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关键词： Oral Squamous Cell Carcinoma (OSCC)   Salivary TNF alpha   Gold nanoparticles (AuNPs)   Antibody-based detection   And predictive biomarkers  

摘要： Objectives: To assess the efficacy of the AuNP-enhanced ELISA in the detection of salivary TNF-alpha in OSCC and evaluate its predictive value for survival. Design: A longitudinal study was conducted on 40 OSCC patients and 10 healthy controls. Saliva was collected at a regular interval and TNF alpha levels were measured using ELISA and AuNP-enhanced ELISA. Descriptive statistics were carried out for demographic, clinical, and biomarker data. The efficacy of ELISA and AuNPenhanced ELISA was estimated and compared using the ROC curve. Kaplan-Meier survival analysis and Cox proportional hazards models were used to assess the survival outcome. A neural network model was performed to estimate TNF-alpha levels over time in OSCC patients. Results: OSCC patients (ELISA is 47.52 f 20.23 and Gold nano-enhanced ELISA is 57.63 f 24.99) exhibited significantly elevated TNF alpha levels compared to controls (ELISA is 10.13 f 3.07and Gold nano-enhanced ELISA is 12.07 f 3.66). Gold nano-enhanced ELISA (AUC of 0.995) demonstrated superior sensitivity than ELISA (AUC of 0.986), while Gold nano-enhanced ELISA achieves an even higher in detecting elevated TNF alpha levels. KaplanMeier analysis shows that Gold nano-enhanced ELISA outperforms ELISA in capturing survival trends, with better survival for TNF-alpha levels above the cutoff at 9 months (70 % vs. 60 %) and 24 months (40 % vs. 0 %). The neural network model poorly predicted TNF- levels over the period (AUC = 0.447). Conclusions: The gold nano-enhanced TNF alpha detection method is effective in detecting TNF alpha levels between OSCC patients and controls, demonstrating superior sensitivity in identifying survival trends over time compared to traditional ELISA.

关键词： genomic full-length   HLA-DRB1*03:19   new HLA allele   PacBio sequencing  

摘要： Genomic full-length sequence of HLA-DRB1*03:19 was identified in a Chinese individual by PacBio sequencing.

关键词： IL-6/STAT3   Breast cancer   Tumor evolution   Epigenetics   Adaptive plasticity   Non-coding RNA networks  

摘要： The IL-6/STAT3 signaling pathway has long been recognized as a critical driver of breast cancer progression, therapy resistance, and immune evasion. However, conventional approaches targeting this path that yielded limited success suggesting an incomplete understanding of oncogenic potential. We propose a groundbreaking hypothesis that IL-6/STAT3 functions as a dynamic evolutionary force in breast cancer, enabling tumor cells to engage in rapid adaptive plasticity, akin to an evolutionary intelligence system. We propose that STAT3 is an epigenetic architect that reconfigures chromatin landscapes and affects non-coding RNA networks to help tumors survive stress. STAT3 has traditionally been a transcription factor, but new data reveals it directly remodels chromatin. In breast cancer cells, STAT3 alters chromatin accessibility via interacting with histone-modifying enzymes such HATs and HDACs. This variation is important because it highlights the unknown function of STAT3 as a direct chromatin regulator rather than a transcription factor. We hypothesize that STAT3-driven epigenetic modifications enable cancer cells to transition between immune-resistant and immune-responsive states, contributing to tumor heterogeneity and therapy resistance. This novel conceptualization shifts the focus from direct pharmacological inhibition to identifying molecular 'decision points' where IL-6/STAT3 activity dictates cancer cell fate. Future research should explore innovative interventions aimed at disrupting these adaptive mechanisms, thereby transforming breast cancer from an evolving malignancy into a therapeutically vulnerable disease.

关键词： Osteoarthritis (OA)   m6A methylation   Chondrocyte   WTAP   IL-33  

摘要： Osteoarthritis (OA) is a multifactorial degenerative disorder entailing cartilage loss and progressive joint failure. m6A RNA methylation could impact multiple disorders, including OA. In this study, m6A methylation regulator WTAP was down-regulated in OA cartilage, accompanied by significantly lower m6A methylation levels in OA tissues. In the DMM-induced mice OA model and IL-1 beta- or TNF-alpha-stimulated chondrocytes, WTAP and m6A methylation levels were decreased, but IL-1 beta, IL-6, and TNF-alpha cytokine expressions were elevated. In vivo and in vitro, WTAP overexpression increased m6A methylation levels but reduced proinflammatory cytokine contents. Furthermore, WTAP overexpression (OE) increased chondrocyte viability and proliferation, aggrecan and collagen II protein, and decreased cell apoptosis, MMP3, MMP13, and ADAMTS5. WTAP-mediated m6A methylation of IL-33 and impaired IL-33 mRNA stability. IL-33 OE caused no changes to WTAP expression;however, IL-33 OE partially attenuated WTAP OE-induced IL-33 downregulation. IL-33 overexpression inhibited chondrocyte viability and proliferation, decreased aggrecan and collagen II but elevated MMP3, MMP13, and ADAMTS5, and increased cell apoptosis and proinflammatory cytokine contents. More importantly, IL-33 eliminated the effects of WTAP OE on chondrocytes. Therefore, WTAP is down-regulated in OA;WTAP improves chondrocyte proliferation and function, thereby ameliorating OA through mediating m6A methylation of IL-33 and impairing IL-33 mRNA stability.

关键词： Mycoplasma hyopneumoniae   Mhp597   Vimentin   IFN-I  

摘要： Infection with Mycoplasma hyopneumoniae (M. hyopneumoniae) leads to chronic infectious pneumonia in pigs, resulting in significant distress and economic losses in the global pig industry. The pathogen secretes various proteins, including toxins, adhesins, and virulence-related enzymes, which facilitate adhesion, invasion, and immune evasion processes between bacteria and the host. However, the effector proteins of M. hyopneumoniae are predominantly uncharacterized. In this study, we demonstrate that the nuclease Mhp597 functions as a potential effector protein of M. hyopneumoniae, and we elucidate its mechanism of action in facilitating immune evasion. Our findings indicate that Mhp597 exhibits high expression efficiency in host cells and significantly inhibits IFN-alpha and IFN-beta protein expression. Using yeast two-hybrid and co-immunoprecipitation experiments, we established that Mhp597 interacts with porcine alveolar macrophage vimentin (Vim) via specific amino acid residues (Arg 232, Lys 256, Phe 263, and Lys 317). Further analysis revealed that Mhp597 inhibited the phosphorylation of TBK1 and IRF3 via Vim, thereby suppressing type I interferon (IFN-I) production and promoting the proliferation of M. hyopneumoniae within host cells. In conclusion, this study provides the first detailed account of the molecular mechanism by which Mhp597 negatively regulates the TBK1-IRF3-IFN-I signaling pathway through Vim, thus facilitating immune evasion and proliferation of M. hyopneumoniae within host cells. These findings enhance our understanding of the pathogenic mechanisms of M. hyopneumoniae and suggest potential molecular targets for the development of novel therapeutic strategies.

关键词： HLA-DPA1*02:02:02:22   HLA-genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-DPA1*02:02:02:22 allele differs from HLA-DPA1*02:02:02:01 by a single nucleotide substitution in intron 1.

关键词： macrophages   cancer   inflammation   interleukin 1   tumor microenvironment  

摘要： While highlighting the complexity and heterogeneity of tumor immune microenvironments, the application of single-cell analyses in human cancers has identified recurrent subsets of tumor-associated macrophages (TAMs). Among these, interleukin (IL)-1 beta+ TAMs - cells with high levels of expression of inflammatory response and tissue repair genes, but with limited capacity to stimulate cytotoxic immunity - are emerging as key drivers of pathogenic inflammation in cancer. In this review we discuss recent literature defining the phenotypical, molecular, and functional properties of IL-1 beta+ TAMs, as well as their temporal dynamics and spatial organization. Elucidating the biology of these cells across tumor initiation, progression, metastasis, and therapy could inform the design and interpretation of clinical trials targeting IL-1 beta and/or other inflammatory factors in cancer immunotherapy.

关键词： ulcerative colitis   ustekinumab   vedolizumab   anti-TNF   real-world evidence (RWE)   RWE comparison  

摘要： Background: Real-world evidence studies of ustekinumab (UST) in ulcerative colitis (UC) are needed because randomized controlled trials do not represent unselected patient populations in everyday clinical practice. Patients with UC were recruited when starting biologic therapy for the first time or switching to a new biologic therapy. This study assessed the effectiveness of maintenance therapy with UST in comparison to anti-TNF or vedolizumab (VDZ) at 12 months. Methods: Between 2020 and 2022, 507 UC patients starting biologic therapy for the first time or switching to a new biologic therapy were enrolled at 34 inflammatory bowel disease (IBD)-specialized centers in Germany. After excluding patients receiving other biologics or small molecules, as well as those with stomas or missing outcomes, the final sample consisted of 476 patients. The outcomes were clinical response, clinical remission (CR), and steroid-free remission. Propensity score (PS) adjustment with inverse probability of treatment weighting was used to reduce the effect of confounding due to physician selection of therapy. Results: A total of 476 patients with UC were included in the analysis (UST: 147, anti-TNF: 168, VDZ: 161). Treatment persistence over 12 months differed significantly (P < .001) between UST (93.9%), VDZ (87.0%), and anti-TNF (75.0%). The PS-weighted effectiveness of UST in the mITT analysis at month 12 was not significantly different from anti-TNF or VDZ (CR: UST 26.9%, anti-TNF 34.7%, VDZ 40.9%;P = .063). Conclusions: In the prospective RUN-UC study with PS-weighted groups, UST showed higher treatment persistence but no significant difference in maintenance effectiveness compared to anti-TNF or VDZ in UC.

关键词： alveolar epithelial cell   caspase-1   interleukin-37   NLRP3   ventilator-induced lung injury  

摘要： Mechanical ventilation is an effective strategy for managing acute respiratory distress syndrome (ARDS), but it can also exacerbate lung injury, leading to ventilator-induced lung injury (VILI). To investigate the protective role of interleukin-37 (IL-37) in the pathogenesis of VILI, we used two approaches, human IL-37 transgenic (IL37tg) mice and administration of recombinant human IL-37 (rIL37) in wild-type (WT) mice subjected to mechanical ventilation. Lung histopathology was evaluated, inflammatory cytokine levels (IL-1 beta, IL-6, TNF-alpha) were measured, and inflammasome activation was assessed by analyzing NLRP3 and Caspase-1 expression. As a result, IL37tg mice exhibited significantly attenuated lung injury compared to WT controls, characterized by improved histological morphology, reduced lung injury scores, and decreased infiltration of macrophages and neutrophils. Similarly, rIL37 administration markedly reduced lung injury and decreased inflammatory cytokine levels. Immunofluorescence analysis revealed colocalization of the alveolar cell marker surfactant protein D (SP-D) and IL-37. Furthermore, IL-37 suppressed NLRP3 inflammasome activation, as evidenced by reduced NLRP3 and Cleaved-Caspase-1 levels in both the IL37tg mouse model and the rIL37 treatment group. These findings suggest that IL-37 effectively protects against VILI by inhibiting inflammation in lung tissues through inhibition of the NLRP3 inflammasome. Therefore, IL-37 may serve as a potential therapeutic target for the prevention and treatment of VILI in the future.