific PAD4-knockout mice (PAD4 Ne-KO) by deleting Padi4 under the S100A8 promoter. Post-infection, clinical scores, survival, and body weight were monitored. Brain tissues and bone marrow-derived neutrophils (BMDNs) were collected for analysis. Key methods included qPCR, Western blotting, histology/immunofluorescence, flow cytometry, and TEM to assess pyroptosis, inflammation, and immune cell infiltration. Findings were further validated using blood samples from HFMD patients. In this study, we investigated how the Caspase-1/GSDMD pathway mediates neutrophil extracellular trap (NET) release and drives CVA6-induced neuroinflammation. CVA6 infection increased neutrophil numbers in mouse brain and peripheral blood, along with elevated MPO-DNA—a NET marker. In BMDNs, degranulation and NET formation occurred by 24 hpi, accompanied by Caspase-1/GSDMD activation. Caspase-1 knockout prolonged survival and reduced GSDMD-N expression in brain neutrophils; pharmacological Caspase-1 inhibition decreased mature IL-1β and IL-18 in brain tissue and suppressed CVA6 replication in BMDNs. Together, in vitro and in vivo data indicate that Caspase-1/GSDMD activation and NETosis critically contribute to CVA6-induced brain injury. This was confirmed by GSDMD knockout or disulfiram-mediated GSDMD inhibition, both of which markedly reduced NET release and neuropathology. Notably, global neutrophil depletion worsened infection—suggesting a protective role—whereas neutrophil-specific PAD4 knockout improved survival. Clinically, GSDMD expression showed a significant positive correlation with NETosis markers in patient samples from CVA6-infected individuals. These findings enhance understanding of enteroviral pathogenesis, identify GSDMD as a promising therapeutic target, and provide a novel framework for developing precision interventions that reduce excessive inflammation without impairing essential host defenses.

ObjectiveStudies have indicated that combining Maackia amurensis seed lectin with first-line chemotherapeutic agents enhances the efficacy of treatment for oral squamous cell carcinoma. The study aimed to investigate the underlying mechanism of Maackia amurensis seed lectin in the treatment of oral squamous cell carcinoma.MethodsGene Expression Omnibus dataset mining, reverse transcription-quantitative polymerase chain reaction, and western blot analysis were performed to identify the expression of SRY-box transcription factor 2, methyltransferase 3, and YTH domain-containing protein 1 in oral squamous cell carcinoma. The N6-methyladenosine methylation levels of SRY-box transcription factor 2 were detected though methylated RNA immunoprecipitation. The effects of Maackia amurensis seed lectin and SRY-box transcription factor 2 on oral squamous cell carcinoma cells were determined via Cell Counting Kit-8 and colony formation assays.ResultsThe results demonstrated that increased expression of SRY-box transcription factor 2 in oral squamous cell carcinoma is correlated with elevated levels of N6-methyladenosine modification, and treatment with Maackia amurensis seed lectin reduces the N6-methyladenosine modification level and SRY-box transcription factor 2 expression. Moreover, overexpression of SRY-box transcription factor 2 reversed the inhibitory effects of Maackia amurensis seed lectin on oral squamous cell carcinoma cell proliferation and colony formation.ConclusionsMaackia amurensis seed lectin may inhibit oral squamous cell carcinoma cell proliferation by suppressing N6-methyladenosine modification-mediated SRY-box transcription factor 2 expression, thereby improving chemotherapy sensitivity in oral squamous cell carcinoma.