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关键词： Optical biosensor   Multi-resonance analysis   IL-6   IL-8   OSCC   Point-of-care diagnostics   Semi-distributed interferometer   Biomarker detection   Surface functionalization  

摘要： Biomarker-based diagnostics offer a promising approach for early cancer detection, while simultaneous analysis of multiple biomarkers can further improve disease diagnosis by enhancing sensitivity and specificity of the detection. This work presents a multi-resonance analysis strategy for the simultaneous detection of oral cancer biomarkers interleukin-6 and interleukin-8 in artificial saliva with a Fiber-Bragg grating-assisted semi-distributed interferometer-based probe. The analysis of the sensor response takes advantage of the entire spectral feature, which enhances the robustness and reliability of the detection results. Unlike single-feature approaches, multi-resonance analysis ensures greater resilience to spectral distortions, since the spectral features of the proposed sensor exhibit varying sensitivity to biomolecular interactions. The sensor demonstrated a limit of detection (LoD) of 480 aM for IL-6 and 23.4 fM for IL-8 in artificial saliva with high specificity to target proteins.

关键词： Hydroxychloroquine   IgA nephropathy   network pharmacology   TNF   toll-like receptor signaling pathway  

摘要： Background IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the *** PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was *** 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine *** This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.

关键词： lower extremity flap   locoregional flap   microsurgery   National Surgical Quality Improvement Project (NSQIP)   plastic surgery   chirurgie plastique   lambeau locor & eacute   gional   lambeau sur les membres inf & eacute   rieurs   microchirurgie   NSQIP  

摘要： Introduction: Soft tissue flaps are an integral and versatile tool to help manage soft tissue defects of varying severities. These complex procedures can be done by a variety of specialties and can lead to a variety of postoperative complications. Locoregional flaps are the middle rung of the reconstructive ladder and can be performed by surgeons of various training pathways. The profile of patients and their complications when stratified by surgical specialty is unknown. The purpose of this study was to compare short-term postoperative outcomes between surgical subspecialists performing a locoregional flap of the lower extremity to determine factors influencing complication rates. Methods: The National Surgical Quality Improvement Project (NSQIP) database was queried using Current Procedural Terminology code 15,738 to identify adult patients undergoing a muscle, myocutaneous, or fasciocutaneous lower extremity flap procedure from 2016 to 2019. We examined the primary outcome of a pooled wound complication rate with secondary outcomes including the individual NSQIP wound- and nonwound complications. Results: A total of 1324 patients were identified. Plastic surgeons performed 926 (70%) procedures, general surgeons performed 243 (18%) procedures, orthopedic surgeons performed 89 (7%) procedures, and vascular surgeons performed 66 (5%) procedures. On multivariate analysis, surgical subspecialty was not associated with the primary outcome, but malignancy-related operations and nonelective status were considered significant. Conclusions: Patient characteristics, but not surgeon subspecialty, account for the variation in patient outcomes in lower extremity flap reconstruction. Larger, prospective studies examining these outcomes are needed to further characterize complication risk factors in this patient population. Introduction : Les lambeaux de tissus mous sont un outil essentiel et polyvalent pour g & eacute;rer les anomalies des tissus mous de diverses gravit & eacut

关键词： Pain   Extracellular vesicle   MSC   Neuron   MicroRNA  

摘要： Mesenchymal stem cell-derived extracellular vesicle (MSC-EV) has shown promise for pain relief, but its efficacy is limited. Preconditioning MSC with tumor necrosis factor-alpha (TNF-alpha) may enhance their therapeutic potential;however, the impact on analgesia and underlying mechanisms remains unclear. Here, we investigated the analgesic effects of EV from TNF-alpha-preconditioned MSC (T-EV) in a chronic constriction injury (CCI) mouse model and examined the molecular mechanisms involved. Following intrathecal injection, T-EV produced greater improvements in mechanical and thermal pain thresholds than control MSC-EV (C-EV), achieving enhanced pain relief for two weeks. Whole-cell patch-clamp recordings revealed that T-EV markedly decreased both the firing rate and action potential amplitude of dorsal root ganglion (DRG) neurons. RNA sequencing revealed that T-EV was enriched in miR-101b-3p. Silencing miR-101b-3p in T-EV abolished their enhanced analgesic effects and reversed DRG hyperexcitability. Moreover, miR-101b-3p was shown by luciferase assays to bind directly to the 3 ' UTR of Nav1.6, suppressing its expression. Engineered MSC-derived nanovesicle overexpressing miR-101b-3p replicated the increased pain relief observed with T-EV. These findings demonstrate that TNF-alpha preconditioning improves the analgesic potency of MSC-EV by delivering miR-101b-3p, which downregulates Nav1.6 and decreases DRG hyperexcitability. This study supports the therapeutic potential of miR101b-3p-enriched vesicle as a novel strategy for treating neuropathic pain.

关键词： Allogeneic   Major histocompatibility complex   Immune evasion   Alginate scaffolds   Gene expression   Histology  

摘要： The allogeneic administration of equine mesenchymal stem/stromal cells (MSCs) has numerous advantages over autologous therapy, but their interactions with the patient's immune system need to be further elucidated. These interactions can be influenced by factors such as the compatibility between donor-receptor for the major histocompatibility complex (MHC) and by the MHC expression levels, which can change under different conditions like inflammatory exposure and chondrogeneic differentiation. In this study, we evaluated the local immune response induced by chondrogeneically differentiated (MSC-chondro), pro-inflammatory primed (MSC-primed) and basal (MSC-na & iuml;ve) MSCs, and how this response changes the immunomodulatory and immunogenic profiles of MSCs in vivo. Equine MSCs were embedded in alginate scaffolds and subcutaneously implanted into autologous, MHC-matched and MHC-mismatched horses. Scaffolds were recovered at different time-points for histologic and gene expression analyses, and the procedure was repeated to assess the effect of a second administration. Our results suggest that MHC-compatibility may play a key role in attenuating the local immune response induced by MSCs, which may be related to the upregulation of immunomodulatory genes in the three MSC types in vivo. In contrast, when MSCs were administered into MHC-mismatched horses, expression of immunogenic genes was higher across all MSC conditions. Therefore, the conditions in which MSCs are administered may not affect the long-term local immune response, but MHC-matched administration would favour the immune evasion of MSCs, thus being advisable especially when repeated MSC administrations are required. Comprehensively investigating the in vivo immune response against equine allogeneic MSCs is crucial for advancing veterinary cell therapies.

关键词： IL-6   Pulmonary fibrosis   Fibroblast-to-Myofibroblast transition   STAT3   PD-L1  

摘要： Pulmonary fibrosis is a fatal lung disease. Owing to its unknown pathogenesis, treatment options are limited. Interleukin (IL)-6, a multifunctional cytokine, is overexpressed in pulmonary fibrosis and may contribute to its development through multiple pathways, mainly the signal transduction and transcriptional activator 3 (STAT3) signaling pathway. Moreover, programmed cell death ligand 1 (PD-L1), an immune checkpoint molecule, is crucial in immune regulation and also shows abnormal expression in pulmonary fibrosis, potentially involved in fibrogenesis. PD-L1 may be regulated by IL-6 in pulmonary disorders. Given the pivotal role of IL-6 and PD-L1 in the pathogenesis of pulmonary fibrosis, this study aimed to explore the effect and mechanism of blocking IL-6 on PD-L1 expression and pulmonary fibrosis. We established the pulmonary fibrosis model by instilling bleomycin (BLM) intratracheally into mice and stimulating human fetal lung fibroblasts 1 (HFL1s) with transforming growth factor-beta 1 (TGF-(31). Upon inhibition of IL-6 signaling or reduction of PD-L1 expression, we analyzed the tissue morphology, protein expression and function. We observed elevated expression of IL-6 and PD-L1 in pulmonary fibrosis models. Blocking IL-6 relieved BLM-induced lung tissue destruction, diminished collagen production and deposition and inhibited the expression of alpha smooth muscle actin (alpha-SMA), Vimentin, and Collagen I. Blocking IL-6 could reverse fibroblast-to-myofibroblast transformation induced by TGF-(31 in HFL1s via inhibiting the STAT3 signaling pathway. Interestingly, targeting IL-6/STAT3 signaling could also downregulate PD-L1 expression. Inhibiting PD-L1 could mitigate pulmonary fibrosis. Our findings provide new molecular targets for exploring the pathogenesis and treatment of pulmonary fibrosis.

摘要： [This retracts the article DOI: 10.3892/ol.2018.7914.].

关键词： Lumpy skin disease virus   ORF142   cGAS/STING   Autophagy   Immune evasion  

摘要： Lumpy skin disease (LSD), caused by the Lumpy skin disease virus (LSDV), poses a significant threat to the global cattle farming industry. Viral proteins evolved the ability to escape host immune responses. Here, we demonstrate that LSDV infection inhibits interferon-(3 (IFN-(3) production in Madin-Darby bovine kidney (MDBK) cells, even in the presence of Sendai virus (SEV) inducers. Through further investigation, we identify multiple genes at both ends of the LSDV genome that strongly inhibit IFN-(3 or NF-kappa B activation of the promoter. Notably, ORF142 selectively inhibits IFN-(3 promoter activity but fails to inhibit NF-kappa B promoter activity. Subsequently, we reveal that ORF142 negatively regulate the cGAS/STING-mediated IFN-I production. Overexpression of ORF142 suppresses IFN-(3 and interferon-stimulated response element (ISRE) activity, while the absence of ORF142 upregulates the transcription levels of IFN-(3 and interferon-stimulated genes (ISGs) in MDBK cells. Mechanistically, ORF142 interacts with STING to facilitate autophagy-lysosomal degradation by recruiting NBR1, thereby impeding the activation of downstream signaling molecules, such as IRF3, and inhibiting IFN-I production. In conclusion, our findings elucidate the immune evasion mechanism of ORF142 encoded by LSDV, offering insights for the development of antiviral drugs or attenuated live vaccines to mitigate LSD.

关键词： IL-32   Mycobacterium tuberculosis   Macrophage   RNA-Seq   TNF pathway   AEBP1  

摘要： Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, survives in host macrophages, the primary effector and antigen-presenting cells involved in the host immune response. We previously showed that Interleukin-32 (IL-32) is significantly increased in the peripheral blood plasma of tuberculosis patients, can act as an anti-MTB agent. However, the underlying molecular mechanism for its effect remains unknown. Here, we showed that inhibiting IL-32 with monoclonal antibody increases MTB loads that was positively correlated with higher antibody concentrations and longer exposure times. RNA-Sequencing result indicated that 3797 genes were shown to be up-regulated in response to IL-32 inhibition, while 1365 genes were down-regulated. GO and KEGG analysis indicated that classical signaling pathways, including TNF, cell cycle, and Wnt were significantly enriched. Consistent expression trends were observed in NF-kappa B pathway-related antibacterial factors that are functionally capable of inhibiting MTB. Using differentially expressed gene and protein-protein interaction analysis, AEBP1 was the gene with the most significant difference in expression and regulated by IL-32. These findings suggest a dynamic molecular and cellular mechanism by which IL-32 positively regulates the AEBP1I kappa B alpha-NF-kappa B-TNF-alpha axis to inhibit MTB infection in human macrophages.

关键词： checkpoint blockades   immunotherapy   response prediction   MHC-I pathway   tumor mutational burden   TMB  

摘要： Immune checkpoint inhibitors produce durable antitumor effects in various cancers, but not all patients respond. High tumor mutational burden (TMB) is a known predictor of clinical benefit. In this study, we focused on the MHC-I-dependent neoantigen presentation pathway to enhance predictive capabilities beyond TMB. Using pan-cancer immunogenomic analyses of somatic mutation data from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we analyzed 33 cancer types. Objective response rates (ORRs) to PD-1/PD-L1 inhibitors were evaluated in relation to immune characteristics, including TMB, neoantigen load, MHC-I gene expression, and CD8+ T cell fraction. Spearman's rank correlation was used to assess these relationships. TMB s howed the strongest correlation with ORR (r=0.783, P=2.17x10-5). However, integrating TMB, HLA-A expression, and CD8+ T cell fraction significantly improved predictive accuracy (r=0.865, P=1.80x10-6). Validation in external cohorts confirmed these findings, revealing notable differences in MHC-I pathway activity between responders and non-responders to immunotherapy. Our results demonstrate that the MHC-I antigen presentation pathway is strongly associated with response to PD-1/PD-L1 inhibitors. Importantly, combining antigen expression, processing, presentation, and recognition features provides superior predictive power compared to TMB alone. This integrated approach could improve treatment outcome predictions and advance personalized immunotherapy strategies.